DAA combination therapy (eg with ABT-072 or ABT-333) for use in the treatment of HCV

专利摘要:
SUMMARY The present invention presents interferon and ribavirin free therapies for the treatment of HCV. Preferably, the treatment takes place for a shorter treatment time, such as no more than 12 weeks. In one aspect, the therapies include administering at least two direct-acting antiviral agents without interferon and ribavirin to a subject with HCV infection. For example, the therapies include administering, to a subject, effective amounts of therapeutic agent 1 (ABT) or therapeutic agent 2 (= ABT-333) or therapeutic agent 3 (= ABT-072) or therapeutic agent 4 (ABT), and encytochrome. P450 inhibitor (eg ritonavir).
公开号:SE1450020A1
申请号:SE1450020
申请日:2012-10-19
公开日:2014-01-10
发明作者:Barry M Bernstein；Rajeev M Menon；Amit Khatri；Sven Mensing；Sandeep Dutta；Daniel E Cohen；Thomas J Podsadecki；Scott C Brun；Walid M Awni；Emily O Dumas；Cheri E Klein
申请人:Abbvie Inc；
IPC主号:

专利说明:

[4] Liver pathology, which includes liver cirrhosis and hepatocellular carcinoma.
[5] Methods for treating HCV infection in a subject. The methods of one aspect of the present invention provided include administering at least two direct acting antiviral agents (DAAs) for a period of not more than twelve weeks, or for another period mentioned herein. Preferably, the treatment time is twelve weeks. The treatment time can also be no more than eight weeks. Preferably, the two or more direct-acting antiviral agents (DAAs) are administered in amounts effective to obtain a sustained virologic response (SVR) or to achieve another desired measure of efficacy in a subject. The subject is not administered with ribavirin during the administration time of the at least two DAAs. In other words, the procedures exclude the administration of ribavirin to the subject during the treatment regimen. The subject is also not administered interferon during the treatment regimen. In other words, the procedures exclude the administration of interferon to the subject, thus avoiding the side effects associated with interferon. In certain embodiments, the methods further comprise administering a cytochrome P-450 inhibitor (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more of the DAAs.
[6] Treat HCV infection in a subject. The methods comprise administering According to another aspect, methods are provided for (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3, and combinations thereof, and (c) a cytochrome P-450 inhibitor to the subject for a period of not more than twelve weeks, or for another time mentioned herein (eg, the treatment regimen may be for a period of not more than 8 weeks) .
[7] Treat a population of subjects with an HCV infection. The Methods According to another aspect, methods are provided for comprising administering at least two DAAs to the subjects for a period of not more than 12 weeks. Preferably, the at least two DAAs are administered to the subjects in amounts effective to result in SVR or other efficacy measure in at least about 50% of the population, preferably at least about 70% in the population.
[8] Described below, the DAAs may be selected from the group consisting of In the foregoing methods as well as in the methods such as protease inhibitors, nucleoside or nucleotide polymerase inhibitors, non-nucleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS4A5 inhibitors, NS4A , cyclophilin inhibitors, and combinations thereof. For example, in certain embodiments, the DAAs used in the present methods comprise or contain at least one HVC protease inhibitor and at least one HCV polymerase inhibitor. The HCV polymerase inhibitor may be a nucleotide polymerase inhibitor, a nucleoside polymerase inhibitor or a non-nucleoside polymerase inhibitor. The HCV polymerase inhibitor may also be a non-nucleotide polymerase inhibitor. 10 15 20 25 30
[9] Agent 1 (as described below) and the HCV polymerase inhibitor is therapeutic In some embodiments, the HCV protease inhibitor is therapeutic agent 2 and / or therapeutic agent 3 (also described below). As an example, therapeutic agent 1 is administered in a total daily dose ranging from about 100 mg to about 250 mg, or administered at least once daily in a dose ranging from about 150 mg to about 250 mg, and therapeutic agent 2 is administered in a total daily dose ranging from about 300 mg to about 1800 mg, or administered at least twice daily in doses ranging from about 200 mg to about 400 mg. In some embodiments, the HCV protease inhibitor is therapeutic agent 1 and the non-nucleoside HCV polymerase inhibitor is therapeutic agent 3. As an example, therapeutic agent 1 may be administered in a total daily dose of about 100 mg, alternatively about 200 mg, or alternatively about 250 mg; and therapeutic agent 3 is administered in a total daily dose of about 400 mg. Ritonavir (or other cytochrome P-450-3A4 inhibitor) may be co-administered with therapeutic agent 1 to improve the pharmacokinetics and bioavailability of therapeutic agent 1.
[10] In some embodiments, the at least two DAAs comprise at least one HCV protease inhibitor and at least one NS5A inhibitor. Preferably, the HCV protease inhibitor is therapeutic agent 1 and the NS5A inhibitor is therapeutic agent 4. As an example, therapeutic agent 1 may be administered in a total daily dose ranging from about 100 mg to about 250 mg, and therapeutic agent 4 may be administered in a total daily dose ranges from about 25 mg to about 200 mg. Ritonavir (or other cytochrome P-450-3A4 inhibitor) may be co-administered with therapeutic agent 1 to improve the pharmacokinetics and bioavailability of therapeutic agent 1.
[11] Described herein, the DAAs may be administered according to any effective dosing regimen as well as the dosing schedule procedures and / or any effective dosing frequency, for example, they may each be administered daily. Each DAA can be administered either separately or in combination, and each DAA can be administered at least once a day, at least twice a day, or at least three times a day. In some preferred embodiments, therapeutic agent 3 is administered once daily (QD) or twice daily (BID), and therapeutic agent 1 is administered once daily.
[12] A method of treating HCV infection comprising administering at least In certain aspects, the present technology provides a two DAAs for a period of not more than twelve weeks to a subject in need thereof, the subject not being administered with either interferon or ribavirin during said time. In some aspects, the at least two DAAs are administered in an amount effective to result in SVR. Some methods further comprise administering a cytochrome P450 inhibitor to the subject. In some aspects, the time is no more than eight weeks.
[13] At least two direct-acting antiviral agents (i) Compound 1 or a In certain aspects of the present technology, they comprise pharmaceutically acceptable salt thereof, which is co-administered or co-formulated with ritonavir, and (ii) Compound 2 or a pharmaceutically acceptable salt hence.
[14] The antiviral agents (i) Compound 1 or a pharmaceutically acceptable salt In other aspects, they comprise at least two direct acting thereof, which is co-administered or co-formulated with ritonavir, and (ii) Compound 3 or a pharmaceutically acceptable salt thereof.
[15] The antiviral agents (i) Compound 1 or a pharmaceutically acceptable salt In another aspect, they comprise at least two direct acting thereof, which is co-administered or co-formulated with ritonavir, and (ii) Compound 4 or a pharmaceutically acceptable salt thereof.
[16] The antiviral agents (i) Compound 1 or a pharmaceutically acceptable salt In another aspect, they comprise at least two direct acting thereof, which is co-administered or co-formulated with ritonavir, (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and ( iii) Compound 4 or a pharmaceutically acceptable salt thereof.
[17] The antiviral agents a drug combination selected from the group In another aspect, they comprise at least two direct effects consisting of: a combination of PSI-7977 and PSI-938, a combination of BMS-790052 and MNS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, GS-9190 and GS-9451, a combination of Bl-10 15 20 25 30 201335 and B | -27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danoprevir and R7128. In another aspect, the at least two direct-acting antiviral agents comprise a combination of PSI-7977 and BMS-790052 (daclatasvir). In another aspect, the at least two direct-acting antiviral agents comprise a combination of PSI-7977 and BMS-650032 (asunaprevir). In another aspect, the at least two direct-acting antiviral agents comprise a combination of PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another aspect, the at least two direct-acting antiviral agents comprise a combination of TMC-435 and daclatasvir.
[18] A method of treating HCV infection in a subject comprising: In other aspects, the present technology provides an administering (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3, and combinations thereof, and (c) a cytochrome P450 inhibitor to the subject and for a period of not more than twelve weeks, wherein the therapeutic agent 1, the at least one polymerase inhibitor, and the cytochrome P450 inhibitor are administered in amounts which are effective to result in SVR in the subject.
[19] A method of treating a population of subjects with an HCV In another aspect, the present technology provides infection, the method comprising administering at least two DAAs to the subjects for a period of not more than 12 weeks, wherein the at least two DAAs are administered to the subjects in amounts and for a time that are effective in acquiring an SVR in at least about 70% of the population.
[20] Combining at least two DAAs for use in the treatment of an HCV In another aspect, the present technology presents an infection in which the duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks).
[21] Combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and In another aspect, the present technology presents a Compound 2 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV infection. The treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The treatment time can also be, for example, no more than eight weeks (eg the time is 8 weeks; or the time is 7, 6, 5, 4 or 3 weeks). Treatment does not include administering interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (eg cobicistat) is administered with Compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 2 (or the salt thereof) may be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) may be administered once daily, together with ritonavir or another CYP3A4 inhibitor (eg cobicistat), and Compound 2 (or the salt thereof) may be administered twice daily. In another example, Compound 1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, eg cobicistat) are co-formulated in a single composition and administered simultaneously (eg a bunch daily) . In another example, Compound 1 (or the salt thereof) co-formulated with ritonavir (or other CYP3A4 inhibitor, eg cobicistat) is administered once daily; and Compound 2 (or the salt thereof) is administered twice daily. As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment-naïve patient, an HCV treatment-accustomed patient, one who does not respond to interferon (eg one who does not respond at all), or one who is not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 10 weeks, and the subject as treated is a naive patient who is infected with HCV genotype 2. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient who is infected with HCV genotype 2. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In a another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 10 15 20 25 30 3. In another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient who are infected with HCV genotype 3. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient who is infected with HCV genotype 3. In another example, the treatment lasts for 8 weeks, and the subject who is being treated is a naive patient who is infected with HC V genotype 3. In another example, the treatment lasts for 12 weeks, and the subject being treated is a patient who does not respond (e.g. one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a patient who does not respond (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 10 weeks, and the subject being treated is an unresponsive patient (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responding patient (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 8 weeks, and the patient being treated is an unresponsive patient (eg one who does not respond at all) who is infected with HCV genotype 1.
[22] Combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and In another aspect, the present technology presents a Compound 3 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV infection. The treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The treatment time can also be, for example, no more than eight weeks (eg the time is 8 weeks; or the time is 7, 6, 5, 4 or 3 weeks). Treatment does not include administering interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (eg cobicistat) is administered with Compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) may be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) may be administered once daily, together with ritonavir or another CYP3A4 inhibitor (eg cobicistat), and Compound 3 (or the salt thereof) may be administered twice. Daily. In another example, Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) may be administered once daily. In another example, Compound 1 (or the salt thereof) and ritonavir (or other CYP3A4 inhibitor, eg cobicistat) are co-formulated in a single composition and administered simultaneously (eg once daily). In another example, Compound 1 (or the salt thereof), ritonavir (or other CYP3A4 inhibitor, eg cobicistat) and Compound 3 (or the salt thereof) are co-formulated in a single composition and co-administered (eg a once daily). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b. As a non-limiting example, the patient being treated may be infected with HCV genotype 2 or 3. As another non-limiting example, the patient may be an HCV treatment-naïve patient, an HCV treatment-accustomed patient, one who does not respond to interferon ( eg one who does not respond at all), or one who is not a candidate for interferon treatment. In one example, treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 10 weeks, and the subject as b ehandlas is a naive patient who is infected with HCV genotype 2. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient who is infected with HCV genotype 2. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient who is infected with H CV genotype 3. In another example, the treatment lasts for 12 weeks, and the subject being treated is one who does not respond to treatment (e.g. one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is one who does not respond (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 10 weeks, and the subject being treated is one who does not respond (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 9 weeks, and the subject being treated is one who does not respond (eg one who does not respond at all) who is infected with HCV genotype 1. In another example, the treatment lasts for 8 weeks, and the subject being treated is one who does not respond (eg one who does not respond at all) who is infected with HCV genotype 1.
[23] Combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and In another aspect, the present technology presents a Compound 4 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV infection. Treatment involves administering DAAs to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[24] Combination of Compound 1 (or a pharmaceutically acceptable salt thereof), In another aspect, the present technology presents a Compound 2 (or a pharmaceutically acceptable salt thereof) and Compound 4 (or a pharmaceutically acceptable salt thereof) for use in treatment of HCV infection. The treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[25] Combining at least two DAAs for use in treating HCV-1 another aspect, the present technology presents an infection, said composition comprising a combination selected from: a combination of PSI-7977 and PSI-938 , a combination of BMS-790052 and BMS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, GS-9190 and GS-9451, a combination of BI-201335 and B1-27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danoprevir and R7128. The treatment comprises administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[26] Combining at least two DAAs for use in treating HCV- In another aspect, the present technology presents an infection, said composition comprising a combination selected from: a combination of PSI-7977 and BMS-790052 , a combination of PSI-7977 and BMS-650032, a combination of PSI-7977, BMS-790052 and BMS-650032, a combination of INX-189 and BMS-790052, a combination of INX-189 and BMS-650032, or a combination of INX-189, BMS-790052 and BMS-650032.
[27] 7977, or a combination of at least two DAAs, for use in another aspect, the present technology presents PSI treatment of HCV infection, said composition comprising a combination selected from: a combination of mericitabine and danoprevir, a combination of INX-189, daclatasvir and BMS-791325, and a combination of PSI-7977 and GS-5885.
[28] 7977, or a combination of at least two DAAs, for use in another aspect, the present technology presents PSI treatment of HCV infection, said combination comprising a combination selected from: a combination of mericitabine and danoprevir, a combination of INX-189, daclatasvir and BMS-791325, and a combination of PSI-7977 and GS-5885.
[29] Combination of at least two DAAs for use in treating HCV-1 another aspect, the present technology presents an infection, said combination comprising a combination selected from: a combination of tegobuvir and GS-9256, a combination of BMS-791325, asunaprevir and daclatasvir, and a combination of TMC-435 and daclatasvir.
[30] In another aspect, the present technology presents a combination of PSI-7977 and BMS-790052 for use in the treatment of HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the period is 12 weeks; or the actual period is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[31] In another aspect, the present technology presents a combination of PSI-7977 and TMC-435 for use in treating HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[32] Combination of danoprevir and mercitabine for use in the treatment of In another aspect, the present technology presents an HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than sixteen weeks (eg the time is 16 weeks; or the time is 14, 12 or 10 weeks). The treatment time can also be less than ten weeks. Treatment does not involve administering either interferon or ribavirin. Treatment also includes co-administration of ritonavir or another CYP3A4 inhibitor (eg cobicistat) with danoprevir to improve the pharmacokinetics of danoprevir. The two DAAs can be administered simultaneously or sequentially. For example, one DAA may be administered once daily and another DAA may be administered twice daily. In another example, the two DAAs are administered once daily. In another example, the two DAAs are co-formulated in a single composition and administered simultaneously (eg, once daily). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b.
[33] Combination of INX-189, daclatasvir and BMS-791325 for use in the treatment of HCV infection. The treatment involves administering DAA- In another aspect, the present technology presents a combination to a subject infected with HCV. The duration of the treatment regimen is not more than sixteen weeks (eg the time is 16 weeks; or the time is 14, 12 or 10 weeks). The treatment time can also be less than 10 weeks. Treatment does not include administering either interferon or ribavirin. Treatment may include administering ritonavir or another CYP3A4 inhibitor (eg cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA may be administered once daily and another DAA administered twice daily. In another example, the two DAAs are administered once daily. In another example, the two DAAs are co-formulated in a single composition and administered simultaneously (eg, once daily). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b.
[34] In another aspect, the present technology presents a combination of PSI-7977 and GS-5885 for use in the treatment of HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than sixteen weeks (eg the time is 16 weeks; or the time is 14, 12 or 10 weeks). The treatment time can also be less than ten weeks. Treatment does not include administering either interferon or ribavirin. Treatment may include administering ritonavir or another CYP3A4 inhibitor (eg cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA may be administered once daily and another DAA may be administered twice daily. In another example, the two DAAs are administered once a day. In another example, the two DAAs are co-formulated in a single composition and administered simultaneously (eg, a bunch daily). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment-naïve patient, an HCV treatment-accustomed patient, one who does not respond. On interferon (eg one who does not respond at all), or one who is not a candidate for interferon treatment. In one example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 10 weeks, and the subject treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient who is infected with HCV genotype 3. In another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype In another example, the treatment lasts for 16 weeks, and the subject being treated is one who does not respond to treatment (e.g. one who does not respond at all) who is infected with HCV genotype 1.
[35] Combination of TMC-435 and daclatasvir for use in the treatment of another aspect, the present technology presents an HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is not more than twelve weeks (eg the time is 12 weeks; or the time is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
