Summary Basis of Decision for Epclusa

Clinical Pharmacology

Epclusa is a fixed-dose single tablet regimen of sofosbuvir and velpatasvir. Both sofosbuvir and velpatasvir exhibit high potency and specificity as individual agents against hepatitis C virus (HCV) as compounds that target the HCV non-structural protein 5B (NS5B) and non-structural protein 5A (NS5A), respectively.

The clinical pharmacology section included reports on human pharmacodynamic and pharmacokinetic studies.

The effect of food intake on the relative bioavailability of sofosbuvir and velpatasvir administered as a fixed-dose combination tablet (Epclusa) was evaluated. The results show that the pharmacokinetics of both sofosbuvir and velpatasvir are increased by administration of Epclusa with food; however, in the Phase III clinical studies the response rates were similar for patients who received Epclusa with food or without food.

Sofosbuvir and GS-331007 (primary circulating metabolite of sofosbuvir) are not inhibitors or inducers of cytochrome P450 (CYP) or UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1) enzymes. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Sofosbuvir and velpatasvir are substrates of efflux drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), while GS-331007 is not. Medicinal products that are potent P-gp inducers and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. rifampin, St. John’s wort (Hypericum perforatum) and carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir leading to reduced therapeutic effect of Epclusa and potential loss of virologic response. These agents should not be used with Epclusa.

The safety and efficacy of Epclusa have not been established in patients with severe hepatic impairment (Child-Pugh Class C). Based on pharmacokinetic data, no dose adjustment of Epclusa is required for patients with Child-Pugh Class C hepatic impairment. Monitoring of liver function including direct bilirubin is recommended in patients with decompensated cirrhosis.

The safety and efficacy of Epclusa have not been established in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m²) or end stage renal disease (ESRD) requiring hemodialysis.

A thorough QT study did not demonstrate QTc prolongation in healthy subjects receiving therapeutic or supratherapeutic doses of sofosbuvir or velpatasvir. No QT prolongation studies for Epclusa are required at this time.

The Phase II non-pivotal studies established that the optimal sofosbuvir/velpatasvir regimen for the treatment of subjects with genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis was sofosbuvir 400 mg with velpatasvir 100 mg for 12 weeks.

Overall, the data from the submitted clinical pharmacology studies are considered sufficient.

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

Clinical Efficacy

Combination Therapy

All Phase III studies were conducted with the fixed dose combination, sofosbuvir 400 mg plus velpatasvir 100 mg. In the Phase III studies Epclusa was taken without regard to food intake.

The efficacy of Epclusa was evaluated in three Phase III studies (ASTRAL-1, ASTRAL-2, ASTRAL-3) with data available from a total of 1,035 patients with genotype 1 to 6 chronic HCV infection without cirrhosis or with compensated cirrhosis. The efficacy of Epclusa was also evaluated in one Phase III study (ASTRAL-4) in 267 patients with HCV infection with decompensated cirrhosis.

Sustained virologic response (SVR), defined as HCV ribonucleic acid (RNA) less than the lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12), was the primary endpoint to determine the HCV cure rate.

The demographics and baseline characteristics for the patients in studies ASTRAL-1, ASTRAL-2, ASTRAL-3, and ASTRAL-4 were balanced across the treatment groups for each study.

In the ASTRAL-1 study, a total of 624 patients with genotype 1, 2, 4, or 6 HCV were randomized in a 5:1 ratio to treatment with Epclusa for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV were enrolled to the Epclusa group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis.

In the ASTRAL-2 study, patients with chronic genotype 2 HCV infection were randomized in a 1:1 ratio to treatment with Epclusa for 12 weeks (number of patients [n] = 134) or sofosbuvir with ribavirin (SOF + RBV) for 12 weeks (n = 132). Randomization was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus [vs.] treatment-experienced).

In the ASTRAL-3 study, patients with chronic genotype 3 HCV infection were randomized in a 1:1 ratio to treatment with Epclusa for 12 weeks (n = 277) or SOF + RBV for 24 weeks (n = 275). Randomization was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve vs. treatment-experienced).

