GSK Reaches ‘First Base’ In Hep B Functional Cure But Has More To Prove
9% Disease Free After Phase II Study
Executive Summary
GSK is the first to raise the functional cure rate with its antisense drug, Phase II data suggest, but the company is looking for ways to boost responses across hepatitis B patients in its Phase III study.
Recent weeks have seen a flurry of Phase III trial readouts from GSK, ranging from a definite ‘win’ (for its RSV vaccine) to a clear failure (with myeloma therapy Blenrep) in the company’s efforts to bring a new generation of blockbusters to market. The firm has now added to this with Phase II results showing a small number of patients have achieved a functional cure when treated with its chronic hepatitis B (CHB) candidate bepirovirsen. (Also see "GSK’s Blenrep Hit By Trial Failure, Raising Questions About Its Future In The Myeloma Market" - Scrip, 7 Nov, 2022.)
The data might not be a clear win just yet, but do set up GSK to move in to Phase III in the first half of 2023, ahead of competitors with similar candidate drugs.
The study showed that 9% of patients who received the treatment in combination with standard nucleoside/nucleotide analogues (NA) drugs achieved a functional cure, six months after having stopped receiving bepirovirsen. A parallel study arm where patients did not receive NA drugs saw this figure reach 10%.
This is a big step forward compared with the typical 1%-2% of patients who achieve a functional cure on NA therapy alone. But GSK knows it must try to improve on this 9%-10% in its forthcoming Phase III study in order to really make a big impression on the disease, with an estimated 296 million people carrying the infection worldwide, and resulting in around 900,000 deaths each year.
First Base Towards A Functional Cure
These end-of-study results from GSK’s B-Clear Phase IIb study were presented at the American Association for the Study of Liver Diseases meeting in Washington D.C. and published in the New England Journal of Medicine on 8 November.
GSK’s medicine development leader Melanie Paff told Scrip the results had created a buzz at the congress, as this level of response has never been achieved before.
Melanie Paff
Having had a father who was a professional baseball player, Paff said the results were not a “home run” but were a clear “first base” towards a functional cure for CHB. “What seeing here is the code finally being cracked, we are starting to unravel the immune dysfunction we see in this very heterogeneous disease.”
Matching or exceeding those responses in its Phase III study will be vital for GSK. The antisense oligonucleotide, licensed from Ionis Pharmaceuticals three years ago, has emerged as one of its brightest blockbuster hopes, which it forecasts could earn more than £2bn in non-risk adjusted peak year sales.
GSK is still finalizing the design of this pivotal study, which will explore sequential and combination regimens, and build on signs that some patient sub-groups are most likely to respond.
Its aim is to keep one step ahead of its rivals who have their own candidates not far behind in Phase II development, and all aimed at the same functional cure goal. These include small interfering ribonucleic acid (siRNA) prospects from Roche and Vir and TLR-8 agonist selgantolimod from Gilead, which is also working on a combination with Vir (see table), though none have yet reached the same proof-of-concept stage as GSK.
Virus Bounces Back When Treatment Stops
The trial studied the drug in 457 participants (227 receiving concurrent nucleoside/nucleotide analogues (NA) and 230 not receiving NA therapy), monitoring the treatment’s effect on two key biomarkers of functional cure, hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA.
The most promising results were in Arm A of the study, where bepirovirsen 300 mg was started with a loading dose and then taken for 24 weeks. Six patients (9%) who took the drug for 24 weeks in combination with NA treatment still had no signs of the virus six months after having stopped treatment. This is still quite a drop from the 28% on this regimen who showed no signs of the virus at the end of the 24-week treatment phase – indicating a familiar pattern where once treatment stops, the hepatitis B virus bounces back in many individuals.
As patients otherwise need lifelong NA therapy to maintain viral suppression, the company is looking at ways to reach a functional cure for more patients, where sustained viral suppression allows the immune system to return to normal working order.
Combination And Long-Term Studies
Alongside the planned Phase III study of bepirovirsen as a monotherapy, the company has a number of Phase II combination studies already underway.
The Phase II B-TOGETHER study involves an initial course of up to 24 weeks of bepirovirsen followed by up to 24 weeks of pegylated interferon.
Also in Phase II is GSK4388067A, a viral vector-based targeted immunotherapy which is administered after bepirovirsen to help boost the patient’s immune response and the clearance of the infected liver cells.
Equally important will be proving that the functional cure reached by some patients can be sustained indefinitely. For that reason, patients will be enrolled in the follow-on B-Sure trial which will last for an extra 33 months. This will include criteria for stopping NA therapy with the possibility of demonstrating functional cure in patients who successfully stop all medication and continue to demonstrate no serologic evidence of HBsAg or HBV DNA.