默沙东抗艾药Isentress扩大适应症已获FDA批准
上周四，FDA批准了美国默沙东公司抗艾药Isentress的扩大适应症，即用于治疗那些感染了艾滋病毒但尚未接受过任何治疗的患者。

Isentress是目前唯一获准的整合酶抑制剂类抗艾新药，它在2007年末就已经获准用于那些之前采用过其他抗艾药治疗但效果不理想的患者。

新适应症的获准将进一步推动该药的销量，去年，这种药物的销售额达到3.61亿美元。医生在开具处方时，经常将Isentress与Truvada（由Gilead公司销售）联用。

Isentress可以阻断一种名为整合酶的蛋白，从而防止病毒中的遗传物质与人类细胞相结合。目前，Gilead公司也正在研发一种具有相似作用机理的新型抗艾药。

默沙东公司表示，在临床实验过程中，Isentress的耐受性良好，副作用少。此外，实验还证实，对于那些采用过其他抗艾药治疗但失败的患者，Isentress+标准疗法在抑制HIV病毒方面的作用是单用标准疗法的2倍。

而对于那些此前未接受过治疗的患者，Isentress+ Truvada在降低病毒水平的效果稍好于Truvada+ Efavirenz（默沙东早先上市的同类老药）。

raltegravir片剂是FDA批准用于治疗艾滋病的新药。raltegravir片剂(Isentress)是默克公司生产的新型抗艾药物，获FDA批准与其它抗逆转录病毒药物联用于已接受过治疗但病毒仍在复制，且人免疫缺陷病毒-1(HIV-1)毒株对多种抗逆转录病毒药物耐药的成年患者治疗HIV-1感染。

商品名：整合酶抑制剂

英文名：Isentress(Raltegravir)

别名：L-900612，MK-051

研制公司：美国Merck公司

适应证：与其他抗逆转录病毒药物联用，治疗那些经过其他药物治疗后仍发生病毒复制并且对多种抗逆转录病毒药物产生抗性的HIV感染者。

不良反应：最常见的raltegravir相关性不良反应主要为恶心、头痛、腹泻、疲劳、瘙痒、便秘、出汗，较为温和，易于控制。

药理作用：Raltegravir属于整合酶抑制剂，能通过阻止病毒DNA整合入宿主DNA而阻止病毒复制和感染新的细胞。整合酶抑制剂能更有效地阻止病毒的早期复制，从而阻止病毒库的产生。

药动学：Raltegravir动物体内外的药动学研究显示，口服给药，最佳给药时间为每隔l2小时l次。对健康志愿者单剂量(100～1600mg)及多剂量(400～800mg)连续10d给与本品的药动学参数为：单剂量给药后，药物吸收迅速(tmax=0．5～1．3h)，体内二室模型分布，消除半衰期7～12h，生物利用度好，不受高脂饮食及性别的影响；多剂量给药两天后达到稳态血浆浓度。

临床研究：临床试验表明，raltegravir对经过和未经高效抗逆转录病毒(HAART)治疗的患者均疗效显著。Ⅲ期临床试验结果显示，一天两次使用raltegravir和鸡尾酒疗法的病人中，未能检测到HIV的病人为60％；仅接受鸡尾酒疗法的病人中，未能检测到HIV的占35％。

Isentress gains indication for use in treatment-naïve HIV patients
has approved an expanded indication for Isentress (raltegravir tablets, from Merck), a HIV-1 integrase strand transfer inhibitor, in combination with other antiretrovirals for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients, including treatment-naïve patients. Isentress was previously indicated for use only in treatment-experienced adults with evidence of viral replication and HIV-1 strains resistant to multiple antiretrovirals.  The expanded indication is based on results from a 48-week, randomized, double-blind, active control trial in treatment-naïve patients that evaluated the safety and efficacy of Isentress plus emtricitabine plus tenofovir versus Sustiva (efavirenz, from Bristol-Myers Squibb) plus emtricitabine plus tenofovir. The proportion of patients with HIV RNA <50 copies/mL was 87% for patients treated with Isentress compared to 82% of patients treated with Sustiva. The difference between Isentress and Sustiva with respect to HIV RNA <50 copies/mL is 4.7% (95% confidence interval: -1.3%, 10.6%).

                                  Isentress is available in a 400mg dosage strength.

