默沙东HIV药物Isentress新标签获FDA批准

默沙东（Merck & Co）7月1日宣布，FDA已批准了艾生特（Isentress，通用名：拉替拉韦，raltegravir）薄膜衣片的新标签。

Isentress是一种整合酶抑制剂，作为HIV组合疗法的一部分用于HIV-1感染成人患者的治疗。已更新的处方信息包括了STARTMRK研究中为期240周的研究结果，该研究是迄今为止在初治HIV-1感染成人患者中开展的、评价一种整合酶抑制剂的历时最久的双盲III期非劣性研究。研究结果表明，与包含依非韦伦（efavirenz）的HIV组合疗法相比，含Isentress的HIV组合疗法显示出了长期的病毒抑制及更强的免疫反应，同时在为期240周时间内，在既往未治疗（初治）HIV-1感染成人患者中显示出了长期的安全性和耐受性。

Isentress作为一种整合酶抑制剂，旨在与其他抗逆转录病毒（ARV）制剂联合用药，用于HIV-1成人感染者。该适应症是基于有关Isentress的3个双盲对照研究中对血浆HIV-1 RNA水平的分析数据，其中2个研究为期96周，在既往接受过3类ARV【非核苷类逆转录酶抑制剂（NNRTI）、核苷类逆转录酶抑制剂（NRTI）、蛋白酶抑制剂（PI）】治疗的患者中开展。另一个研究为期240周，在初治患者中开展。

尽管HIV临床护理在不断演进，但对于HIV-1成人感染者而言，Isentress将继续作为一个重要的临床治疗选择。对于临床医生而言，考虑在HIV-1初治成人患者中启动含Isentress组合疗法时，这些为期240周的研究数据非常重要。

英文原文：FDA Approves New U.S. Labeling for ISENTRESS® (raltegravir) to Include 240-Week Results from STARTMRK Study of ISENTRESS Containing Regimen in Previously Untreated HIV-1 Infected Adult Patients

Monday, July 1, 2013 5:05 pm EDT WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved new labeling for ISENTRESS® (raltegravir) Film-coated Tablets, Merck’s integrase inhibitor for the treatment of HIV-1 infection in adult patients as part of combination HIV therapy. The updated prescribing information now includes 240-week results from the STARTMRK study, the longest double-blind Phase III non-inferiority study evaluating an integrase inhibitor in treatment-naïve adult patients with HIV-1 infection. The results show that the regimen containing ISENTRESS in combination therapy demonstrated long-term viral suppression and a greater immunologic response than the efavirenz-containing regimen, as well as a proven, long-term safety and tolerability profile through 240 weeks in previously untreated (treatment-naïve) adult HIV-1 infected patients.

ISENTRESS is an integrase inhibitor indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adult patients through 96 weeks and one was conducted in treatment-naïve adults through 240 weeks.

The use of other active agents with ISENTRESS (raltegravir) is associated with a greater likelihood of treatment response.

Severe, potentially life-threatening and fatal skin reactions have been reported with ISENTRESS. Additionally, during the initial phase of combination ARV treatment, immune reconstitution syndrome may occur. (See Important Selected Safety Information below.)

“As the care of HIV evolves, ISENTRESS continues to be an important treatment option for adult patients with HIV-1,” said Jürgen Rockstroh, M.D., University of Bonn, Bonn-Venusberg, Germany. “These 240-week results are important for physicians to consider when initiating treatment with ISENTRESS in combination therapy in treatment-naïve adult patients with HIV-1.”

“Merck has been at the forefront of HIV research for close to 30 years. The discovery of ISENTRESS and its clinical development program are a testament to Merck’s long-term commitment to the research and development of medicines for HIV,” said Daria Hazuda, Ph.D., vice president of Early Development and Discovery Sciences Research for infectious diseases, Merck.

STARTMRK study design

STARTMRK was a multi-center, double-blind, randomized, active-controlled, Phase III non-inferiority study. In the study, 563 previously untreated HIV-1 infected adult patients with HIV-1 RNA greater than 5,000 copies/mL received either 400 mg ISENTRESS orally twice daily (n=281) or 600 mg efavirenz orally once daily (n=282), each in combination with tenofovir/emtricitabine. The primary endpoint of the study was a reduction in HIV-1 viral load to less than 50 copies/mL at week 48. Secondary endpoints included ARV activity, as measured by the proportion of patients achieving HIV-1 viral load to less than 50 copies/mL at 96 weeks, as well as achieving viral load less than 400 copies/mL and change from baseline in CD4 cell count, both measured at 48 and 96 weeks. Pre-specified exploratory endpoints also included the proportion of patients achieving HIV-1 viral load to less than 50 copies/mL at 240 weeks, as well as change from baseline in CD4 cell count at 240 weeks. Safety was evaluated throughout the study period. Merck presented the 240-week STARTMRK study results for the first time at AIDS 2012 in Washington, D.C. and the results were subsequently published in Journal of Acquired Immune Deficiency Syndromes (JAIDS) in May 2013.

ISENTRESS (raltegravir) in combination therapy shows long-term efficacy in previously untreated adult HIV-1 patients through 240 weeks

In the STARTMRK trial, the regimen containing ISENTRESS was non-inferior to the regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL) at 240 weeks. At the study entry, the geometric mean baseline plasma HIV-1 RNA for patients was over 100,000 copies/mL (103,205 copies/mL for those on a regimen containing ISENTRESS (raltegravir) and 106,215 copies/mL for patients on a regimen containing efavirenz). Results for the 240-week analysis showed long-term viral suppression (HIV-1 RNA less than 50 copies/mL) for patients on the regimen containing ISENTRESS of 66 percent and 60 percent for the regimen containing efavirenz [treatment difference of 6.6 percent of patients with 95 percent confidence interval (CI): -1.4 percent, 14.5 percent].

The regimen containing ISENTRESS demonstrated a greater immunologic response than the regimen containing efavirenz at 240 weeks. Patients on the regimen containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm3 compared to 217 cells/mm3 for patients on the regimen containing efavirenz. From study entry to week 240, patients on the regimen containing ISENTRESS had a mean baseline increase in CD4 cell count of 295 cells/mm3 versus 236 cells/mm3 for patients on the regimen containing efavirenz.

Safety and tolerability profile for ISENTRESS (raltegravir) through 240 weeks in STARTMRK

In the STARTMRK trial, through 240 weeks, there was a low incidence of drug-related adverse reactions of moderate to severe intensity that occurred in greater than or equal to 2 percent of patients treated with ISENTRESS. These adverse drug reactions as compared to efavirenz were insomnia (4 percent, in both arms), headache (4 percent versus 5 percent), nausea (3 percent versus 4 percent), fatigue (2 percent versus 3 percent) and dizziness (2 percent versus 6 percent). "Moderate" reactions were defined as discomfort enough to cause interference with usual activity. "Severe" reactions were defined as incapacitating with inability to work or do usual activity.

Patients on the regimen containing ISENTRESS also demonstrated a lower treatment discontinuation rate due to clinical adverse reactions versus patients on the regimen containing efavirenz through 240 weeks (5 percent versus 10 percent, respectively). Additionally, ISENTRESS in combination therapy had less effect on lipids [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol] and triglycerides fasting serum lipids at week 240, as shown in the table below.