[36] Methods for treating HVC infection, the methods comprising In another aspect, the present invention presents administering at least two direct acting antiviral agents (DAAs) to a subject in need thereof, and wherein the treatment does not include administering either interferon or ribavirin to the subject. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks. The subject being treated may be, for example, a treatment-naive patient. The subject may also be a patient accustomed to treatment, or one who does not respond to interferon (eg one who does not respond at all).
[37] The at least two DAAs (i) Compound 1 or a pharmaceutically acceptable salt In an embodiment of this aspect of the invention, comprises thereof, and (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and wherein said process further comprises to administer ritonavir to the subject. Ritonavir improves the pharmacokinetics or drug exposure of Compound 1. Treatment may be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks.
[38] The at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable embodiment of this aspect of the invention, an acceptable salt thereof, and (ii) Compound 4 or a pharmaceutically acceptable salt thereof , and wherein said method further comprises administering ritonavir to the subject to improve the pharmacokinetics or drug exposure of Compound 1. The treatment may be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks. The subject being treated may, for example, be an HCV treatment-naïve patient. The subject may also be a HCV treatment patient or one who does not respond to interferon (eg one who does not respond at all). Preferably, the subject being treated is infected with HCV genotype 1, e.g. genotype 1a. As another non-limiting example, the subject is infected with HCV genotype 3.
[39] The at least two DAAs comprise (i) Compound 1 or a pharmaceutical In another embodiment of this aspect of the invention, acceptable salt thereof, (ii) Compound 2 or a pharmaceutically acceptable salt thereof and (iii) Compound 4 or a pharmaceutically acceptable salt thereof, and said method further comprising administering ritonavir to the subject to improve the pharmacokinetics or drug exposure of Compound 1. The treatment may be, for example and without limitation, for not more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks. The subject being treated may, for example, be an HCV treatment-naïve patient.
[40] The at least two DAAs comprise an HCV protease inhibitor and an HCV-1 Another embodiment of this aspect of the invention, polymerase inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks.
[41] The at least two DAAs comprise an HCV protease inhibitor and a non-In another embodiment of this aspect of the invention, nucleoside or non-nucleotide HCV polymerase inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[42] The at least two DAAs comprise an HCV protease inhibitor and a nucleoside in another embodiment of this aspect of the invention, or nucleotide HCV polymerase inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks. The subject being treated may, for example, be an HCV treatment-naïve patient. The subject may also be a patient accustomed to treatment or one who does not respond to interferon (eg one who does not respond at all).
[43] In another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV protease inhibitor and an HCV NS5A inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks. The subject being treated may, for example, be an HCV treatment-naïve patient. The subject may also be a patient accustomed to treatment or one who does not respond to interferon (eg one who does not respond at all). Preferably, the subject being treated is infected with HCV genotype 1, e.g. genotype 1a. As another non-limiting example, the subject being treated is infected with HCV genotype 3.
[44] In another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV polymerase inhibitor and an HCV NS5A inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also be for 8 weeks.
[45] The at least two DAAs comprise an HCV non-nucleoside or HCV non-nucleotide polymerase inhibitor and an HCV NS5A inhibitor. The treatment may be, for example and without limitation, for not more than 12 weeks, such as 8, 9, In another embodiment of this aspect of the invention, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[46] In another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV nucleoside or HCV nucleotide polymerase inhibitor and an HCV NS5A inhibitor. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[47] In another embodiment of this aspect of the invention, the at least two DAAs include PSI-7977 and TMC-435. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[48] The at least two DAAs include TMC-435 and daclatasvir. The treatment may, in another embodiment of this aspect of the invention, be, for example and without limitation, for not more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[49] The at least two DAAs include PSI-7977 and daclatasvir. The treatment may, in another embodiment of this aspect of the invention, be, for example and without limitation, for not more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[50] The at least two DAAs include PSI-7977 and GS-5885. The treatment may be, for example and without limitation, for not more than 12 weeks, such as 8, 9, In another embodiment of this aspect of the invention, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[51] The at least two DAAs include mericitabine and danoprevir. The treatment In another embodiment of this aspect of the invention, it may be, for example and without limitation, for not more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[52] In another embodiment of this aspect of the invention, the at least two DAAs comprise BMS-790052 and BMS-650032.
[53] In another embodiment of this aspect of the invention, the at least two DAAs include INX-189, daclatasvir and BMS-791325.
[54] Methods for treating treatment-naïve subjects with HCV genotype 1- In another aspect, the present invention presents infection, the method comprising administering an effective amount of PSI-7977 to said patient, and wherein the treatment does not include administering either interferon or ribavirin to the subject. The treatment can be, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.
[55] The present invention provides methods for treating HCV infection. In another aspect of the invention, it comprises the methods comprising administering at least two DAAs, to a subject in need thereof, for a time sufficient to achieve a sustainable virological response. Treatment does not include administration of either interferon or ribavirin. Any of the DAA combinations described herein can be used. The time may be, for example, not more than 8 weeks, or preferably, not more than 12 weeks.
[56] [0056] generally a complete course of treatment, i.e. no subsequent interferon- A treatment regimen according to the present technology constitutes containing regimen is intended. Thus, a treatment or use described herein generally does not include any subsequent interferon-containing treatment. Preferably, a treatment or use described herein does not include any subsequent ribavirin-containing treatment.
[57] The invention will become apparent in the following detailed description. It is apparent from other features, objects and advantages of the present invention that the detailed description is to be considered as an illustration only, as preferred embodiments of the invention are indicated, and not as a limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.
[58] Expected inhibitory effects at varying concentrations of Compound 1 Figure 1 is a 3D surface diagram illustrating deviations from and Compound 2 in a genotype 1b HCV replicon assay.
[59] Compound 1 and Compound 2 exhibited synergistic, additive or Figure 2 is a contour diagram showing concentrations at which antagonistic interactions in the genotype 1b-HCV replicon assay. 10 15 20 25 30 39
[60] Expected inhibitory effects at varying concentrations of Compound 1 Figure 3 is a 3D surface diagram illustrating deviations from and Compound 4 in a genotype 1b HCV replicon assay.
[61] Compound 1 and Compound 4 exhibited synergistic, additive or Figure 4 is a contour diagram showing concentrations at which antagonistic interactions in the genotype 1b-HCV replicon assay.
[62] Containing HCV genotype 1a replicon constructs that survive after Figure 5A is a bar graph showing the percentage of cells three weeks of exposure to therapeutic agent 1, therapeutic agent 2, therapeutic agent 4, or a combination of some or all of these therapeutic agents. agents in the presence of G418.
[63] Surviving 1a-H77 replica cells grown in the presence of G418, and Figure 5B is another bar graph showing the percentage of two or three DAA combinations, for approximately three weeks.
[64] Figure 5C depicts the effect of Compound 1, Compound 4 and a combination thereof in long-term HCV RNA reduction assays with 1a-H77 replicon cell lines.
[65] A combination thereof in long-term HCV RNA reduction assays with 1b-Con1- Figure 5D demonstrates the effect of Compound 1, Compound 4 and replicon cell lines.
[66] Confidence interval for the SVR percentage at different treatment times for a 2- Figure 6A shows the predicted median and 90% DAA regimen without ribavirin; wherein the 2 DAAs include Compound 1 (in combination with ritonavir, i.e. Compound 1 / r) and Compound 2.
[67] Confidence interval for the SVR percentage at different treatment times for a 2- Figure 6B illustrates the predicted median and 90% DAA regimen without ribavirin; wherein the 2 DAAs include Compound 1 (in combination with ritonavir, i.e. Compound 1 / r) and Compound 4.
[68] Figure 6C shows the predicted median and 90% confidence interval for the SVR percentage at different treatment times for a 3-DAA course without ribavirin; wherein the 3 DAAs include (i) Compound 1 (in combination with ritonavir, i.e. Compound 1 / r), (ii) Compound 2 and (iii) Compound 4.
[69] The observed percentage of subjects with HCV RNA lower than LOD over time in a clinical study.
[70] Versus the observed percentage of subjects with SVR12 in another clinical study.
[71] Figure 9 shows the predicted median and 90% confidence interval for SVR levels at different treatment times with a 2-DAA regimen containing BMS-790052 and BMS-650032.
[72] Figure 10 shows the predicted median of SVR levels at different treatment times with a 3-DAA regimen containing Compound 1 / r, Compound 4 and PSI-7977.
[73] Figure 11 shows the predicted median and 90% confidence interval for different SVR percentages at different treatment times for a 1-DAA regimen containing PSI-7977 and ribavirin.
[74] Figure 12 depicts the predicted median and 90% confidence interval for the SVR percentage at different treatment times for a 2-DAA regimen containing daclatasvir (BMS-790052) 60 mg QD and PSI-7977 400 mg QD.
[75] Figure 13 shows the predicted median and 90% confidence interval for the SVR percentage at different treatment times for a 2-DAA regimen containing TMC-435 150 mg QD and PSI-7977 400 mg QD.
[76] Confidence interval for the SVR percentage at different treatment times for a 2-DAA regimen containing danoprevir 100 mg BID and mercitabine 750 mg BID.
[77] Figure 15 depicts the predicted median and 90% confidence interval for the SVR percentage at different treatment times for a 2-DAA regimen containing GS-9190 (tegobuvir) 30 mg BID + GS-9451 200 mg QD + GS-5885 90 mg QD.
[78] Confidence interval for the SVR percentage at different treatment times for one of the following DAA combination regimens: (1) GS-9451 200 mg QD + GS-7977 (PSI-7977) 400 mg QD; (2) GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 Figure 7 shows the predicted response-response model versus Figure 8 demonstrates the predicted response-response model Figure 14 illustrates the predicted median and 90% Figure 16 shows the predicted the median and 90% 41 mg 25 41 mg QD; and (3) GS-9451 200 mg QD + GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 mg QD.
[79] Confidence interval for the SVR percentage at different treatment times for a 2-DAA regimen containing TMC-435 150 mg QD and daclatasvir (BMS-790052) 60 mg QD.
[80] Therapeutic agent 1 to a subject. Therapeutic agent 1 is Compound 1 / N Q o Oï / QWH N | N 'fil O N / H () or a pharmaceutically acceptable salt thereof. Compound 1 is also known as (2R, 6S, 13aS, 14aR, 16aS, Z) -N- (cyclopropylsulfonyl) -6- (5-methylpyrazine-2-carboxamido) -5,16-dioxo-2- (phenanthridine-6 -yloxy) -1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-hexadecahydrocyclopropa [e] pyrrolo [1,2-a] [1 , 4] diazacyclopentadequin-14a- The present methods may include administering a carboxamide. Compound 1 is a potent HCV protease inhibitor. The synthesis and formulation of Compound 1 are described in U.S. Patent Application Publication No. US 2010/0144608, U.S. Provisional Application No. 61 / 339,964 filed March 10, 2010, and U.S. Patent Application Publication No. US 2011/0312973 March 8, 2011. All of these applications are incorporated herein by reference in their entirety. Therapeutic agent 1 includes various salts of Compound 1. Therapeutic agent 1 may be administered in any suitable amount, such as, for example, in doses ranging from about 0.01 to about 50 mg / kg body weight, alternatively from about 0.1 42 to about 25 mg / kg body weight. As a non-limiting example, therapeutic agent 1 may be administered in a total daily dosage amount in the range of from about 50 mg to about 250 mg, preferably from about 100 mg to about 250 mg, and includes, but is not limited to, for example, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, and appropriate amounts therebetween.
[81] Preferably with therapeutic agent 1 to enhance the pharmacokinetics of Ritonavir or another cytochrome P-450 inhibitor, Compound 1 is co-administered.
[82] The present methods may include administering therapeutic agent 2 to a subject. Therapeutic agent 2 is Compound 2 or a salt thereof.
[83] Compound 2 is also known as N- (6- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) naphthalene 2-yl) methanesulfonamide As described in, for example, International Publication WO 2009/039127, therapeutic agent 2 includes various salts of Compound 2, such as sodium salts, potassium salts and choline salts. Therapeutic agent 2 also includes crystalline forms of Compound 2 and its salts such as solvate, hydrate and solvent-free crystalline forms of Compound 2 and its salts. Compositions comprising therapeutic agent 2 may be formulated as described in, for example, International Publication WO 2009/039127 which is incorporated herein by reference.
[84] Particular crystalline form of Compound 2. In certain embodiments, Therapeutic Agent 2 may be administered as a free acid, salt or Therapeutic Agent 2 as a sodium salt. Therapeutic agent 2 can be administered in any suitable amount, such as, for example, idoseri in the range of from about 5 mg / kg to about 30 mg / kg. As a non-limiting example, therapeutic agent 2 may be administered in a total daily dosage amount in the range of from about 300 mg to about 1800 mg, or from about 400 mg to about 1600 mg, or from about 600 mg to about 1800 mg, or from 800 mg to 1600 mg or any amount in between. In some embodiments, the total daily dose of therapeutic agent 2 is about 600 mg. In some embodiments, the total daily dose of therapeutic agent 2 is about 800 mg. In some embodiments, the total daily dose of therapeutic agent 2 is about 1200 mg. In some embodiments, the total daily dose of therapeutic agent 2 is about 1600 mg.
[85] Therapeutic agent 3 or a salt thereof to a subject. Therapeutic Agent 3 is The present methods may include administering Compound 3 or a salt thereof.
[86] Compound 3 is also known as (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2 -methoxystyryl) phenyl) methanesulfonamide.
[87] Particular crystalline form of Compound 3. In certain embodiments, Therapeutic Agent 3 may be administered as a free acid, salt or Therapeutic Agent 3 as a potassium salt. Therapeutic agent 3 may be administered in any suitable amount, such as, for example, idoser in the range of from about 0.5 mg / kg to about 15 mg / kg, or from about 1 mg / kg to about 10 mg / kg. As a non-limiting example, therapeutic agent 3 may be administered in a total daily dosage amount in the range of from about 100 mg to about 600 mg. In some embodiments, the total daily dose of therapeutic agent 3 is about 300 mg. In some embodiments, the total daily dose of therapeutic agent 3 is about 320 mg. In some embodiments, the total daily dose of therapeutic agent 3 is about 400 mg. In some embodiments, the total daily dose of therapeutic agent 3 is about 600 mg.
[88] Therapeutic agent 4 or a salt thereof to a subject. Therapeutic Agent 4 is The present methods may include administering Compound 4 or a salt thereof.
[89] Compound 4 is also known as dimethyl (2S, 2'S) -1,1 '- ((2S, 2'S) -2,2' - (4,4 '- ((2S, 5S) -1- (4 -tert-butylphenyl) pyrrolidine-2,5, diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl) bis (3-methyl-1-oxobutane-2 1-diyl) carbamate Compound 4 may be prepared as described in, for example, U.S. Publication U.S. 2010/0317568, which is incorporated herein by reference.
[90] Salt form. Therapeutic agent may be administered in any suitable amount Therapeutic agent 4 may be administered as a free acid or in any form, such as, for example, in doses ranging from about 0.1 mg / kg to about 200 mg / kg body weight, or from about 0 mg. , 25 mg / kg to about 100 mg / kg, or from about 0.3 mg / kg to about 30 mg / kg. As a non-limiting example, therapeutic agent 4 may be administered in a total daily dosage amount in the range of from about 5 mg to about 300 mg, or from about 25 mg to about 200 mg, or from about 25 mg to about 50 mg, or the amount anywhere in between. In some embodiments, the total daily dose of therapeutic agent 4 is about 25 mg.
[91] HCV treatment includes an interferon treatment regimen, e.g.
[92] Demanding, and can lead to temporary disability in some cases. A significant proportion of interferon / ribavirin-based treatments may be physical by patients experiencing a range of side effects ranging from a flu-like syndrome (most commonly experienced within a few days after weekly interferon injection) to severe adverse conditions including anemia , cardiovascular disorders and psychiatric problems such as suicide or suicidal ideation. The latter are generally aggravated by physiological stress experienced by patients. Ribavirin also has a number of side effects, which include anemia, high pill burden (eg 5-6 tablets a day split BID) and teratogenicity that limits its use in women of childbearing potential. .
[93] In the case of HCV infection without the use of interferon or ribavirin and during a The present methods provide effective treatment for a shorter period of time, such as a treatment time of not more than twelve weeks, alternatively not more than eleven weeks, alternatively not more than ten weeks, alternatively not more than nine weeks, alternatively not more than eight weeks, alternatively not more than seven weeks, alternatively not more than six weeks, alternatively not more than five weeks, alternatively not more than four weeks, or alternatively not more than three weeks.
[94] The technology methods for treating HCV infection in a subject In certain embodiments, the present invention provides for administering at least two DAAs in the absence of interferon and ribavirin for a period of not more than twelve weeks, alternatively not more than eight weeks. In other words, the present methods exclude interferon and ribavirin, or the subject does not receive interferon or ribavirin during the treatment period. The at least two DAAs can be co-administered or can be administered independently (with the same or different dosing frequencies) and can be administered once a day, alternatively twice a day, or three times a day.
[95] Daily administration of two or more DAAs, wherein a first DAA may, in certain embodiments, comprise the treatment methods administered once a day, twice a day, or three times a day, and a second DAA may be administered once a day. day, twice a day, or three times a day. In some embodiments, a third DAA may be administered once daily, twice daily, or three times daily.
[96] Present methods of HVC treatment. Such a measure is fast Various measures can be used to express the effectiveness of the rapid virological response (RVR), which means that HCV is not detectable in the subject after 4 weeks of treatment, e.g. , after 4 weeks of administration of two or more DAAs. Another measure is early virological response (EVR), which means that the subject has a> 2log10 reduction in virological load after 12 weeks of treatment. Another measure is complete EVR (cEVR), which means that HCV is not detectable in the subject's serum after 12 weeks of treatment. Another measure is extended RVR (eRVR), which means that both RVR and cEVR are achieved, i.e. HCV cannot be detected at weeks 4 and 12. Another measure is the presence or absence of a detectable virus at the end of therapy (EOT). Another measure is SVR, which here means that virus is not detectable at the end of therapy and for at least 8 weeks after the end of therapy (SVR8); preferably, the virus is not detectable at the end of therapy and for at least 12 weeks after the end of therapy (SVR12); more preferably, the virus is not detectable at the end of therapy and for at least 16 weeks after the end of therapy (SVR16); and most preferably, the virus is not detectable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24). SVR24 is often considered a functional definition of cure; and a high SVR level at less than 24 weeks after treatment (eg SVR8 or SVR12) may be predictive of a high SVR24 level. Similarly, a high SVR level at less than 12 weeks after treatment (eg SVR4 or SVR8) may be predictive of a high SVR12 level. A high EOT grade (eg at week 8 or week 12) may also be indicative of a significant SVR12 or SVR24 grade.
