Summary Basis of Decision for Sunvepra

Clinical Pharmacology

Asunaprevir, the active ingredient in Sunvepra, is an inhibitor of the hepatitis C virus (HCV) non structural protein 3/4A (NS3/4A) serine protease complex. This NS3/4A enzyme complex is responsible for processing the HCV polyprotein to yield mature viral proteins required for viral replication. Asunaprevir is most active against NS3/4A protease complexes representing the HCV genotype 1 (GT-1).

Various formulations were used in the Phase I and II studies. A hard gel capsule was used in the early Phase I clinical pharmacology studies and a film coated tablet in the later Phase I and Phase II clinical pharmacology studies. Both had low bioavailability and the pharmacokinetics were strongly influenced by food. To improve oral bioavailability and alleviate the food effect, a soft gel capsule was developed for the Phase III studies. Clinical biopharmaceutical studies were submitted and successfully bridged the various formulations from Phase I/II to the Phase III soft gel capsule (and final market formulation).

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the Phase II and III clinical studies of Sunvepra-containing regimens. Frequencies of ALT/AST elevations were also higher in studies of Sunvepra in combination with Daklinza conducted in Japan than in global studies of this regimen. In a supporting study (HALLMARK NIPPON) conducted in Japan, 7% of patients had ALT >5 times the upper limit of normal (ULN) while 2% of patients in the global study HALLMARK DUAL had ALT >5 times ULN. The potential for hepatotoxicity is stated in a Serious Warnings and Precautions box in the Sunvepra Product Monograph.

In a dedicated hepatic impairment study, patients with moderate and severe hepatic impairment had considerably increased systemic exposure to asunaprevir, the medicinal ingredient of Sunvepra. Sunvepra is contraindicated for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score =7) and patients with decompensated liver disease. Mild hepatic impairment had no apparent effect on exposure.

Sunvepra was associated with several drug-drug interactions some of which have led to contraindications; specifically drugs dependent on cytochrome P450 (CYP) enzyme CYP2D6 for clearance, moderate or strong inducers and inhibitors of CYP3A, and strong inhibitors of organic anion transporting polypeptide (OATP) 1B1 or 2B1. Possible drug drug interactions are discussed in the Sunvepra Product Monograph.

Overall, the clinical pharmacological data support the use of Sunvepra for the specified indication.

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

Clinical Efficacy

The efficacy and safety of Sunvepra in combination with Daklinza as an all-oral regimen were evaluated in two Phase III studies with genotype 1b (GT-1b) patients only; the pivotal study HALLMARK DUAL (number of patients [n] = 747) and a supporting study HALLMARK NIPPON (n = 222). The efficacy and safety of Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin were evaluated in the Phase III HALLMARK QUAD study (n = 398) in genotype 1(GT-1) and genotype 4 (GT-4) patients. In all studies, the primary endpoint was the sustained virologic response (SVR) defined as hepatitis C virus ribonucleic acid (HCV RNA) levels below the lower limit of quantification (LLOQ) at post-treatment Week 12 (SVR12).

Sunvepra in Combination with Daklinza for the Treatment of Patients with Hepatitis C Virus Genotype 1b

HALLMARK DUAL (Study AI447028) was a pivotal, global, open-label study that included patients with chronic HCV GT-1b infection and compensated liver disease who were treatment naïve, null or partial responders to peginterferon alfa and ribavirin, or who were intolerant of or ineligible to receive interferon-based therapy. The study design also included a deferred treatment design for patients in the treatment-naïve cohort. That is, patients in the treatment- naïve cohort were randomized 2:1 to receive Sunvepra 100 mg twice daily (bid) plus Daklinza 60 mg once daily (qd) for 24 weeks or placebo for 12 weeks (the placebo group were rolled over into another study and offered treatment with Sunvepra plus Daklinza for 24 weeks). The purpose of the deferred treatment design was to collect comparative safety data rather than to compare virologic response between study groups; as it was expected that no patients will respond virologically while receiving placebo.

HALLMARK NIPPON (Study AI447026) was a supportive open-label study that included Japanese patients with chronic HCV GT-1b infection and compensated liver disease who were non-responders (null or partial responders) to interferon alfa or beta and ribavirin, or who were intolerant of or ineligible to receive interferon-based therapy.

