Biotech Values

[dewophile]

JNJ abstract

EFFICACY AND SAFETY OF COMBINATION TREATMENT WITH siRNA JNJ-73763989 AND CAPSID
ASSEMBLY MODULATOR JNJ-56136379 (BERSACAPAVIR) IN HBEAG NEGATIVE
VIROLOGICALLY SUPPRESSED CHRONIC HEPATITIS B PATIENTS: FOLLOW-UP WEEK 48 END
OF STUDY RESULTS FROM REEF-2

Background: REEF-2 (NCT04129554) assessed the efficacy and safety of JNJ-3989, JNJ-6379, and nucleos(t)ide
analogs (NA) in virologically suppressed hepatitis B e antigen negative (HBeAg-) chronic hepatitis B (CHB) patients.
Methods: In this phase 2b, double-blind, multicenter, placebo-controlled study, HBeAg- CHB patients with hepatitis B
surface antigen (HBsAg) >100 IU/mL on NA treatment for ≥2 years were randomized (2:1) to receive add-on JNJ3989 + JNJ-6379 (active) or placebos (control). All treatments, including NA, were discontinued after 48 weeks followed
by 48 weeks of follow-up (FU; total study duration: 96 weeks). Here, we report end of study (EOS; FU Week 48 [FU
W48]) results. Results: Of 130 patients randomized (85 active, 45 control), 121 (81 active, 40 control) completed the
study. Mean (SE) changes in HBsAg from baseline were greater in the active versus control arm at Week 48 (W48;
end of treatment; -1.89 [0.06] vs -0.06 [0.01] log10 IU/mL) and FU W48 (EOS; -1.46 [0.07] and -0.49 [0.12] log10 IU/mL).
71.1% and 46.9% of patients in the active arm achieved HBsAg <100 IU/mL at W48 and FU W48, respectively,
compared with 2.4% and 15.0% in the control arm. 19.7% and 14.8% of patients in the active arm achieved HBsAg
<10 IU/mL at W48 and FU W48, respectively, versus 0% and 7.5% in the control arm. No patients in the study achieved
HBsAg loss (<0.05 IU/mL) without restarting NA at FU Week 24 (primary endpoint) or at FU W48. Of those who stopped
NA, fewer patients in the active versus control arm restarted NA (6/77 [7.8%] vs 12/41 [29.3%]). Of patients not on NA
at FU W48, more in the active versus control arm had HBV DNA <2000 IU/mL with HBsAg <100 IU/mL (31/71 [43.7%]
vs 3/28 [10.7%]) and HBV DNA <lower limit of quantitation with HBsAg <100 IU/mL (12/71 [16.9%] and 0/28 [0%]).
More frequent and pronounced off-treatment ALT flares (ALT ≥3× upper limit of normal and ≥3× nadir) and
virologic relapses (HBV DNA >2000 IU/mL) were observed in the control versus active arm during FU. The frequency
of adverse events was similar between the active and control arms during FU (65.5% vs 68.3%), and there were no
deaths. Conclusion: Treatment with JNJ-3989 + JNJ-6379 + NA for 48 weeks was generally safe and well tolerated.
After stopping all treatments, including NA, at W48, no patient achieved the primary endpoint, but lower HBsAg levels
and greater HBV DNA suppression were observed for patients in the active arm after 48 weeks of FU.

GSK abstract

BEPIROVIRSEN (BPV) IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION
CONTROLLED BY NUCLEOS(T)IDE ANALOGUE THERAPY: HBV DNA AND HBsAg LOSS 6
MONTHS AFTER END OF BPV TREATMENT (B-CLEAR STUDY)

Background: Bepirovirsen (BPV; GSK3228836), an antisense oligonucleotide, targets all hepatitis B virus (HBV)
mRNAs and decreases viral proteins. The B-Clear trial investigated BPV efficacy and safety in patients (pts) with
chronic hepatitis B (CHB) on and not on nucleos(t)ide analogues (NA). We present end-of-study (24 weeks [wks] offBPV treatment) results for pts on NA. Methods: Multicenter, randomized, partial-blind (investigator unblinded), parallelcohort study in pts with CHB. Pts with alanine aminotransferase (ALT)≤2×upper limit of normal, HBV DNA<90
IU/mL and hepatitis B surface antigen (HBsAg)>100 IU/mL were randomized (3:3:3:1) to 1 of 4 treatment arms to
receive up to 300 mg BPV administered as two subcutaneous injections weekly for 12 or 24 wks with or without loading
doses (see arms in Figure). Pts were stratified by baseline hepatitis B e antigen (HBeAg; positive/negative) and HBsAg
level (≤3/>3log10 IU/mL). Primary outcome: proportion of pts achieving HBsAg<lower limit of detection (LLOD) and
HBV DNA<lower limit of quantification (LLOQ) maintained for 24 wks without additional antiviral medication after
planned BPV end of treatment (EOT). Safety was assessed via adverse event (AE) monitoring. Results: Intent-to-treat
population included 227 pts (73% male, 52% Asian, 69% HBeAg negative, 72% HBsAg >3log10 IU/mL). Primary
outcome was achieved in 6 (9%), 6 (9%), 2 (3%) and 0 pts in Arms 1-4, respectively; data at specific study visits are
shown in Figure. A greater proportion of pts with low (≤3log10 IU/mL) vs high (>3log10 IU/mL) baseline HBsAg levels
achieved the primary outcome (Arm 1: 16% vs 6%). Primary outcome was achieved in a similar proportion of HBeAg
negative and positive pts (Arm 1: 10% vs 6%). Serious AEs (SAEs) were reported in 6 (3%) pts and treatment-related
SAEs in 1 (<1%) pt. Treatment was discontinued in 13 pts (6%); 8 (4%) pts had an AE that led to discontinuation. Most
common AEs were injection site reactions (64%), pyrexia (14%) and ALT increase (11%). There were no clinically
meaningful differences in AEs across treatment arms. Conclusion: BPV 300 mg x24 wks (Arm 1) and BPV 300 mg
x12 wks + 150 mg x12 wks (Arm 2) were the most efficacious treatment regimens. Pts with low vs high (Arm 1: 16% vs
6%) baseline HBsAg were more likely to achieve HBsAg and HBV DNA loss for 24 weeks after BPV EOT. There were
no safety signals to preclude further development. Funding: GSK [209668/NCT04449029] [on behalf of the B-Clear

From the webcast it sounds like GSK is in fact hoping to start a phase 3 in the subgroup of patients that had low baseline SAg levels and 16% cure rate. We'll see if FDA is on board. On the one had this is more than triple the efficacy w interferon therapy with much better tolerability - OTOH 16% leave a lot to be desired (not to poo poo the data - this is an achievement and probably the most promising asset anyone has in HBV, but it really could use a boost here - maybe GSK will in license or buy ENTA since they don't have a core inhibitor?! I'm genuinely curious if they see any synergy w sequential intereferon therapy early next year)