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698
INTERIM RESULTS OF A PHASE 1 STUDY OF RO7062931,
A NOVEL LIVER-TARGETED SINGLE-STRANDED
OLIGONUCLEOTIDE (SSO) WITH LOCKED NUCLEIC ACID (LNA)
THAT TARGETS HBV TRANSCRIPTS.
Edward J. Gane1, Cynthia Wat2, Sudip Das3, Bernadette
Surujbally3, Christian Schwabe4, Katerina Glavini5, Miriam
Triyatni5, Vedran Pavlovic3, Henrik Mueller6, Simon Buatois5
and Joseph Grippo7, (1)Auckland Clinical Studies, Auckland,
New Zealand, (2)Roche Products Ltd, Welwyn, United
Kingdom, (3)Roche Innovation Centre Welwyn, (4)Auckland
Clinical Studies, (5)Roche Innovation Centre Basel, (6)Roche
Pharma Research and Early Development, Roche Innovation
Center Basel, Basel, Switzerland, (7)Roche Innovation Centre
New York
Background: RO7062931 is a N-acetylgalactosamine
(GalNAc) conjugated SSO LNA, complementary to messenger
RNAs (mRNAs) of the HBV genome. Asialoglycoprotein
receptor (ASGPR) mediated hepatocyte uptake results in
hybridization of the SSO LNA and HBV mRNAs, and subsequent
RNAse H mediated degradation Pre-clinical in-vitro and invivo
studies with RO7062931 showed potent antiviral activity
against HBV transcripts across all HBV genotypes tested.
Methods: The first-in-human, randomized, placebo-controlled
Phase I study of RO7062931 (NCT03505190) consists of
two parts; Part 1 involves single ascending doses (SAD) of
RO7062931/placebo in healthy volunteers (HVs), and Part
2 involves multiple ascending doses (MAD) of RO7062931/
placebo in patients with chronic hepatitis B (CHB) The
objectives of the study are to evaluate the safety, tolerability,
pharmacodynamics and pharmacokinetics of subcutaneous
administration of RO7062931 Results from Study Part 1 are
presented herein Results: 60 HVs were randomised across
6 dose cohorts, in a 8:2 ratio, to RO7062931 (0.1 to 4 mg/
kg dose) or placebo A total of 78 non-serious AEs were
reported in 40 (67%) subjects, of which the majority were
mild in intensity 15 AEs were considered related to the study
drug by the investigator, of which 14 were mild Injection Site
Reactions No serious adverse events (SAEs) or withdrawals
due to AEs were reported There were no dose-related trends
in the nature, incidence, or severity of AEs Laboratory safety
parameters were unremarkable, and there were no clinically
significant changes observed in other safety parameters (e.g.
vital signs, ECG parameters) PK analysis demonstrates that
RO7062931 appears rapidly in plasma with a median Tmax
ranging from 2 to 3 hours (Figure) Majority of drug is cleared
from plasma within 24-36 hours A second slower phase
of terminal elimination with mean half-life of 100 hours is
observed, which likely represents redistribution from tissues
Over 24 hours, small amounts (1-5%) of RO7062931 were
detected in the urine depending on dose Plasma and urine
PK were utilized as surrogate markers to explore the ASGPR
liver shuttle kinetics Conclusion: RO7062931 was safe and
well tolerated in HVs, with a predictable PK profile expected
for a GalNAc-conjugated SSO Study Part 2 in patients with
CHB is currently ongoing.
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发表于 2019-11-3 18:49