[97] The DAAs and / or the duration of the treatment regimen with the two or more DAAs effective (a) to provide an RVR of a subject, or an EVR of a subject, or a cEVR of a subject, or an eRVR in a subject, or an absence of detectable virus in EOT in a subject. In some embodiments, the amounts of the two or more embodiments include the present methods of treating a population of subjects with an HCV infection (eg, treatment-naïve subjects), and the methods comprise administering at least two DAAs to the subjects for a period of not more than 12 weeks, or for another time described herein, wherein the at least two DAAs are administered to the subjects in amounts effective to provide an SVR (e.g. SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment) in at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively at least about 100% of the population. In some embodiments, the present methods comprise treating a population of IFN-accustomed subjects (eg, those not responding to interferon) with an HCV infection, and the methods comprise administering at least two DAAs to the subjects over a period of time. of not more than 12 weeks, or for any other time described herein, the two DAAs being administered to the subjects in amounts effective to provide an SVR (eg SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment) in at least about 50% of the population, or at least about 55% of the population, or at least about 60% of the population, or at least about 65% of the population. In other embodiments, the amount of DAAs and the treatment time are effective to provide one or more of an SVR (eg, SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment), an RVR, an EVR, a cEVR, an eRVR, or an absence of detectable virus in EOT, in at least about 50% of the population, alternatively at least about 55% of the population, alternatively at least about 60% of the population, alternatively at least about 65% of the population, alternatively at least about 70 % of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively at least about 100% of the population. For example, the present methods comprise administering at least two DAAs in amounts and for times effective to provide an SVR (eg, SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment) in a subject. . In some embodiments, the present technology provides an SVR (eg, SVR at 8 weeks post-treatment, or SVR at 24 weeks post-treatment) in at least about 50% of the population, alternatively at least about 55% of population, in at least about 60% of the population, preferably in at least about 65% of the population, preferably in at least about 70% of the population, preferably in at least about 75% of the population, more preferably in at least about 80% of the population, and most preferably in at least about 90% of patients treated. In some embodiments, a treatment according to the present technology provides an RVR or a level of HCV RNA in the blood vessel that is not detectable at four (4) weeks of treatment (preferably in addition to an SVR).
[98] Not limited to, a protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, an HCV NS3B inhibitor, an HCV NS4A inhibitor, an HCV NS5B inhibitor, an HCV entry inhibitor. HCV entry inhibitor), a cyclophilin inhibitor, a CD81 inhibitor, or an internal ribosome entry site inhibitor.
[99] In another example of this aspect of the technology, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In another example, the combination of two or more DAAs includes GS-5885, GS-9190 and GS-9451. In another example, the combination of two or more DAAs includes BI-201335 and B1-207127. In another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs comprises INX-189 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS 650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir.
[100] Using a combination of two or more DAAs, and for a period of It was unexpected that an interferon-free and ribavirin-free treatment of no more than 12 weeks can achieve a significant SVR. In some cases, such treatment may achieve an SVR in at least 75% of patients, and in some cases, such treatment may achieve an SVR in at least 85% of patients, and in specific cases, such treatment may achieve an SVR in at least 75% of patients. at least 90% of patients. It was also unexpected that an interferon-free and ribaviron-free treatment using a combination of two or more DAAs, and for a period of no more than 12 weeks, can achieve a significant SVR in those who do not respond to interferon (e.g. those who do not respond at all), for example, such treatment may achieve an SVR in at least about 50% of patients in a population with those who do not respond to interferon, preferably at least about 60% of patients in a population with those who do not respond on interferon, more preferably at least about 65% of patients in a population with those who do not respond to interferon.
[101] A method of treating an HCV infection, comprising administering Thus, the present technology presents, in one aspect, an effective amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 8 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds partially to interferon, or one who does not respond to interferon, or a patient who is unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3.
[102] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 7 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient may be a treatment-naive patient, a treatment-accustomed patient, which includes but is not limited to one who relapses, one who responds in part to interferon, one who does not respond to interferon (eg, one who does not respond at all to interferon), or a patient who is unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and an HCV polymerase inhibitor (eg, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least an HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least two HCV polymerase inhibitors (eg, a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For example, the combination of at least two or more DAAs may be a combination of at least two HCV protase inhibitors. For example, the combination of at least two or two DAAs may be a combination of at least two HCV NS5A inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (eg a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated or co-administered with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or two DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example of this aspect of the technology, the combination of two or more DAAs includes PSI-7977 and PSI-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In another example, the combination of two or more DAAs includes GS-5885, GS-9190 and GS-9451. In another example, the combination of two or more DAAs includes Bl-201335 and Bl-207127. In another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In another example, the combination of two or more DAAs comprises danoprevir (with ritonavir) and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes mericitabine and danoprevir. In another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In another example, the combination of two or two DAAs includes PSI-7977 and GS-5885. In another example, the combination of two or more DAAs comprises PSI-7977, Compound 1 (with ritonavir) and Compound 4. In another example, the method of administering an effective amount of PSI-7977 to a patient in need thereof as the sole DAA instead of two or more DAAs. In another example, the method comprises administering 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In another example, the method comprises administering 150 or 250 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 once daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily.
[103] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 6 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes but is not limited to one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g., one who does not respond to interferon at all ), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[104] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or two DAAs to a patient in need thereof. The treatment lasts for 5 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds partially to interferon, or one who does not respond to interferon (e.g., one who does not respond at all to interferon ), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and an HCV polymerase inhibitor (eg, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least an HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least two HCV polymerase inhibitors (eg, a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleotide polymerase inhibitor). nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For example, the combination of at least two or more DAAs may be a combination of at least two HCV protase inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least two HCV-NS5A inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (eg a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor. the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example of this aspect of the technology, the combination of two or more DAAs includes PSI-7977 and PSI-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In another example, the combination of two or more DAAs includes GS-5885, GS-9190 and GS-9451. In another example, the combination of two or more DAAs includes BI-201335 and B1-207127. In another example, the combination of two or more DAAs comprises telaprevir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In another example, the combination of two or more DAAs comprises danoprevir (with ritonavir) and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatase virus). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs comprises INX-189 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes mericitabine and danoprevir. In another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In another example, the combination of two or more DAAs comprises PSI-7977 and GS-5885. In another example, the combination of two or more DAAs comprises PSI-7977, Compound 1 (with ritonavir) and Compound 4. In a another example, the method comprises administering an effective amount of PSI-7977 to a patient in need thereof as the single DAA instead of two or more DAAs. In another example, the method comprises administering 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In another example, the method comprises administering 150 or 250 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 once daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Other DAAs or other DAAs may also be included in the treatment regimen according to this aspect of the technology.
[105] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 4 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g., one who does not respond at all on interferon), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[106] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 3 weeks (or even shorter, depending on the patient's condition) and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds partially to interferon, or one who does not respond to interferon (e.g., one who does not respond at all to interferon ), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and an HCV polymerase inhibitor (eg, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least two HCV polymerase inhibitors (eg, a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleotide polymerase inhibitor). nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For example, the combination of at least two or more DAAs may be a combination of at least two HCV protease inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least two HCV NS5A inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (eg a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or two DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example of this aspect of the technology, the combination of two or more DAAs includes PSI-7977 and PSI-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In another example, the combination of two or more DAAs includes GS-5885, GS-9190 and GS-9451. In another example, the combination of two or more DAAs includes Bl-201335 and Bl-207127. In another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In another example, the combination of two or more DAAs comprises danoprevir (with ritonavir) and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes mericitabine and danoprevir. In another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In another example, the combination of two or more DAAs comprises PSI-7977 and GS-5885. In another example, the combination of two or more DAAs comprises PSI-7977, Compound 1 (with ritonavir) and Compound 4. In a another example, the method comprises administering an effective amount of PSI-7977 to a patient in need thereof as the single DAA instead of two or more DAAs. In another example, the method comprises administering 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In another example, the method comprises administering 150 or 250 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 once daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Other DAAs or other DAAs may also be included in the treatment regimen according to this aspect of the technology. 10 15 20 25 30 71
[107] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 24 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naive patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, one who does not respond to interferon (e.g., or one who does not respond at all on interferon), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[108] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts in the range from 13 to 23 weeks (eg the treatment time is chosen from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administration of any interferon or any ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g., one who does not respond at all on interferon), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (eg, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least two HCV polymerase inhibitors (eg, a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For example, the combination of at least two or more DAAs may be a combination of at least two HCV protease inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least two HCV NS5A inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (eg, a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside inhibitor). or nucleotide polymerase inhibitor, or a combination of at least one HCV-NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV-NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleaside inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 10 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example of this aspect of the technology, the combination of two or more DAAs comprises P81-7977 and P81-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In another example, the combination of two or more DAAs includes BM8-790052 and BM8-650032. In another example, the combination of two or more DAAs includes 68-5885, 68-9190 and 68-9451. In another example, the combination of two or more DAAs includes Bl-201335 and Bl-207127. In another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs comprises 68-5885 and 68-9451. In another example, the combination of two or more DAAs comprises danoprevir (with ritonavir) and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BM8-790052 (daclatasvir). In another example, the combination of two or more DAAs includes P8I-7977 and BM8-650032 (asunaprevir). In another example, the combination of two or more DAAs includes P81-7977, BM8-650032 (asunaprevir) and BM8-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BM8-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BM8-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BM8-650032 (asunaprevir) and BM8-790052 (daclatasvir). In another example, the combination of two or more DAAs includes mericitabine and danoprevir. In another example, the combination of two or more DAAs includes INX-189, daclatasvir and BM8-791325. In another example, the combination of two or more DAAs includes P8I-7977 and 68-5885. In another example, the method comprises administering an effective amount of P81-7977 to a patient in need thereof as the single DAA instead of two or more DAAs. In another example, the method comprises administering 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In another example, the method comprises administering 150 or 250 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 once daily.
[109] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 12 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds partially to interferon, or one who does not respond to interferon (e.g., one who does not respond at all to interferon ), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and one HCV polymerase inhibitor (eg, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor). , or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. For example, the combination of two or more DAAs may be a combination of at least two HCV polymerase inhibitors (eg, a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleotide polymerase inhibitor). nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For example, the combination of at least two or two DAAs may be a combination of at least two HCV protease inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least two HCV NS5A inhibitors. For example, the combination of at least two or more DAAs may be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (eg a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) may be co-formulated with ritonavir. In another example of this aspect of the technology, the combination of two or more DAAs includes PSI-7977 and PSI-938. In another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In another example, the combination of two or more DAAs includes GS-5885, GS-9190 and GS-9451. In another example, the combination of two or two DAAs includes BI-201335 and B1-207127. In another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In another example, the combination of two or more DAAs comprises danoprevir with ritonavir and R7128. In another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs comprises INX-189 and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs comprises mericitabine and danoprevir. In another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In another example, the combination of two or more DAAs comprises PSI-7977 and GS-5885. In another example, the combination of two or more DAAs comprises PSI-7977, Compound 1 (with ritonavir) and Compound 4. In a another example, the method comprises administering an effective amount of PSI-7977 to a patient in need thereof as the single DAA instead of two or more DAAs. In another example, the method comprises administering 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In another example, the method comprises administering 150 mg or 250 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 once daily. In another example, the method comprises administering 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method of administering 100 or 150 mg of Compound 1 together with 100 g of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Other DAAs or other DAAs may also be included in the treatment regimen according to this aspect of the technology.
[110] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts 11 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g. one who does not respond to interferon at all), or a patient who is unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[111] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 10 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g., one who does not respond at all on interferon), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[112] A method of treating HCV comprising administering an effective In another aspect, the present technology presents an amount of a combination of two or more DAAs to a patient in need thereof. The treatment lasts for 9 weeks and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-accustomed patient, which includes, but is not limited to, one who relapses, one who responds in part to interferon, or one who does not respond to interferon (e.g., one who does not respond at all on interferon), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or 1b; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered at approximately the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.
[113] The technology of interferon-free and ribavirin-free treatment comprising administering two DAAs daily, the two DAAs including an HCV polymerase inhibitor, for example PSI-7977, and an NS5A inhibitor, for example In another embodiment, it provides present BMS-790052, for a period of not more than twelve weeks (eg not more than eleven weeks), preferably not more than eight weeks.
[114] The technology provides a method of treating hepatitis C virus infection of a subject In certain embodiments, the present subject comprises administering daily an HCV protease inhibitor and an HCV polymerase inhibitor to the subject in the absence of interferon and ribavirin. for a period of not more than twelve weeks, preferably not more than eight weeks.
[115] Can be used herein to treat a treatment-naïve patient or the methods of the present technology described in the treatment of a patient. Patients accustomed to treatment include those who do not respond to interferon (non-responders) (eg those who do not respond at all (now / I-responders)), those who respond partially (eng: partia / responders) (patients whose HCV RNA levels decreased but never became detectable), and those who relapsed (patients who achieved levels of HCV RNA that could not be detected during therapy but who returned). Methods of the present technology can also be used to treat patients who are not candidates for interferon therapy. Patients who are not candidates for interferon therapy include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon therapy, patients with medical conditions that prevent them from taking interferon therapy, and patients who have an increased risk of side effects or infection by taking interferon.
[116] Inhibitor, e.g. ritonavir, either in the same or in a separate pharmaceutical In some embodiments, a cytochrome P450 composition is administered as the protease inhibitor (eg, Compound 1 (or a pharmaceutically acceptable salt thereof)) to enhance pharmacokinetics. A cytochrome P450 inhibitor reduces the metabolism of certain protease inhibitors, such as Compound 1, thereby improving the pharmacokinetics and bioavailability of the protease inhibitor, for example Compound 1. More preferably, is Compound 1 (or a pharmaceutically acceptable salt thereof). co-formulated with ritonavir in the same dosage form. Other cytochrome P450 inhibitors, such as cobicistat, may also be administered instead of ritonavir, to enhance the pharmacokinetics of Compound 1 (or a pharmaceutically acceptable salt thereof).
