Summary Basis of Decision for Sovaldi

Clinical Pharmacology

The medicinal ingredient of Sovaldi, sofosbuvir (SOF), is a nucleotide analog NS5B polymerase inhibitor that has a direct antiviral action against the hepatitis C virus (HCV). It blocks a specific step in the replication of the HCV virus. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

The clinical pharmacology included reports on the human pharmacodynamic and the pharmacokinetic studies. Results from these studies showed that no dosage adjustment is recommended for patients with mild or moderate renal impairment or mild, moderate or severe hepatic impairment. Overall, the clinical pharmacological data support the use of Sovaldi for the specified indication.

One patient developed the primary treatment-emergent Sovaldi resistance mutation (S282T) in a Phase II study, in which the patient received Sovaldi in monotherapy. Therefore, Sovaldi must not be administered as monotherapy and must only be used in combination with either peginterferon alfa (PEG)+ribavirin (RBV) or RBV for the treatment of HCV.

For further details, please refer to the Sovaldi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Sovaldi [sofosbuvir (SOF)] was evaluated in four Phase III clinical studies: NEUTRINO, FISSION, POSITRON and FUSION.

The study NEUTRINO was a Phase III, multicentre, open-label, single-arm study that investigated the efficacy and safety of Sovaldi with peginterferon alfa 2a (PEG) and ribavirin (RBV) for 12 weeks in treatment-naïve patients with chronic genotype 1, 4, 5, or 6 HCV infection. A total of 327 patients were treated for 12 weeks with SOF (400 mg once daily)+PEG (180 μg/week)+RBV (1,000 or 1,200 mg/day). The primary efficacy endpoint was the proportion of patients with sustained virologic response at 12 weeks (SVR12), defined as HCV ribonucleic acid (RNA) less than the lower limit of quantification (LLOQ) 12 weeks after discontinuation of treatment in the full analysis set population.

The overall treatment response 12 weeks post-treatment (SVR12) rate was 90.2% amongst treatment-naïve patients with chronic genotype 1, 4, 5, or 6 HCV infection. By comparison, the SVR12 rate for chronic HCV genotype 1 in combination with the NS3/4A protease inhibitors (telaprevir and boceprevir) was approximately 70%, with SVR rates slightly lower for genotype 4 and 6. No patients had the on-treatment virologic failure (breakthrough, rebound or non-response). HCV RNA levels declined rapidly, with a decline of approximately 5 log₁₀ after 1 week of treatment, which was maintained throughout the remainder of treatment. These results demonstrated that the combination of SOF+interferon (INF)+RBV suppresses HCV RNA quickly and in a very potent manner. None of the patients developed the primary treatment-emergent Sovaldi resistance mutation (S282T). Specified subgroups that have classically been considered to be harder to treat were analysed. These subgroups all had SVR rates of ~80% or higher, with the exception of patients with cirrhosis, who had an SVR rate of 79.6%. Blacks/African Americans had an SVR rate of 87%, while those with either a cytosine-thymine (CT) or thymine-thymine (TT) IL28B genotype had an SVR rate of 87.1% (compared to 97.9% for the CC genotype). Classically, genotype 1a has normally been harder to treat than genotype 1b. However, the SVR12 rate for Sovaldi against genotype 1a was 92%, compared to 82% for genotype 1b. For those with genotypes 4, 5, and 6, the SVR12 rate was 97.1% (34/35 patients, with only 1 patient with genotype 5, and 6 patients with genotype 6, all of whom achieved SVR12).

Due to the limited number of patients with genotype 5 and 6 CHC enrolled in the NEUTRINO study [number of patients (n) = 1 and n = 6, respectively], the indication for chronic HCV infection for patients with genotype 5 and 6 CHC was not authorized considering the limited data available regarding the use of Sovaldi in those patients.

Three Phase III studies (FISSION, POSITRON and FUSION) were conducted to support the indication and dosing recommendation for the treatment of genotypes 2 and 3 chronic HCV infection.

FISSION was a Phase III, randomized, open-label, active-controlled study that evaluated the efficacy and safety of SOF+RBV administered for 12 weeks, in comparison with the current standard of care treatment with PEG+RBV administered for 24 weeks for the treatment of genotype 2 and 3 CHC infection. A total of 499 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or PEG-INF (180 µg/week)+RBV (800 mg/day) for 24 weeks. The primary efficacy endpoint of SVR12 was comparable between treatment groups. In the SOF+RBV group, the SVR12 rate was 67.2% compared to the SVR12 rate of 66.7% in the PEG+RBV group. The results of the protocol defined statistical analysis showed a difference of 0.3% between the two treatment groups, with a 95% confidence interval (CI) of -7.5 to 8.0%. The lower bound of the two-sided 95% CI for the difference between groups (SOF+RBV or PEG+RBV) was -7.5, demonstrating the non-inferiority of SOF+RBV versus (vs.) PEG+RBV. In the SOF+RBV group, HCV genotype 2 patients had higher SVR12 rates compared to HCV genotype 3 patients (95% vs. 56%, respectively). Within each genotype, relapse accounted for most treatment failures with HCV genotype 3 (relapse rate of 40%) compared to HCV genotype 2 (relapse rate of 5%).

