The Potential Role of Simeprevir for the Treatment of Hepatitis C

Cristina del Barrio Gascón; Maria Buti


Future Virology. 2015;10(2):67-75. 

In This Article

Clinical Efficacy in Patients With Chronic Hepatitis C

Dose-finding Study

The appropriate SMV dose was selected after Phase II studies. In patients with chronic HCV infection, the steady-state pharmacokinetics of SMV was evaluated following monotherapy or combination therapy with PEG-IFN/RBV, at doses of 25–200 mg q.d. A more-than-dose-proportional increase in exposure was seen in both treatment-naive and treatment-experienced HCV patients at SMV doses above 75 mg q.d. At a dose increase from 75 to 200 mg q.d. (2.67-fold), the mean AUC at 24 h (AUC24h) increased approximately eightfold, and an increase from 150 to 200 mg q.d. resulted in a 2.7-fold to fourfold increase in AUC24h. The absorption rate was not affected by the dose: median tmax time to reach Cmax (tmax) was 4 to 6 h. No relevant differences in the plasma pharmacokinetic profile of SMV were found after multiple-dose administration of different formulations.[16]

SMV 150 mg q.d. was the dose selected in Phase III studies in the global program and 100 mg q.d. in Japan. In an ongoing Phase III study in China and Korea, both 100 and 150 mg q.d. are being explored.

SMV in Combination With PEG-IFN/RBV in Naive Patients With Chronic HCV Genotype 1 Infection: QUEST-1 & QUEST-2 Studies

SMV has been studied in treatment-naive HCV genotype 1-infected adult patients in two multicenter, randomized, double-blind, placebo-controlled and two-arm studies.

In QUEST-1, a Phase III trial undertaken in 13 countries (Australia, Europe, the USA, Puerto Rico and New Zealand), 394 patients (aged ≥18 years, stratified by HCV subtype and host IL28B genotype), were randomly assigned in a 2:1 ratio to receive SMV (150 mg once daily, orally) plus PEGylated interferon (IFN) alfa-2a plus RBV (PEG-IFN/RBV) for 12 weeks followed by PEG-IFN/RBV (SMV group) or placebo orally plus PEG-IFN/RBV for 12 weeks, followed by PEG-IFN/RBV (placebo group). Treatment duration was 24 weeks or 48 weeks in the SMV group according to response-guided therapy (RGT) criteria (i.e., HCV RNA <25 IU/ml [undetectable or detectable] at week 4 and <25 IU/ml [undetectable] at week 12) and 48 weeks in the placebo group.[17]

Treatment with SMV plus PEG-IFN alfa-2a/RBV was found to be superior to the placebo regimen of PEG-IFN/RBV. SVR 12 weeks after planned end of treatment (SVR12) was achieved in 80% of patients versus 50%, respectively (p < 0.0001).

In the QUEST-2 Phase III study, conducted in 14 countries (Europe, the USA and South America), HCV genotype 1-naive patients were randomly assigned 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive one of the following regimens: SMV (150 mg once daily, orally), PEG-IFN alfa-2a (180 μg once weekly, subcutaneous injection) or PEG-IFN alfa-2b (according to body weight), plus RBV 1000–1200 mg/day or 800–1400 mg/day, orally (SMV group), or placebo (once daily, orally), PEG-IFN alfa-2a or 2b/RBV for 12 weeks, followed by PEG-IFN alfa-2a or 2b/RBV (placebo group). Total treatment duration was 24 weeks or 48 weeks (SMV group) based on RGT criteria, as in QUEST-1.

SVR12 was achieved in 81% of 257 patients in the SMV group and 50% of 134 in the placebo group (p < 0.0001). The incidence of adverse events was similar in the two groups at 12 weeks (96 vs 97%) and for the entire treatment (97 vs 99%), regardless of the PEG-IFN alfa used.[18] In a pooled analysis of QUEST-1 and 2, 88% of patients treated with SMV plus PEG-IFN/RBV achieved RGT criteria and were eligible for 24 weeks of treatment. The SVR12 rate was 88% in these patients. 8% of patients did not meet RGT criteria and the SVR rate in this group was 25%. On-treatment failure occurred in 8% of patients treated with SMV triple therapy and 33% of those treated with PEG-IFN/RBV alone (Table 1).[19]

SVR12 analyzed according to HCV subtype and the presence of Q80K mutations showed the highest rates in genotype 1b (85%) and the lowest in genotype 1a with the Q80K mutation (58%).

The degree of fibrosis had an impact on SVR rates. SVR with SMV triple therapy was 84% in patients with a METAVIR score of F0-F2, 73% in those with F3, and 60% in those with F4. A similar decrease in SVR rates according to fibrosis stage was observed in the PEG-IFN/RBV group.

Both studies showed that addition of SMV to PEG-IFN alfa-2a or 2b plus RBV improved SVR rates in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with PEG-IFN alfa/RBV. In both studies, the most common adverse events during therapy were headache, fatigue, pyrexia and influenza-like illness. In QUEST-2, the incidence of rash or photosensitivity was higher in patients receiving SMV than in those with the placebo regimen (24 vs 11%, and 4 vs <1%, respectively). The incidence of anemia was similar in the SMV and placebo groups: 14 versus 16%, respectively, at 12 weeks, and 21 versus 28%, respectively, over the total treatment. Adverse events in the first 12 weeks of treatment led to discontinuation of SMV or placebo treatment in less than 1% of patients in each group. In QUEST-1, fatigue (40 vs 38% patients, respectively) and headache (31 vs 37%, respectively) were the most common adverse events. The incidence of anemia (16 vs 11%, respectively) and rash (27 vs 25%) was similar in the two groups. Addition of SMV did not increase the severity of patient-reported fatigue or limitation of daily activities and it shortened the duration of these effects.