[117] Co-administered with DAAs, either sequentially or simultaneously, in the same or Cytochrome P450 inhibitors, such as ritonavir, may have different compositions. In some embodiments, cytochrome P450 inhibitors are administered to improve the pharmacokinetics of at least one of the DAAs. Without binding to any theory, a cytochrome P450 inhibitor can and does reduce the development of resistant strands of HCV when co-administered with a DAA, thus contributing to efficacy in the form of shorter treatment. In certain embodiments, ritonavir is co-administered with therapeutic agent 1. In certain embodiments, ritonavir is co-administered with therapeutic agent 1 in the same compositions.
[118] The technology comprises a method of treating HCV infection comprising in certain embodiments, the present administering administering at least one protease inhibitor and at least one HCV polymerase inhibitor during a course of treatment of no more than, or less than, eight weeks in the absence of interferon and ribavirin. In some embodiments, the HCV polymerase inhibitor is Compound 1 (or a pharmaceutically acceptable salt thereof).
[119] The technology provides a method of treating HCV infection without using In certain embodiments, the present interferon and ribavirin provide, the method comprising administering at least two DAAs to a patient in need of such treatment, wherein the at least two The DAAs include at least one protease inhibitor and at least one HCV polymerase inhibitor. In some embodiments, the at least two DAAs include therapeutic agent 1 with at least one HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor is at least one non-nucleoside polymerase inhibitor. In certain embodiments, the non-nucleoside polymerase inhibitor is therapeutic agent 2 or therapeutic agent 3 or a combination thereof. 10 15 20 25 30 93
[120] The technology provides a method of treating HCV infection without using In certain embodiments, the present interferon and ribavirin provide, the method comprising administering an HCV protease inhibitor, preferably therapeutic agent 1, with at least one HCV-NS5A inhibitor to a patient in need of such treatment. In some embodiments, the NS5A inhibitor is therapeutic agent 4.
[121] In certain embodiments of the present technology, there is provided a method of treating an HCV infection without the use of interferon and ribavirin, the method comprising administering at least three DAAs to a subject for no more than 8 weeks without administering interferon or ribavirin. The at least three DAAs may be at least one protease inhibitor, at least one HCV polymerase inhibitor, and at least one NS5A inhibitor. In a preferred embodiment, the at least one protease inhibitor is therapeutic agent 1, the at least one polymerase inhibitor is therapeutic agent 2 or therapeutic agent 3, and the least single NS5A inhibitor is therapeutic agent 4.
[122] Limited to, therapeutic agent 1, telaprevir (Vertex), boceprevir (Merck), Bl-201335 (Boehringer lngelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Other suitable protease inhibitors include, but are not limited to, ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BMS-650032 ( BMS), danoprevir (RG7227 / ITMN-191, Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX-136 (ldenix), IDX-316 (ldenix), IDX-320 (ldenix), MK -5172 (Merck), narlaprevir (Schering-Plow Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec), vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Vertex), VX -813 (Vertex), VX-985 (Vertex), or a combination thereof.
[123] Uses in the present technology include, but are not limited to, Therapeutic Agent 2, Therapeutic Agent 3, GS-9190 (Gilead), B1-207127 (Boehringer Angelheim), and VX-222 (VCH-222) (Vertex). & ViraChem).
[124] Preferred NS5A inhibitors include, but are not limited to, therapeutic agent 4, BMS-790052 (BMS) and GS-5885 (Gilead). Non-limiting examples of suitable NS5A inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052 (BMS), BMS-824393 ( GS-5885 (Gilead), PP1-1301 (Presidio), PPI-461 (Presidio), A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or a combination thereof.
[125] Includes alisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis), or a combination thereof.
[126] Non-limiting examples of suitable HCV input inhibitors include ITX-4520 (iTherx), ITX-5061 (iTherx), or a combination thereof.
[127] The present methods include, but are not limited to, AP-HO05, A-831 (Arrow Therapeutics) (NS5A Inhibitor), A-689 (Arrow Therapeutics) (NS5A Inhibitor), 1NX08189 (Inhibitex) (Polymerase Inhibitor) ), ITMN-191 (intermune / Roche), NS3 / 4A protease inhibitor), VBY-376 (protease inhibitor) (Virobay), ACH-1625 (Achillion, protease inhibitor), lDX136 (ldenix, protease inhibitor), lDX316 (ldenitor, proteasin) , VX-813 (Vertex), SCH 900518 (Schering-Plow), TMC-435 (Tibotec), ITMN-191 (intermune, Roche), MK-7009 (Merck), IDX-Pl (Novartis), R7128 (Roche) , PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF-4878691 (Pfizer), IDX-184 (ldenix), IDX-375 (ldenix, NS5B polymerase inhibitor), PPI-461 (Presidio), BILB-1941 (Boehringer) lngelheim), GS-9190 (Gilead), BMS-790052 (BMS), CTS-1027 (Conatus), GS-9620 (Gilead), PF-4878691 (Pfizer), RO5303253 (Roche), ALS-2200 (Alios BioPharmaNertex) , ALS-2158 (Alios BioPharma / vertex), GSK62336805 (GlaxoSmithKline), or a combination thereof.
[128] Methods for treating patients with genotype 1 HCV infection, such as Specific Examples of Other DAA Agents Suitable for In Certain Embodiments, the present technology presents 1a or 1b. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin.
[129] Methods for treating patients with genotype 2 or 3-HCV infection.
[130] Procedures for treating patients with HCV infection. The Methods In some embodiments, the present technology comprises administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (e.g., a period of 12 weeks), preferably no more than 8 weeks (t eg a period of 8 weeks), treatment does not include administration of interferon or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 2. Suitably, the patient may be a treatment-naïve patient, a treatment-accustomed patient, or one who does not respond to interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a. In some embodiments than the patient infected with HCV genotype 1b. In some embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some embodiments, the patient is infected with HCV genotype 3a. The treatment according to this aspect can also only be effective against other HCV genotypes. The treatment time may be not more than 12 weeks, preferably not more than 8 weeks, and includes but is not limited to, not more than 11 weeks, not more than 10 weeks, not more than 9 weeks, but preferably not more than 8 weeks. not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks (eg the time is 12 weeks, or the time is 8 weeks). Therapeutic agent 1 and therapeutic agent 2 may be administered in therapeutically effective amounts to provide an SVR (eg, an SVR8, SVR12, SVR16, or SVR24) after a treatment time of not more than 12 weeks, preferably not more than 8 weeks. The total daily dose of therapeutic agent 1 may be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg. mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg . Therapeutic agent 2 can be administered with therapeutic agent 1 in any of the doses of therapeutic agent 1 described above. The total daily dose of therapeutic agent 2 may be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg. In certain embodiments, ritonavir may either be co-administered with or administered separately from therapeutic agent 1. Suitable doses of ritonavir include, but are not limited to, the range from about 50 mg to about 400 mg per day, preferably from about 100 mg per day. In certain embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatment for no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.
[131] Methods of Treating Patients with HCV Infection That Are Not In Certain Embodiments, the present technology presents candidates for interferon therapy. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (e.g. a period of 8 weeks), treatment does not include administration of interferon or ribavirin. Patients who are not candidates for interferon therapy include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon therapy, patients with medical conditions that prevent them from taking interferon, and patients who have an increased risk of side effects when taking interferon. Non-candidates for interferon therapy may be infected with HCV genotype 1 or 2, for example, genotype 1a or genotype 1b. A non-candidate for interferon therapy may be infected with HCV genotype 2, such as genotype 2a or 2b. Treatment according to this aspect may also be effective against other HCV genotypes. In certain embodiments, patients who are not candidates for interferon therapy may be treated with a combination of at least 2 DAAs without interferon and without ribavirin for a treatment period of not more than 12 weeks, which includes but is not limited to, not more than 11 weeks, not more than 10 weeks, not more than 9 weeks, but preferably not more than 8 weeks, not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks ( eg the time is 12 weeks, or the time is 8 weeks). The two DAAs include at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. Suitably, the at least one HCV protease inhibitor may be therapeutic agent 1 and the at least one HCV polymerase inhibitor may be therapeutic agent 2. Therapeutic agent 1 and therapeutic agent 2 may be administered in therapeutically effective amounts to provide an SVR (eg an SVR8, SVR12, SVR16, or SVR24) after a treatment period of not more than 12 weeks, preferably not more than 8 weeks. The total daily dose of therapeutic agent 1 may be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg. mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg . Therapeutic agent 2 can be administered with therapeutic agent 1 in any of the doses of therapeutic agent 1 described above. The total daily dose of therapeutic agent 2 may be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In certain embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatment for no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.
[132] Procedures for treating patients with HCV infection. The Methods In another aspect, the present technology presents comprises administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks ( eg a period of 8 weeks), treatment does not include administration of interferon or ribavirin. The combination comprises therapeutic agent 1, therapeutic agent 2 and therapeutic agent 4. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a.
[133] Methods of treating patients with genotype 1-HCV infection, such as In certain embodiments, the present technology presents genotype 1a or 1b. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin.
[134] Methods of Treating Patients with Genotype 2 or 3-HCV Infection, In some embodiments, the present technology presents such as genotype 2a, 2b or 3a. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 3. The treatment time may be not more than 12 weeks, and includes but is not limited to, not more than 11 weeks, not more than 10 weeks, not more than 9 weeks , but preferably not more than 8 weeks, not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks (eg the time is 12 weeks, or the time is 8 weeks). Therapeutic agent 1 and therapeutic agent 3 may be administered in therapeutically effective amounts to provide an SVR (eg, an SVR8, SVR12, SVR16, or SVR24) at a treatment time of not more than 12 weeks, preferably not more than 8 weeks. The total daily dose of therapeutic agent 1 may be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg. mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg . Therapeutic agent 3 can be administered with therapeutic agent 1 at any of the doses of therapeutic agent 1 described above.
[135] Procedures for treating patients with HCV infection. The Methods In some embodiments, the present technology comprises administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (e.g., a period of 12 weeks), preferably no more than 8 weeks (t eg a period of 8 weeks), treatment does not include administration of interferon or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 3. Suitably, the patient may be a treatment-naive patient, a treatment-accustomed patient, or one who does not respond to interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a. In some embodiments than the patient infected with HCV genotype 1b. In some embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some embodiments, the patient is infected with HCV genotype 3a. Treatment according to this aspect of the technology can also only be effective against other HCV genotypes.
[136] Methods for treating patients with HCV infection that are not In certain embodiments, the present technology presents candidates for interferon treatment. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin. The combination includes therapeutic agent 1 and therapeutic agent 3. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions who prevents them from taking interferon, and patients who are at increased risk of side effects when taking interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a.
[137] Methods of treating patients with HCV genotype 1 infection, such as in certain embodiments, present the present technology 1a or 1b. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin.
[138] Procedures for treating patients with HCV infection. The Methods In certain embodiments, the present technology presents a method of administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg, a period of 12 weeks), preferably not more than 8 weeks (eg 8 weeks), treatment does not include administration of interferon or ribavirin. The combination includes therapeutic agent 1 and therapeutic agent 4. Patients may be treatment-naïve patients or treatment-accustomed patients.
[139] Procedures for treating patients with HCV infection. The Methods In some embodiments, the present technology comprises administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (e.g., a period of 12 weeks), preferably no more than 8 weeks (t eg a period of 8 weeks), treatment does not include administration of interferon or ribavirin. The combination includes therapeutic agent 1 and therapeutic agent 4. Patients may be treatment-naïve patients or treatment-accustomed patients.
[140] Methods for treating patients with HCV infection who are not In certain embodiments, the present technology presents candidates for interferon therapy. The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin. The combination includes therapeutic agent 1 and therapeutic agent 4. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions who prevents them from taking interferon, and patients who are at increased risk of side effects when taking interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a.
[141] Methods of treating patients with HCV infection that are such that in certain embodiments, the present technology presents no response to interferon (eg, those that do not respond at all). The methods comprise administering a combination of at least 2 DAAs to such a patient for no more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (eg a period of 8 weeks ), the treatment not including administration of interferon or ribavirin. Patients who do not respond to interferon can be treated with a combination of at least 2 DAAs without interferon and without ribavirin, the two DAAs including therapeutic agent 1 and therapeutic agent 4. Therapeutic agent 1 and therapeutic agent 4 can be administered in therapeutically effective amounts to provide an SVR (eg an SVR8, SVR12, SVR16, or SVR24) after a treatment time of not more than 12 weeks (eg a period of 12 weeks), preferably not more than 8 weeks (t .ex. a period of 8 weeks). Patients who do not respond to interferon therapy include those who respond in part to interferon therapy and those who relapse after interferon therapy. Patients who do not respond to interferon therapy may have HCV genotype 1, such as genotype 1a. Patients who do not respond to interferon therapy may have HCV genotype 1b. Patients who do not respond to interferon therapy may have HCV genotype 2 or 3, such as 2a. Patients who do not respond to interferon therapy may have HCV genotype 2b. Patients who do not respond to interferon therapy may have HCV genotype 3a. In some embodiments, treatment with other HCV genotypes is contemplated.
[142] In a method of treating HCV infection comprising administering a In certain embodiments, the present technology presents an effective amount of a combination of two or more DAAs without ribavirin to a patient in need thereof. The treatment does not last for more than 12 weeks (eg the time is 12 weeks), which includes but is not limited to, not more than 11 weeks, not more than 10 weeks, not more than 9 weeks, but preferably not more than 8 weeks (eg the time is 8 weeks), not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, and does not include administration of either interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies.
[143] A combination of at least one HCV protease inhibitor and at least one HCV in one example, the combination of two or more DAAs may be polymerase inhibitor (eg a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor , or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor).
[144] Be a combination of at least one HCV protease inhibitor and at least one HCV in another example, a combination of two or more DAAs may be NS5A inhibitor. In one example, the combination of two or more DAAs comprises GS-5885 (an NS5A inhibitor) and GS-9451 (a protease inhibitor or an NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose in the range of from about 3 mg to about 200 mg, alternatively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, which includes, but is not limited to to, for example, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg . GS-9541 may be administered in combination with any of the daily doses of GS-5885 described above. GS-9451 may be administered in a total daily dose ranging from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, which includes, but is not limited to, about 100 mg, about 150 mg, about 200 mg. mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.
[145] In another example, the present technology provides at least two DAAs comprising at least two HCV polymerase inhibitors. In certain embodiments, the at least two HCV polymerase inhibitors comprise at least one nucleoside or nucleotide analog polymerase inhibitor. In some embodiments, the two HCV polymerase inhibitors comprise at least two nucleoside or nucleotide analog polymerase inhibitors. Suitable nucleotide analog polymerase inhibitors include PSI-7977 (Pharmasset) and PSI-938 (Pharmasset). Suitable daily doses of at least one nucleoside or nucleotide analog polymerase inhibitor include the range from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, which includes, but is not limited to, for example, about 100 mg, about 150 mg. about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. For example, a suitable combination includes a total daily dose of PSI-7977 of about 400 mg and a total daily dose of PSI-938 of about 300 mg, alternatively a total daily dose of about 200 mg PSI-7977 and a total daily dose. of approximately 300 mg PSI-938. In another example, the combination of two or more DAAs comprises at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. In some embodiments, the least protease inhibitor TMC-435 and the least polymerase inhibitor are a nucleotide / nucleoside analog polymerase inhibitor, for example PSI-7977, or for example TMC-647055. Suitably, the at least one protease inhibitor is provided, e.g. TMC-435, in a total daily dose ranging from about 25 mg to about 250 mg, alternatively from about 25 mg to about 200 mg, alternatively from about 50 mg to about 200 mg, alternatively from about 75 mg to about 150 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg; and the at least one polymerase inhibitor (eg, PSI-7977) in a total daily dose ranging from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, which includes, but is not limited to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. For example, a combination may be a total daily dose of about 75 mg TMC-435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 150 mg TMC-435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 75 mg TMC-435 and about 200 mg PSI-7977, alternatively about 150 mg TMC-435 and about 200 mg PSI-7977 , alternatively about 100 mg TMC-435 and about 200 mg PSI-7977, alternatively about 75 mg TMC-435 and about 100 mg PSI-7977, alternatively about 100 mg TMC-435 and about 100 mg PSI-7977, alternatively about 150 mg TMC-435 and about 100 mg PSI-7977, and may include other suitable combinations.
[146] DAAs danoprevir (protease inhibitor) and R7128 In another example, include the combination of two or more (nucleoside polymerase inhibitor). In certain embodiments, danoprevir may be administered in a total daily dose ranging from about 100 mg to about 2000 mg, alternatively from about 200 mg to about 1800 mg, alternatively from about 400 mg to about 1800 mg, which includes, but is not limited to. to, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, or other amounts in between. R7128 may be administered in a total daily dose in the range of from 100 mg to about 2000 mg, alternatively from about 200 mg to about 2000 mg, alternatively from about 1000 mg to about 2000 mg, which includes, but is not limited to, for example, about 150 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg, about 10 15 20 25 30 119 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some examples, the total daily dose of danoprevir is about 200 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 200 mg, alternatively it is the total daily dose of danoprevir is about 1000 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 1800 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of danoprevir is about 1000 mg and the total daily the dose of R7128 is about 400 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose is n of danoprevir about 1800 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 1000 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 1800 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 2000 mg, alternatively the total daily dose of danoprevir is about 1000 mg and the total daily dose of R7128 is about 2000 mg, alternatively the total daily dose of danoprevir is approximately 2000 mg and the total daily dose of R7128 is approximately 2000 mg, alternatively the total daily dose of danoprevir is approximately 1800 mg and d a total daily dose of R7128 is approximately 2000 mg. In suitable embodiments, danoprevir and R7128 may be administered with ritonavir, suitably in an amount ranging from about 100 mg to about 400 mg per day, preferably about 100 mg per day. 10 15 20 25 30 120
