Exciting New Hepatitis C Therapies Approved at the End of 2017

In 2017, research on 3 drug combinations for the treatment of hepatitis C virus (HCV), which were in phase 2 studies, was discontinued,¹ meaning that there are no longer direct acting antivirals (DAAs) in the pipeline for HCV treatment and cure in the foreseeable future. Thankfully, in 2017, 2 new drug therapies, Vosevi (sofosbuvir/ velpatasvir/voxilaprevir; Gilead) and Mavyret (glecaprevir/pibrentasvir; AbbVie) were approved by the US Food and Drug Administration (FDA) for the treatment and cure of HCV.^2,3

Vosevi, a combination of sofosbuvir and velpatasvir, 2 previously approved drugs, with the new drug voxilaprevir, offers a new treatment option for patients who previously failed regimens that included a nonstructural protein 5A (NS5A) drug or sofosbuvir without an NS5A inhibitor.⁴ In clinical studies, Vosevi was compared in adults with HCV genotypes 1 through 6 against placebo and in adults with genotypes 1 through 3 against sofosbuvir and velpatasvir.³ In both trials, approximately 96% of the patients who received Vosevi were considered cured, which was defined as having undetected viral levels within the blood after 12 weeks of treatment.³

The release of Vosevi on the market as a fixed-dose, 1-pill, once-daily regimen is significant in the fact that it provides another therapy option that effectively cures hard-to-treat patients infected with the most common genotypes of HCV (see Table 1 for indications).⁴ This newly developed drug is unique in being the only drug available on the market for treatment-experienced patients with genotypes 4 through 6 who previously failed a DAA.⁵ It also stands out from Harvoni (ledipasvir/ sofosbuvir) in its inclusion of patients with genotype 3. Overall, it has become the recommended drug of choice for DAA treatment-experienced patients with genotypes 1, 3, 4, 5, and 6 per American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) updates on the HCV Guidelines website.⁵ However, Vosevi is not recommended in the guideline updates in treatment-experienced patients with genotype 2; Epclusa (sofosbuvir/ velpatasvir) remains the preferred recommendation.⁵ It is also important to note that unlike Harvoni, Vosevi is only approved for patients without cirrhosis or with compensated cirrhosis, whereas Harvoni can be used to treat patients with decompensated cirrhosis.⁴ Lastly, testing for resistance-associated substitutions is not recommended in patients prescribed Vosevi as this has not been shown to affect sustained viral response rates.⁵

A few months after the approval of Vosevi, AbbVie was granted FDA approval for its new HCV treatment, Mavyret.² A combination of glecaprevir and pibrentasvir, Mavyret is the first HCV treatment regimen with a potential duration of 8 weeks.⁶ Other FDA-approved treatment options have a standard regimen duration of 12 weeks. Mavyret treats and cures treatment-naïve patients with genotypes 1 through 6 without cirrhosis and with compensated cirrhosis (Child- Pugh A) and patients with genotype 1 who were previously treated with either a NS5A inhibitor or a nonstructural protein 3/4A (NS3/4A) protease inhibitor.² It is important to note that the indication for previous treatment does not include a regimen containing a combination of a NS5A inhibitor and a NS3/4A protease inhibitor.² In addition, Mavyret treatment regimens are available for patients who are diagnosed with moderate to severe kidney disease or those receiving hemodialysis.⁶ The AASLD and IDSA HCV Guidelines website has strongly recommended Mavyret as a treatment option since its release, and with the allure of a brief 8-week treatment duration, it is likely Mavyret will be used more frequently in the future.⁵

In clinical trials, when Mavyret was used to treat patients with genotypes 1 through 6 without cirrhosis or with mild cirrhosis for 8, 12, or 16 weeks, no virus was detected in the blood samples of 92% to 100% of patients, indicating that the HCV infection was cured.² Thus depending on indication, the duration varies for these 3-pill, once-daily regimens, as depicted in Tables 2⁶ and 3⁶.

