Source: European Medicines Agency (EU) Revision Year: 2021 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 two Phase 2 studies. Patients with chronic HDV infection and active hepatitis were included. The population of both studies was mainly Caucasian, HDV genotype 1 was predominant.
A multicentre, open-label, randomised phase 2 clinical study evaluated the efficacy and safety of three doses of bulevirtide (2 mg/day, 5 mg/day and 10 mg/day) for 24 weeks in patients with chronic hepatitis D with liver cirrhosis, or who failed previous interferon therapy, or for whom such therapy was contraindicated (including history of interferon intolerance). Study participants received either daily subcutaneous injections of bulevirtide 2 mg/day, 5 mg/day and 10 mg/day on top of tenofovir (tablets), or tenofovir alone for 24 weeks. 50% of the study participants had liver cirrhosis at baseline. Participants had compensated liver disease, mean age was 40.2 (9.5) years, 66.9% were male, 85.6% were Caucasians, 13.6% Asians and 0.8% Black. Patients had active hepatitis with mean levels ALT of 115 (79.5) U/L. Patients with HIV and active HCV infection were excluded. Baseline characteristics were comparable between treatment arms. The primary endpoint of the study was undetectable HDV RNA or decrease by ≥2log10 from baseline to week 24.
The table below summarises the efficacy results in mITT population at week 24:
| HDV RNA response | Arm Α: (n=28) 2mg bulevirtide + TDF | Arm Β: (n=32) 5mg bulevirtide + TDF | Arm C: (n=30) 10mg bulevirtide + TDF | Arm D: (n=28) TDF |
|---|---|---|---|---|
| Patients with undetectable HDV RNA or decrease by ≥2log10 from baseline to week 24 | 53.6%* | 50.0%* | 76.7%* | 3.6% |
| Patients with undetectable HDV RNA or decline by ≥2log10 and normal ALT at week 24 | 21.4%* | 28.1%* | 36.7%* | 0.0% |
| Patients with ALT normalisation | 42.9%* | 50.0%* | 40.0%* | 7.1% |
* p-value ≤0.05 TDF=tenofovir disoproxil fumarate
ALT values ≤31 U/L for female and ≤41 U/L for male were considered normal
In this study, 25 participants developed anti-drug antibodies (ADA). No evidence of these ADA on the pharmacokinetics nor on the efficacy of Hepcludex was observed.
In study 203, 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 subjects developed virological breakthrough, possibly related to medication non-adherence.
The European Medicines Agency has deferred the obligation to submit the results of studies with Hepcludex in one or more subsets of the paediatric population for the treatment of chronic hepatitis D infection (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetic properties of bulevirtide were characterised after intravenous and subcutaneous administration. The exposure of bulevirtide increased disproportionally while the clearance and 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 8.7µM, 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.
No data is available in patients younger than 18 years of age.
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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