[147] The combinations of two or more DAAs may be at least one protease inhibitor and In some other examples of the present technology, at least one NS5A inhibitor may be. In some examples, the least single protease inhibitor is an NS3 protease inhibitor. In some embodiments, the at least one protease inhibitor and the at least one NS5A inhibitor include BMS-650032 (BMS) and BMS-790052 (BMS), respectively. In suitable embodiments, BMS-650032 may be administered in a total daily dose in the range of from about 300 mg to about 1500 mg, alternatively from about 500 mg to about 1500 mg, which includes, but is not limited to, for example, about 300 mg. about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg, and BMS-790052 ( BMS) may have a total daily dose in the range of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, which includes, but is not limited to, for example, about 10 mg, about 20 mg, about 30 mg. mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In suitable examples, the daily dose of BMS-650032 (BMS) is about 1200 mg and the daily dose of BMS-790052 (BMS) is about 60 mg, alternatively the total daily dose of BMS-650032 (BMS) is about 300 mg and the total daily dose of BMS-790052 (BMS) is approximately 60 mg.
[148] The combinations of two or more DAAs may be at least one nucleoside or In some other examples of the present technology, nucleotide polymerase inhibitor, at least one protease inhibitor, and at least one NS5A inhibitor may be present. In some examples, the least single protease inhibitor is an NS3 protease inhibitor. In some embodiments, the least single nucleoside or nucleotide polymerase inhibitor is INX-189, the least single protease inhibitor is BMS-650032 (asunaprevir), and the least single NS5A inhibitor is BMS-790052 (daclatasvir). Such embodiments are particularly contemplated for treating a patient infected with HCV genotype 1, such as genotype 1a or 1b (particularly genotype 1a), as well as patients infected with other HCV genotypes, such as genotype 2 or 3. embodiments, INX-189 may be administered in a total daily dose in the range of from about 5 mg to about 400 mg, alternatively from about 25 mg to about 200 mg, which includes, but is not limited to, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. In suitable embodiments, BMS-650032 may be administered in a total daily dose ranging from about 300 mg to about 1500 mg, alternatively from about 500 mg to about 1500 mg, which includes, but is not limited to, for example, about 300 mg. , about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg, and BMS-790052 (BMS) may have a total daily dose in the range of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, which includes, but is not limited to, for example, about 10 mg. about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In suitable examples, the total daily dose of BMS-650032 (BMS) is about 1200 mg and the total daily dose of BMS-790052 (BMS) is about 60 mg, alternatively the total daily dose of BMS-650032 (BMS) is about 300 mg. mg and the total daily dose of BMS-790052 (BMS) is approximately 60 mg.
[149] May be a combination of at least one HCV protease inhibitor, at least one HCV- In another example, the combination of two or more DAAs may be polymerase inhibitor, and at least one HCV NS5A inhibitor. In one example, the combination of two or more DAAs includes GS-5885 (an NS5A inhibitor), GS-9190 (tegobuvir, a non-nucleoside polymerase inhibitor), and GS-9451 (a protease inhibitor or an NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose in the range of from 3 mg to about 200 mg, alternatively from 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, which includes, but is not limited to, , for example, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg , about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 10 20 20 25 30 122 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg , or about 200 mg, and 68-9190 is provided in a daily dose in the range of from about 10 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, which includes, but is not limited to, for example, about 10 mg. , about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and 68-9451 may be administered in a daily dose in the range of from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, which includes, but is not limited to, for example, about 100 mg, about 150 mg. , about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. Suitable examples include approximate daily amounts of about 30 mg 68-5885, about 60 mg 68-9190 or about 200 mg 68-9451; alternatively about 60 mg 68-5885, about 60 mg 68-9190, and about 200 mg 68-9451; alternatively about 90 mg 68-5885, about 60 mg 68-9190, and about 200 mg 68-9451. In certain embodiments, 68-9190, 68-9451 and 68-5885 are administered with ritonavir or a suitable equivalent, preferably in an amount ranging from about 100 mg to about 400 mg per day, preferably about 100 mg per day. In another example, the combination of two or more DAAs may be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV-N85A inhibitor.
[150] The technology comprises an interferon-free treatment comprising daily administering two DAAs without ribavirin, the two DAAs including an HCV polymerase inhibitor, for example PSI-7977, and an N85A inhibitor, for example BM8-790052, during a time of not more than eleven weeks, preferably not more than eight weeks. PSI-7977 and BM8-790052 are administered in an effective amount to provide an SVR at a treatment time of not more than eleven weeks. In another embodiment, the present one provides not more than ten weeks, not more than nine weeks, not more than eight weeks, not more than seven weeks, not more than six weeks, not more than five weeks, not more than four weeks, or not more than three weeks. Patients can be treatment-naïve patients or treatment-accustomed patients. In some embodiments, patients may have HCV genotype 1, such as 1a or 1b. In some embodiments, patients may have genotype 2 or 3, such as 2a, 2b or 3a. PSI-7977 may be provided in a total daily dose in the range of from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, which includes, but is not limited to, for example, about 100 mg, about 100 mg. 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg. BMS-790052 may be administered in combination with PSI-7977 at any daily dose of PSI-7977 as above. BMS-790052 (BMS) may have a total daily dose in the range of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, which includes, but is not limited to, for example, about 10 mg, about 20 mg. mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In a suitable example, PSI-7977 is administered in a total daily dose of 400 mg and BMS-790052 is administered in a total daily dose of 60 mg.
[151] Are reported from a number of sources are provided below: The chemical structures of some of these HCV inhibitors such as: ut * v Ewa Telaprevir 124 .S / fi- u f! I i , N, _ _ \ ”__ . »__, _._. '-» “5 TMC-435 (TMC-435350) Vaniprevir, MK-7009 10 125 F ..
[152] BMS-791325 is preferably herein, BMS-791325 may also be. See also 10 publications at http: // wvvw1 .easl.eu / easl2011 / program / Posters / Abstract680.htm; and http: llcâinicaitriais.Qov/show/NCTGQ664í525. For GS-5885, see publications under http://wvvvv.natap.org/2011/EASL/EASL_68.htm; http: // wvvvv1 .easl.eu/easl2011/program/ Posters/Abstract1097.htm; and 15 httpz / Icåinicaltriaisgov / cQ / showihiílï fi1353248.
[153] Each HCV inhibitor or DAA described herein encompasses its suitable salt forms when used in therapeutic treatments or pharmaceutical formulations. 10 15 20 25 131
[154] Treatment regimens according to the present technology. In each course of treatment The following table shows non-limiting examples of daily, at least two DAAs with or without ritonavir, administered to an HCV patient undergoing such treatment. Each treatment is free of interferon and free of ribavirin. Each course of treatment may also include administering one or more of your additional DAAs to the patient.
[155] For example, two or two drugs used in a curative matrix comprising a water-soluble polymer and optionally a surfactant may be co-formulated in amorphous forms or molecularly dispersed in one. wherein according to another example, therapeutic agent 1 and ritonavir (RTV) are formulated in an amorphous form or are molecularly dispersed in a matrix comprising a water-soluble polymer and optionally a surfactant, and therapeutic agent 3 is combined with amorphous Compound 1 and RTV in a single solid dosform. In a further example, Compound 1 and RTV are formulated in dosage forms other than that of therapeutic agent 3.
[156] Are free of interferon, with two or more DAAs, without ribavirin, and with or Additional non-limiting examples of treatment regimens, such as without ritonavir or an appropriate equivalent, include the following: (a) therapeutic agent 1 in a total daily dose in the range of 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with ritonavir or an appropriate equivalent, and therapeutic agent 4 in a total daily dose in the range of 5 mg to 150 mg (preferably 5 mg mg, 25 mg, 50 mg or 100 mg); (b) therapeutic agent 1 in a total daily dose in the range of 5 mg to 200 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with ritonavir or a suitable equivalent, therapeutic agent 4 in a total daily dose in the range from 5 mg to 200 mg (preferably 25 mg or 100 mg), and therapeutic agent 2 in a total daily dose ranging from 200 mg to 800 mg (preferably 400 mg or 800 mg); (c) therapeutic agent 1 in a total daily dose in the range of 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with ritonavir or an appropriate equivalent, therapeutic agent 3 in a total daily dose in the range from 100 mg to 600 mg (preferably 400 mg), and therapeutic agent 4 in a total daily dose ranging from 5 mg to 300 mg (preferably 25 mg to 200 mg, more preferably 25 mg); (d) therapeutic agent 1 in a total daily dose ranging from 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with ritonavir or an appropriate equivalent, and therapeutic agent 2 in a total daily dose in range from 200-800 mg; (e) GS-5885 in a total daily dose in the range of 3-200 mg (preferably 30-90 mg). GS-9190 in a total daily dose in the range of 30-90 mg (preferably 60 mg), and GS-9451 in a total daily dose in the range of 100-500 mg (preferably 200 mg); (f) GS-5885 in a total daily dose in the range of 3 mg to 200 mg (preferably 30 mg, 60 mg or 90 mg), and GS-9451 in a total daily dose in the range of 100 mg to 500 mg (preferably 200 mg); (g) B1-2013 in a total daily dose in the range of from 100 mg to 400 mg (preferably 120 mg, 240 mg), and B1-207127 in a total daily dose in the range of from 300 mg to 3600 mg (preferably 1200 mg or 1500 mg, 1800 mg or 2100 mg); (h) PSI-7977 in a total daily dose in the range of 100 mg to 500 mg (preferably 100 mg, 200 mg), and TMC-435 in a total daily dose in the range of 25 mg to 200 mg mg (preferably 75 mg, 100 mg or 150 mg); (i) telaprevir in a total daily dose in the range of 1000 mg to 2500 mg (preferably 1500 mg or 2250 mg), and VX-222 in a total daily dose in the range of from 100 mg to 800 mg (preferably 100 mg, 200 mg , 400 mg, 600 mg or 800 mg); (j) 1NX-189 in a total daily dose in the range of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), and daclatasvir (BMS-790052) in a total daily dose in the range of 10 mg to 200 mg mg (preferably 60 mg); (k) INX-189 in a total daily dose in the range of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), and Asunaprevir (BMS-650032) in a total daily dose in the range of 300 mg to 1500 mg mg (preferably 1200 mg); and (1) INX-189 in a total daily dose in the range of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), daclatasvir (BMS-790052) in a total daily dose in the range of 10 mg to 200 mg mg (preferably 60 mg), and Asunaprevir (BMS-650032) in a total daily dose ranging from 300 mg to 1500 mg (preferably 1200 mg). In each of these examples, ritonavir or an appropriate equivalent may be added to any of these treatments as described and may be added to any of these treatments in a total daily dose as described in the present technology; preferably ritonavir is co-formulated with therapeutic agent 1 or danoprevir; wherein the dose of ritonavir is preferably 100 mg.
[157] Effective in treating HCV infection against HCV genotypes 1, 2, 3, 4, 5, 6, which include subgenotypes such as 1a, 1b, 2a and 3a.
[158] Total daily dose of DAAs of the present technology is administered The treatments of the present technology may be Generally and depending on the condition of the patient, it may (either as a single or divided dose) in amounts ranging from about 0.001 mg / kg to about 200 mg / kg, or in the range from about 0.001 mg / kg to about 30 mg / kg, or in the range from about 0.001 mg / kg to about 30 mg / kg, or in the range from about 0.01 mg / kg to about 10 mg / kg (ie mg of the compound or salt per kg of body weight), and includes all amounts or ranges therebetween, which include, but are not limited to, increments of 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, and multiple factors thereof (eg 0.25x, 0.5x, 1x, 2x, 3X, 5X, 10X, 10X, 100X, etc.). Suitable doses of DAAs of the present technology include, but are not limited to, the range from about 25 mg to about 2000 mg, the range from about 25 mg to about 1500 mg, the range from about 25 mg to about 1500 mg. about 1600 mg, the range from about 25 mg to about 1000 mg, the range from about 25 mg to about 800 mg, the range from about 25 mg to about 500 mg, the range from about 25 mg to about 250 mg, the range from about 50 mg to about 250 mg about 2000 mg, the range from about 50 mg to about 1500 mg, the range from about 50 mg to about 1600 mg, the range from about 50 mg to about 1000 mg, the range from about 50 mg to about 800 mg, the range from about 50 mg to about 500 mg, the range from about 50 mg to about 250 mg,, and includes, but is not limited to, for example, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg. , about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg , about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 165 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 250 mg, and includes each increment therebetween, which includes increments of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 10 mg, about 15 mg, about 15 mg, about 15 mg. 20 mg, about 25 mg, and multiples thereof (e.g. 0.25x, 0.5x, 1x, 2x, 3x, 5x, 10x, 100x, etc.). However, it will be appreciated that the specific dose level for each particular patient will depend on a variety of factors including the activity of the particular compound being used, age, body weight, general health, sex, diet, time of administration, route of excretion, rate of excretion, drug combination, and severity of the disease undergoing treatment.
[159] Any amount such as, for example, in doses ranging from about 0.3 mg / kg The cytochrome P-450 inhibitor may be administered in any suitable range to about 2 mg / kg or in the range from about 0.6 mg. / kg to about 1.5 mg / kg. As a non-limiting example, the cytochrome P-450 inhibitor may be administered in a total daily dosage amount in the range of from about 25 mg to about 300 mg, or in the range of from about 50 mg to about 250 mg, or in the range of from about 100 mg. to about 200 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose ranging from about 100 mg to about 400 mg, preferably about 100 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a daily dose of about 25 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a daily dose of about 50 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 75 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 100 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 125 mg.
[160] And without limitation, simultaneously or sequentially, and at the same or different The single or multiple DAAs may be administered, for example frequencies. For example, one DAA may be administered immediately before or after the administration of another DAA. A short delay or time slot may exist between the administration of one DAA and that of another DAA. The frequency of administration may also be different. For example, a first DAA may be administered once a day and a second DAA may be administered two or three times a day. For example, a first DAA, with or without ritonavir, may be administered once daily, and a second DAA may be administered twice daily.
[161] In a single dosage form. Non-limiting examples of suitable dosage forms The DAAs of the present technology may be co-formulated include liquid dosage forms or solid dosage forms. For example, a dosage form of Compound 1 is described as a solid dosage form in U.S. Patent Application Publication No. US 2011/0312973, filed March 8, 2011, entitled "Solid Compositions", the entire contents of which are incorporated herein by reference. More preferably, the dosage form is a solid dosage form in which at least one of the DAAs is in an amorphous form, or even more preferably molecularly dispersed, in a matrix comprising a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant. The other DAAs may also be in an amorphous form or molecularly dispersed in the matrix, or formulated in different form (s) (eg in a crystalline form).
[162] Different dosage forms. It will be appreciated that the total daily dose of the DAAs of the present technology may be formulated in the compounds and the compositions to be administered will be determined by the attending physician within the scope of sound medical judgment.
[163] Naive subject administering therapeutic agent 1 at a dose of 150 mg, and in one embodiment, comprises a method of treating a ritonavir at a dose of 100 mg, once daily; and therapeutic agent 2 at a dose of 400 mg or 800 mg twice daily. The treatment lasts for 12 weeks, and at the end of the treatment the subject has no detectable virus.
[164] Naive subject administering therapeutic agent 1 in a dose of 50 mg, and in one embodiment, comprises a method of treating a ritonavir in a dose of 100 mg, once a day; therapeutic agent 2 in a dose of 400 mg or 800 mg twice. The treatment lasts for 12 weeks, and at the end of the treatment the subject has no detectable virus.
[165] Naive subject administering therapeutic agent 1 at a dose of 250 mg, and in one embodiment, comprises a method of treating a ritonavir at a dose of 100 mg, once daily; and therapeutic agent 2 in a dose of 400 mg BID. The treatment lasts for 12 weeks, and at the end of the treatment the subject has no detectable virus.
[166] Treating a naive subject to administer therapeutic agent 1 in a dose of I in another embodiment, comprises a method of 150 mg, and ritonavir in a dose of 100 mg, once daily; and therapeutic agent 2 in a dose of 400 mg BID. The treatment lasts for 12 weeks, and at the end of the treatment the subject has no detectable virus.
[167] Treating a subject not responding to peginterferon + ribavirin (P / RBV) In yet another embodiment, a method of administering therapeutic agent 1 at a dose of 150 mg, and ritonavir at a dose of 100 mg, Once a day; and therapeutic agent 2 in a dose of 400 mg BID. The treatment lasts for 12 weeks, and at the end of the treatment the subject has no detectable virus.
[168] Treating a subject not responding to peginterferon + ribavirin (P / RBV) In yet another embodiment, a method of administering therapeutic agent 1 at a dose of 50 mg QD, therapeutic agent 2 at a dose of 400 mg mg BID, and ritonavir at a dose of 100 mg QD for 12 weeks.
[169] Naive subject to administering therapeutic agent 1 in a total daily dose of 150 In one embodiment, a method of treating one mg, therapeutic agent 3 in a total daily dose of 400 mg, and ritonavir in a dose of 100 mg once a day for 12 weeks. At the end of treatment, the subject has no detectable virus.
[170] Treating a naive subject to administer therapeutic agent 1 in a total In another embodiment, a method of daily dose of 100 mg or 200 mg QD, therapeutic agent 4 in a total daily dose of 25 mg, ritonavir in a single dose of 100 mg QD for 12 weeks. At the end of treatment, the subject has no detectable virus.
[171] Treating a naive subject administering therapeutic agent 1 in a total In yet another embodiment, a daily dose method of 100 mg or 150 mg QD comprises therapeutic agent 2 in a dose of 400 mg BID, therapeutic agent 4 in a total daily dose of 25 mg QD, ritonavir in a dose of 100 mg QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.
[172] The following examples are given by way of illustration, and are not to be construed as illustrating the embodiments and limitations described above. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art from the present description.
[173] The scope of this description. Without being limited by any theory, Examples 1-3 may be by way of illustration and in no way limit the unexpected synergistic effects of combining different classes of HCV inhibitors (eg, a combination of a protease inhibitor (such as Compound 1). ) and a polymerase inhibitor (such as Compound 2), or a combination of a protease inhibitor (such as Compound 1) and an NS5A inhibitor (such as Compound 4) contribute to the effectiveness of the short-term interferon- and ribavirin-free treatments of the present technology. 10 15 20 25 30 140