SMV in Relapsers: The PROMISE Study

In patients who had previously relapsed on IFN/RBV, SMV in combination with PEG-IFN/RBV was evaluated in the PROMISE study. This was a randomized, double-blind, placebo-controlled, Phase III trial undertaken to assess the efficacy, safety and tolerability of SMV plus PEG-IFN/RBV for the treatment of chronic HCV genotype 1 infection in patients who had relapsed after previous IFN-based therapy. Patients were randomly assigned (2:1) to groups given SMV (150 mg, q.d.) and PEG-IFN/RBV (n = 260) or placebo and PEG-IFN/RBV (n = 133) for 12 weeks. Patients were then given PEG-IFN/RBV alone for 12 or 36 weeks (SMV group, based on RGT criteria) or 36 weeks (placebo group).[20]

SMV and PEG-IFN/RBV was significantly superior to placebo and PEG-IFN/RBV: SVR12 rates were 79.2 versus 36.1%, respectively (43.8% difference; 95% CI: 34.6–53.0; p < 0.001). Among patients given SMV, 92.7% met RGT criteria and were eligible to complete PEG-IFN + RBV at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given SMV and 3.1% given placebo. On-treatment failure and relapse rates were lower in patients receiving SMV and PEG-IFN/RBV than in those given placebo and PEG-IFN/RBV (3.1 vs 27.1%, and 18.5 vs 48.4%, respectively). Patients receiving SMV did not have adverse events beyond those that occurred in the group given PEG-IFN/RBV alone (Table 1).[20]

Most adverse events were grades 1 or 2, and the incidence of anemia and rash was similar in the two groups. Patients in both groups reported similar severity of fatigue and functional impairment during the study, but the duration of these effects was shorter in patients receiving SMV.

In summary, addition of SMV to PEG-IFN/RBV was generally well-tolerated and yielded an SVR12 rate of 79.2%. In most patients (92.7%) receiving SMV, therapy could be shortened to 24 weeks. SVR12 rates for SMV/PEG-IFN/RBV were not affected by subgroup (fibrosis stage, genotype subgroup or IL28B genotype). However, lower SVR12 rates were observed in SMV patients with the GT 1a Q80K polymorphism at baseline.

SMV in Combination With PEG-IFN/RBV in Previous Nonresponders to PEG-IFN/RBV: The ATTAIN Study

The ATTAIN study is a Phase III randomized, double-blind study to evaluate the efficacy, safety and tolerability of SMV versus TPV in combination with PEG-IFN/RBV in chronic HVC genotype 1 treatment-experienced patients who were partial or null responders to previous PEG-IFN/RBV therapy.[21]

A total of 384 patients were randomly assigned to receive TPV plus PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV, and 379 to receive the same therapeutic schedule with SMV.[18] Liver cirrhosis was documented in 18 and 15% of patients, respectively, and approximately 55% were genotype 1b. In prior null responders, SVR12 occurred in 43% treated with SMV/PR and 46% treated with TPV/PR. In prior partial responders, 69.7% receiving SMV/PR and 68.5% receiving TPV/PR achieved SVR12. The endpoint of the study was noninferiority in SVR12 rates, which was shown for SMV/PR versus TPV/PR in prior nonresponders.[19] SVR12 rates were similar for the two treatment regimens across subgroups (fibrosis stage, IL28B, genotype subtype and prior treatment response) (Table 1). The percentage of patients with adverse events was lower with SMV/PR and there were notably fewer events leading to permanent treatment discontinuation compared with TPV/PR.[20]

Patients Coinfected With HCV & HIV-1: The C-212 Study

The open-label, multicenter C212 study examined the efficacy of SMV plus PEG-IFN/RBV in patients with chronic HCV and HIV coinfection.[22] The inclusion criteria were treatment-naive or treatment-experienced adult (>18 years) patients with genotype 1 infection. Treatment-naive patients and relapsers without liver cirrhosis received RGT with SMV plus PEG-IFN/RBV, whereas treatment-naive patients, relapsers with cirrhosis, partial responders and null responders received SMV plus PEG-IFN/RBV for 48 weeks. At baseline, 13% of patients had cirrhosis, 73% had a non-CC IL28B subgenotype and 82% were white. SVR12 rates were 79% in naive patients, 87% in prior relapsers, 70% in partial responders and 57% in null responders. SVR12 was achieved in 75% of antiretroviral-treated patients compared with 62% of those not taking these drugs. The safety profile of the regimen was similar to that seen in HCV monoinfected patients. In summary, HCV/HIV-1 coinfected patients, regardless of their prior HCV treatment history, should be treated in the same way as HCV monoinfected patients, except for coinfected patients with cirrhosis who should receive 36 weeks of PEG-IFN/RBV after completing 12 weeks of SMV-PEG-IFN/RBV (total treatment duration, 48 weeks).[23]