Data from ISENTRESS®, Merck's HIV Integrase Inhibitor, in Patients Whose HIV is Controlled on a Lopinavir/Ritonavir-Based Therapy Presented at the 16th Conference on Retroviruses and Opportunistic Infections

MONTREAL--(Business Wire)--
Merck & Co., Inc. (NYSE: MRK):

* Switching from Lopinavir/Ritonavir-Based to ISENTRESS-Based CombinationAntiretroviral Therapy Significantly Improved Total Cholesterol, Triglycerides,Non-HDL-Cholesterol at Week 12
* Switching from Lopinavir/Ritonavir-Based to ISENTRESS-Based CombinationAntiretroviral Therapy did not Demonstrate Non-Inferior Virologic Efficacy

Two Phase III studies (SWITCHMRK-1 and -2) evaluating theeffectofswitchingpatientswhoseHIViscontrolledonalopinavir/ritonavir-based regimen to aregimen containing Merck & Co., Inc.'s HIV integrase inhibitor ISENTRESS®(raltegravir) tablets showed that ISENTRESS significantly improved totalcholesterol, triglycerides and non-HDL-cholesterol. Also, the study showedthatISENTRESS did not demonstrate non-inferior virologic efficacy at maintainingviral load suppression. As a result of theviralloadfindings in these trials,Merck discontinued these two studies.

Findings from the 24-week interim analyses of SWITCHMRK-1 and -2 were presentedtoday at the 16th Conference on Retroviruses and Opportunistic Infections (CROI)in Montreal, Canada.

ISENTRESS is the first integrase inhibitor approved for use in combination withother antiretroviral agents for the treatment of HIV-1 infection intreatment-experienced adult patients with evidence of viral replication withHIV-1 strains resistant to multiple antiretroviral agents. This indication isbased on analyses of plasma HIV-1 RNA levels up through 48 weeks in two
controlled studies of ISENTRESS. These studies were conducted in clinicallyadvanced, three-class antiretroviral [nucleoside reverse transcriptaseinhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) andprotease inhibitors (PIs)] treatment-experienced adults. In these studies theuse of other active agents with ISENTRESS is associated with a greaterlikelihood of treatment response. The safety and efficacy of ISENTRESS have notbeen established in treatment-naïve adult or pediatric patients.

As with all HIV treatment regimens, ISENTRESS should be used with other activeantiviral agents.

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others.
During the initial phase of treatment, patients responding to antiretroviraltherapy may develop an inflammatory response to indolent or residualopportunistic infections (such as Mycobacterium avium complex, cytomegalovirus,Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis or reactivation ofvaricella zoster virus), which may necessitate further evaluation and treatment.

Study results

In one study, Protocol 032 (also called SWITCHMRK-1), 81 percent of patientsreceiving a regimen with ISENTRESS maintained undetectable viral levels (lessthan 50 copies/mL) compared with 87 percentofpatientsreceivingaregimenwithlopinavir/ritonavir. In the second study, Protocol 033 (also calledSWITCHMRK-2), the regimen with ISENTRESS maintained undetectable viral load
levels in 88 percent of patients compared with 94 percent of patients receivinga regimen with lopinavir/ritonavir. In both studies, switching treatment to aregimen with ISENTRESS resulted in significantly greater decreases in totalcholesterol, triglycerides and non-HDL-cholesterol (p<0.001) compared tocontinuing the lopinavir/ritonavir-based regimen.

Primary endpoints from the study include mean percent change in fasting lipids(total cholesterol, triglycerides, non-HDL and LDL) at Week 12, proportion ofpatients with viral load suppressed to undetectable levels (less than 50copies/mL) at Week 24 and safety and tolerability at Week 24.

ISENTRESS did not demonstrate non-inferiority in maintaining viral loadsuppression

In regard to suppression of viral load, results at Week 24 showed that ISENTRESSdid not demonstrate non-inferiority (one of the primary endpoints for bothtrials) as compared to lopinavir/ritonavir as measured by proportion ofpatientswithundetectable viral levels. These results were based on an intent-to-treatanalysis which assumes all study dropouts are virologic failures.

The viral load results are represented in the chart below:

HIV Viral Load (vRNA) Summary at Week 24

Number (%) of Patients
      
                      Protocol 032      Protocol 033                                
                      Lopinavir/Ritonavir               ISENTRESS       Lopinavir/Ritonavir  ISENTRESS 
vRNA <50 copies/mL    152/174 (87.4)    139/172 (80.8)  167/178 (93.8)  154/175 (88.0) 
vRNA <400 copies/mL   156/174 (89.7)   48/172 (86.0)    173/178 (97.2)  164/175 (93.7) 

Based on post-hoc data collection, 84 percent (27 out of 32) of patients withconfirmed virologic failure (viral levels greater than 50 copies/mL) in thegroup receiving ISENTRESS reported that their regimen at study entry was nottheir first antiretroviral regimen; and 66 percent (18 out of 27) of thesepatients reported a history of virologic failure on prior regimens.