[174] Hepatoma cell lines Huh7. It is derived from HCV genotype 1b (Con1), and is Material: A replicon cell line was derived from the human a bicistronic subgenomic replicon, substantially similar to those described in Science 285 (5424): 110-3 (1999). The first cistron of the construct contains a firefly luciferase reporter and a neomycin phosphotransferase selectable marker. Replica cells were maintained in Dulbecco's Modified Eagle Media (DMEM) containing 100 IU / mL penicillin, 100 mg / ml streptomycin (in vitro), 200 mg / ml G418, an aminoglucoside antibiotic (in vitrogen) and 10% fetal bovine serum. , FBS) at 37 ° C and 5% CO 2.
[175] 5000 cells per well in a 96-well plate in 100 μl DMEM containing 5% Replica cell culture: Replica cells were seeded at a density of FBS. The following day, Compounds 1 and 2 were diluted in dimethyl sulfoxide (DMSO) to generate a 200X strain in a series of 6 double dilutions. The dilution series was then diluted an additional 100-fold in the medium containing 5% FBS.
[176] Evaluate Interaction Effects of Therapeutic Agent 1 and Therapeutic Agent 2 Combination Studies: Combination studies were performed to include in the replicon assay as described above. The purpose of these studies was to determine if there are doses or concentrations of each compound where synergy or antagonism is demonstrated with the other compound. Three experiments with three plates in each experiment were performed on three separate days.
[177] The dilutions of the second compound in a chessboard manner. The dilutions of each compound combined with the tested concentrations were chosen to ensure that the EC50 for each individual compound is in the middle of the dilution range of the series. Medium with inhibitor (s) was added to the cell culture plates already containing 100 μl of DMEM with 5% FBS. The cells were incubated in a tissue culture incubator at 37 ° C and 5% CO 2 for 14 days. The inhibitory effects of the compounds on HCV replication were determined by measuring the activity of a luciferase reporter gene using a luciferase assay system kit (Promega) following the manufacturer's instructions. Passive lysis buffer (30 μl, Promega) was added to each well, and the plates were incubated for 15 minutes with rocking to lyse the cells. Luciferin solution (100 μl, Promega) was added to each well and the luciferase activity was measured with a Victor II luminometer (Perkin-Elmer).
[178] Approach to solving this drug-drug interaction problem.
[179] And the predicted value was calculated for each concentration combination for A difference between the actual observed inhibition ratio of each plate in each experiment to determine if the observed combined effect was greater than the theoretical additive effect Z calculated according to the equation above. For each concentration combination, the replicates (across all plates and experiments) were used to calculate a mean difference between observed and predicted inhibition rate, its standard error and its two-sided 95% confidence interval (Cl). 10 15 20 25 30 142
[180] Concentration combination based on the following 2 rules: First, Synergy or antagonism was determined for one, the 95% Cl of the mean difference between observed and predicted inhibition rate at each concentration combination was calculated. If the lower limit of the 95% Cl is greater than zero, the drug combination would be considered to have a synergistic effect; if the upper limit of the 95% Cl is less than zero, the drug combination would be considered to have an antagonistic effect; otherwise no significant antagonism or synergy is shown at this concentration combination_
[181] The effect has its relative mean difference, the absolute mean difference divided. Second, the synergistic or antagonistic with its corresponding observed mean inhibition must be greater than 1%. By doing this, small differences in statistical significance caused by a very small variance could be excluded.
[182] The inhibitory effect on replicons produced by each drug Combination of therapeutic agent 1 and therapeutic agent 2: alone or in combination with the other at concentrations up to ten-fold above EC50 was examined in genotype 1b (Con1) replicon with a titration pattern similar to a chessboard (double serial dilutions) in a standard three-day antiviral assay. The concentrations tested were chosen to ensure that the EC50 values of the compounds were in the middle of the serial dilution range. For Compound 1, the concentrations ranged from 0.031 nM to 1.0 nM. For Compound 2, the concentrations ranged from 0.125 nM to 4.0 nM. Synergy, additiveness and antagonism were evaluated using the Pritchard and Shipman model.
[183] Is illustrated in Figures 1 and 2, as well as in Table 2. In the 3D surface diagram in Figure 1, Results: The results from the assay analysis are deviations from expected interactions between Compound 1 and Compound 2 pure additives at concentrations associated with a horizontal plane at 0%. Synergistic interactions between Compound 1 and Compound 2 appear as a peak above the horizontal plane with a height corresponding to the percentage above the calculated additivity. Antagonistic interactions 143 between Compound 1 and Compound 2 appear as a pit or depression below the horizontal plane with a negative value characterizing the percentage below the calculated additive. Synergistic interactions appear as dark gray, additive interactions appear as white, and antagonistic interactions appear as spotted.
[184] As illustrated in the 3D surface diagram in Figure 1 and in most concentrations of Compound 1 and Compound 2. In particular, there is a concentration region showing synergy at most concentrations of Compound 1 and at dose concentrations in the range of the lower range to the middle range of Compound 2.
[185] And Compound 2 with statistically significant synergistic or antagonistic Table 2 below shows concentration combinations of Compound 1 effects based on Prichard's and Shipman's model analysis. Before each concentration combination, Table 2 includes the mean difference in the observed and predicted inhibition rate, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.
[186] Compound 2 shown in the table statistically significant synergistic effects.
[187] Demonstrates that the combination of therapeutic agent 1 and therapeutic According to Table 2, all the combinations of Compound 1 with the Results presented in Figures 1 and 2, as well as in Table 2 agent 2 achieve attainability or synergy at most of the concentration combinations of the two agents. . Taken together, these in vitro replicon results suggest that therapeutic agent 2 should produce a significant antiviral effect in patients when administered in combination with therapeutic agent 1 in patients infected with HCV. 144 Table 2 Mean difference in inhibition fraction: __ Compound Compound Observed - Standard error in Lower 95% -ig Upper 95% -ig 2, nM 1, nM Expected mean difference confidence limit confidence limit, 125, 1250O 0.06176 0.023352 0.007912 0.11561 , 125, 25000 0.05321 0.022199 0.002024 0.10440, 125, 5000O 0.01176 0.002680 0.005583 0.01794, 250, 25000 0.06626 0.02063O 0.018692 0.11384, 250 , 5000O 0.01061 0.002677 0.004438 0.01679, 500, 0625O 0.04373 0.014897 0.009375 0.07808, 500, 1250O 0.10416 0.026757 0.042454 0.16586, 500, 25000 0.09327 0.019859 0.047471 0.13906, 500, 5000O 0.01422 0.003333 0.006535 0.02191 1.00, 0625O 0.06696 0.020488 0.019715 0.11421 1.00, 1250O 0.14103 0.021289 0.091939 0.19013 1.00, 25000 0.11027 0.016762 0.071617 0.14892 1.00, 5000O 0.01365 0.002312 0.008315 0.01898 2.00, 0625O 0.05974 0.007690 0.042004 0.07747 2.00, 12500 0.10032 0.011820 0.073066 0.12758 2.00, 25000 0.07117 0.009428 0.049428 0.09291 4.00 , 03125 0.03235 0.003950 0.023236 0.04145 4.00, 0625O 0.05141 0.00431 0.041470 0.06136 4.00, 1250O 0.06572 0.004692 0.054901 0.07654 4.00, 25000 0.03452 0.004775 0.023509 0.04553 Example 2. Synergistic concentrations of Compound 1 and Compound 4 in genotype 1b HCV rep | iconana | ys 5 Material: The replica cell line was derived from the human hepatoma cell line Huh7. It is derived from HCV genotype 1b (Con1), and is a bicistronic subgenomic replicon, substantially similar to those described in Science 285 (5424): 110-3 (1999). The first cistron of the construct contains a firefly luciferase reporter and a neomycin phosphotransferase selectable marker. Replica cells were maintained in Dulbecco's Modified Eagle Media (DMEM) containing 100 IU / mL penicillin, 100 mg / ml streptomycin (in vitro), 200 mg / ml G418 and 10% fetal bovine serum , FBS) at 37 ° C and 5% CO 2.
[189] Replica cell culture: Replica cell cells were seeded at a density of 5000 cells per well in a 96-well plate in 100 μl DMEM containing 5% FBS. The following day, the compounds were diluted in dimethyl sulfoxide (DMSO) to generate a 200X strain in a series of 6 double dilutions.
[190] Evaluating the interaction effects of therapeutic agent 1 and therapeutic agent 4 Combination studies: Combination studies were performed to include in the replicon assay as described above. The purpose of these studies was to determine doses or concentrations of each compound where synergy or antagonism is demonstrated with the other compound. Three experiments with three plates in each experiment were performed on three separate days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were analyzed in each plate. In addition, 36 concentration combinations of the two compounds for each plate were analyzed. The variable analyzed was the inhibition fraction of the luciferase signal.
[191] The dilutions of the second compound in a chessboard manner. The dilutions of each compound combined with the tested concentrations were selected to ensure that the EC50 for each individual compound is in the middle of the dilution range of the series. Medium with inhibitor (s) was added to the cell culture plates already containing 100 μl of DMEM with 5% FBS. The cells were incubated in a tissue culture incubator at 37 ° C and 5% CO 2 for three days. The inhibitory effects of the compounds on HCV replication were determined by measuring the activity of a luciferase reporter gene using a Luciferase Assay System kit (Promega) according to the manufacturer's instructions. Passive lysis buffer (30 μl, Promega) was added to each well, and the plates were incubated for 15 minutes with rocking to lyse the cells.
[192] To calculate theoretical additive effects (described in Example 1) was used in Combination Analysis: Prichard's and Shipman's approach the present example.
[193] And the predicted value was calculated for each concentration combination for the difference between the actual observed inhibition ratio of each plate in each experiment to determine if the observed combined effect was greater than the theoretical additive effect Z calculated from Prichard's and Shipman's equation. For each concentration combination, the replicates (across all plates and experiments) were used to calculate a mean difference between observed and predicted inhibition rate, its standard error, and its two-sided 95% confidence interval.
[194] [0194] was determined based on the same rules as defined in Example 1.
[195] The inhibitory effects in replicons produced by each individual Synergy or antagonism of a concentration combination Combination of therapeutic agent 1 and therapeutic agent 4: drug or in combination with the other at concentrations up to ten-fold above EC50 was examined in genotype 1b (Con1) -replicator with a titration pattern similar to a chessboard (double serial dilutions) in a standard three-day antiviral assay. The concentrations tested were chosen to ensure that the ECSO values of the compounds were in the middle of the serial dilution range. For Compound 4, the concentrations in the range were from 0.0002 nM to 0.0063 nM, and for Compound 1, the concentrations in the range were from 0.023 nM to 0.75 nM. Synergy, additivity and antagonism were evaluated using Pritchard's and Shipman's model.
[196] [0196] is illustrated in Figures 3 and 4, as well as in Table 3. In the 3D surface diagram in Figure 3, Results: The results of the assay analysis deviations from expected interactions between Compound 1 and Compound 4 are pure additives at concentrations that are associated with a horizontal plane at 0%. Synergistic interactions between Compound 1 and Compound 4 appear as a peak above the horizontal plane with a height corresponding to the percentage above the calculated additivity. Antagonistic interactions between Compound 1 and Compound 4 appear as a pit or depression below the horizontal plane with a negative value characterizing the percentage below the calculated additivity. Synergistic interactions appear as dark gray, additive interactions appear as white, and antagonistic interactions appear as spotted.
[197] As illustrated in the 3D surface diagram in Figure 3 and in the koncent est concentrations of Compound 1 and Compound 4. In particular, there is a concentration region showing synergy at the lower dose concentrations of Compound 4. and at dose concentrations in the middle of the range for Compound 1.
[198] And Compound 4 with statistically significant synergistic or antagonistic Table 3 below shows concentration combinations for Compound 1 effects based on Prichard's and Shipman's model analysis. For each concentration combination, Table 3 includes the mean difference between the observed and predicted inhibition rate, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.
[199] Compound 4, shown in the table, has statistically significant synergistic effects.
[200] Demonstrates that the combination of Therapeutic Agent 4 and Therapeutic Results presented in Figures 3 and 4, as well as in Table 3 Agent 1 achieves additivity at most of the concentration combinations of the two agents and achieves synergy at certain concentration combinations, in particular, at low concentrations of therapeutic agent 4 and at concentrations in the mid-range of therapeutic agent 1. Taken together, these in vitro replicon results suggest that therapeutic agent 4 should produce a significant antiviral effect in patients when administered in combination with therapeutic agent 1 in infected patients. with HCV.
[201] Similar results were also demonstrated for the combination of therapeutic agent 2 and therapeutic agent 4, where additivity was observed at the itivest concentration combinations of the two agents and synergy was observed at low concentrations of therapeutic agent 2 and therapeutic agent 4.
[203] Compared to three DAA combinations. In the colony survival assay, 1a- Figure 5B illustrates the percentage of colonies surviving two H77 replicon cells in the presence of a DAA combination and G418 for approximately three weeks, with the cells containing resistant replicon variants having formed colonies after this time. The cells were stained with crystal violet and counted.
[204] Compounds 1 and 4 in long-term HCV RNA reduction assays in genotype 1- Figures 5C and 5D show the effect of a combination of replicon cell lines. In long-term replicon RNA reduction assays, 106 replica cells were placed on a plate in the absence of G418. The inhibitors at concentrations either 10-fold (10 OX) or 100-fold (100X) above their respective ECSO values were added, and the cells were grown to approximately 95% consistency (4 days). At each passage, 106 cells were removed and frozen, and another 106 cells were transferred to another vial of fresh medium and inhibitors. RNA was extracted from 106 cells and HCV RNA was measured in a Real-Time RT-PCR assay. Figures 5C and 5D show that in both 1a and 1b replica cells, the combination of Compound 1 and 4, each 10-fold above EC50, was more effective at clearing replica cells than 100-fold above EC50 of each inhibitor alone.
[205] Or 4 in genotype 1 replicons were also determined. For Compound 1, the predominantly resistant variants selected by Compound 1, 2 included the predominantly resistant variants in the 1a-H77 replicons R155K, D168A and D168V with fold resistance of 26, 48 and 128, respectively; and the predominant resistance variants in 1b-Con1 replicons include R155K, A156T and D168V with fold resistance of 48, 9 and 190, respectively. For Compound 2, the predominant resistance variants in 1a-H77 replicons include C316Y, M414T, Y448C and S556G with fold resistance of 1600 36, 980 and 15, respectively; and the predominant resistance variants in 1b-Con1 replicons include C316Y, M414T and D559G with fold resistance of 1400, 26 and 100, respectively. For Compound 4, the predominant resistance variants in 1a-H77 replicons M28T, M28V, Q30R, Y93C and Y93H with fold resistance include 9000, 60, 800, 1700 and 41000, respectively; and the predominant resistance variants in 1b-Con1 replicons include Y93H with a week resistance of 55. These experiments also showed that in genotype 1a a number of variants selected by Compound 2 or 4 gave higher resistance levels than those selected by Compound 1, and that in genotype -1 b gave a variant (C316Y) selected by Compound 2 a higher level of resistance than those selected by either Compound 1 or Compound 4.
[206] DAAs (eg a combination of an HCV protease inhibitor and an HCV The examples above show that the combination of two different classes of polymerase inhibitor, or a combination of an HCV protease inhibitor and an HCV NS5A inhibitor, or a combination of an HCV polymerase inhibitor and an HCV-NS5A inhibitor) may lead to an improved barrier of resistance in patients compared to a single single DAA, while the combination of three different classes of DAAs (e.g. a combination of an HCV protease inhibitor, an HCV polymerase inhibitor and an HCV NS5A inhibitor) can lead to an even more significant resistance barrier. An improvement in the resistance barrier achieved through co-administration of multiple DAAs of different classes or with different mechanisms of action is expected to correlate with increased efficacy in patients.
[207] Were treated with a 2-DAA combination for 12 weeks. Treatment was Ten previously untreated subjects infected with HCV genotype 1 interferon- and ribavirin-free and designed to last for 12 weeks. The 2-DAA combination included Compound 1 / r (200/100 mg QD) and Compound 4 (25 mg QD). At week 3 of treatment, seven of the ten subjects showed no detectable HCV RNA; and the remaining three subjects had HCV RNA levels lower than 25 IU / mL. At week 4, eight subjects showed no detectable HCV RNA, and the remaining two showed (or were thought to have) an HCV RNA level lower than 25 IU / mL. At week 5, nine subjects showed no detectable HCV RNA and the remainder had an HCV RNA level lower than 25 IU / mL. At weeks 6 and 7 of treatment, all ten subjects were tested and no detectable HCV RNA was found. At weeks 9, 10, 11, and 12 of treatment, one subject showed viral breakthrough, and the remaining nine subjects showed no detectable HCV RNA. 10 15 20 25 30 152
[208] [0208] at least seven subjects no detectable HCV RNA. At week 4 after treatment, At week 2 after treatment (post-treatment), seven subjects showed no detectable HCV RNA. At week 8 after treatment, seven subjects showed no detectable HCV RNA. At week 12 after treatment, six subjects showed no detectable HCV RNA. At week 24 after treatment, at least two subjects showed no detectable HCV RNA.
[209] Were treated with the same regimen in this Example. At week 3 of treatment, Ten previously untreated subjects infected with HCV genotype 2, eight of the ten subjects showed no detectable HCV RNA, one of which had a viral recurrence, and one had HCV RNA levels lower than 25 lU / mL. At week 5 of treatment, nine out of ten subjects showed no detectable HCV RNA, and one had a breakthrough. At weeks 10, 11, and 12 of treatment, at least seven of the ten subjects were tested and showed no detectable HCV RNA. At week 2 after treatment, six subjects showed no detectable HCV RNA; and two additional subjects had breakthroughs. At week 4 after treatment, five subjects showed no detectable HCV RNA. At week 8 after treatment, six subjects showed no detectable HCV RNA. At week 4 after treatment, five subjects showed no detectable HCV RNA, Genotype 3
[211] Infected with HCV genotype 3 with the same cure in this Example. At week 3, similarly, ten previously untreated subjects 4, 5, 6, 7, 8, 9, 10, 11 and 12 of the treatment were treated, two subjects showed no detectable HCV RNA. At weeks 2 and 4 after treatment, it was confirmed that the same two subjects had no detectable HCV RNA. A number of subjects appeared to have breakthroughs during treatment.
[212] At week 24 after treatment, at least three subjects showed no detectable HCV RNA. Example 15 Use of 3-DAA combination without interferon and ribavirin to treat treatment-naïve subjects infected with genotype 1
[213] Were treated with a B-DAA combination for 12 weeks. Treatment was Twelve previously untreated subjects infected with HCV genotype 1 interferon- and ribavirin-free. The 3-DAA combination included Compound 1 / r (150/100 mg QD), Compound 2 (400 mg BID), and Compound 4 (25 mg QD). The weight-based dosage of ribavirin ranged from 1000 to 1200 mg which was divided twice daily.
[214] At week 3 of treatment, seven of the twelve subjects had no detectable HCV RNA, and the remaining five subjects had HCV RNA levels lower than 25 IU / mL. At week 4 of treatment, nine of the twelve subjects showed no detectable HCV RNA, and the remaining three subjects had HCV RNA levels lower than 25 IU / mL. At weeks 6 and 8, all twelve subjects showed no detectable HCV RNA. At weeks 10 and 12, eleven of the twelve subjects showed no detectable HCV RNA, and one subject had detectable HCV RNA.
[215] Twelve subjects and showed no detectable HCV RNA. At week 8 after At weeks 2 and 4 after treatment, at least ten of the treatments were tested, at least seven of the twelve subjects were tested and showed no detectable HCV RNA. Two subjects appeared to have a breakthrough during or after treatment. Further tests showed that at week 12 after treatment, at least nine of the original twelve subjects showed no detectable HCV RNA.
[216] Drug combination showed that approximately 91% (or approximately 97% if non-virological defects were removed) SVR4 grade, and approximately 82% (or approximately 90% if non-virological defects were removed) SVR12 grade, after 12- The weekly treatment regimen of A major clinical study using the same treatment-naïve patients. Among these patients, the SVR4 and SVR12 degrees (with non-virological defects removed) in genotype 1a patients were approximately 96% and 86%, respectively. All its SVR4 and SVR12 grades were based on observed data. 10 15 20 25 30 154 Example 6. Clinical modeling for interferon-free DAA combination therapies
