新药跟踪(10/14/02): ACH-126, 443

liver411

(注)核苷类逆转录酶抑制剂(NRTIs)：ACH-126，443是左旋核苷类抗HIV、抗HBV药物，对线粒体无毒性作用，药物的早期研究显示，其抗病毒的活性是3TC(拉米)的10～20倍，并拥有良好的生物利用度，细胞内的药物半衰期长达24小时，属于作用较强的核苷类抗病毒药物，特别针对那些耐核苷类药物的病毒，临床前期药代动力学及线粒体安全性的研究显示，它可作为抗病毒药的有效成份用于疾病治疗的全过程。
　　
[B]New Anti-HBV Agent Shows Potency and Safety in Small Study[/B]

By Ronald Baker, PhD

ACH-126, 443 is an L-nucleoside with potent in vitro anti-HBV activity, a promising safety profile and excellent oral bioavailability. The drug is a once daily oral agent that is in development by Achillion Pharmaceuticals. Results of a small, blinded, placebo controlled safety and activity study were presented at the 42nd ICAAC in San Diego (September 27-30, 2002)

Study ACH 443-001 evaluated the safety and anti-HBV activity of oral doses for 14 days in adults with chronic HBV. Six subjects were randomized 5:1 to active drug or placebo in sequential dose groups of 1, 5, 10, 20, 50 and 100 mg once daily. Drug was administered as a solution buffered with commercial antacid.

Plasma HBV DNA levels were determined twice weekly on treatment and after 14 days off treatment (day 28). Clinical and laboratory safety was assessed on days 7, 14 and 28.

Results

Forty subjects were enrolled. 85% were male with a median age of 39 years and broad ethnicity: white (33%), Asian (43%), black (10%), Hispanic (10%). Median baseline HBV DNA was 7.0 log10 and ALT was 78 IU/mL. Baseline characteristics were balanced across dose groups. On treatment, there were no clearly dose- or drug-related adverse events.

Occasional mild nausea, not dose-related, was attributed to the antacid. Changes in liver enzymes on or after treatment were not dose-related and were attributable to disease-related fluctuations.

Mean plasma HBV DNA levels after 14 days showed no change from baseline in the placebo group, a 0.5 log10 decline at 1 mg/day and declines of 1.5 - 2.5 log10 in the higher dose groups, with a suggestion of a dose response. DNA and ALT levels returned toward baseline after 14 days off treatment, but no flares above baseline were observed.

The researchers conclude that ACH-126,443 is a well-tolerated, once-daily oral agent that within 7 - 14 days exhibited rapid, potent anti-HBV activity comparable or superior to that seen with other potent agents. Further development is on-going with enteric-coated tablets.

About ACH-126,443

ACH-126, 443 has demonstrated in vitro activity against both wild-type and lamivudine-resistant strains of HBV. Clinical studies are planned in 2002 to evaluate the efficacy of the agent in patients with lamivudine-resistant strains of HBV. Pre-clinical studies have also demonstrated that ACH-126, 443 effectively inhibits HIV, including lamivudine-resistant and multi-drug resistant strains.
10/14/02

Reference
N Afdhal and others. V-690. Rapid, Potent Anti-HBV Activity of ACH-126,443 in a Phase 1/2 Trial in Chronic Hepatitis B Infection Abstract 690 (slide session). 42nd ICAAC. September 27-30, 2002. San Diego, CA.



(Hepatitis B Fund)