"The observation that treatment with ISENTRESS did not achieve non-inferiorityas measured by the proportion of patients with a viral load of less than 50copies/mL as compared withlopinavir/ritonavirbasedregimensunderscoresthecomplicatedconsiderations involved in selecting the optimal treatment regimenfor patients. Physicians should carefully evaluate all patient background
information and previous treatment outcomes, including any change in viral loador tolerability concerns, when introducing a new therapy or considering a switchin treatment regimen," said Joseph Eron, M.D., professor of medicine, DivisionofInfectious Diseases, University of North Carolina Chapel Hill School ofMedicine.

Clinical adverse experiences of all severities were similar among patientstreated with ISENTRESS as compared to those treated with thelopinavir/ritonavir-based regimen respectively (69.9 percent vs. 62.9 percent inProtocol 033; 62.6 percent vs. 60.9 percent in Protocol 032) and drug-relatedadverse events (13.1 percent vs. 19.7 percent in Protocol 033; 13.8 percent vs.
10.9 percent in Protocol 032).

Protocols 032 and 033 stoppedAs a result of the viral load findings in these trials, Merck has stoppedProtocols 032 and 033 and has notified the appropriate regulatory agencies andtrial investigators for ISENTRESS about these data. At this time, onlypreliminary data are available for Protocols 032 and 033 and Merck is conductingthorough analyses of both studies to better understand the results.

"Merck remains committed to understanding appropriate utilization of ISENTRESSin a broad spectrum of HIV patients, and has alerted the appropriate regulatoryagencies and trial investigators for ISENTRESS of these findings," said RobinIsaacs, M.D., vice president, Clinical Research, Merck Research Laboratories.
"We will conduct continued analyses of these findings as soon as completeresults are available."

ISENTRESS significantly improved total cholesterol, triglycerides, non-HDLcholesterol at Week 12

In regard to the co-primary endpoints ofbothstudies,thedatademonstratedthatpatientsswitchedtoISENTRESShadsignificantdecreases in totalcholesterol, triglycerides and non-HDL cholesterol. There was no statisticaldifference in mean percent change from baseline in LDL. Results from the twostudies are represented in the chart below.

Mean Percent Change from Baseline in Fasting Lipid Parameters at Week 12;p<0.001

Protocol 032     Protocol 033                                                     
Lopinavir/       ISENTRESS Lopinavir/     ISENTRESS        
Ritonavir        Ritonavir                                         
Base    Mean % change    Base  Mean % change    Base    Mean % change Base  Mean % change 
                          line mean                      line mean    line mean   ine mean                   
Total cholesterol (TC)   205    1    217   -13    211    1            214           -12           
Triglycerides* TG)       164    4   190    -41    219    8            210           -43           
Non-HDL cholesterol (non-HDL-C)    158    2       166    -15 164 3    68           -15           
LDL-C           105           2      116        -2        104  1    104    4             
HDL-C           47     1       49      -1       48     -3     46            -1            
*Median value presented for triglycerides                                                                                                                                   
Study Background

Protocol 032 and 033 studies are multi-center, double-blind, randomized,active-controlled non-inferiority studies to evaluate the safety, tolerabilityand efficacy of ISENTRESS in patients who are well controlled (viral load lessthan 50 copies/mL) on a stable lopinavir/ritonavir based regimen (400/100 mgtwice daily) and were randomized to switch to ISENTRESS or continue on
lopinavir/ritonavir. In these studies, 354 patients in Protocol 033 and 348patients in Protocol 032 were randomized to remain on thelopinavir/ritonavir-based regimen or be switched to ISENTRESS 400 mg twicedaily.

Patients enrolled in the study were required to be stable on thelopinavir/ritonavir-containing regimen, defined as having viral load suppressedto less than 50 copies/mL for at least three months, and were taking at leasttwo nucleoside reverse transcriptase inhibitors (NRTIs) as part of theirregimen. Because patients were enrolled in the study regardless of whether theyhad been on previous regimens prior to their lopinavir/ritonavir-based regimen,and regardless of the number of treatment failures previously experienced, thepatient population in these studies had very diverse treatment experiences.

Additional important safety information about ISENTRESS

Due to rifampin's potent induction of uridine diphosphateglucoronosyltransferase (UGT) 1A1, the recommended dosage of ISENTRESS is 800 mgtwice daily during coadministration with rifampin. Caution should be used whencoadministering ISENTRESS with other strong inducers of UGT1A1 due to reducedplasma concentrations of ISENTRESS.

The most common adverse reactions of moderate to severe intensity (less than orequal to two percent) which occurred at a higher exposure adjusted rate comparedto placebo are headache, nausea, asthenia and fatigue.