[217] Optimal doses and times for HCV-free, interferon-free HCV treatments. This example describes a new clinical model for evaluating which uses combinations of different DAAs. This model reasonably predicted the efficacy of numerous DAA combinations in interferon-free and short-term treatments.
[218] Between DAA exposures and antiviral efficacy in HCV-infected subjects.
[219] Numerous DAAs have been extensively documented to select mutants that follow short monotherapy times (eg, less than 1 week). The viral dynamic model in this Example included single and double mutants. In more detail, the model included 2 single mutants and a double mutant for each of the 2-DAA combination regimens. Thus, a 2-DAA combination regimen (eg, a combination of a protease inhibitor and an NS5A inhibitor) included 2 single mutants and a double mutant. A 3-DAA combination (eg, a combination of a protease inhibitor, a polymerase inhibitor, and an NS5A inhibitor, such as a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor (NNPI), and an NS5A inhibitor) included 3 simple and 2 double mutants.
[220] Target cell), infected cell and viral dynamics. The differential equations that the Model has 3 components: hepatocytes (uninfected or describes the dynamics of the 3 components are as follows: (1) Dynamics for hepatocytes (uninfected or target cell) dT / dt = s - de * T- (1-n) * ß * T * (VLWT + VLPoly + VLProt + VLNS5A + VLNS5AProt + VLPo | yProt) (2) Dynamics of infected cell 155 (a) Infected with wild-type virus d IWT / dt = (1 -n) * ß * T * VLWT - ö * IWT (b) Infected with polymerase mutant virus d | Po | y / dt = (1-n) * ß * T * VLPo | y - ö * | Po | y 5 (c) Infected with protease mutant virus d lProt / dt = (1 - n) * ß * T * VLProt - ö * lProt (d) Infected with NSSA mutant virus d | NS5A / dt = (1 -n) * [3 * T * VLNS5A - ö * INS5A (e) Infected with protease NSöA stud / mutant virus 10 d | NS5AProt / dt = (1-n) * ß * T * VLNS5AProt - ö * | NS5AProt (f) Infected with protease polymerase double mutant virus d | Pd | yPrdudt = (1-n) * ß * T * vLPd | yPrdt - s * | Pd | yPrdt (3) Viral dynamics 15 (a) wild-type virus d vLvvT / dt = (1-s * d) * d * (1-Eff1) * | vvT + d * (d * (1) -Eff2) * Fir1 * | Pd | y + d * (1- Effsymtz fl prdt + d * (1-Eff4) * Fit3 * | Ns5A) - d * vLvvT (b) polymerasmut antvirus d vLPdw / dt = (1- d -q>) * d * (1-Eff2) * Fit1 * | Pd | y + d * p * (1-Eff1) * | vvT + d * d * (1- 20 Eff5) * Fit4 * | Pd | y-Prdt - d * vLPo | y (c) proteasmutantvirus d vLPrdt / dt = (1- d - 2 * <|>) * d * (1-Eff3) * Fit2 * | Prdt + d * d * (1-Eff3) * | vvT + <|> * (d * (1- Eff5) * Fit4 * | Pd | yPrdt + d * (1-Eff6) * Fit5 * | Ns5APrdt) - d * vLPrdt 1 56 (d) NSSA mutant virus d vLNssA / dt = (1- il - <|>) * p * (1-Eff4) * Fit3 * | Ns5A + il * p * (1-Eff1) * | vvT + <|> * p * (1- EffßyrFits fl NsßAProt - c * vLNs5A (e) NS5A- and protease stud / mutant virus 5 d VLNS5APr0t / dt = (1-2 * <|>) * p * (1-Eff6) * Fit5 * | NS5APr0t + <1) * (p * (1 - Eff4) * Fit3 * | NS5A + p * (1-Eff3) * Fit2 * | Pr0t) - c * VLNS5APr0t (f) Poly- and protease mutant double mutant virus d VLPolyProt / dt = (1-2 * tl)) * p * (”l -Eff5) * Fit4 * | P0 | yPr0t + <|> * (p * (1-Eff2) * Fit1 * | P0 | y + p * (1 - Eff3) * Fit2 * | Pr0t) - C * VLPO | yPr0t 10 The parameters used in the equations above are described in Table 5.
[222] Parameter Description of production rate for wild-type virus c elimination rate for the virus Eff1, Eff2, Eff3, inhibition of production of wild-type, polymerase, Eff4 protease and NS5A mutant Eff5, Eff6 inhibition of production of polymerase-protease and NS5A, respectively protease double mutant Fit1, Fit2, Fit3 suitability of polymerase, protease and NS5A mutant compared to wild-type virus Fit4, Fit5 suitability of polymerase protease and NS5A protease double mutant compared to wild-type virus IWT, lPoly, lprot, number of cells infected with wild-type polymerase , protease lNS5A and NS5A mutants lPoly-Prot, number of cells infected with polymerase protease | NS5A-Prot and NS5A protease double mutant VLWT, VLPoly, viral load for wild-type virus, polymerase, protease VLProt, VLNS5A and NS5A mutant virus VLPoly-Prot, viral load for polymerase protease and VLNS5A-Prot NS5A protease double mutant As shown in the differential equations for viral dynamics, incl. the effect of DAA is inhibited as an inhibition of viral load production.
[223] Incorporated as follows: (1 -Eff1) = (1-EffDAA1) * (1-EffDAA2) * (1-EffDA / μg) For DAA combinations, the effect was assumed to be multiplicative and
[224] The effect of ribavirin (RBV) can also be added to infection rate ß as an Emax model. In the presence of ribavirin, the rate of infection decreases by a factor (1-n) where f] = COÛCRBV / (Ecso-Rsv + COFICRBV)
[225] The model does not include a double mutant to polymerase + NS5A inhibitors. In a 3-DAA regimen, a polymerase + NS5A double mutant is often wild-type for the protease inhibitor. Thus, this dual mutant is not expected to significantly affect clinical outcomes for a 3-DAA course simulation. On the other hand, the model can be easily adapted to simulate a 2-DAA regimen containing a polymerase inhibitor and an NS5A inhibitor by treating the polymerase inhibitor (eg PSI-7977) as a protease inhibitor in the model.
[226] Detection (LOD) in viral load assays is 10 IU / mL. Assuming the lowest available detection limit (Limit of about 3 virion particles per IU), this amounts to about 0.5 million viruses in the body at LOD. Thus, subjects must be treated for a significant period of time after their viral load falls below LOD to achieve This time depends on the potency of the compounds and the individual response to the treatment.
[227] Threshold value concept. For simulations, it was assumed that an HCV-infected subject To predict the time required for cure, an achieved SVR was used when the viral load amounts to less than 1 virion in the total plasma and extracellular fluid volume (approximately 15,000 mL), i.e. viral load measurement of <1 copy / 15000 mL or <0.33 IU / 15000 mL. This translates to about 5 log IU / mL. Cf. Snoeck E et al., Clin Pharmacol Ther. 87 (6): 706-13 (2010), in which subjects were estimated to achieve SVR when the predicted number of infected cells fell below 1, based on data from patients treated with peg-IFN and ribavirin. While such low viral loads cannot be measured experimentally, they can be simulated using the viral dynamic model.
[228] Any combination of DAAs, with or without interferon, and with or The model can be used to predict SVR for which without ribavirin.
[229] Interferon-free treatment regimens with various combinations of Compound 1, As a non-limiting example, various Compound 2 and / or Compound 4, with or without ribavirin, were evaluated with the model of this Example. The following approach was used to include mutants in the model: a. One single mutant per DAA b. One double mutant per DAA combination
[230] For a combination of two DAAs, e.g., a combination of Compound 1 and Compound 2, the model included a mutant resistant to Compound 1, a mutant resistant to Compound 2, and a double mutant resistant to both Compound 1 and Compound 2. Compound 1 is co-administered or co-formulated with ritonavir (or another pharmacokinetic enhancer) to enhance its drug exposure.
[231] [0231] included in the modeling. In the 3-DAA regimens, a Compound 2 / Compound 4- A double mutant to Compound 2 and Compound 4 was not a double mutant was probably the wild type of Compound 1 due to the high potency and resistance profile of Compound 1. Thus, Compound 2 / is not expected. The compound 4 double mutant affects the clinical outcome of treatments containing Compound 1.
[232] Mutants observed for the individual DAAs in phase 1b and 2a studies (eg clinical studies M10-351, M12-116 and M11-602). For dual single mutants included in the model were based on 160 mutants with resistance to 2DAA classes, the susceptibility (EC50) to the drug of dual mutants was assumed to be a combination of the 2 single mutants. Thus, the single mutants were D168V and M414T for Compound 1 and Compound 2, respectively, and the double mutant was D168V-M414T. In this scenario, the D168V mutant would be less sensitive to Compound 1 but would be as sensitive to Compound 2 as to wild-type virus.
[233] With wild-type virus was based on values obtained from in vitro replicon studies.
[234] Model adaptation, while the mutation rate was based on Baseline prevalence of the mutants, was estimated below literature values. Both baseline prevalence and mutation rate determined mutant adaptation.
[235] Treatment-naïve HCV-infected subjects were used to construct Pharmacokinetic data and viral load data from the 140 model. For modeling, the number of target cells at the baseline, number of infected cells at the baseline, rate of death of target cells and mutation rates were based on literature values. See, e.g., Snoeck et al. supra; Rong et al. Sci Transl Med. 2 (30): 30ra32 (2000); Neal and Pravin, ACOP 2009 (http://2009.go-acop.org/sites/all/assets/webform/Lauren- Neal_ACoP_2009.pdf); Neumann et al. Science 282 (5386): 103-7 (1998); Shudo et al. Antivir Ther. 13 (7): 919-26 (2008); and Dahari et al. J Theor Biol. 247 (2): 371-81 (2007). The rate of virus production and the rate of infection of viruses were derived from other parameters in the model.
[236] 2.2.1. Fifty subjects and 50 replicates were simulated for each treatment. A Clinical Test Simulations was performed with Trial Simulator version dropout rate of subjects from the study due to some reason was assumed to be 8% over 24 weeks based on available literature on tests in subjects with HCV. All simulations were performed assuming 100% compliance. Covariates included in the simulations were genotype 1a / 1b status. Simulated clinical outcomes included: (1) percentage of subjects below the detection limit (LOD) of 10 IU / mL, and (2) percentage of subjects achieving SVR.
[237] [0237] and time for SVR. Over 80 scenarios were simulated to predict the percentage of subjects with SVR after administration of various 2-DAA and 3-DAA combinations (eg Compound 1 + Compound 2, or Compound 1 + Clinical test simulations were performed to determine optimal dose of Compound 4, or Compound 1 + Compound 2 + Compound 4), without RBV, at a dose range for each DAA (eg Compound 1 / ritonavir at 250/100, 150/100 or 100/100 mg QD, Compound 4 at 5 , 25 or 100 mg QD, and Compound 2 at 400 or 800 mg BlD) and over a range of treatment times (eg 2, 4, 6, 8, 10, 12, 16 and 24 weeks).
[238] Subjects with viral load less than a -5log IU / mL threshold for SVR. Selected and relevant results from the simulation for the 2- and 3-DAA combinations of Compound 1, 2 and / or 4 are shown in Figures 6A, 6B, 6C for two Optimal doses and times were predicted based on percentages of different doses of Compound 1. Figure 6A shows the predicted median SVR percentage (“% SVR”) and 90% confidence interval (the vertical bar at the top of each SVR percentage column) for different treatment times using a combination of Compound 1 and Compound 2; Figure 6B shows the predicted median and 90% confidence interval for different treatment times when using a combination of Compound 1 and Compound 4; and Figure 6C shows the predicted median and 90% confidence interval for different treatment times using a combination of Compound 1, Compound 2 and Compound 4. In each simulation, RBV was included and Compound 1 was used with 100 mg ritonavir, and the subjects are HCV genotype 1, treatment-naïve patients. 10 15 20 25 30 162 SVR24 is lower than SVR12 in some cases due to dropouts; where longer times are not necessarily predicted to improve SVR but could result in more dropouts resulting in lower SVR.
[239] The model predicted that with 8-12 weeks of dosing, at least 80 to 90% of subjects could achieve SVR with 2- and 3-DAA combinations. The model also predicted that times shorter than 8 weeks could cure a significant number of subjects. A 2-DAA regimen was predicted to cure over 40% of subjects and a 3-DAA regimen was predicted to cure approximately 60% of subjects at only 6 weeks of dosing. Dosage for times over 12 weeks was not expected to significantly increase the percentage of subjects with SVR. Addition of the third DAA was predicted to shorten the treatment time by 2 to 4 weeks as optimal times for the 3-DAA combination of Compound 1, Compound 2 and Compound 4 were predicted to be 8-10 weeks.
[240] Figures 6A, 6B and 6C illustrate predictions for DAA combinations without ribavirin. The model also predicts similar or comparable SVR percentages for these DAA combinations when used with ribavirin. In addition, the effect of interferon (eg, pegylated interferon) can also be added by incorporating interferon like a DAA but without any resistant mutants.
[241] Examination of different viral parameters and their effect on dose, time and SVR.
[242] Includes 150/100 mg Compound 1 / ritonavir QD + 400 mg Compound 3 QD + The model was used to simulate a treatment regimen as weight-based amounts of RBV BlD for 12 weeks. Subjects under treatment included 11 treatment-naïve subjects aged between 18 and 65 years. All subjects underwent 12 weeks of treatment with Compound 1 and ritonavir (Compound 1 / r) dosed in combination with Compound 3 and ribavirin (RBV). Compound 1 (150 mg once daily (QD)) was dosed with 100 mg QD ritonavir, 400 mg QD Compound 3, and weight-based amounts of RBV to 163 treatment-naïve subjects infected with genotype (GT) 1-HCV .
[243] Treatment regimen. The regimen included three groups of patients. In Group 1, the model was also used to simulate another previously treated untreated subject infected with an HCV infection with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon. The subjects included 19 treatment-naive subjects aged between 18 and 65 years. One subject discontinued the study in week 3. All the remaining 18 subjects completed 12 weeks of treatment with Compound 1 / r dosed in combination with Compound 2 and RBV. Compound 1 (250 mg QD) was dosed with 100 mg QD of ritonavir, 400 mg of BID of Compound 2, and RBV to treatment-naïve subjects infected with GT1-HCV.
[244] Infection with a protease inhibitor (in combination with ritonavir), a I Group 2, previously untreated subjects were treated with HCV polymerase inhibitor and ribavirin. The treatment was without interferon. The subjects included 14 treatment-naive subjects aged between 18 and 65 years. One subject discontinued the study in week 1. Thus, a total of 13 subjects were studied. All thirteen subjects completed 12 weeks of treatment with Compound 1 / r dosed in combination with Compound 2 and RBV. Compound 1 (150 mg QD) was dosed with 100 mg QD of ritonavir, 400 mg BID of Compound 2, and RBV to treatment-naïve subjects infected with GT1-HCV.
[245] Peginterferon + ribavirin (P / RBV) with a protease inhibitor (in combination with I Group 3, those not responding to ritonavir), a polymerase inhibitor, and ribavirin were treated. The treatment was without interferon. The subjects included 17 who did not respond to P / RBV between the ages of 18 and 65. The subjects were treated with Compound 1 / r which was dosed in combination with Compound 2 and RBV for 12 weeks. Compound 1 (150 mg QD) was dosed with 100 mg QD of ritonavir, 400 mg of BID of Compound 2, and RBV to those not responding to P / RBV and infected with GT1-HCV.
[246] The predicted mean value relative to the observed percentage SVR (“% SVR”) after 12 weeks of treatment is shown in Figure 8. 95% confidence intervals for the predicted data (the vertical bar at the top of each respective predicted SVR percentage column ) was also indicated. As shown in Figure 8, the predicted SVR percentages were well in line with the observed SVR percentages.
[247] Examples provided a quantitative method for reasonably predicting the SVR of the viral dynamic model of exposure-response in this various combinations of antiviral compounds. Based on the exposure antiviral response modeling and clinical trial simulations, it is shown that (1) addition of a third DAA to a 2-DAA combination may reduce optimal treatment time and / or increase SVR; (2) 8-12 weeks of dosing is the optimal treatment time for 2- and 3-DAA combinations of Compound 1 / r, Compound 2 and Compound 4; and (3) times shorter than 8 weeks of interferon-free treatment have been predicted to cure a significant percentage of subjects.
[248] Percentage of interferon-free treatment regimens containing BMS-790052 and BMS-650032 without ribavirin, based on existing published clinical data including two Phase 1 and a Phase 2 study of BMS-790052 and a Phase 1 and a Phase 2a study of BMS-650032. Figure 9 shows the predicted median SVR percentage and 90% SVR confidence interval for different treatment times for a 2-DAA regimen containing The model described above was also used to predict SVR-10 15 20 25 30 165 BMS-790052 ( 60 mg QD) and BMS-650032 (600 BID) in genotype 1 naive subjects. The combination of BMS-790052 (60 mg QD) plus BMS-650032 (600 BID) in genotype 1 naïve subjects was predicted to achieve improved SVR for times of 12 weeks or more with predicted SVRs of approximately 70% at 10 weeks of dosing . Similar regimens, but containing ribavirin, or regimens with similar doses of BMS-790052 and BMS-650032, with or without ribavirin, are expected to achieve similar SVR numbers.
[249] Ribavirin for genotype 1 patients based on existing clinical data. 3-DAA- Similarly, a 3-DAA regimen without interferon was modeled and the regimen contains 200/100 mg QD of Compound 1 / r, 50 mg QD of Compound 4 and 400 mg QD of PS | -7977. Figure 10 shows the predicted median SVR number for different treatment times with this 3-DAA combination. This 3-DAA combination was predicted to have over 60% SVR at 6 weeks and over 80% SVR at times of 8 weeks, 10 weeks, 12 weeks or longer treatment.
[250] Contains single DAA or single DAA with ribavirin. For example, model predictions for PS | -7977 + ribavirin were obtained at different times to treat HCV genotype 1 treatment-naïve patients. Figure 11 shows the predicted model can also be used to predict SVR for courses such as the median and 90% confidence interval for the SVR percentage for different treatment times with such a course containing PS | -7977 (as the only DAA; 400 mg QD) and ribavirin (600 mg BID). The 90 'Vo confidence interval for the predicted SVR (the vertical bar at the top of each respective predicted SVR percentage column) is also indicated in Figure 11. The prediction was based on already published clinical data for PS | - 7977. The SVR number for PS | -7977 + ribavirin was predicted to be approximately 75-90% after 12 weeks of dosing, and approximately 55-75% after 8 weeks of dosing, in genotype 1 subjects. Similar SVR percentages for genotype 1 treatment-naïve patients are expected for similar regimens containing similar PS1-7977 QD doses (eg, 200-600 mg QD) but without ribavirin.
[251] Data from two Phase 1 and a Phase 2 study of Daclatasvir (BMS-790052) and a Phase 1 and a Phase 2 study of PSI-7977 were used to estimate the pharmacokinetic and viral dynamic model parameters.
[253] Danoprevir and Mercitabine to Estimate the Pharmacokinetic and Viral In addition, data from a Phase 1 and a Phase 2 study of the dynamic model parameters were used. Ritonavir was co-administered with Danoprevir to improve the pharmacokinetics of Danoprevir. Predictions for a 2-DAA combination with Danoprevir and Mercitabine in genotype 1-naïve patients are shown in Figure 14. The model predicts that after 16 weeks of dosing with the combination of Danoprevir and Mercitabine without ribavirin, at least 90% of HCV patients can achieve SVR.
[254] Data from Phase 1 and Phase 2 studies of GS-9190 (Tegobuvir), GS-9451 and GS-5885 were used to estimate the pharmacokinetic and viral dynamic model parameters. Predictions for the combination of GS-9190 (Tegobuvir), GS-9451 and GS-5885 and without ribavirin in genotype 1-naïve patients are shown in Figure 15. The model predicts that by following a 12-week dose with the combination of GS-9190 (Tegobuvir) + GS-9451 + GS-5885 + RBV and without ribavirin, approximately 70% of genotype 1-naïve patients can achieve SVR and after 24 weeks of treatment,> 80% of genotype 1-naïve patients can achieve SVR.
[255] Data from Phase 1 and Phase 2 studies of GS-9151 and GS-7977 (PSI-7977) were used to estimate the pharmacokinetic and viral dynamic model parameters. Predictions for the combination of GS-9151 and GS-7977 (PSI-7977) and without ribavirin in genotype 1-naïve patients are shown in Figure 16.
[256] Data from Phase 1 and Phase 2 studies of GS-5885 and GS-7977 (PSI-7977) were used to estimate the pharmacokinetic and viral dynamic model parameters. Predictions for the combination of GS-5885 and GS-7977 (PSI-7977) and without ribavirin in genotype 1-naïve patients are shown in Figure 16.
[257] Data from Phase 1 and Phase 2 studies of 68-9451, GS-5885 and GS-7977 (PSI-7977) were used to estimate the pharmacokinetic and viral dynamic model parameters. Predictions for the combination of GS-9451, GS-5885 and GS-7977 (PSI-7977) and without ribavirin in genotype 1-naïve patients are shown in Figure 16.
[258] The model assumes that after 12 weeks of dosing with the combination of GS-9451 and GS-7977 (PSI-7977), or the combination of GS-5885 and GS-7977 (PSI-7977), or a combination of GS-9451, GS-5885 and GS-7977 (PSI-7977), and in the absence of ribavirin, approximately 90% of genotype 1 naive patients can achieve SVR.
[259] Data from a Phase 1a study of TMC-435 and from two Phase 1 and two Phase 2 studies of daclatasvir (BMS-790052) were used to estimate the pharmacokinetic and viral dynamic model parameters. Predictions for the combination of TMC-435 and daclatasvir in genotype 1-naïve patients are shown in Figure 17.
[260] The model predicts that after 12 weeks of dosing with the combination of TMC-435 and daclatasvir (BMS-790052), approximately 80% of genotype 1 naive patients can achieve SVR.
[261] The invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to exactly what is described.
Modifications and variations are possible in light of the above descriptions or may be acquired from the practice of the invention. Thus, it can be noted that the scope of the invention is defined by the claims and their equivalents.

