Regulatory Decision Summary for Hepcludex

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Hepcludex (bulevirtide), filed by Gilead Sciences Canada, Inc.

This submission was filed for Hepcludex (bulevirtide) 2 mg powder for solution for subcutaneous injection for the treatment of chronic hepatitis delta virus (HDV) infection in adults with compensated liver disease. Upon review of the submitted data package, Health Canada authorized Hepcludex (bulevirtide) 2 mg powder for solution for subcutaneous injection for the treatment of chronic hepatitis delta virus (HDV) infection in adults with compensated liver disease.

This submission was filed and reviewed under the Priority Review Policy.

Chronic hepatitis delta (CHD) is caused by a defective ribonucleic acid (RNA) virus that requires the presence of the hepatitis B virus (HBV) surface antigen (HBsAg) for its complete replication and transmission, and, as such, this form of hepatitis only occurs in individuals also living with HBV. Chronic HBV and HDV coinfection is known to be the most severe form of viral hepatitis and is associated with rapid progression to cirrhosis and liver failure and a significantly increased risk of hepatocellular carcinoma compared with HBV infection alone. Currently, there are no approved therapies for people living with CHD in Canada. Historically, pegylated interferon (PEG-IFN) has been used off-label in HDV RNA positive patients. However, its use has been limited due to toxicity and poor tolerability.

Hepcludex (bulevirtide) is a 47- amino acid, N-terminally myristoylated, HBV large envelope protein-derived lipopeptide that binds specifically to the sodium taurocholate cotransporting polypeptide (NTCP) and acts as a potent, selective entry inhibitor of HDV into hepatocytes. In this way, de novo infection of hepatocytes is prevented via entry inhibition. It is administered subcutaneously (SC) once daily (OD).

The efficacy of Hepcludex was primarily evaluated in the pivotal phase III trial MYR301, a randomized, open-label, multicenter, parallel-group study evaluating the efficacy and safety of Hepcludex in adult patients, aged 18 to 65 years, with CHD and compensated liver disease. A total of 150 patients were randomized in a 1:1:1 ratio to a delayed treatment (DT) group (observation period of 48 weeks followed by Hepcludex 10 mg SC OD for 96 weeks) (N = 51) or to receive immediate treatment with Hepcludex 2 mg SC OD for 144 weeks (N = 49) or Hepcludex 10 mg SC OD (N = 50) for 144 weeks. The mean (standard deviation [SD]) age of enrolled patients was 42 (8.4) years and most patients were male (57.3%). The majority of patients were white (82.7%). Mean (SD) HDV RNA levels were 5.04 (1.336) log₁₀ IU/mL and mean alanine transaminase (ALT) levels were 111 (69) units/Liter (U/L). The majority of patients were receiving concomitant oral anti-HBV medication (60.7%), and most patients had a history of previous IFN therapy (56.0%). Approximately half of the patients (47.3%) had cirrhosis present at the time of randomization.

After 48 weeks, Hepcludex 2 mg demonstrated statistically significant superiority when compared to DT in achieving a combined virologic (undetectable HDV RNA or HDV RNA decreased ≥2 log₁₀ IU/mL from baseline) and biochemical (ALT normalization) response. The proportion of patients (95% confidence interval [CI]) who achieved the combined response at Week 48 for the Hepcludex 2 mg group was 44.9% (30.7%-59.8%) compared to 2.0% (0.0%-10.4%) in the DT group (P < 0.0001). Prespecified statistical analysis compared the proportion of patients achieving undetectable HDV RNA at Week 48 in the Hepcludex 2 mg treatment arm versus the Hepcludex 10 mg treatment arm as the key secondary efficacy endpoint. The difference in proportions of responders at Week 48 with undetectable HDV RNA between the Hepcludex 10 mg vs Hepcludex 2 mg was 7.8% (96% CI: -8.5% to 24.3%) which was not statistically significant (P = 0.4139). However, 12.2% (95% CI: 4.6%-24.8%) of patients in the Hepcludex 2 mg arm achieved undetectable HDV RNA compared to no patients in the DT group. Ongoing benefit of Hepcludex 2 mg was observed through the 144-week treatment period of the pivotal trial, and results from a phase II supportive trial (MYR203) were generally consistent with those from the pivotal trial in demonstrating benefit of Hepcludex 2 mg in patients with CHD and compensated liver disease.

