Hepatitis B: can GSK’s bepirovirsen deliver functional cure?
GSK’s antisense oligonucleotide is looking to further prove its value in disrupting viral replication via a Phase III test.
By Urtė Fultinavičiūtė
Last month, GSK provided an early look at positive Phase IIb data that got the hepatitis B field excited. Results show that bepirovirsen could potentially lead to functional cure, which means that the candidate lowered hepatitis B surface antigen (HBsAg) to undetectable levels.
The Phase IIb data is a “major breakthrough,” says Dr Pietro Lampertico, professor of gastroenterology at the University of Milan. This is the first time in a decade whereby a new candidate was able to show lowered HBsAg to undetectable levels after weeks of treatment, Lampertico explains.
With GSK gearing to initiate a Phase III bepirovirsen trial in the first half of 2023, this is the first time an antisense oligonucleotide candidate would be investigated at this stage. It’s also been years since a new hepatitis B agent would be studied at Phase III, notes Dr Jordan Feld, senior scientist at Toronto General Hospital Research Institute.
As such, all eyes are on GSK on how it will design its forthcoming study, and if the asset’s efficacy profile sustains in the next development stage.
While there is initial positive Phase IIb data, more results from this study are needed. Experts say there are still questions about the candidate’s potential for durable efficacy, as well as concerns around liver inflammation. There are also doubts if bepirovirsen, by itself, would deliver functional cure for many.
Phase IIb hepatitis B data has caveats
GSK, formerly GlaxoSmithKline, presented positive interim analysis at this year’s EASL Liver Congress from the Phase IIb B-clear trial (NCT04449029) investigating bepirovirsen in treatment-naïve patients and ones already taking nucleotide analogues (NA). In the trial’s secondary endpoint, 28% of patients on NA (n=68) and 29% of treatment-naïve participants (n=70) experienced lowered HBsAg and hepatitis B virus (HBV) levels with 300mg bepirovirsen at the end of the 24-week treatment. NAs suppress HBV to undetectable levels but must be taken long term, if not indefinitely.
Final B-clear data is expected later this year. Phase IIb investigator Dr Man-Fung Yuen notes the asset’s potential for durable efficacy at 48 weeks after the first dose, which is the trial’s primary endpoint, will be a key efficacy indicator.
Dr Man-Fung Yuen, hepatology professor at the University of Hong Kong and B-clear trial principal investigator
Bepirovirsen is likely to have some lingering efficacy impact after the therapy is stopped, notes Yuen, who is also a hepatology professor at the University of Hong Kong. “I would be comfortable to say that the sustained effects would last for at least six months after stopping the therapy,” he says.
In a Phase IIa trial (NCT03020745), declined HBsAg levels rebounded after two weeks but participants received a lower dose than in the Phase IIb. The best performing Phase IIa cohort in terms of durability was given the drug once weekly at 120mg for 12 weeks. In Phase IIb, the positive data was from patients given a 300mg weekly dose at 24 weeks.
Even if B-clear durability data is positive, it would still be too early for efficacy conclusions, says Dr Way-Kay Seto, clinical professor, School of Clinical Medicine, at the University of Hong Kong. The Phase IIb data is too small, he adds. While the Phase IIb had 457 patients, it had multiple arms investigating different doses.
There are also side-effect questions that need to be addressed. Phase IIb data shows an increase in alanine aminotransferase (ALT), which is a marker for liver inflammation. ALT flares can occur due to drug-induced injury or the immune system attacking the virus in the liver, Yuen explains. In the latter, the larger the HBsAg drop, the higher chance of an ALT flare, he adds. Regardless of what causes the flare, liver damage is still a risk, and thus patients need extensive monitoring, he notes.
A GSK spokesperson says, in the Phase IIb, treatment-related serious adverse events (AEs) were observed in less than 1% of patients receiving NA and 1% of treatment-naïve patients, with no clinically meaningful differences in AEs across treatment arms.作者: StephenW 时间: 2022-7-29 14:46
300mg出现CRP升高,大部分是头几次注射,后面就消退了,健康人也会有,所以应该是和药物有关。CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers
作者: tim889 时间: 2022-7-30 00:35
Safety and tolerability
The most common treatment-emergent adverse events (TEAEs) were local injection site reactions (Table 2). Injection site reactions were reported in zero, three (50%) and three (25%) treatment-naïve patients in the placebo, bepirovirsen 150 mg and bepirovirsen 300 mg arms, respectively, and in zero and two (40%) on-NA patients in the placebo and bepirovirsen 300 mg arms, respectively. Pyrexia was commonly reported in treatment-naïve patients (one patient (16.7%) each in the placebo and bepirovirsen 150 mg arms; three patients (25%) in the bepirovirsen 300 mg arm).
TEAEs were mostly mild (division of acquired immune deficiency syndrome (DAIDS) grade 1: 52 of 69 events); the remainder were moderate (DAIDS grade 2: 16 of 69 events), except for one treatment-naïve patient in the bepirovirsen 300 mg treatment group who experienced a serious adverse event (DAIDS grade 4) of alanine aminotransferase (ALT) increase (described in the ‘ALT increase’ section).
Treatment-related TEAEs were reported in four (66.7%), six (50.0%) and one (16.7%) treatment-naïve patients in the bepirovirsen 150 mg, bepirovirsen 300 mg and placebo groups, respectively. The most common treatment-related TEAEs in treatment-naïve patients were injection site pruritus (bepirovirsen 150 mg, n = 2 (33%); bepirovirsen 300 mg, n = 1 (8.3%)), injection site erythema (bepirovirsen 150 mg, n = 0 (0%); bepirovirsen 300 mg, n = 3 (25%)) and nausea (bepirovirsen 150 mg, n = 1 (16.7%); bepirovirsen 300 mg, n = 2 (16.7%)). Injection site swelling, ALT increase and myalgia were each considered treatment-related in two patients (16.7%) in the bepirovirsen 300 mg arm. In on-NA patients, injection site bruising, injection site swelling, injection site erythema and pyrexia were each reported in one patient (20.0%) in the bepirovirsen 300 mg arm.
An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB. In most patients, levels increased on day 2 with peak levels observed pre-dose on day 4 (see example patient in Supplementary Fig. 3a). Levels were substantially recovered by day 8, suggesting the day 4 dose did not lead to further CRP increases. There were generally no CRP spikes at later time points, and no symptoms were consistently associated with CRP elevations. CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers (Supplementary Fig. 3b and unpublished data).
Aside from ALT, aspartate aminotransferase (AST; described below) and CRP effects, there were no clinically significant changes in laboratory tests related to bepirovirsen treatment. Transient prolongations in activated partial thromboplastin time were observed 3–5 h after administration of both bepirovirsen doses on day 1 and day 22. The magnitudes of these prolongations were not clinically relevant, with a maximum observed value of 43.9 s (~1.21× upper limit of normal (ULN); ULN = 36.5 s) in two participants in the bepirovirsen 300 mg treatment group. There were no bleeding or bruising events associated with the elevations and little or no coincidental prolongation of prothrombin time.
There were no observations of complement activation related to bepirovirsen dosing and no clinically significant findings in other safety assessments (for example, electrocardiogram, physical examination, concomitant medication usage). 作者: newchinabok 时间: 2022-7-30 19:47