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PS-080
Short term RNA interference therapy in chronic hepatitis B using
JNJ-3989 brings majority of patients to HBsAg < 100 IU/ml
threshold
Man-Fung Yuen1, Stephen Locarnini2, Tien Huey Lim3,
Simone STRASSER4, William Sievert5, Wendy Cheng6,7,
Alex Thompson8, Bruce Given9, Thomas Schluep9, James Hamilton9,
Gavin Cloherty10, DannyWong1, Christian Schwabe11, Kathy Jackson2,
Carlo Ferrari12, Ching Lung Lai1, Robert G. Gish13,14, Edward Gane11.
1The University of Hong Kong, Hong Kong, China; 2Victorian Infectious
Disease Reference Laboratory, Victoria, Australia; 3Middlemore Hospital,
Auckland, NewZealand; 4Royal Prince Alfred Hospital, Sydney, Australia;
5Monash Health and Monash University, Melbourne, Australia; 6Royal
Perth Hospital, Perth, Australia; 7Linear Clinical Research, Perth,
Australia; 8St. Vincent’s Hospital, Melbourne, Australia; 9Arrowhead
Pharmaceuticals, Pasadena, United States; 10Abbott Diagnostics, Abbott
Park, United States; 11Auckland Clinical Studies, Auckland, NewZealand;
12University of Parma, Parma, Italy; 13Stanford University, Palo Alto,
United States; 14The Hepatitis B Foundation, Doylestown, United States
Email: [email protected]
Background and aims: RNAi with JNJ-3989 (previously ARO-HBV)
has shown promising reductions in circulating CHB viral parameters
based on its design to silence mRNA from cccDNA and integrated
sources (AASLD 2018). The ongoing phase 2 portion of AROHBV1001
assesses 3 doses of JNJ-3989 administered weekly to monthly in
HBeAg pos (e pos) or neg (e neg) CHB patients. Herein we report
reductions in HBsAg levels below important literature proposed
thresholds and exploration of loading dose effect.
Method: CHB patients (n = 56) received 3 subcutaneous doses of JNJ-
3989. CHB cohorts 2b–5b (n = 4, e pos or neg, NUC treated or not)
received monthly doses of 100, 200, 300 or 400 mg. Cohorts of e pos,
NUC naïve and experienced CHB (cohorts 8, 9 respectively, n = 4 each)
received 300 mg monthly. Loading dose cohorts (all n = 4, e pos or e
neg, NUC treated or not) received bi-weekly or weekly doses of
100 mg (cohorts 6 and 7) or weekly doses of 200 mg (cohort 10) or
300 mg (cohort 11). Baseline NUC untreated CHB in any cohort
receive NUCs from day1, continuing after JNJ-3989 dosing ends.
HBsAg results reported are through day 113, 56 days after 3rd
monthly dose when available or most recent in patients with data at
least 14 days data following 3rd dose. In total, current HBsAg data is
reported for 40 patients and safety for 56. Further data will be
available at time of presentation.
Results: No serious AEs or dropouts have been reported. Injection site
AEs (all mild) occurred in ∼12% of 171 injections. Mean max log10
declines in HBsAg were: 100 mg 1.9, 200 mg 1.7, 300 mg 1.7 and
400 mg 2.0 logs in cohorts 2b–5b and 2.3 in cohort 8, 2.5 in cohort 9.Giving JNJ-3989 more frequently (cohorts 6, 7,10,11) did not increase
rate or extent of HBsAg knockdown; duration persisted at least 6
weeks after last dose. 97% (34 of 35) of patients reaching day 85 after
first dose have > 1.0 log HBsAg reduction. Of 40 patients with ≥ 14
days follow-up after 3rd dose 3 had HBsAg < 100 IU/ml at baseline
while currently 32 have achieved HBsAg < 100, 14 ≤ 10, 5 ≤ 1. Other
viral parameters (HBV DNA, RNA, HBcrAg, HBeAg) above LLOQ at
baseline improved.
Conclusion: Monthly RNAi reduced all measurable viral products,
including HBsAg in e pos and e neg CHB. JNJ-3989 rapidly reduces
HBsAg to thresholds associated with improved chances of HBsAg
sero-clearance with characteristics desirable for a cornerstone
therapy in finite regimens aimed at HBsAg clearance in CHB. JNJ-
3989 has been safe and well tolerated.
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发表于 2019-4-1 07:17
