Tobevibart, Elebsiran Receive FDA Breakthrough Therapy Designation for Chronic HDV

Mark Eisner, MD, MPH

Credit: Vir Biotechnology

Vir Biotechnology has announced tobevibart and elebsiran have received US Food and Drug Administration (FDA) Breakthrough Therapy designation and European Medicines Agency (EMA) Priority Medicines (PRIME) designation for the treatment of chronic hepatitis delta (CHD).¹

According to a December 12, 2024, press release, the designations are supported by positive safety and efficacy data from the phase 2 SOLSTICE trial and follow FDA Fast Track designation and EMA Committee for Orphan Medicinal Products (COMP) positive opinion on orphan drug designation earlier this year.¹

“Chronic hepatitis delta has devastating effects on liver and overall health, yet people living with this condition are still waiting for highly effective therapeutic options,” Mark Eisner, MD, MPH, executive vice president and chief medical officer of Vir Biotechnology, said in a press release.¹ “The Phase 2 SOLSTICE trial data suggests that tobevibart and elebsiran can rapidly and deeply suppress the hepatitis delta virus, driving it to undetectable levels. Receiving FDA Breakthrough Therapy and European PRIME designations recognizes this combination’s potential to transform the lives of people living with CHD. We look forward to advancing the Phase 3 ECLIPSE program as quickly as possible.”

An investigational broadly neutralizing monoclonal antibody targeting the hepatitis B surface antigen, tobevibart is designed to inhibit the entry of hepatitis B and hepatitis delta viruses into hepatocytes and to reduce the level of circulating viral and subviral particles in the blood. It has been engineered to have an extended half-life and is administered subcutaneously. In addition to CHD, tobevibart is currently in clinical development for the treatment of patients with chronic hepatitis B.¹

An investigational hepatitis B virus-targeting small interfering ribonucleic acid (siRNA), elebsiran is designed to degrade hepatitis B virus RNA transcripts and limit the production of hepatitis B surface antigen. Current data suggests it may have direct antiviral activity against both hepatitis B virus and hepatitis delta virus. Elebsiran is administered subcutaneously and is currently in clinical development for the treatment of patients with chronic hepatitis B and patients with chronic hepatitis delta.¹

The phase 2 multi-center, open-label, randomized SOLSTICE study evaluated the safety, tolerability, and efficacy of tobevibart, both alone or in combination with elebsiran, in patients with CHD. Primary endpoints include the proportion of participants with undetectable hepatitis delta virus RNA, defined as HDV RNA ≥ 2 log10 decrease from baseline or below limit of detection, up to week 24; alanine aminotransferase (ALT) normalization, defined as ALT below upper limit of normal up to week 24; and treatment-emergent adverse events and serious adverse events up to 118 weeks. Secondary endpoints include the proportion of participants with undetectable HDV RNA and different timepoints and up to 192 weeks.¹

In the trial, participants were randomized to receive tobevibart 300 mg monotherapy every 2 weeks (n = 33) or a combination of tobevibart 300 mg and elebsiran 200 mg every 4 weeks (n = 32). In addition, the participants from previous tobevibart or elebsiran monotherapy cohorts were able to rollover to receive the combination of tobevibart 300 mg and elebsiran 200 mg every four weeks (n = 13).²

SOLSTICE data were presented in an oral session at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, and showed 100% of participants across combination arms achieved an HDV RNA ≥2 log 10 decrease or below limit of detection at week 24 that was sustained over time in all participants at week 36 and those in the rollover cohort that reached week 60.²

HDV RNA target not detected (TND) was achieved in 41% of participants across combination arms at week 24 and rose to 64% at week 36. By week 60, this reached 80% of participants in the rollover cohort having achieved no detectable viral RNA.²

Results showed ALT decreased in most participants between day 1 and week 24 and normalized in 47% of participants in the combination de novo cohort and 56% in the rollover cohort by week 24, with rates sustained at week 36.²

Of note, the safety profile of tobevibart and elebsiran was consistent with previous studies, with influenza-like illness being the most common treatment-emergent adverse event and no study-related discontinuations in the combination arms.²

According to the release from Vir, the phase 3 ECLIPSE registrational program evaluating tobevibart and elebsiran in CHD is planned to commence in the first half of 2025.¹

References

1. ^{Businesswire. Vir Biotechnology Receives FDA Breakthrough Therapy Designation and EMA PRIME Designation for Tobevibart and Elebsiran in Chronic Hepatitis Delta. December 12, 2024. Accessed December 12, 2024. https://www.businesswire.com/news/home/20241212919029/en/Vir-Biotechnology-Receives-FDA-Breakthrough-Therapy-Designation-and-EMA-PRIME-Designation-for-Tobevibart-and-Elebsiran-in-Chronic-Hepatitis-Delta}
2. ^{Vir Biotechnology. Vir Biotechnology Presents Positive Chronic Hepatitis Delta Clinical Trial Data and Announces Initiation of Phase 3 Registrational Program. November 18, 2024. Accessed December 12, 2024. https://investors.vir.bio/news/news-details/2024/Vir-Biotechnology-Presents-Positive-Chronic-Hepatitis-Delta-Clinical-Trial-Data-and-Announces-Initiation-of-Phase-3-Registrational-Program/default.aspx}