Creatine kinase elevations were observed in subjects who received ISENTRESS.
Myopathy and rhabdomyolysis have been reported; however, the relationship ofISENTRESS to these events is not known. ISENTRESS should be used with caution inpatients at increased risk of myopathy or rhabdomyolysis, such as patientsreceiving concomitant medication known to cause these conditions.

About ISENTRESS

ISENTRESS is the first medicine to be approved in a class of antiretroviraldrugs called integrase inhibitors. ISENTRESS works by inhibiting the insertionof HIV-1 DNA intohuman DNA by the integrase enzyme. Inhibitingintegrasefromperformingthisessential function limits the ability of the virus to replicateand infect new cells. Therearedrugsinusethatinhibittwootherenzymescritical to the HIV-1 replication process - protease and reverse transcriptase -but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

In October 2007, the U.S. Food and Drug Administration granted ISENTRESSaccelerated approval and in January 2009 traditional approval for use incombination with other antiretroviral agents for the treatment of HIV-1infection in treatment-experienced adult patients with evidence of viralreplication and HIV-1 strains resistant to multiple antiretroviral agents.ISENTRESS is a single 400 mg tablet taken twice daily without regard to food.
During coadministration with rifampin, the recommended dosage of ISENTRESS is800 mg twice daily with or without food. ISENTRESS does not require boostingwith ritonavir.

Merck HIV research

Merck is committed to developing innovative therapies that offer advances in thetreatment of infectious diseases - including HIV. Merck's efforts to developinvestigational treatments for HIV and AIDS have been under way for morethan20yearsandcontinue today. Merck began its HIV integrase inhibitor research in1993 and was the first to demonstrate inhibition of HIV integrase in vitro andin vivo.

Prevalence of HIV and AIDS

In 2006, more than one million Americans were living with HIV and AIDS, and itis estimated that approximately more than 56,000 new cases of HIV and AIDS areiagnosed each year in the United States.

Worldwide, an estimated 33 million people are infected with HIV and AIDS, andmore than two million new infections occurred in 2007.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicatedto putting patients first. Established in 1891, Merck currently discovers,develops, manufactures and markets vaccines and medicines to address unmetmedical needs. TheCompany devotes extensive efforts to increase access tomedicines through far-reaching programs that not only donate Merck medicines buthelp deliver them to the people who need them. Merck also publishes unbiasedhealth information as a not-for-profitservice. For more information, visitwww.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is definedin the Private Securities Litigation Reform Act of 1995. These statements arebased on management's current expectations and involve risks and uncertainties,whichmaycause results to differ materially from those set forth in thestatements.
The forward-looking statements may includestatementsregardingproduct development, product potential or financial performance. Noforward-looking statement can be guaranteed and actual results may differmaterially from those projected.
Merck undertakes no obligation to publiclyupdate any forward-looking statement, whether as a result of new information,
future events, or otherwise. Forward-looking statements in this press releaseshould be evaluated together with the many uncertainties that affect Merck'sbusiness, particularly those mentioned in the risk factors and cautionarystatements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, andin any risk factors or cautionary statements contained in the Company's periodicreports on Form 10-Q or current reports on Form 8-K, which the Companyincorporates by reference.

Prescribing information and patient prescribing information for ISENTRESS® isattached.

ISENTRESS® is a registered trademark of Merck & Co., Inc., Whitehouse Station,N.J., USA

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ISENTRESSsafely and effectively. See full prescribing information for ISENTRESS.

ISENTRESS (raltegravir) TabletsInitial U.S. Approval:2007
RECENT MAJOR CHANGES

Indications And Usage (1) 01/2009

Dosage And Administration (2) 01/2009

Warnings And Precautions (5) 01/2009

INDICATIONS AND USAGE

ISENTRESS is a human immunodeficiency virus integrase strand transfer inhibitor(HIV-1 INSTI) indicated:

* In combination with other antiretroviral agents for the treatment of HIV-1infection in treatment-experienced adult patients who have evidence of viralreplication and HIV-1 strains resistant to multiple antiretroviral agents (1).

The safety and efficacy of ISENTRESS have not been established intreatment-naïve adult patients or pediatric patients (1).

DOSAGE AND ADMINISTRATION

* 400 mg administered orally, twice daily with or without food (2).
* During coadministration with rifampin, 800 mg twice daily (2).

DOSAGE FORMS AND STRENGTHS

Tablets: 400 mg (3).

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Monitor for Immune Reconstitution Syndrome (5.1).

ADVERSE REACTIONS

* The most common adverse reactions of moderate to severe intensity