Near-Term Approval Expected for Three New Combination Medications in Hepatitis C

Recent drug approvals and continuing breakthroughs in research are creating additional treatment options for patients with hepatitis C.

Ledipasvir/Sofosbuvir (Gilead)

Gilead has filed for US Food and Drug Administration (FDA) approval of a fixed-dose combination of the NS5A inhibitor ledipasvir and Gilead’s polymerase inhibitor sofosbuvir for treatment of genotype 1 hepatitis C virus (HCV) infection in the United States.¹

The combination tablet is expected to include 90 mg of ledipasvir and 400 mg of sofosbuvir for use over an 8-week to 12-week treatment period, depending on patient characteristics. According to Norbert Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, genotype 1 HCV is the most common type of HCV infection, affecting 75% of infected individuals in the US. The combination tablet helps patients achieve sustained viral response (SVR) “without the need for interferon injections or ribavirin,”1according to Bischofberger. A series of phase III studies, ION-1, ION-2, and ION-3, demonstrated the efficacy of the combination tablet in nearly 2000 patients.^1-4

In the phase II ION-1 study, a total of 865 previously untreated patients with genotype 1a HCV infection (12% of whom had cirrhosis) achieved SVR at 12 weeks (SVR12) with rates of 99% while on 12 weeks of ledipasvir and sofosbuvir, and a 99% SVR with 12 weeks of ledipasvir, sofosbuvir, and ribavirin. Ribavirin use did not boost SVR12 rates, which were numerically lower in patients receiving the combinations that included ribavirin.^1-4

In the phase III ION-2 study, 440 patients with genotype 1 HCV infection who had not achieved SVR12 with prior interferon-based treatment, had SVR12 rates of 94% with 12 weeks of ledipasvir and sofosbuvir and 99% with 24 weeks of ledipasvir and sofosbuvir.^1-4

In the phase III ION-3 study, a total of 647 previously untreated patients with genotype 1a HCV infection (none of whom had cirrhosis) achieved SVR12 rates of 94% with 8 weeks of ledipasvir and sofosbuvir. Ribavirin use did not boost SVR12 rates.^1-4

Common adverse events (AEs) in phase II and III trials included fatigue, headache, insomnia, and nausea. Discontinuation rates from AEs were very low.^1-4

Daclatasvir/Asunaprevir (Bristol-Myers Squibb)

Bristol-Myers Squibb has submitted new drug applications for FDA approval of the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir. According to Brian Daniels, MD, senior vice president, global development and medical affairs, research and development, Bristol-Myers Squibb, “These FDA submissions represent a major step towards offering daclatasvir-based regimens to US HCV patients, many of whom continue to have high unmet medical needs.”⁵

In the phase III HALLMARK-DUAL study of daclatasvir and asunaprevir in patients with genotype 1b HCV, investigators reported results with the interferon-free, ribavirin-free combination in previously untreated patients, and in previous nonresponders to interferon and ribavirin. In 205 previously untreated patients (including patients with cirrhosis), 12 weeks of treatment with daclatasvir/asunaprevir led to a 90% SVR12 rate. Of 168 previous nonresponders, 12 weeks of treatment resulted in an 82% SVR12 rate. SVR12 rates in 192 patients who were ineligible for, or intolerant to, previous therapy were also 82%. Treatments were well tolerated, with few grade 3 or 4 laboratory abnormalities.⁶

Simeprevir/Sofosbuvir (Janssen/Gilead)

Janssen has submitted a new drug application for FDA approval of the combination of Janssen’s protease inhibitor, simeprevir, with Gilead’s polymerase inhibitor, sofosbuvir, in previously untreated and previously treated patients with genotype 1 HCV.⁷

Although both medications are available and are already being used together, the combination tablet may be more convenient to use and may be less expensive than seeking reimbursement for each drug separately. In a press release, Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development, stated, “This filing brings us closer to potentially offering these patients a once-daily all-oral treatment combination that includes the direct-acting antiviral agents simeprevir and sofosbuvir.”⁷

Results of the phase II COSMOS study showed that 12 weeks of treatment with sofosbuvir and simeprevir led to a 93% SVR12 rate in 80 patients with genotype 1b infection who had moderate or no fibrosis of the liver and who had failed to achieve SVR with prior therapy. Addition of ribavirin to the regimen boosted SVR12 rates moderately, to 96%. A 24-week regimen of the simeprevir/sofosbuvir combination, however, led to a 100% SVR12 rate, even in patients with unfavorable mutations, advanced fibrosis, compensated cirrhosis, and in previous nonresponders. In clinical trials, fatigue, headache, and nausea were the most common AEs. Phase III trials, OPTIMIST-1 and OPTIMIST-2 are ongoing.^8-10

References

1. Gilead website. Gilead Files for U.S. Approval of Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Hepatitis C [press release]. http://www.gilead.com/news/press-releases/2014/2/gilead-files-for-us-approval-of-ledipasvirsofosbuvir-fixeddose-combination-tablet-for-genotype-1-hepatitis-c. Accessed August 2014.

2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med.2014;370(20):1889-1898.

3. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.

4. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.

5. BMS website. Bristol-Myers Squibb Submits NDAs for Daclatasvir and Asunaprevir to US FDA for the Treatment of Hepatitis C [press release]. http://news.bms.com/press-release/bristol-myers-squibb-submits-ndas-daclatasvir-and-asunaprevir-us-fda-treatment-hepatit. Accessed August 2014.

6. Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. 2014;Jul 26. pii: S0140-6736(14)61059-X.

7. HIVandHepatitis.com. Janssen Seeks Approval of Simeprevir + Sofosbuvir for HCV Genotype 1. http://www.hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/4682-janssen-seeks-supplemental-approval-of-simeprevir-sofosbuvir-for-hcv-genotype-1. Accessed August 2014.

8. Page MR. COSMOS Hepatitis C Trial Results Announced. http://www.specialtypharmacytimes.com/news/COSMOSHepatitis-C-Trial-Results-Announced. Accessed August 2014.

9. ClinicalTrials.Gov. Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Participants With Chronic Hepatitis C Virus Infection Without Cirrhosis. http://clinicaltrials.gov/ct2/show/NCT02114177. Accessed August 2014.

10. ClinicalTrials.gov. Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Participants With Genotype 1 Chronic Hepatitis C Virus Infection and Cirrhosis. http://clinicaltrials.gov/ct2/show/NCT02114151. Accessed August 2014.