In the ASTRAL-4 study, patients with Child-Pugh Class B cirrhosis were randomized in a 1:1:1 ratio to treatment with Epclusa for 12 weeks (n = 90), Epclusa + RBV for 12 weeks (n = 87), or Epclusa for 24 weeks (n = 90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate). No patients with genotype 5 HCV infection were enrolled.

The ribavirin dose was weight-based (1,000 mg daily administered in two divided doses for patients <75 kg and 1,200 mg for those =75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 studies or in combination with Epclusa in the ASTRAL-4 study. The RBV dose adjustments were performed according to the Product Monograph for RBV.

Serum HCV RNA values were measured during the clinical studies using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a LLOQ of 15 IU/mL.

Efficacy Results for HCV Patients without Cirrhosis or with Compensated Cirrhosis

The ASTRAL-1 study adequately supports the use of Epclusa, one tablet daily for 12 weeks, in the treatment of genotype 1, 2, 4, 5 and 6 HCV‑infected patients without or with compensated cirrhosis. The study met its primary efficacy endpoint demonstrating that the SVR12 rate of 99.0% (95% confidence interval [CI]: 97.9% to 99.6%) in genotype 1, 2, 4, 5, and 6 HCV-infected patients treated for 12 weeks with Epclusa was statistically superior to the pre-specified SVR12 performance goal of 85% (p<0.001).

High SVR12 rates were achieved across all HCV genotypes and subgroups:

• Among patients with cirrhosis, the SVR12 rate was 99.2%.
• Among patients with prior treatment failure, the SVR12 rate was 99.5%.
• Among patients with baseline NS5A resistance-associated variants (RAVs), the SVR12 rate was 99.2%.

In the ASTRAL-2 study, the SVR12 rate for the Epclusa 12 Week group (99.3%, 133/134; 95% CI: 95.9% to 100%) was shown to be non-inferior to the SVR12 rate in the SOF + RBV 12 Week group (93.9%, 124/132; 95% CI: 88.4% to 97.3%). In fact, there was also sufficient evidence to demonstrate the statistical superiority of treatment with Epclusa for 12 weeks over SOF + RBV for 12 weeks for SVR12 (p = 0.018). In both treatment groups, HCV RNA levels declined rapidly with similar decreases in HCV RNA. Genotype 2a and 2b were the predominant HCV subtypes in patients who were randomized and treated in ASTRAL-2. Approximately 60% and 10% of patients in the Epclusa 12 Week group had pretreatment NS5A and non-structural protein 5B (NS5B) RAVs, respectively. The most prevalent NS5A RAV observed was L31M in 51% of patients. Despite the presence of pre-treatment NS5A and NS5B RAVs, no patients in the Epclusa 12 Week group experienced virologic failure in this study.

In the ASTRAL-3 study, treatment with 12 weeks of Epclusa was compared with 24 weeks of SOF + RBV in patients with chronic genotype 3 HCV infection. The SVR12 rate for the Epclusa 12 Week group (95.3%) was statistically non‑inferior to the SVR12 rate for the SOF + RBV 24 Week group (80.4%). The strata-adjusted difference (95% CI) in the proportions was 14.8% (9.6% to 20.0%). The superiority of treatment with Epclusa for 12 weeks over SOF + RBV for 24 weeks for SVR12 was also demonstrated (p<0.001). Across the two treatment groups, the SVR12 rates consistently favoured the Epclusa 12 Week group over the SOF+RBV 24 Week group.

• For patients with cirrhosis, the SVR12 rates for the Epclusa 12 Week group vs. the SOF + RBV 24 Week group were 91.3% and 66.3%, respectively.
• For treatment-experienced patients, the SVR12 rates for the Epclusa 12 Week group vs. the SOF + RBV 24 Week group were 90.1% and 63.4%, respectively.

Among the 16% of Epclusa‑treated patients with baseline NS5A RAVs, the SVR12 rate was numerically lower (88%) compared with patients without baseline NS5A RAVs (SVR12 rate of 97%). All patients with NS5B nucleoside inhibitor (NI) RAVs in the Epclusa 12 Week group achieved SVR12. All 10 Epclusa-treated patients with virologic relapse had the NS5A RAV Y93H detected at relapse time points. No Epclusa-treated patients had NS5B NI RAVs emerge at relapse.