权利要求:
Claims (22)
[1]
A combination of at least two direct acting antiviral agents (DAAs) for use in the treatment of HCV, said at least two DAAs comprising PSI-7977 and GS-5885, and wherein said treatment does not include administration of either interferon or ribavirin, and wherein said treatment lasts for 8, 9, 10, 11 or 12 weeks, and wherein said treatment is for a patient infected with HCV genotype 1.
[2]
The combination of claim 1, wherein said patient is a treatment-naïve patient
[3]
The combination of claim 1, wherein said patient is infected with HCV genotype 1a.
[4]
The combination of claim 1, wherein the two DAAs are administered once daily.
[5]
The combination of claim 1, wherein the two DAAs are co-formulated into a single composition and co-administered once daily.
[6]
The combination of claim 2, wherein GS-5885 is administered 90 mg QD and PSI-7977 is administered 400 mg QD.
[7]
A combination according to claim 6, wherein said treatment lasts for 8 weeks.
[8]
A combination according to claim 6, wherein said treatment lasts for 12 weeks.
[9]
The combination of claim 1, wherein said treatment lasts for 8 weeks. 10 15 20 25 30
[10]
The combination of claim 9, wherein said patient is a treatment-naive patient.
[11]
The combination of claim 1, wherein said treatment lasts for 12 weeks
[12]
The combination of claim 11, wherein said patient is a treatment-naive patient.
[13]
A combination of at least two direct-acting antiviral agents (DAAs) for use in the treatment of HCV, said at least two DAAs comprising PSI-7977 and an HCV-NS5A inhibitor, and wherein said treatment does not include administration of either interferon or ribavirin, and said treatment lasting 8, 9, 10, 11 or 12 weeks, and said treatment being for a patient infected with HCV genotype 1.
[14]
The combination of claim 13, wherein said patient is a treatment-naive patient.
[15]
The combination of claim 13, wherein said patient is infected with HCV genotype 1a.
[16]
The combination of claim 13, wherein the two DAAs are administered once daily.
[17]
The combination of claim 13, wherein the two DAAs are co-formulated into a single composition and co-administered once daily.
[18]
The combination of claim 14, wherein PSI-7977 is administered 400 mg of QD.
[19]
The combination of claim 13, wherein said treatment lasts for 8 weeks.
[20]
The combination of claim 19, wherein said patient is a treatment-naive patient. 5
[21]
The combination of claim 13, wherein said treatment lasts for 12 weeks.
[22]
The combination of claim 21, wherein said patient is a treatment-naive patient. 10

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法律状态:
2017-08-08| NAV| Patent application has lapsed|

优先权:

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申请号 | 申请日 | 专利标题

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US201161550360P| true| 2011-10-21|2011-10-21|

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US201161562176P| true| 2011-11-21|2011-11-21|

---

US201261587197P| true| 2012-01-17|2012-01-17|

---

US201261600468P| true| 2012-02-17|2012-02-17|

---

US201261619883P| true| 2012-04-03|2012-04-03|

---

US201261656253P| true| 2012-06-06|2012-06-06|

---

US201261711793P| true| 2012-10-10|2012-10-10|

---

PCT/US2012/061085|WO2013059638A1|2011-10-21|2012-10-19|Combination treatmentof daas for use in treating hcv|

---