Summary Basis of Decision for Hepcludex

Clinical Pharmacology

Bulevirtide is a 47-amino acid, N-terminally myristoylated, hepatitis B virus (HBV) large envelope protein-derived lipopeptide that acts as a potent, selective entry inhibitor of hepatitis delta virus (HDV) into hepatocytes. Bulevirtide blocks the entry of HBV and HDV into hepatocytes by binding to and inactivating the essential HBV and HDV entry receptor sodium taurocholate cotransporting polypeptide (NTCP).

The clinical pharmacology data for bulevirtide were provided from two Phase I studies (MYR101 and MYR102), four Phase II studies (MYR201, MYR202, MYR203, and MYR204), and one Phase III study (MYR301).

Across MYR201, MYR202, MYR203, MYR204, and MYR301, 479 patients who received at least 1 dose of bulevirtide provided at least 1 blood sample for the quantification of bulevirtide plasma concentration. Of the 479 patients, 160 patients were administered the proposed 2 mg/day dosing regimen for 12 to 144 weeks. This sample represented the intended patient population (i.e., patients with chronic hepatitis delta [CHD]), except for 15 patients in MYR201 (Part 1) who had chronic hepatitis B but not CHD. At the proposed 2 mg dose, mean steady-state bulevirtide plasma concentrations measured approximately 1 hour post administration ranged from 10.9 ng/mL to 36.4 ng/mL. Non-clinical in vitro studies demonstrated that bulevirtide inhibited the infection of human hepatocytes by laboratory HDV strains with half-maximal inhibitory concentration (IC₅₀) values ranging from 0.023 nM to 0.75 nM, and inhibited the infection of human hepatocytes by clinical isolates from HDV-infected patients with IC₅₀ values ranging from 0.046 nM to 0.332 nM. Therefore, at the proposed clinical dose, bulevirtide plasma concentrations at steady state are 2.7- to 291-fold higher than the IC₅₀ values measured for laboratory HDV strains, and 6.0- to 163-fold higher than the IC₅₀ values measured for clinical isolates from HDV-infected patients. Furthermore, bulevirtide plasma concentrations at steady state are 13.6- to 45.5-fold higher than concentrations shown to induce 50% NTCP receptor occupancy in chimpanzees. Together, these data indicate that bulevirtide plasma concentrations achieved at the proposed dose are clinically relevant and expected to induce antiviral effects in vivo.

Across all studies, bulevirtide exposure was higher than dose proportional. Mean steady-state plasma concentrations measured 1 hour post dose and Day 14 maximum concentrations (C_max) were 8- to 15-fold higher, respectively, in patients administered 10 mg bulevirtide compared to patients administered 2 mg bulevirtide. At the proposed clinical dose, repeat dosing resulted in approximately 2-fold higher plasma concentrations compared to single dosing. This was accompanied by an approximately 40% decrease in clearance upon repeat dosing, consistent with bulevirtide accumulation in the plasma following repeat dosing. The higher than dose-proportional increases in exposures and plasma drug accumulation are expected to be partly a result of saturation of the NTCP, competition with bile acids for NTCP binding (levels of which are increased following repeat dosing and at higher bulevirtide doses), and bile acid-induced surface NTCP downregulation. Together, this causes a reduced number of vacant NTCP receptors to which bulevirtide can bind, resulting in elevated amounts of bulevirtide in extrahepatic compartments, including plasma.

In the Phase II/III clinical studies, 24.6% of patients developed anti-drug antibodies (ADAs) while receiving the 2 mg/day dose of bulevirtide. A subgroup analysis of these patients showed no clinically significant effect of ADAs on the plasma concentrations of bulevirtide. This was also supported by population pharmacokinetic analysis that showed 22% higher bulevirtide exposure in patients who were ADA positive versus those who were ADA negative, following the administration of 2 mg bulevirtide. Thus, bulevirtide exposures appear comparable between ADA-positive and ADA-negative participants with no trend of lower bulevirtide exposure in ADA-positive participants and the observed difference in exposure is not expected to affect the efficacy and safety of the drug.

