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LB-25
First Results with RNA Interference (RNAi) in
Chronic Hepatitis B (CHB) Using ARO-HBV
Dr. Edward J. Gane1, Prof. Stephen Locarnini2, Dr. Tien Huey
Lim3, Prof. Simone I. Strasser4, Prof. William Sievert5, Dr.
Wendy Cheng6,7, Prof. Alexander Thompson8, Dr. Bruce D
Given9, Dr. Thomas Schluep9, Dr. James Hamilton9, Dr. Zhen
Li9, Dr. Gavin Cloherty10, Danny Ka Ho Wong11, Dr. Christian
Schwabe1, Mrs. Kathy Jackson2, Prof. Carlo Ferrari12, Prof.
Ching Lung Lai11, Dr. Robert G. Gish13,14 and Prof. Man-Fung
Yuen11, (1)Auckland Clinical Studies, (2)Victorian Infectious
Disease Reference Laboratory, (3)Middlemore Hospial, (4)
A.W. Morrow Gastroenterology and Liver Centre, Royal
Prince Alfred Hospital, (5)Monash Medical Centre, (6)
Gastroenterology and Hepatology, Royal Perth Hospital, (7)
Linear Clinical Research, (8)Department of Gastroenterology,
St Vincent’s Hospital Melbourne, (9)Arrowhead
Pharmaceuticals, (10)Infectious Disease Research, Abbott
Laboratories, (11)Medicine, The University of Hong Kong, (12)
University of Parma, (13)Stanford University, (14)Hepatitis B
Foundation
Background: RNAi has shown promise as a potential
component of finite therapy for patients with chronic hepatitis
B (CHB) based on its ability to silence HBV mRNA thereby
reducing all viral products, most notably HBsAg. Clinical utility
has been limited by IV delivery and/or safety concerns. AROHBV
is composed of two siRNAs, each directly conjugated
to N-acetyl galactosamine to drive hepatocyte delivery.
Administered subcutaneously (SQ), it is designed to silence
all mRNA from cccDNA and host integrated viral DNA,
without need for additional delivery elements. Methods:
Normal healthy volunteer (NHV) cohorts (4 active, 2 placebo)
received single SQ doses of 35, 100, 200, 300 or 400 mg.
CHB cohorts 2b-5b (n=4, HBeAg pos or neg, NUC treated or
not on NUCs) received monthly doses x 3 of 100, 200, 300 or
400 mg. Cohorts of HBeAg pos, NUC naïve and experienced
CHB (cohorts 8, 9 respectively, n=4 each) are receiving 300
mg monthly x 3. NUC untreated receive NUCs from day1.
Results reported are from 28 days after 3rd dose (day 85)
when available or most recent. Results: No serious AEs or
dropouts in NHVs or CHBs have been reported. AEs were
mild and similar in occurrence for active or placebo. Injection
site AEs (all mild) occur in ~11% of injections. For cohorts
2b-5b (n=16 active), 14 were BLQ for HBV DNA and 13 were
HBeAg negative at baseline; 14 on chronic NUCs. In CHB,
mean (max) log10 reductions in HBsAg were: 100 mg 2.0
(4.0) through Day 85, 200 mg 1.6 (2.2) through Day 85, 300
mg 1.5 (2.2) through Day 85 and 400 mg 1.7 (3.0) through day
71 in cohorts 2b-5b and 1.5 (3.0) in cohort 8 through day 43
and 1.0 (1.3) through day 15 in cohort 9. All patients reaching
day 85 have > 1.0 log10 reduction in HBsAg with additional
HBsAg decreases observed after the second and third doses.
Of these 24 CHB, 21 had HBsAg >100 IU/ml at baseline
and currently 17 have achieved HBsAg <100, 7 ≤10, 4 ≤1.
In CHB with other viral parameters above LLOQ at baseline,
all have improved following ARO-HBV, including reduction to
BLQ in: HBV DNA (2 of 7), HBV RNA (8 of 14), HBeAg (0 of
11) and HBcrAg (3 of 15). Conclusion: ARO-HBV has been
well tolerated in NHVs and CHB. ~11% of SQ injections were
associated with mild injection site AEs. Monthly RNAi with
ARO-HBV effectively reduces all measurable viral products,
including HBsAg. ARO-HBV has characteristics desirable
for RNAi to become a cornerstone therapy in finite regimens
aimed at HBsAg clearance in CHB. |
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发表于 2018-12-8 18:36