In the HALLMARK DUAL study, a high proportion of patients infected with GT-1b responded to the Sunvepra in combination with Daklinza therapy. With respect to the primary endpoint, the SVR12 rates were as follows: 90.6% SVR12 in treatment-naïve patients, 82.4 % SVR12 in prior non-responders (partial or null responders), and 82.6% SVR12 in interferon intolerant/ineligible patients. Similar high SVR12 rates were also reported for the supporting NIPPON study. Overall, these results indicated that the dual therapy (Sunvepra in combination with Daklinza) was an effective, oral, peginterferon alfa- and ribavirin-free treatment regimen for the indicated populations of treatment-naïve, prior non-responders, and interferon intolerant/ineligible patients. Overall, the Sunvepra in combination with Daklinza therapy demonstrated high and comparable SVR12 rates across all subgroups of baseline host factors including age (<65 and ≥65 years), gender, cirrhosis status, interleukin (IL)-28B polymorphism, prior treatment history (prior null or partial responders to HCV therapy, or interferon/ribavirin-based therapy intolerant/ineligible) and patients with varying degree of viral load, for example (e.g.) a viral load of <800,000 IU/mLor >800,000 IU/mL. Based on available long-term follow-up data, patients who achieved SVR12 following treatment with Sunvepra in combination with Daklinza continued to achieve long-term efficacy. The dual therapy provides another treatment option for certain patient populations.

Sunvepra in Combination with Daklinza, Peginterferon Alfa, and Ribavirin for the Treatment of Patients with Hepatitis C Virus Genotype 1 or 4

HALLMARK QUAD (Study AI447029) was a pivotal, global, single-arm, open-label study that included adults with compensated liver disease who were partial or null responders to therapy with peginterferon alfa 2a or 2b and ribavirin.

In the HALLMARK QUAD study, Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin was shown to be an effective treatment regimen with demonstrated high SVR12 rates of 93%-100% in difficult to treat GT-1 and GT-4 interferon-tolerant patients who were prior-non-responders (null or partial responders) to prior peginterferon alfa and ribavirin treatment. The SVR12 rates were consistently high across all subgroups of host factors (including age, gender, cirrhosis status, IL-28B polymorphism, prior null or partial response to HCV therapy) and viral factors (such as viral load). The SVR12 rates achieved with Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin therapy in GT-1 prior partial responders and prior null responders was 93-94%.

Indication

The proposed indication for Sunvepra at the time of filing was as follows:

“Sunvepra (asunaprevir) is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic HCV infection in adults with compensated liver disease (including cirrhosis) in combination with:

• Daklinza (daclatasvir), an NS5A replication complex inhibitor, for patients with HCV genotype 1b infection;
• Daklinza, peginterferon alfa, and ribavirin for patients with HCV genotype 1 or 4 infection.

The following points should be considered when initiating treatment with Sunvepra:

• Sunvepra must not be administered as monotherapy.
• Treatment regimen is dependent on viral genotype.
• Sunvepra has not been studied in patients who have previously failed therapy with a treatment regimen that includes Sunvepra or other HCV protease inhibitors.”

Minor revisions were made to the original proposed indication to simplify the wording and specify the genotypes that Sunvepra is indicated for. The revised recommended indication is as follows:

“Sunvepra (asunaprevir) is indicated in combination with other agents for the treatment of chronic hepatitis C (CHC) in adult patients with hepatitis C virus (HCV) genotypes 1 or 4 and compensated liver disease, including cirrhosis.

The following points should be considered when initiating treatment with Sunvepra:

• Treatment with Sunvepra should be initiated and monitored by a physician experienced in the treatment of CHC.
• Sunvepra must not be administered as monotherapy.
• Treatment regimen is dependent on viral genotype and subtype.
• Sunvepra has not been studied in patients who have previously failed therapy with a treatment regimen that includes asunaprevir or other HCV protease inhibitors.”

Clinical Safety

More than 3,000 patients have been exposed to Sunvepra (asunaprvir) in Phase I, Phase II, and Phase III studies, including 2,912 patients with HCV. In nine completed and ongoing Phase II and Phase III studies, a total of 2,159 patients with HCV have been exposed to the recommended dose of Sunvepra at 100 mg bid softgel capsule or the equivalent 200 mg bid tablet form.

The all-oral therapy of Sunvepra (100 mg bid) in combination with Daklinza (60 mg qd) had a favourable safety and tolerability profile compared to interferon/ribavirin-based therapy regimens in HCV GT-1b patients who are treatment naïve, treatment-experienced, or ineligible/intolerant to interferon/ribavirin based therapy, including patients with compensated cirrhosis and the elderly. Unlike interferon/ribavirin based regimens, clinically important adverse events (AEs) of myelosuppression (anemia, neutropenia), thrombocytopenia, depression, or influenza-like symptoms were not observed with the Sunvepra in combination with Daklinza (interferon/ribavirin free) regimen.