Clinical studies excluded geriatric patients (65 years of age and older) and patients with moderate to severe renal impairment, decompensated liver disease/moderate or severe hepatic insufficiency (Child Pugh B or C), hepatitis C virus/human immunodeficiency virus coinfection, or patients who were pregnant. Therefore, the pharmacokinetics of bulevirtide in these populations is unknown. Dedicated studies in patients with renal impairment and hepatic impairment are ongoing but were not available at the time of the submission, which is conveyed in the product labelling. Clinical studies included 60 patients with mild renal impairment; population pharmacokinetic analysis indicated no clinically significant change in exposure in these patients. In addition, 205 patients had compensated cirrhosis (Child Pugh A; mild hepatic impairment); no effect on the pharmacokinetics of bulevirtide was observed in these patients. As the majority of patients were White (more than 80%), the pharmacokinetic data for non-White patients are limited, population pharmacokinetic analysis did not identify race as a covariate that significantly altered the pharmacokinetics of bulevirtide.

In a clinical drug-drug interaction study, levels of NTCP substrates (total bile acids and taurocholic acid) increased by 19.2- and 125-fold, respectively, following bulevirtide administration, which is consistent with the mechanism of action of bulevirtide. Additionally, coadministration of bulevirtide and tenofovir increased the exposure of the cytochrome P450 (CYP) 3A4 substrate midazolam by approximately 40%. No safety concerns were noted. Information related to these potential drug-drug interactions is provided in the Product Monograph for Hepcludex.

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

Clinical Efficacy

The efficacy of Hepcludex 2 mg for the treatment of adult patients with chronic HDV infection with compensated liver disease was evaluated in the pivotal Phase III MYR301 study and the supportive Phase II MYR203 study.

MYR301 was a Phase III, randomized, open-label, multicentre, parallel-group study that evaluated the efficacy and safety of Hepcludex in adult patients aged 18 to 65 years with positive serum anti-HDV antibody results or positive polymerase chain reaction results for serum/plasma HDV ribonucleic acid (RNA) for 6 months or more prior to screening. In total, 150 patients were randomized in a 1:1:1 ratio to receive a delayed treatment (Hepcludex 10 mg subcutaneously once daily for 96 weeks after an observation period of 48 weeks; 51 patients) or to receive an immediate treatment with Hepcludex 2 mg subcutaneously once daily for 144 weeks (49 patients) or Hepcludex 10 mg subcutaneously once daily (50 patients) for 144 weeks. The mean age of enrolled patients was 42 (standard deviation [SD]: 8.4) years and the majority of patients were male (57.3%) and White (82.7%). Mean HDV RNA levels were 5.04 (SD: 1.336) log₁₀ IU/mL and mean alanine aminotransferase (ALT) levels were 111 (SD: 69) U/L. The majority of patients were receiving concomitant oral anti-HBV medication (60.7%), and most patients had a history of previous interferon (IFN) therapy (56.0%). Approximately half of the patients had cirrhosis present at the time of randomization (47.3%).

The primary endpoint of the study was a combined response at Week 48, defined as a virologic response (undetectable HDV RNA or a 2 log₁₀ IU/mL or greater decrease in HDV RNA from baseline) with a biochemical response (ALT normalization). After 48 weeks, Hepcludex 2 mg demonstrated statistically significant superiority in the primary efficacy endpoint when compared to delayed treatment. The proportion of patients who achieved the combined response at Week 48 in the Hepcludex 2 mg group was 44.9% (95% confidence interval [CI]: 30.7% to 59.8%) compared to 2.0% (95% CI: 0.0%, 10.4%) in the delayed treatment group. This yielded a difference in proportions of 42.9% (96% CI: 27.0% to 58.5%; p<0.0001).

The key secondary endpoint was the proportion of patients with undetectable HDV RNA at Week 48. The proportion of patients who achieved undetectable HDV RNA at Week 48 was 20.0% (95% CI: 10.0% to 33.7%) in the Hepcludex 10 mg group compared to 12.2% (95% CI: 4.6% to 24.8%) in the Hepcludex 2 mg group, yielding a difference in proportions of 7.8% (96% CI: -8.5% to 24.3%) which was not statistically significant (p = 0.4139). However, 12.2% (95% CI: 4.6% to 24.8%) of patients in the Hepcludex 2 mg group achieved undetectable HDV RNA compared to no patients in the delayed treatment group.

Other secondary endpoints included the two components of the primary endpoint. The proportion of patients who achieved ALT normalization at Week 48 was 51.0% (95% CI: 36.3% to 65.6%) in the Hepcludex 2 mg group compared to 11.8% (95% CI: 4.4% to 23.9%) in the delayed treatment group, yielding a difference in proportions of 39.3% (95% CI: 20.0% to 55.8%; p<0.0001). The proportion of patients achieving virologic response was 73.5% (95% CI: 58.9% to 85.1%) in the Hepcludex 2 mg group compared to 3.9% (95% CI: 0.5% to 13.5%) in the delayed treatment group, yielding a difference in proportions of 69.5% (95% CI: 54.1% to 81.9%; p<0.0001). Decrease in liver stiffness from baseline was also assessed at yearly intervals as a secondary endpoint. At Week 48, there was a mean decrease in liver stiffness from baseline of -3.06 kPa (95% CI: -4.67 kPa to -1.45 kPa) in the Hepcludex 2 mg group compared to 0.87 kPa (95% CI: -0.79 kPa to 2.53 kPa) in the delayed treatment group (p = 0.0009). Liver stiffness decreased further with ongoing treatment.

