Simeprevir Capsules (Olysio)
By William T. Elliott, MD, FACP, and
James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field
A second-generation, non-structure protein (ns3/4a) protease inhibitor has been approved by the FDA for the treatment of chronic hepatitis C infection. Simeprevir is marketed by Janssen Therapeutics as Olysio.
Simeprevir is used in combination with peginterferon-alpha and ribavirin (PR) for the treatment of hepatitis C virus (HCV) genotype 1 with compensated liver disease, including cirrhosis.1
Simeprevir is given once daily with food and in combination with PR. The combination is given for 12 weeks and followed by 12 weeks of PR for treatment-naïve patients and prior relapsers and 36 weeks for prior non-responders.1 Treatment should be discontinued if HCV RNA is ≥ 25 IU/mL at week 4, 12, or 24.
Simeprevir has significantly less pill burden (one capsule daily) compared to the first generation HCV protease inhibitors that require 6-12 pills in divided doses. In contrast to the first-generation agents, simeprevir is well tolerated. The incidence of adverse reactions for simeprevir plus PR is similar to PR alone.2 Simeprevir has not been associated with significant alterations in hemoglobin values or neutrophil counts.
Simeprevir + PR showed less antiviral activity in patients infected with genotype 1a Q80K polymorphism.1,2 Efficacy for the combination is not much different than PR alone (58% vs 50%) for treatment-naïve subjects and numerically higher, but low, for those who relapsed (47% vs 30%). Simeprevir is not recommended for those infected with genotype 1a with Q80K polymorphism.1,2 Screening prior to initiation of therapy is recommended. The incidences of adverse reactions that are higher compared to placebo are rash (28% vs 20%), photosensitivity (5% vs 1%), pruritus (22% vs 15%), grade 1 hyperbilirubinemia (27% vs 15%), and dyspnea (12% vs 8%). The frequency of adverse reactions may be higher in patients of East Asian ancestry due to higher systemic exposure to simeprevir. Coadministration with moderate-to-strong CYP3A4 inducers or inhibitors should be avoided.
Simeprevir is a NS3/4A protease inhibitor similar to boceprevir and telaprevir, which are NS3 protease inhibitors. However, simeprevir is chemically different (macrocyclic vs an alpha-ketoamide). The efficacy and safety were evaluated in two phase 3 studies in treatment-naïve subjects, one in subjects who relapsed on prior interferon therapy, and one phase 2b study in subjects who failed prior therapy with PR.2 In the treatment-naïve studies, subjects were randomized to simeprevir (150 mg daily), PR (n = 521), or placebo and PR (n = 264). The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Overall, SVR12 from pooled data was 80% for simeprevir and 50% for placebo. In the third phase 3 study, subjects who relapsed after prior PR were randomized to simeprevir and PR (n = 260) or placebo + PR (n = 133). SVR12 response rates were 79% compared to 37%. Simeprevir showed greater activity than placebo + PR for all IL28B genotypes and METAVIR fibrosis scores. The phase 2b study included prior relapse, prior partial responders, and prior null responders. SVR24 compared to PR were 77% vs 37%, 65% vs 9%, and 53% vs 19%, respectively. Simeprevir is generally well tolerated with less than 2% of subjects discontinuing treatment in the first 12 weeks compared to 1.3% for placebo + PR.1
Simeprevir is a second-generation, non-structure protein protease inhibitor for the treatment of HCV genotype 1. Compared to the first-generation agents, it appears to have similar efficacy to that reported for boceprevir and telaprevir. The absolute differences in SVR (treatment minus placebo) were 30% for treatment-naïve patients and 42% for relapsers compared to 25% and 33%, and 40% and 59% for boceprevir and telaprevir, respectively.1,3 It has a much lower pill burden and appears to be better tolerated. However, it is less active in HCV genotype 1a with Q80 polymorphism.1,4 This is clinically relevant as prevalence of Q80L polymorphism is 48% of the genotype 1a population.2,4 Its primary competitor on the market will not be the first-generation agents but the nucleotide analog polymerase inhibitor sofosbuvir, which will be reviewed in the next issue. The wholesale cost for simeprevir is $22,120 for 4 weeks.
- Olysio Prescribing Information. Titusville, NJ: Janssen Therapeutics; November 2013.
- http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM371624.pdf. Accessed December 22, 2013.
- Butt AA, Kanwal F. Boceprevir and telaprevir in the management of hepatitis C virus-infected patients. Clin Infect Dis 2012;54:96-104.
- Bae A, et al. Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 2010;54:5288-5297.