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83
SAFETY AND PHARMACODYNAMICS OF THE GALNACsiRNA
AB-729 IN SUBJECTS WITH CHRONIC HEPATITIS B
INFECTION
Man Fung Yuen1, Elina Berliba2, Yoon Jun Kim3, Jacinta
A Holmes4, Young-Suk Lim5, Simone I. Strasser6, Christian
Schwabe7, Alina Jucov2, Amy C.H. Lee8, Emily P Thi8, Troy
Harasym8, G R Pamulapati8, Paratosh Wattamwar8, Jeevan
Kunta8, Michael J Sofia8, Heather Sevinsky9, Kevin Gray9,
Timothy Eley9, Gaston R. Picchio9, Karen Sims9 and Edward J.
Gane7, (1)Medicine, The University of Hong Kong, (2)Nicolae
Testemitanu State University of Medicine and Pharmacy of the
Republic of Moldova, (3)Department of Internal Medicine and
Liver Research Institute, Seoul National University Hospital,
Seoul, Republic of Korea, (4)Gastroenterology, St. Vincent’s
Hospital, Melbourne, (5)Department of Gastroenterology,
Liver Center, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Republic of Korea, (6)Aw Morrow
Gastroenterology and Liver Transplant Centre, Royal Prince
Alfred Hospital, (7)Auckland Clinical Studies, Auckland,
New Zealand, (8)Research/Discovery, Arbutus Biopharma,
Warminster, PA, (9)Clinical Development, Arbutus Biopharma,
Warminster, PA
Background: AB-729 is an RNA interference (RNAi)
therapeutic that targets hepatocytes using a covalently
conjugated N-Acetylgalactosamine (GalNAc) technology that
enables subcutaneous (SC) delivery In preclinical models
AB-729 reduces all HBV transcripts, resulting in inhibition
of viral replication and reductions in hepatitis B surface
antigen (HBsAg) Here we report preliminary safety and
pharmacodynamic (PD) results following administration of AB-
729 in subjects with chronic hepatitis B (CHB) from an ongoing
first-in-human study. Methods: Part 1 examined single doses
of AB-729 or placebo in healthy subjects In Part 2 noncirrhotic,
HBeAg positive or negative CHB subjects currently
taking nucleos(t)ide antiviral (NA) therapy with HBV DNA
below the limit of quantitation and ALT up to 5xULN received
single doses of AB-729 60mg, 90mg, or 180mg Assessments
included safety and PD through at least 12 weeks post-dose
Part 3 is evaluating multiple dose regimens of AB-729 for 6
months at varying dose levels/intervals Results: There have
been no serious adverse events (AEs) or discontinuations
due to AEs to date In Part 2, 19 AEs were observed among
the 16 CHB subjects dosed, most of which were mild 11/19
were assessed as related; of which 7 were mild to moderate
injection-related AEs (mostly pain) At 180mg, there were two
transient Grade 1 ALT elevations and one unrelated Grade
3 ALT/AST elevation in the context of acute gastroenteritis
ALT/AST levels remained normal or at the same grade (in
one subject) as pre-study levels for all subjects in the 60mg
and 90mg cohorts Following single dose AB-729, continuous
declines in mean HBsAg were observed through 12 weeks
post-dose (Figure) At Week 12, HBsAg declines ranged from
-0 62 to -2 14 log10 (60mg), -0 79 to -1 87 log10 (90mg) and -0 69
to -1 62 log10 (180mg) Evaluation of AB-729 60mg at dosing
intervals of every 4 weeks and every 8 weeks is ongoing, and
available safety and PD data will be reported Conclusion:
AB-729 was generally safe and well tolerated following single
SC doses, with no clinically relevant ALT/AST changes in the
60mg and 90mg cohorts Robust mean declines in HBsAg
were observed following single doses of 60mg, 90mg and
180mg in CHB subjects that continued through 12 weeks post
single dose, supportive of a dosing interval of monthly or less
frequently in multiple dose studies. |
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发表于 2020-10-19 16:54