MYR203 was a key supportive Phase II multicentre, open-label, randomized, comparative, parallel-arm study in adult patients with CHD. Patients 18 to 65 years of age with positive HDV RNA and ALT greater than or equal to the upper limit of normal (ULN) but less than 10 times the ULN at screening and the presence of hepatitis B surface antigen (HBsAg) and anti-HDV antibodies for at least 6 months prior to screening were eligible for enrollment. Exclusion criteria included a history of, or current, decompensated liver disease and a Child-Pugh score greater than or equal to 6. Ninety patients were enrolled and randomized (15 patients each) to receive one of the following treatments or treatment combinations for a period of 48 weeks: pegylated interferon alfa-2a (PEG-IFNα), Hepcludex 2 mg + PEG-IFNα, Hepcludex 5 mg + PEG-IFNα, Hepcludex 2 mg, Hepcludex 10 mg + PEG-IFNα, or Hepcludex 5 mg twice daily + tenofovir. The mean age of enrolled patients was 36.8 (SD: 7.7) years, and the majority of patients were male (63.3%). In the Hepcludex 2 mg group, the mean baseline ALT level was 108.3 (SD: 67.1) U/L and the mean baseline HDV RNA level was 6.339 (SD: 0.641) log₁₀ IU/mL. The study population closely reflected that of the pivotal study. Although the study objectives were similar to those described in MYR301, post hoc analysis was required in order to compare endpoints between the two studies. Therefore, these results are presented as descriptive only.

Post hoc analysis for the combined response (undetectable HDV RNA or a greater than 2 log₁₀ IU/mL HDV RNA decline with ALT normalization) demonstrated that the highest number of responders was observed in the Hepcludex 2 mg monotherapy group with 8 out of 15 patients (53.3%; 95% CI: 26.6% to 78.7%) achieving a response. In contrast, only 2 out of 15 patients (13.3%; 95% CI: 1.7% to 40.5%) and 4 out of 15 patients (26.7%; 95% CI: 7.8% to 55.1%) achieved a response in the PEG-IFNα group and the Hepcludex 2 mg + PEG-IFNα group, respectively. The HDV RNA response (undetectable HDV RNA) at Week 48 was a secondary endpoint. In the groups receiving PEG-IFNα only or Hepcludex 2 mg only, 2 out of 15 patients (13.3%; 95% CI: 1.7% to 40.5%) were HDV RNA responders at Week 48 in each group. However, the proportion of HDV RNA responders was 12 out of 15 patients (80.0%; 95% CI: 51.9% to 95.7%) in the Hepcludex 2 mg + PEG-IFNα combination group, suggesting a possible synergistic effect with respect to virologic response.

Overall, the efficacy results from the pivotal MYR301 study and the supportive MYR203 study adequately demonstrate the ability of Hepcludex to provide benefit for adult patients with CHD who have compensated liver disease, particularly in the context of no other currently approved therapies for CHD.

Indication

The New Drug Submission for Hepcludex was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Hepcludex (bulevirtide) is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in adults with compensated liver disease.

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

Clinical Safety

The safety of Hepcludex 2 mg for the treatment of adult patients with CHD and compensated liver disease was primarily evaluated in the pivotal Phase III MYR301 study (see Clinical Efficacy section). Additional safety data were obtained from pooled data from the pivotal study and the two supportive studies (MYR203 and MYR204). In these Phase II studies, Hepcludex was administered at doses of 2 mg to 10 mg daily as monotherapy or as a combination treatment with Peg-IFNα for a period of at least 48 weeks. Of note, MYR204 included only a 10 mg monotherapy treatment group. In total, of 64 patients and 115 patients received Hepcludex 2 mg monotherapy and Hepcludex 10 mg monotherapy, respectively.

