默沙东（Merck & Co）近日在英国格拉斯哥举行的第12届HIV药物治疗国际大会上公布了实验性HIV药物doravirine一项IIb期临床试验的48周积极数据，doravirine是一种实验性新一代非核苷类逆转录酶抑制剂（NNRT）。此前，默沙东已在第21届逆转录病毒和机会性感染大会（CROI 2014）公布了该项IIb期临床试验的24周疗效和安全性数据。截至目前，doravirine在临床取得的抗病毒疗效及整体安全性令人鼓舞，默沙东已计划在年底启动doravirine的III期临床研究。
该IIb期研究是一项随机、双盲、剂量范围试验（NCT01632345），在初治HIV成人感染者中开展，调查了4种剂量doravirine（25mg、50mg、75mg、100mg，每日一次）联合替诺福韦/恩曲他滨（tenofovir/emtricitabine，TDF/FTC，每日一次）相对于依非韦伦（efavirenz，600mg）/TDF/FTC组合疗法的疗效、安全性和耐受性。主要疗效分析是达到病毒学应答（＜40拷贝/毫升）的患者百分比。该研究由2部分组成：第一部分为剂量范围阶段，确定doravirine的剂量；第二部分为扩展阶段，根据第一部分的试验数据，已选择100mg剂量doravirine用于该项研究的第二部分，直至96周。
此次公布的是该IIb试验第一部分剂量范围阶段的48周数据。数据表明，在48周时，doravirine 4个剂量组（25，50，100，200mg）实现病毒学应答（＜40拷贝/毫升）的患者比例为76%（126/166）,依非韦伦治疗组实现病毒学应答的患者比例为71%（30/42）。研究中，所有治疗组CD4细胞计数相对基线均表现升高，与24周的研究结果相一致。安全性方面，doravirine治疗组药物相关不良事件总发生率较低（36.7%，N=166）,依非韦伦组较高（57.1%，N=42）。
doravirine又名MK-1439，是一种实验性、新一代、非核苷类逆转录酶抑制剂（NMRTI），目前正调查用于HIV-1感染的治疗。在临床前研究中，doravirine针对HIV-1表现出强劲的抗病毒活性。在早期临床研究中，doravirine表现出的药代动力学特性支持每日一次给药，同时并未表现出显著的食物影响。
英文原文：Merck Announces Data from 48-Week Phase 2b Study of Investigational HIV Therapy Doravirine (MK-1439) in Treatment-Naive Patients
Phase 3 Clinical Trial Enrollment Scheduled to Start by the End of 2014
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of results from a Phase 2b clinical trial evaluating the safety and efficacy of once-daily oral doravirine, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), plus tenofovir/emtricitabine (TDF/FTC) compared to efavirenz plus TDF/FTC in previously untreated patients with HIV-1 infection. Results were presented as a poster (#0434) and oral presentation by Dr. Josep M. Gatell, head, Infectious Diseases and AIDS Units-IDIBAPS, Hospital Clinic, Barcelona, at the 12th International Congress on HIV Drug Therapy being held in Glasgow, United Kingdom, Nov. 2-6.
The primary safety analysis from the expansion phase of the study compared the incidence of central nervous system (CNS) adverse events (AEs) by Week 8 in patients who received doravirine 100 mg plus TDF/FTC (n=108) versus patients who received efavirenz with TDF/FTC (n=108). The results showed a significantly lower incidence of one or more of reported CNS AEs (all causality) among the doravirine-treated group compared to the efavirenz-treated group (22.2 % vs. 43.5 %, respectively; p<0.001). The most common (occurring in more than 5 percent of patients) CNS AEs in the doravirine-and efavirenz-treated groups, respectively, were dizziness (9.3 % vs. 27.8 %), insomnia (6.5 % vs. 2.8 %), abnormal dreams (5.6 % vs. 16.7 %) and nightmares (5.6 % vs. 8.3 %).
Interim results for this ongoing Phase 2b study, including the primary efficacy analysis for dose selecion based on 24-week data from the dose-ranging cohort of the study, were previously presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in March 2014.
“This program underscores Merck’s ongoing commitment to the research and development of new therapeutic options for patients with HIV,” said Dr. Hedy Teppler, executive director, Infectious Diseases, Merck Research Laboratories. “We are encouraged by the antiviral activity and the overall tolerability profile of doravirine and look forward to initiating Phase 3 studies.”
Additional follow-up data through 48 weeks of treatment showed a 76 percent (n=126/166) overall virologic response rate (HIV RNA <40 c/ml) for all doravirine doses (25, 50, 100 and 200 mg) that is comparable to 71 percent (n=30/42) reported for patients administered efavirenz (600 mg). In addition, all treatment groups showed increased CD4 cell counts relative to baseline, consistent with the 24-week findings.
After 48 weeks of treatment, patients in the dose ranging part of the study who received doravirine demonstrated a lower overall incidence of drug-related adverse events (36.7%; n=166) than those who received efavirenz (57.1%; n=42). The most commonly reported drug-related clinical adverse events in the doravirine and efavirenz groups respectively were abnormal dreams (10.2% vs. 9.5%); nausea (7.8% vs. 2.4%); fatigue (7.2% vs. 4.8%); diarrhea (4.8% vs. 9.5%) and dizziness (3.0% vs. 23.8%). Doravirine-treated patients also had a lower incidence of laboratory abnormalities in routine clinical tests including increased total cholesterol (6.8% for doravirine vs. 31.6% for efavirenz) and LDL cholesterol (6.3% for doravirine vs. 18.4% for efavirenz).
Merck plans to initiate the first Phase 3 clinical trial of doravirine by the end of 2014, NCT02275780. The study will enroll treatment-naïve patients and compare the efficacy, safety and tolerability of doravirine and ritonavir-boosted darunavir, both in combination with other anti-retroviral therapy.
about the Phase 2b Study
The Phase 2b randomized, double blind, dose-ranging clinical trial (NCT01632345) evaluated the efficacy, safety and tolerability of once-daily doravirine (25, 50, 100 and 200 mg) compared to once-daily efavirenz 600 mg, both in combination with TDF/FTC, in previously untreated HIV-1 infected patients. The study has two parts:
In Part 1, the dose-ranging phase, patients received once daily doravirine (N=166) at one of four doses (25, 50, 100 or 200 mg) or efavirenz (n=42), both in combination with TDF/FTC. The doravirine dose to be used in Part 2 of the Phase 2b study and in Phase 3 was selected based on the Week 24 safety and efficacy data in doravirine-treated patients. After dose selection, all doravirine-treated patients were switched to the selected dose (100 mg doravirine) for the expansion phase of the study.
! \) q' n- G1 e' _+ Y& H" h5 @In Part 2, the expansion phase, an additional 132 patients were enrolled to receive 100 mg doravirine (n=66) or efavirenz (n=66), both in combination with TDF/FTC, to enable an assessment of the CNS safety and tolerability profile of doravirine.
0 X7 x3 o- c% M, \# u U1 \6 }The planned total treatment duration in the Phase 2 study is 96 weeks.
about Doravirine
Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being developed by Merck for the treatment of HIV-1 infection. In preclinical studies, doravirine showed potent antiviral activity against HIV-1. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of a once-daily dosing schedule and did not show a significant food effect.
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