Based on the data provided, the efficacy conclusions for patients without cirrhosis or with compensated cirrhosis are as follows:

• Epclusa for 12 weeks provides high SVR12 rates across all HCV genotypes and in many different HCV subtypes, with a uniform treatment regimen across all HCV genotypes.
• Epclusa for 12 weeks provides high SVR12 rates in subgroups of patients historically associated with poorer response to treatment including those with cirrhosis, prior treatment failure, or pre-treatment NS5A RAVs.
• Consistent with the high overall SVR12 rate, the virologic failure rate was low and due to relapse, which occurred only in subjects with genotype 1 or 3 HCV infection.
• Virologic failure was associated with emergence or persistence of NS5A RAVs (primary Y93H) in all patients. No patient developed S282T mutation in NS5B.
• Patients with creatinine clearance (CLcr) <60 mL/min as calculated by the Cockcroft-Gault equation were excluded from the studies; there was no specific efficacy outcome analysis provided based on mild renal impairment.

Efficacy Results for HCV Patients with Decompensated Cirrhosis

The ASTRAL-4 study evaluated the use of Epclusa in HCV patients with decompensated cirrhosis. All three treatment groups (Epclusa alone for 12 weeks, Epclusa and RBV for 12 weeks, and Epclusa alone for 24 weeks) met their primary efficacy endpoints with SVR12 rates that were statistically superior compared with the assumed spontaneous rate of 1%. The p-value was <0.001 for the comparison of the SVR12 for each Epclusa alone treatment group versus the Epclusa plus ribavirin treatment group.

The SVR12 rates were as follows:

• Epclusa 12 Week group: 83.3% (95% CI: 74.0% to 90.4%) of patients (75 of 90) achieved SVR12.
• Epclusa + RBV 12 Week group: 94.3% (95% CI: 87.1% to 98.1%) of patients (82 of 87) achieved SVR12.
• Epclusa 24 Week group: 85.6% (95% CI: 76.6% to 92.1%) patients (77 of 90) achieved SVR12.

Among patients with genotype 1 HCV infection, the SVR12 rate was higher for those in the Epclusa + RBV 12 Week group (95.6%, 65 of 68) compared with the Epclusa 12 Week group (88.2%, 60 of 68) or the Epclusa 24 Week group (91.5%, 65 of 71). Similarly, among patients with genotype 3 HCV infection, the SVR12 rate was higher for those in the Epclusa + RBV 12 Week group (84.6%, 11 of 13) compared with the Epclusa 12 Week group (50.0%, 7 of 14) or the Epclusa 24 Week group (50.0%, 6 of 12).

All patients with genotype 2, 4, or 6 HCV infection achieved SVR12 across all treatment groups with the exception of 1 patient with genotype 2 HCV infection in the Epclusa 24 Week group who died 39 days after completing 28 days of treatment.

There was 1 patient (1.5%) with genotype 1 HCV infection with virologic failure in the Epclusa + RBV 12 Week group compared with 5 patients (7.4%) in the Epclusa 12 Week group and 3 patients (4.2%) in the Epclusa 24 Week group. Among patients with genotype 3 HCV infection, the lowest rate of virologic failure was observed in the Epclusa + RBV 12 Week group with 2 failures (15.4%) compared with 6 (42.9%) in the Epclusa 12 Week group and 5 (41.7%) in the Epclusa 24 Week group.

There were no virologic failures in patients with genotype 2, 4, or 6 HCV infection in any of the treatment groups.

Treatment with Epclusa + RBV for 12 weeks resulted in high SVR12 rates irrespective of genotype, prior treatment history, baseline HCV RNA, and presence of pre-treatment NS5A or NS5B RAVs. Furthermore, there was no impact of demographic factors such as age, sex, body mass index, or IL28B genotype on treatment outcome in the Epclusa + RBV 12 Week group.