In the Hepcludex 2 mg group of MYR301, 24 out of 49 patients (49.0%) experienced adverse events by Week 48 that were assessed by the investigator as related to Hepcludex. The incidence of adverse events remained relatively stable through Week 144 (27 out of 49 patients [55.1%]). The most frequently reported treatment-related adverse events during the first 48 weeks in the Hepcludex 2 mg group were pruritus (5 out of 49 patients [10.2%]), eosinophilia (4 out of 49 patients [8.2%]), and nausea and injection site reactions (3 out of 49 patients [6.1%] each). By Week 144, patients in the Hepcludex 2 mg group experienced events of lymphopenia, thrombocytopenia, fatigue, injection site erythema, vitamin D deficiency, and headache (3 out of 49 patients [6.1%] each); neutropenia, polycythemia, leukopenia, injection site hematoma (2 out of 49 patients [4.1%] each); and abdominal pain, increased ALT, and rash (1 out of 49 patients [2.0%] each). The majority of the adverse events were Grade 1 or 2 in severity. Serious adverse events that occurred by Week 48 were reported in 1 out of 51 patients [2.0%] in the delayed treatment group, 2 out of 49 patients [4.1%] in the Hepcludex 2 mg group, and 1 out of 50 patients [2.0%] in the Hepcludex 10 mg group. None of the serious adverse events experienced by patients receiving Hepcludex 2 mg were considered related to Hepcludex.

Ad hoc analysis of the safety data from the pivotal study demonstrates that the presence or absence of cirrhosis did not impact the proportion of patients who experienced adverse events, Grade 3 or higher adverse events, or serious adverse events. However, a higher proportion of patients with cirrhosis experienced adverse events (including Grade 3 or higher adverse events) associated with cytopenia, as is expected in this population.

Across the pooled studies, the most frequent adverse events reported in the Hepcludex 2 mg treatment groups were increased bile acids (13 out of 64 patients [20.3%]), leukopenia (11 out of 64 patients [17.2%]), injection site reactions (11 out of 64 patients [17.2%]), headache (10 out of 64 patients [15.6%]), thrombocytopenia (8 out of 64 patients [12.5%]), vitamin D deficiency (7 out of 64 patients [10.9%]), and pruritus (7 out of 64 patients [10.9%]). The most frequently reported treatment-related adverse events for Hepcludex 2 mg at Week 48 were increased bile acids (13 out of 64 patients [20.3%]); nausea and pruritus (6 out of 64 patients [9.4%] each); and leukopenia and thrombocytopenia (4 out of 64 patients [6.3%] each). Of note, serum bile salt elevations were reported by the investigator as adverse events related to study treatment in MYR203, whereas in MYR301, only bile salt elevations that were symptomatic or judged by the investigator to be clinically significant were required to be reported as adverse events. Bile salt elevations were generally asymptomatic, not associated with clinical sequelae, and were reversible upon completion of treatment with Hepcludex.

Up to the data cut-off date for the integrated Week 48 safety analysis, no deaths occurred in the Hepcludex development program. Through Week 144 of the pivotal study, one death occurred due to multiple myeloma, which was not considered related to Hepcludex.

Adverse events of special interest were identified based on the mechanism of action of bulevirtide, class effects associated with effective antiviral treatment for HBV and HDV, and available non-clinical and clinical data, including post-market pharmacovigilance. A key risk for Hepcludex is a severe acute exacerbation of hepatitis that may occur after discontinuation of treatment. This risk has been addressed in a Serious Warnings and Precautions box in the Product Monograph for Hepcludex.

Post-treatment hepatic adverse events are a known and expected occurrence with antiviral treatment discontinuation. Although the 144-week data provided from the pivotal MYR301 study included only the on-treatment period, periods of follow-up following treatment discontinuation are available from Phase II studies. In the Phase II MYR204 study, the proportion of patients in the Hepcludex 10 mg group experiencing hepatic adverse events in the post-treatment period was 19 out of 50 patients (38.0%). In the Phase II MYR203 study, the proportions of patients with post-treatment hepatic adverse events in the Hepcludex 2 mg and Hepcludex 10 mg groups were 8 out of 14 patients (57.1%) and 3 out of 15 patients (20.0%), respectively. The majority of these adverse events were increases in ALT, aspartate aminotransferase, and gamma-glutamyl transferase. Most were Grade 1 or 2 in severity, asymptomatic, and resolved upon completion of the studies. Often, they were associated with HDV RNA rebound. Serious adverse events after discontinuation were observed in two patients with CHD after 24 weeks of treatment with Hepcludex 5 mg in studies not included in the pooled safety data (MYR201 and MYR202). All events resolved.

