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LB-10
Phase 1b Efficacy and Safety of NVR 3-778, a First-In-
Class HBV Core Inhibitor, in HBeAg-Positive Patients
with Chronic HBV Infection
Man-Fung Yuen3, Dong Joon Kim4, Frank Weilert5, Henry lik-Yuen Chan6, Jacob P. Lalezari7, Seong Gyu Hwang8
, Tuan T. Nguyen9, Sandy Liaw1, Nathaniel Brown1, Klaus Klumpp
1, Lalo Flores1, George D. Hartman1, Edward J. Gane2;
1Novira Therapeutics,Inc., Doylestown, PA;
2Auckland Clinical Studies, Auckland, New Zealand;
3Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong;
4Chuncheon Sacred Heart Hospital, Hallym University, Gangwon-do, Korea (the Republic of);
5Waikato Hospital, Hamilton, New Zealand;
6Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, Hong Kong;
7Quest Clinical Research, San Francisco, CA;
8CHA Bundang Medical Center, Gyeonggi-do, Korea (the Republic of);
9Research and Education, Inc., San Diego, CA
Background: Current therapies for chronic hepatitis B (CHB)
can suppress HBV replication but long-term therapy is required
in most patients. HBV Core (capsid) protein plays multiple roles
in HBV persistence. NVR 3-778 is an HBV core inhibitor which
can potentially inhibit viral assembly, HBV genome replication,
cccDNA replenishment, and hepatic reinfection cycles. We
report clinical proof-of-concept data for NVR 3-778 from a
multicenter Phase 1b trial in patients with CHB.
Methods:
Safety and efficacy were assessed in 4 dosing cohorts of adults with chronic HBV infection. Patients were 18-65 yrs,, predominantly male, and HBeAg-positive with serum HBV DNA > 20,000 IU/mL . ALT levels could be normal or elevated to less than 7 times upper limit of normal. Patients were randomized to NVR
3-778 capsules (10 patients/cohort in first 2 cohorts, 8/cohort
in last 2 cohorts) or placebo (2 patients/cohort) for 28 days.
The first 3 cohorts received NVR 3-778 doses of 100, 200, or
400 mg QD, and the 4th cohort received 600 mg BD. Safety
evaluations included adverse events (AEs) and safety-related
clinical labs.
Results:
A total of 44 patients were enrolled in the 4 cohorts; 36 received active NVR 3-778 treatment. Safety and tolerability of NVR 3-778 were satisfactory for all cohorts, with no treatment-related discontinuations or serious adverse events (SAEs). AEs and lab abnormalities were generally mild and not related to study drug. A patient in the 100 mg cohort developed a rash involving the hands and feet that was considered to be serious. No other study patients developed a significant rash. Small HBV DNA reductions were apparent with 200 mg and 400 mg QD dose cohorts. With tripling of the daily dose to 1200 mg (600 mg BD) the mean 28-day reduction in serum HBV DNA levels increased substantially to 1.72 log10 (range 1.06-3.71 log10 IU/mL). PK results indicated multi-micromolar concentrations of NVR 3-778 supporting QD or BD dosing, with dose-related increases in drug levels. The study is advancing to evaluation of a combination of NVR 3-778 and peg-interferon. A higher dose will be tested to define a maximal-effect dose for NVR 3-778, and a nucleoside combination regimen will be tested later.
Conclusions:
NVR 3-778 was well-tolerated in patients with CHB. 600 mg BD dosing achieved significant reductions in HBV DNA. When used alone or in combination with current HBV antivirals, NVR 3-778 may contribute substantial efficacy by unique Core-related
mechanisms, toward a goal of increased durable response rates in HBV patients.
Disclosures:
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD, Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and Teaching: Echosens
Sandy Liaw - Employment: Novira Therapeutics
Nathaniel Brown - Consulting: Presidio Pharmaceuticals; Employment: Novira Therapeutics
Klaus Klumpp - Board Membership: Riboscience LLC; Employment: Novira Therapeutics Inc
Lalo Flores - Employment: Novira Therapeutics
George D. Hartman - Management Position: Novira Therapeutics
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie, Janssen, Gilead Sciences, Janssen Cilag, Achillion, Merck, Tekmira; Speaking and Teaching: AbbVie, Gilead Sciences, Merck
The following people have nothing to disclose: Man-Fung Yuen, Dong Joon Kim, Frank Weilert, Jacob P. Lalezari, Seong Gyu Hwang, Tuan T. Nguyen
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发表于 2015-10-21 17:12