Based on the data provided, the efficacy conclusions for patients with decompensated cirrhosis are as follows:

• Epclusa + RBV for 12 weeks provided a highly effective treatment for HCV genotype 1 and 3 infection with a uniform treatment regimen across these HCV genotypes and patient subgroups.
• Although a limited number of patients with genotypes 2 and 4 infections were studied (n = 14), all patients with genotype 2 and 4 infections achieved SVR12 (12‑week treatment groups; with and without ribavirin)
• No patients with genotype 5 were enrolled, and only one patient with genotype 6 was enrolled but was in the 24‑week treatment group.
• Child-Pugh (CPT) Scores and Model for End-Stage Liver Disease scores showed improvement in many patients who achieved SVR12. Long-term follow‑up will further define the clinical impact of HCV eradication in this patient population.
• CPT class C cirrhosis was not studied in sufficient numbers of patients to reach any conclusion on effect in these patients.
• Patients who have HCV infection post-transplantation were not studied.
• Patients with CLcr <50 mL/min as calculated by the Cockcroft-Gault equation were excluded from the study; there was no specific efficacy outcome analysis provided based on mild/moderate renal impairment.

Overall Analysis of Efficacy

Epclusa alone is highly effective in all patient populations with CHC without cirrhosis or with compensated cirrhosis, and offers the benefit of a simple once-daily, fixed-dose combination drug with a short (12‑week) treatment duration. The efficacy and safety data in patients with CHC and decompensated cirrhosis (Child-Pugh B), genotypes 1 or 3 infection, also indicate good activity of Epclusa + RBV for 12 weeks. The outcomes seen in genotype 1 and 3 patients are expected to be applicable to patients with genotype 2, 4, 5, and 6 infection with decompensated cirrhosis for the following reasons: the in vitro pangenotypic activity of sofosbuvir and velpatasvir; the high SVR12 achieved by subjects with genotype 2, 4, 5, 6 HCV infection without cirrhosis or with compensated cirrhosis in ASTRAL-1 and ASTRAL-2; and the limited clinical data where SVR12 was 100% (14/14) for genotypes 2 and 4 in patients with decompensated cirrhosis treated with Epclusa ± RBV for 12 weeks in ASTRAL-4.

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

Indication

The New Drug Submission for Epclusa was filed with the following indications:

Epclusa (sofosbuvir/velpatasvir) is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Following review of the submission, Health Canada recommended the following indication to clearly indicate that Epclusa alone can be used for patients without cirrhosis or with compensated cirrhosis, but for the population with decompensated cirrhosis Epclusa should be used in combination with ribavirin.

Epclusa (sofosbuvir/velpatasvir) is indicated:

• for the treatment of chronic hepatitis C virus (HCV) infection in adults without cirrhosis or with compensated cirrhosis
• in combination with ribavirin for the treatment of HCV infection in adults with decompensated cirrhosis.

Clinical Safety

The clinical safety evaluation of Epclusa was based on pooled data from three randomized, controlled, Phase III studies (ASTRAL-1, ASTRAL-2, and ASTRAL‑3) in patients with HCV infection with compensated liver disease, as well as data from ASTRAL-4, a Phase III study in patients with HCV infection with decompensated liver disease. Safety data from three Phase II studies and five completed Phase I clinical pharmacology studies were also assessed.

A total of 1,035 patients with HCV infection with compensated liver disease who received Epclusa for 12 weeks were included in the Integrated Phase III Safety Population. Relevant baseline and demographic factors were consistent with the broader population of patients with HCV infection.

Patients with decompensated cirrhosis were studied separately in study ASTRAL‑4. Overall, 267 subjects were treated with Epclusa for at least 12 weeks in 3 treatment groups: 90 patients (33.7%) received Epclusa for 24 weeks, 90 patients (33.7%) received Epclusa for 12 weeks, and 87 patients (32.6%) received Epclusa + RBV for 12 weeks. Given the underlying severity of liver disease in these patients, there were higher percentages of patients experiencing Grade 3 or 4 adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation of study drug than observed in studies of Epclusa in patients with compensated liver disease in the Integrated Phase III Safety Population and the Phase II Safety Population. Nevertheless, these events were consistent with expected clinical sequelae of decompensated cirrhosis such as hepatic encephalopathy, gastrointestinal bleeding, and infections.

