Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals
ATC code: J05AX28
Bulevirtide blocks the entry of HBV and HDV into hepatocytes by binding to and inactivating NTCP, a bile salt liver transporter serving as essential HBV/HDV entry receptor.
The clinical efficacy and safety of bulevirtide was investigated in one Phase 3 study and two Phase 2 studies. Patients with chronic HDV infection and active hepatitis were included. The population of these three studies was mainly Caucasian, HDV genotype 1 was predominant.
In Study 301, 100 of 150 patients with chronic HDV infection were randomised to receive immediate treatment with once daily bulevirtide 2 mg (N=49) or to have treatment delayed for 48 weeks (N=51). Randomisation was stratified by the presence or absence of compensated cirrhosis.
Of the 49 patients in the immediate treatment group, mean age was 44 years; 61% were male, 84% were White, and 16% were Asian. Of the 51 patients in the delayed treatment group, mean age was 41 years; 51% were male, 78% were White and 22% were Asian. All 100 patients had infection with HDV genotype 1.
Baseline characteristics were balanced among the immediate and delayed treatment groups. Of the patients who received 2 mg bulevirtide at baseline, mean plasma HDV RNA was 5.1 log 10 IU/mL, mean ALT was 108 U/L, 47% of patients had a history of cirrhosis, and 53% were interferon experienced. During the study (through Week 48), 63% of these patients, received concomitant therapy according to the standard care for their underlying HBV infection: the most common concomitant medications were tenofovir disoproxil fumarate-containing or tenofovir alafenamide-containing products (49%) and entecavir (14%).
The table below presents the virologic and biochemical outcomes for immediate treatment with bulevirtide 2 mg once daily and delayed treatment at Week 48.
| Week 48a | ||
|---|---|---|
| Bulevirtide 2 mg (Immediate Treatment) (N=49) | Delayed Treatment (N=51) | |
| Undetectableb HDV RNA or decrease in HDV RNA by ≥2 log10 IU/mL and ALT normalisationc | 45%d | 2% |
| Undetectableb HDV RNA or decrease in HDV RNA by ≥2 log10 IU/mL | 71%e | 4% |
| ALT normalisationc | 51%e | 12% |
a For the first endpoint, for missing values, the last observation carrying forward (LOCF) was used if COVID-19 related; otherwise, missing = failure; for the second and third endpoints, missing = failure.
b < lower limit of quantification LLOQ (target not detected)
c Defined as an ALT value within the normal range: Russian sites, ≤31 U/L for females and ≤41 U/L for males; all other sites, ≤34 U/L for females and ≤49 U/L for males.
d p-value<0.0001.
e Not multiplicity controlled.
In Study MYR202, 56 of 118 patients with chronic HDV infection and ongoing viral replication who were interferon experienced, had a contraindication to interferon, or were cirrhotic, were randomised to receive bulevirtide 2 mg + TDF (N=28) or TDF alone (N=28) for 24 weeks. At Week 24, 21% of patients in the bulevirtide 2 mg + TDF group achieved a combined response, 54% achieved undetectable HDV RNA (defined as < limit of detection [LOD], where LOD was 14 IU/mL) or decrease by ≥2 log10 IU/mL, and 43% achieved ALT normalisation. At Week 24, no patients in the TDF group achieved a combined response, 4% achieved undetectable HDV RNA or decrease in HDV RNA by ≥2 log10 IU/mL, and 7% achieved ALT normalisation (normal ALT was defined as ≤31 U/L for females and ≤41 U/L for males).
In Study MYR203, a total of 15 patients were treated with bulevirtide 2 mg daily for 48 weeks. In this limited dataset, the efficacy and safety profiles were not substantially different than for patients treated for 24 weeks. Two patients developed virological breakthrough, possibly related to medication non-adherence.
Bulevirtide has the potential to induce antidrug antibodies (ADA), as detected in clinical studies using an enzyme-linked immunosorbent assay (ELISA). In Studies MYR203 and MYR301, a total of 64 patients who were treated with bulevirtide 2 mg monotherapy for 48 weeks were eligible for assessment of ADA prevalence; 18 of these patients (28.1%) were positive for ADA prevalence, of which 3 patients (4.7%) were positive for ADA at baseline.
There is no evidence that the pharmacokinetics, safety, or effectiveness of bulevirtide were altered in these patients.
See section 4.2 and 5.2 for information on paediatric use.
The pharmacokinetic properties of bulevirtide were characterised after intravenous and subcutaneous administration. The exposure of bulevirtide increased disproportionally while the apparent clearance and apparent volume of distribution decreased with higher doses.
The estimated volume of distribution is smaller than total body water. In vitro plasma protein binding is high with >99% of bulevirtide bound to plasma proteins.
No biotransformation study was performed for bulevirtide. Bulevirtide is a linear peptide consisting of L-amino acids, and it is expected to be degraded to smaller peptides and individual amino acids. No active metabolites are expected.
Based on the results of in vitro interaction studies, bulevirtide did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.
No in vitro induction of CYP1A2, CYP2B6 or CYP3A4 by bulevirtide was observed.
Based on the in vitro studies, no clinically relevant interaction is expected for most common efflux transporters (MDR1, BCRP, BSEP, MATE1 and MATE2K) and uptake transporters (OATP2B1, OAT1, OAT3, OCT1 and OCT2). A specific in vitro interaction was identified with the organic anion transporting polypeptides, OATP1B1 and OATP1B3 with IC50 values of 0.5 and 8.7 μM, respectively.
No bulevirtide excretion into urine was detected in healthy volunteers. Elimination via target (NTCP) binding is assumed to be the main route. Both distribution and elimination after multiple dosing were reduced compared to values estimated after the first dose. Accumulation ratios for 2 mg dose for Cmax and AUC were approximately 2-fold. Steady state is assumed to be achieved within the first weeks of administration. After reaching peak concentrations, plasma levels declined with t1/2 of 4-7 hours.
No studies have been conducted with bulevirtide in patients with renal impairment.
No studies have been conducted with bulevirtide in patients with moderate and severe hepatic impairment.
No data is available in patients older than 65 years of age.
The pharmacokinetics of bulevirtide in paediatric patients have not been evaluated in a clinical study. Dosing recommendations for paediatric patients 3 years of age and older weighing at least 10 kg are based on exposure matching the paediatric bulevirtide concentration to concentrations observed in adults with HDV infection treated with bulevirtide 2 mg once daily. Simulated steady-state plasma exposures of bulevirtide weight-based dosing (see section 4.2) once daily by subcutaneous injection in paediatric patients are predicted to be within the safe and efficacious exposures associated with 2 mg bulevirtide once daily by subcutaneous injection in adults.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and toxicity to reproduction and development.
No genotoxicity and carcinogenicity studies were conducted due to the nature and mechanism of action of the product.
A pre- and post-natal development study (PPND) has been completed in rats and did not show any bulevirtide-related toxicity.
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