Viral Hepatitis HBV/HBV Cure: GSK prominently featured bepirovirsen development and J&J siRNA licensing deal

On November 1^st, 2023, GSK hosted their Q3 2023 earnings call and posted a press release, presentation, SEC Form 6-K, and pipeline report on their investor relations page. 

Key Highlights:

• GSK prominently featured bepirovirsen (bepi, ASO) at the earnings presentation and expressed continued excitement about the asset, describing bepi as a “triple-action” therapy that “provides patients with a potential functional cure for chronic hepatitis B.”
  • Bepi’s “triple mechanism of action” was described as its ability to inhibit viral replication, reduce viral DNA and thus the production of viral proteins, and stimulate the body’s innate immune system
• GSK emphasized bepi monotherapy’s efficacy in patients with baseline HBsAg < 3,000 IU/mL (25% SVR24) and acknowledged that sequential PegIFN treatment does not significantly improve functional cure rates.  
  • SVR24 for bepi + PegIFN was 15% compared to ~9% for bepi monotherapy.
  • A full data readout the Ph2b B-TOGETHER (bepi + PegIFN, N=108) study will be presented as an oral presentation at AASLD on November 12, 2023
• GSK expressed excitement about the agreement to obtain exclusive worldwide license to develop and commercialize JNJ-3989 (siRNA) in combination with bepi and indicated expectations that regimen will work in “complementary fashion” to bepi.
  • GSK stated that sequential use of bepi and JNJ-3989 would increase coverage in ITT populations (patients with baseline HBsAg of 3,000 IU/mL and below) and deepen the therapeutic effect
  • GSK intends to initiate a Ph2b study in early 2024 to investigate JNJ-3989 in a sequential regimen with bepi for the treatment of adult non-cirrhotic patients with CHB on NUC therapy
• GSK further confirmed that data from Ph2 B-SURE (N=450) study will be presented at AASLD 2023 as a late-breaking abstract; full details on AASLD late-breaking abstracts will be available on Friday, November 10^th 2023 once embargo is lifted.
  • The Ph2 B-SURE study investigates the long term efficacy of bepi monotherapy, as measured by sustained virologic response, in patients that achieved a complete or partial response in the B-CLEAR study (N= 457)

Assessment:

• At the Q3 2023 earnings call, GSK emphasized a renewed confidence in bepi as the “cornerstone” of a combination therapy for achieving functional cure in CHB.
  • This was a contrast to the sentiments expressed at the Q2 2023 earnings where GSK indicated that there were “development decisions” for several assets in Ph1/2 development, including their lead asset in HBVCure, bepi
• Given GSK’s acknowledgement of lackluster bepi + pegIFN data, it is unlikely that GSK will move forward with another trial testing this combination.
  • PegIFN could still play a role in other combination regimens with bepi.
• Anticipated initiation of a Ph2b bepi (ASO) + JNJ-3989 (siRNA) trial in early 2024 represents the first time that these gene-suppressing technologies would be evaluated together.
  • JNJ-3989 could be utilized to lower HBsAg levels to less than 3,000 IU/mL to increase functional cure rates following the sequential treatment with bepi. However, this regimen may result in concerning adverse events
  • Available Ph2 data for bepi and JNJ-3989 suggest achieving >30% functional cure rate will be challenging; following the completion of a successful pivotal Ph3 trial, an approval as early as 2H 2032 could be a possibility 
• This earnings call did not provide any changes to bepi development timeline expectations; earliest estimated approval for bepi monotherapy remains 2026
  • Bepirovirsen monotherapy has demonstrated underwhelming functional cure rates of ~9% to date