POSITRON was a Phase III, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of 12 weeks of SOF+RBV in patients with chronic genotype 2 or 3 HCV infection who were IFN intolerant, IFN ineligible, or unwilling to take IFN. A total of 278 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or placebo for 12 weeks. The results showed that a significantly higher proportion of patients in the SOF+RBV group achieved SVR12 (77.8%; 95% CI: 71.5−83.2%) compared to placebo (0%; 95% CI: 0.0−5.1%) (p < 0.001). Although this population cannot take interferon and therefore had no available treatment options, this SVR can favorably be compared to historic treatment success rates for genotype 2 and 3 HCV infections. In this study HCV genotype 2 patients had higher SVR12 rates (93%) compared to HCV genotype 3 patients (61%).

FUSION was a Phase III, randomized, double-blind study that evaluated the efficacy and safety of 12 versus 16 weeks of SOF+RBV in treatment-experienced patients with chronic genotype 2 or 3 HCV infection and who had failed prior treatment with an IFN-based regimen. A total of 201 patients were treated with SOF (400 mg)+RBV (1,000-2,000 mg) daily for 12 weeks or SOF (400 mg)+RBV (1,000 or 2,000 mg) daily for 16 weeks. The SVR12 rates in the SOF+RBV 12 week group and the SOF+RBV 16 week group were 50% and 72.6%, respectively, compared to the historical rate of 25% (p<0.001). None of the patients in either treatment group had on-treatment virologic failure. Genotype 2 HCV-infected patients had similar SVR12 rates in the SOF+RBV 12 week and SOF+RBV 16 week groups (86.1% and 93.8%, respectively), whereas genotype 3 HCV-infected patients had higher SVR12 rates in the SOF+RBV 16 week group (61.9%) compared to the SOF+RBV 12 week group (29.7%). Within each treatment group, analyses of SVR12 by subgroup revealed similar SVR12 rates for the age, ethnicity, baseline body mass index, IL28B genotype, and response to prior HCV treatment subgroups. In both the SOF+RBV 12 week and SOF+RBV 16 week treatment groups, higher SVR12 rates were observed in genotype 2 HCV-infected patients compared to genotype 3 HCV-infected patients. Higher SVR12 rates were observed in female patients compared to male patients. In the SOF+RBV 12 week group, a higher SVR12 rate was observed in non-cirrhotic patients (60.9%) compared to cirrhotic patients (30.6%); this difference was less pronounced in the SOF+RBV 16 week group (76.2% vs. 65.6%).

Overall, the data obtained from the clinical studies demonstrated that the Sovaldi-containing regimens met their primary efficacy endpoints and had a favourable safety profile compared with historical and/or current standard-of-care regimens.

For more information, refer to the Sovaldi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Sovaldi was based on data from the pooled Phase III clinical studies (NEUTRINO, FISSION, POSITRON and FUSION) described in the Clinical Efficacy section. These studies included 566 patients who received SOF+RBV combination therapy for 12 weeks, 98 patients who received SOF+RBV combination therapy for 16 weeks, 327 patients who received SOF+PEG+RBV combination therapy for 12 weeks, 243 patients who received PEG+RBV for 24 weeks and 71 patients who received placebo for 12 weeks.

Overall, Sovaldi (400 mg/day) in combination with PEG+RBV and Sovaldi (400 mg/day) in combination with RBV was well-tolerated and provided effective treatment for genotype 1 and 4 CHC infection (NEUTRINO) and genotype 2 and 3 CHC infection (FISSION, POSITRON, FUSION).

In the study NEUTRINO, 304 patients (93.0%) had at least 1 treatment-emergent adverse event (TEAE). The 3 most frequently reported adverse events (AEs) assessed as related to study treatment were fatigue (56.3%, 184 patients), nausea (31.2%, 102 patients), and headache (30.9%, 101 patients). Four serious AEs (SAEs) were assessed as related to a study drug: anemia and cryoglobulinemia (both in one patient) and leukopenia and pyrexia (both in one patient). All of the TEAEs, AEs and SAEs are consistent with the expected safety profile of PEG+RBV treatment. There were no deaths reported in this study. Overall, the proposed regimen of SOF+PEG+RBV was well-tolerated and the safety profile is comparable to what would be seen for PEG and RBV alone for 12 weeks, despite the addition of Sovaldi 400 mg.

Across the clinical studies FISSION, POSITRON and FUSION, SOF + RBV regimens were generally safe and well-tolerated. The incidence of AEs leading to permanent discontinuation of treatment regimen was low in all SOF-containing regimens (0.0−1.5%) and lower than the incidence of AEs leading to permanent discontinuation of treatment regimen in the placebo group in POSITRON (4.2%) and PEG+RBV group in FISSION (10.7%). In the SOF+RBV groups, there were no AEs leading to permanent discontinuation of SOF+RBV that occurred in more than 1 patient. The three most frequently occurring AEs across all groups in the primary safety population were fatigue, headache, and nausea. The incidence of these events was higher in the PEG-containing groups (PEG+RBV or SOF+PEG+RBV), which was consistent with the expected safety profile of PEG+RBV treatment. Other than the expected AEs and laboratory abnormalities associated with RBV, the SOF+RBV 12 week and SOF+RBV 16 week groups had a safety profile similar to the placebo group. No additional AEs to the expected safety profile for RBV or PEG+RBV were identified in the SOF+RBV or SOF+PEG+RBV groups, respectively.

Appropriate warnings and precautions are in place in the approved Sovaldi Product Monograph to address the identified safety concerns.

For more information, refer to the Sovaldi Product Monograph, approved by Health Canada and available through the Drug Product Database.