The safety of Hepcludex 2 mg for the treatment of adult patients with CHD and compensated liver disease was primarily evaluated with the pivotal Phase III trial MYR301 (N = 49). Additional safety data were obtained from an Integrated Summary of Safety which included pooled data from the pivotal trial and supportive studies including two phase II studies (MYR203 and MYR204). A total of 64 patients received Hepcludex 2 mg monotherapy for a minimum of 48 weeks in the pooled data.

For MYR301, the most common treatment-related adverse events (AEs) during the first 48 weeks of the study in the Hepcludex 2 mg group were: headache (9/49, 18.4%), injection site reactions (9/49, 18.4%), pruritus (6/49, 12.2%), fatigue (5/49, 10.2%), nausea (3/49, 6.1%), and dizziness (2/49, 4.1%). The majority of the AEs were Grade 1 or 2 in severity. The serious AEs experienced in each treatment group by week 48 were (DT group: 1/51 [2.0%]; Hepcludex 2 mg group: 2/49 [4.1%]; Hepcludex 10 mg group: 1/50 [2.0%]). None of the serious adverse events (SAEs) experienced by patients receiving Hepcludex 2 mg were considered related to Hepcludex.

Up to the data cutoff date for the integrated Week 48 safety analysis, no deaths occurred in the Hepcludex development program while on study. One death occurred in the pivotal study through Week 144 and was a patient who died due to plasma cell myeloma, and this was not considered related to Hepcludex. The safety results from the 48-week controlled treatment period of the pivotal study MYR301 were consistent with the safety profile through to Week 144 and with the data presented in the Integrated Summary of Safety. Additionally, the safety profile of Hepcludex 2 mg is generally considered comparable in patients with and without cirrhosis.

Key safety considerations for Hepcludex based on its mechanism of action and class effect included bile salt elevations and risk of exacerbation of hepatitis after treatment discontinuation. Dose-dependent bile salt elevations were observed in all Hepcludex containing treatment arms. Little to no accumulation was seen over the 144-week treatment period, with increases plateauing after Week 4. Bile salt elevations were generally asymptomatic, not associated with clinical sequelae, and were reversible upon completion of Hepcludex treatment. Although the pivotal trial data available at the time of submission included only on-treatment periods, several posttreatment hepatic adverse events were observed throughout the earlier clinical development program. The majority of these AEs were ALT increases, aspartate aminotransferase (AST) increases, and gamma-glutamyl transferase (GGT) increases. Often, they were associated with HDV RNA rebound. Most were Grade 1 or 2 in severity, asymptomatic, and resolved.

Clinical studies excluded patients over the age of 65 years, patients with moderate-severe renal impairment, decompensated liver disease/moderate-severe hepatic insufficiency (Child Pugh B or C), HCV/human immunodeficiency viruses (HIV)-co-infection, or patients who were pregnant. Therefore, the pharmacokinetics (PK) of bulevirtide in these populations is unknown. Dedicated studies in patients with renal impairment and hepatic impairment are ongoing but not available at the time of submission; thus, labelling was updated to convey this information. Clinical studies included 60 patients with mild renal impairment, and population PK analysis was used to indicate no clinically significant change in exposure was observed in these patients. In addition, 205 patients had compensated cirrhosis (Child Pugh A; mild hepatic impairment) and no effect on bulevirtide PK was observed in these patients. The majority of patients were white (> 80%), and thus the PK data for non-white patients is limited. Population PK analysis did not identify race as a covariate that significantly altered bulevirtide PK.

At the proposed clinical dose of 2 mg/day, bulevirtide achieves clinically relevant plasma concentrations in patients with CHD that exceed concentrations shown to block HDV infection of human hepatocytes in vitro. In Phase 2 clinical studies, bulevirtide was safe and well-tolerated.

In a clinical drug interaction study, levels of NTCP substrates (total bile acids and taurocholic acid) increased by 19.2-fold and 125-fold respectively following bulevirtide administration, consistent with the mechanism of action of bulevirtide. Additionally, co-administration of bulevirtide and tenofovir increased the exposure of the CYP3A4 substrate midazolam by approximately 40%. No safety concerns were noted and information for these potential drug-drug interactions is provided in the Hepcludex Product Monograph.

Overall, the review of clinical pharmacology studies did not identify issues that would preclude the approval of Hepcludex in the intended patient population. Similarly, overall, the non-clinical program was considered adequate to support the approval of bulevirtide for the proposed indication.

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