Not a home run, but first base: GSK unwraps PhII data on hepatitis B treatment in pursuit of ‘functional cure’
09 Nov 2022
Immunotherapy
At the annual Liver Meeting on Monday, GSK unveiled results from a Phase II trial on its hepatitis B treatment, which it said earlier this year could “lead to a functional cure” for the liver infection.
In 457 patients treated with GSK’s bepirovirsen, 26 had undetectable levels of hepatitis B 24 weeks after treatment — measured by the amount of hepatitis B surface antigen and viral DNA. That amounts to about 6% of all patients, according to the study published in NEJM, but results varied widely between groups of patients.
Preview
Source: Endpts
Melanie Paff (via GSK)
In an interview, GSK’s hepatitis B program development lead Melanie Paff told Endpoints News that analyzing the data on full, partial and non-responders to bepirovirsen, or bepi for short, will enable GSK to figure out what future combinations it could use to increase the functional cure rate.
Patients in each of the four arms of the study got different doses and lengths of treatment. Patients in the first group got 300 mg of bepi for 24 weeks. These patients fared the best in the study, with six patients among those on concurrent nucleotide analogue (NA) therapy and seven among those not on concurrent NA therapy having undetectable hepatitis B levels at 24 weeks — 9% and 10% of each group, respectively.
Patients in the second group got 300 mg bepi for 12 weeks, and then 150 mg for the next 12 weeks. In total, 10 patients had undetectable hepatitis B levels. Following them, patients in group three got only 300 mg of therapy for the first 12 weeks and then placebo for the next 12 weeks, while patients in group four got the vice versa. Three patients in group three had undetectable hepatitis B measurements at the end of the study, while none in group four did.
Notably, those who had lower levels of the hepatitis B antigen at baseline and got the 300 mg for 24 weeks had better responses than those with high levels. Of those with low antigen levels in that first study arm, 16% of the participants on NA therapy and 25% of those not on NA therapy had undetectable measurements of Hep B at the end of the study compared to 6% and 7%, respectively, with high levels of baseline hepatitis B antigen.
Previous studies suggest that nucleoside analogs have a functional cure rate that hovers around 1-5%. In combination with interferon treatment, that number jumps up a bit more.
At the Liver Meeting, Paff said there was a lot of buzz around whether a functional cure should be the endpoint for hepatitis B treatments. “At one time, we thought a functional cure was going to be a moonshot,” Paff said.
“What we’re seeing now with a breakthrough, like we’ve seen with the bepi data, is finally we’ve started to crack that code. We don’t have all of the numbers in the code yet, but we started to crack the code and started to learn a little bit more about how to establish functional cure,” Paff said.
In June, GSK unveiled an early data cut from this study, known as B-Clear, touting that it could “lead to a functional cure” for hepatitis B. The early data were encouraging — in those who got the high dose for 24 weeks, just under 30% had hepatitis B antigen and DNA levels that were too low to detect. With the full cut of data, that number was cut by a third.
GSK says its drug for chronic hep B could ‘lead to a functional cure’ — but will it be alone or in combination?
Now, it’s likely the future of bepi lies in a combination approach. Paff compared the situation to baseball. “Whenever you come to the plate, first thing you want to do is you want to hit a home run, but that’s actually a pretty rare event,” Paff said. But if that doesn’t happen, you want to put one person on each base and round out all the bases.
“Bepi’s on first base,” Paff said. As for the other two bases? GSK is testing bepi followed by a short course of peg interferon therapy, as well as alongside an experimental immunotherapy.
GSK licensed bepirovirsen from Ionis in 2019. The treatment is a single strand of synthetic nucleotides that bind and recruit enzymes to eat hepatitis B RNA.
On the safety front, 74 patients went through a grade 3 or 4 adverse event. The most common adverse event was injection-site reactions. In an editorial in NEJM, Jay Hoofnagle of the National Institute of Diabetes and Digestive and Kidney DiseasesDiabetes and Digestive and Kidney Diseases pointed out that the most concerning adverse event was increased levels of ALT, a liver enzyme, in patients not on concurrent NA therapy. And two hospitalizations from acute hepatitis happened in patients not on NA therapy, “which suggests that bepirovirsen should be combined with NA therapy,” Hoofnagle said.
Hoofnagle also wrote that more answers are needed:
Critical questions remain. Will HBsAg negativity persist beyond 24 weeks? When can NA therapy be safely stopped? What other factors predict response? Will RNA therapy–induced loss of HBsAg materially improve long-term outcomes?
Up next for bepirovirsen is a Phase III trial in 2023.
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