Treatment with Epclusa alone for 12 weeks in the Integrated Phase III Safety Population was generally well‑tolerated irrespective of age, sex, race, or cirrhosis status, with no drug‑related SAEs and very few discontinuations of Epclusa due to AEs (0.2%). No deaths were considered related to treatment with Epclusa. No adverse drug reactions specific to Epclusa have been identified. In patients who received Epclusa alone, headache (21.1%) and fatigue (15.7%) were the most common (incidence ≥10%) AEs reported. As compared with SOF + RBV for 12 or 24 weeks, Epclusa had lower rates of AEs typical of ribavirin‑containing therapy such as anemia, insomnia, irritability, anxiety, and exertional dyspnea.

As compared with patients who received placebo, patients who received Epclusa had higher rates of asymptomatic elevations in creatine kinase (CK) and lipase. Of the 0.8% of patients who received Epclusa and had increased levels of Grade 3 or 4 CK, all of the CK elevations were transient and related to exercise or physical exertion with no cases of rhabdomyolysis. Of the 3.2% of patients who experienced Epclusa Grade 3 or 4 lipase elevations, all were asymptomatic and transient with no clinical cases of pancreatitis. The transient nature of these findings, their resolution with continued dosing, and the lack of concomitant symptomatology suggest that they are not clinically relevant.

Adverse events of interest across a broad range of organ systems (cardiac, dermatologic, hepatic, muscular, pancreatic, psychiatric, and renal) were assessed in the Phase II and Phase III studies. Events were rare, and none were assessed as related to Epclusa. There was no evidence for an association of Epclusa with AEs in any of these categories.

Post-marketing cases of symptomatic bradycardia, and cases requiring pacemaker intervention, have been reported when amiodarone was coadministered with sofosbuvir in combination with another direct acting antiviral drug. The events have generally occurred within hours to days, but cases were observed up to 2 weeks after initiating HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with Epclusa is not recommended. No subjects in the Epclusa clinical development program received amiodarone, and none were reported to have experienced symptomatic bradycardia, cardiac arrest, or pacemaker intervention during treatment with Epclusa. The effect of Epclusa on heart rate among subjects receiving stable beta blocker therapy, calcium channel blockers, or neither was assessed, and no clinically relevant changes or trends were observed in any of the groups. Given the lack of data on amiodarone and Epclusa coadministration, a warning against coadministration of these agents has been included in the Epclusa Product Monograph. This is consistent with guidance provided in the approved Sovaldi and Harvoni Product Monographs.

The efficacy and safety of Epclusa have not been assessed in patients with severe renal impairment (eGFR <30 mL/min) or end-stage renal disease requiring dialysis. The safety of Epclusa in patients enrolled in the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies with mild renal impairment (eGFR <90 mL/min) did not differ from those with normal renal function.

Patients with decompensated liver disease, Child-Pugh Class B, were studied in the Phase III ASTRAL‑4 study where patients were randomized to receive Epclusa for 12 weeks, Epclusa + RBV for 12 weeks, or Epclusa for 24 weeks. Overall, the efficacy data demonstrated the lowest rates of virologic failure in the Epclusa + RBV treatment group. The addition of RBV to Epclusa increased the number of AEs experienced by the patients, largely due to hematologic and psychiatric AEs. Dose modification or treatment interruption of RBV occurred in 36.8% of patients. However, discontinuation of all study drugs due to AEs was still uncommon, occurring in only 4.6% of patients who received Epclusa + RBV. Across all treatment groups, when compared with the safety data from the Integrated Phase III Safety Population, AEs were more common and higher rates of Grade 3 or 4 AEs, SAEs, deaths, and laboratory abnormalities were observed. These events were consistent with the expected clinical sequelae of advanced liver disease such as hepatic encephalopathy, gastrointestinal bleeding, and infections. No safety issues specific to Epclusa were identified in this clinical study of 267 patients with decompensated liver disease.

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