High rates of treatment adherence relative to peginterferon alfa and ribavirin-containing therapies and low rates of premature discontinuations due to AEs were indicative of a favourable tolerability profile of the all-oral Sunvepra in combination with Daklinza therapy. Most on treatment AEs were mild to moderate in intensity, and the rate of AEs leading to discontinuation of study therapy was low at 3.1%, with the most frequent reason being increases in hepatic transaminases. These early discontinuations were not associated with evidence of ongoing hepatic decompensation, and moreover, 16 of 19 patients who discontinued study therapy due to increased transaminases, achieved an SVR. Elevations in ALT or AST levels were previously identified as a potential safety concern from non-clinical studies and clinical data from studies with asunaprevir. The dose in the Sunvepra program was previously reduced from 600 mg bid to 200 mg bid based upon increases of ALT/AST observed at the 600 mg dose.

In the HALLMARK DUAL study (described in the Clinical Efficacy section), no clinically relevant differences were observed in the safety profile of Sunvepra in combination with Daklinza versus placebo during the first 12 weeks of treatment in treatment-naïve patients. Overall, the safety profile of the Sunvepra in combination with Daklinza regimen among cirrhotics was also observed in this data set and showed no differences from non cirrhotics.

The safety profile of Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin for the treatment of HCV infections caused by GT-1 or GT-4 in patients who failed previous interferon/ribavirin based therapy was assessed in the HALLMARK QUAD study (described in the Clinical Efficacy section). The safety profile of Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin was found to be consistent with the historical safety profile of peginterferon alfa and ribavirin alone which includes Grade 3/4 hematologic abnormalities and other AEs characteristic of peginterferon alfa/ribavirin therapy, with the exception of elevated transaminase levels as observed in other Sunvepra studies. There was no clinically meaningful difference in patients with or without cirrhosis, among patients exposed to the Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin regimen.

Potential for Hepatotoxicity

Elevations in ALT or AST levels were observed in Phase II and Phase III clinical studies of Sunvepra-containing regimens. In analyses evaluating Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin, hepatic safety events (particularly associated with increased ALT/AST levels) were reported at a higher rate as compared to placebo in combination with Daklinza, peginterferon alfa, and ribavirin. In addition, these events were reported more frequently in the Japanese studies compared to studies evaluating non-Japanese patients which included Asian subjects from Taiwan and Korea. This was more notable in the frequency of Grade 3/4 ALT or Grade 3/4 AST elevations reported in Japanese studies as compared to non-Japanese studies. The frequency of reported Grade 3/4 ALT elevations was higher in the Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin regimens, as compared to regimens without Sunvepra (that is, placebo in combination with Daklinza, peginterferon alfa, and ribavirin).

In patients treated with Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin, the earliest onset of Grade 3/4 ALT was within 16 days and the latest was 168 days (end of treatment). In general, the median time to reversal of these ALT abnormalities was <4 weeks.

Across the global and Japanese Phase II/III studies using Sunvepra in combination with Daklinza and studies using Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin, there were 4 cases of potential drug-induced liver injuries identified, including 3 patients treated with Sunvepra in combination with Daklinza in Phase III studies, and 1 patient treated with Sunvepra in combination with Daklinza, peginterferon alfa, and ribavirin. There were also 2 cases of potential drug-induced liver injuries among patients treated with higher doses of Sunvepra 600 mg qd in combination with peginterferon alfa and ribavirin. There was no evidence of clinical liver decompensation in any of the identified potential drug-induced liver injury cases, and laboratory abnormalities were reversible after Sunvepra was discontinued.

The Sunvepra Product Monograph was revised to include statements on monitoring of ALT and AST levels once every 2 weeks for the initial 12 weeks of treatment and every 4 weeks thereafter until completion of therapy. Any upward trend in ALT or AST levels warrants more frequent monitoring and if on-treatment elevations in ALT levels 10 times the ULN or greater occur, treatment should be discontinued immediately and not be resumed.

In addition, wording has been added to highlight that cases of potential drug-induced liver injuries have been reported and that AST/ALT elevations were more frequently reported in studies of Sunvepra in combination with Daklinza conducted in Japan than in the global study with this regimen.

Considering the reversibility of the transaminase elevations, the ability to clinically monitor for any increases, and that the physicians administering Sunvepra treatment are experienced in treating HCV patients and are able to manage and understand these ALT/AST elevations, these treatment-emergent elevations can be safely managed in the patient population. The Sunvepra Product Monograph has been adequately revised to address this potential safety issue. The potential of hepatoxicity has been included in a Serious Warnings and Precautions box in the Sunvepra Product Monograph.

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