In the fall of 2017, Merck announced its decision to discontinue 2 of its drug combinations for hepatitis C, MK3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK3682C (ruzasvir/uprifosbuvir) in the midst of phase 2 trials.⁷ In their first phase 2 study, the C-CREST trial observed the safety and efficacy of MK3682B in patients with genotypes 1, 2, and 3 with or without cirrhosis.⁷ With 8 weeks of treatment with MK3682B, patients with genotypes 1, 2, and 3 had cure rates of 96%, 86%, and 95%, respectively.⁷ Efficacy was comparable between patients with and without cirrhosis.⁷ Merck was investigating the treatment of patients with genotype 1 who failed previous therapy with Harvoni or Zepatier (elbasvir/grazoprevir) in the C-SURGE trial, a phase 2 study.⁷ In 1 treatment arm, patients received MK3682B with ribavirin for 16 weeks, while the other arm included patients treated with MK3682B alone for 24 weeks.⁷ Because the trial is not yet completed, the final results will be presented at a future scientific congress, according to Merck’s website.⁷

Both C-CREST and C-SURGE preliminary results indicated that MK3682B was a potential pathway for Merck to release a drug combination for both treatment-naïve and patients who previously failed a DAA treatment. If C-SURGE results show success in treating patients with genotype 1 who have failed treatment with Harvoni or Zepatier, MK3682B could have shared a niche with Vosevi for that hepatitis C indication. However, given that there are several drugs on the market for similar indications in other HCV target genotypes/studied endpoints, Merck ultimately decided to halt its pursuit of new HCV drug marketing while allowing the C-SURGE trial to progress to completion for other potential indications.

Additionally, Janssen announced that it will no longer develop its HCV treatment regimen JNJ-4178, which consists of 3 DAAs: AL-335, odalasvir, and simeprevir.⁸ During phase 2 trials, Janssen announced that the OMEGA-1 study will be completed as planned, but their focus will shift to developing treatments for hepatitis B.^8,9 This decision was made after consideration of the vast availability of treatment regimens on the market for HCV, while there are significantly less manufacturers studying drugs for hepatitis B therapy.⁸

Perhaps these discontinuation announcements signal a slower development in new therapies to be released in the upcoming year due to competition in the HCV field. The new drugs, sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir, released during 2017 offer additional options for HCV, especially for treatment-experienced patients.

Dr. Rojas is an antimicrobial stewardship pharmacist at Valley Hospital Medical Center in Las Vegas, Nevada. She completed a PGY-1 practice residency at the University Medical Center of Southern Nevada in 2011 and received her SIDP antimicrobial stewardship certificate in 2016. She is an active member of SIDP.

Kristine La is a final year PharmD candidate at Roseman University of Health Sciences, with an anticipated graduation date of May 2018.

References:

1. Drug pipeline - quarterly report. HCV Advocate. November 1, 2017. hcvadvocate.org/treatment/drug-pipeline-monthly-report/. Accessed December 7, 2017.
2. FDA approves Mavyret for Hepatitis C. Silver Spring, MD: FDA; August 3, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm570038.htm. Accessed December 7, 2017.
3. FDA approves Vosevi for hepatitis C. Silver Spring, MD: FDA; July 18, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm567467.htm. Accessed December 7, 2017.
4. Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc; 2017.
5. AASLD; IDSA. Retreatment of persons in whom prior therapy failed. HCVGuidelines.org website. hcvguidelines.org/treatment-experienced. Updated September 21, 2017. Accessed January 9, 2018.
6. Mavyret [package insert]. North Chicago, IL: AbbVie, Inc; 2017.
7. Merck Announces Findings for Investigational Triple-Combination Chronic Hepatitis C Therapy Showing High Rates of Sustained Virologic Response in People with Genotypes 1, 2 or 3 Infection. Kenilworth, NJ: Merck; November 13, 2016. investors.merck.com/news/press-release-details/2016/Merck-Announces-Findings-for-Investigational-Triple-Combination-Chronic-Hepatitis-C-Therapy-Showing-High-Rates-of-Sustained-Virologic-Response-in-People-with-Genotypes-1-2-or-3-Infection/default.aspx. Accessed December 7, 2017.
8. Janssen to Discontinue Hepatitis C Development Program. Cork, Ireland: Janssen; September 11, 2017. janssen.com/janssen-discontinue-hepatitis-c-development-program. Accessed December 7, 2017.
9. Evaluation of the efficacy and tolerability of JNJ-3178 (AL-335, odalasvir, and simeprevir) in hepatitis C virus-infected patients without cirrhosis: The Phase IIb Omega-1 Study. Washington DC; American Association for the Study of Liver Diseases; October, 2016. http://www.natap.org/2017/AASLD/AASLD_17.htm. Accessed January 21, 2018.