Overall, the safety profile of Hepcludex appears to be acceptable for the treatment of adult patients with CHD who have compensated liver disease. The safety profile of Hepcludex is considered comparable in patients with and without cirrhosis. Although the safety data set is relatively small, additional rare safety issues can be managed with ongoing post-market pharmacovigilance. The currently identified safety issues can be managed through risk minimization measures such as labelling and monitoring. Appropriate warnings and precautions are in place in the approved Product Monograph for Hepcludex.

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

Pharmacology

The antiviral activity of bulevirtide was characterized in vitro using primary human hepatocytes. Bulevirtide inhibited infection by hepatitis delta virus (HDV) genotypes 1 to 8 carrying hepatitis B virus (HBV) envelope proteins from genotypes A to H with half maximal effective concentration (EC₅₀) values ranging from 0.21 nM to 0.68 nM. The antiviral activity of bulevirtide was also tested using 137 clinical isolates obtained from the Phase II MYR204 study and the Phase III MYR301 study, both described in the Clinical Basis for Decision section. The mean EC₅₀ values for bulevirtide were 0.40 nM, 0.45 nM, and 0.70 nM against HDV-1 (number of clinical isolates [n] = 131), HDV-5 (n = 5), and HDV-6 (n = 1), respectively, while the mean EC₅₀ values for bulevirtide were 0.58 nM, 0.38 nM, and 0.45 nM against HDV clinical isolates carrying the envelopes from HBV genotype A (n = 10), genotype D (n = 122), and genotype E (n = 5), respectively. Moreover, no significant difference in HDV susceptibility to bulevirtide was observed in vitro for virus carrying envelopes with the most commonly found polymorphisms in the preS1 region of HBV genotypes A to D.

Bulevirtide did not induce cytotoxicity in human hepatocytes, hepatic stellate cells, renal proximal tubule cells, and Chinese hamster ovary K1 cells at concentrations up to 92.6 µM, and did not induce secretion of the tumor necrosis factor alpha and interleukine-6 from freshly isolated peripheral blood mononuclear cells at concentrations up to 50 mcg/mL.

No effect of bulevirtide on pulmonary parameters was observed at a predicted plasma exposure in rats that exceeded the maximal predicted plasma exposure in humans at the proposed therapeutic dose. The evaluation of the effect of bulevirtide on the cardiovascular system and the central nervous system was integrated into the repeat-dose toxicology studies described below, in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Pharmacokinetics

The in vitro plasma protein binding of bulevirtide was analyzed by cross-flow filtration. The estimated bulevirtide-bound fractions were greater than 99.9% for rat, dog, rabbit, and human plasma.

Tissue distribution studies were performed in mice, rats, dogs, cynomolgus monkeys, and chimpanzees using different radiolabeled bulevirtide peptides. In Naval Medical Research Institute mice, radiolabelled bulevirtide accumulates mainly in the liver, with maximum radioactivity detected at 5 to 7 hours post subcutaneous dosing. Radioactivity was still detectable in the liver at 48 hours following subcutaneous dosing. In Wistar Han rats, radiolabelled bulevirtide also accumulated quickly in the liver, and high-performance liquid chromatography performed on liver homogenates confirmed that the full-length bulevirtide was detected in the liver up to 24 hours after subcutaneous administration. The biodistribution of radiolabelled bulevirtide was similar in caesarean-derived rats previously immunized with bulevirtide, suggesting that the presence of antibodies against bulevirtide does not influence its distribution to the liver. Similar bulevirtide distribution and persistence in the liver were observed in Beagle dogs following subcutaneous administration and in chimpanzees following intravenous administration.

Considering that bulevirtide is a linear peptide, no specific metabolic studies were performed, in accordance with ICH guidelines. Bulevirtide is expected to be catabolized by peptidases to amino acids. No active metabolites are expected.

Toxicology

The non-clinical toxicology evaluation of bulevirtide consisted of 1 single-dose acute toxicity study in rats, 5 repeat-dose toxicity studies in rats and dogs, 5 development and reproductive studies in rats and rabbits, and 1 immunotoxicity study in rats. Generally, bulevirtide did not produce any toxic effects in these studies up to 2.5 mg/kg/day, which was the highest dose tested.

The genotoxicity and carcinogenicity studies with bulevirtide were not conducted, which is acceptable due to the nature of bulevirtide, the mechanism of action of bulevirtide, and the non-clinical toxicology data.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Hepcludex. In view of the intended use of Hepcludex, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

The quality (chemistry and manufacturing) information submitted for Hepcludex has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored between 2 °C and 8 °C. The in-use shelf life is 2 hours at room temperature (25 °C).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies). A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Hepcludex is of human or animal origin.