FDA Approves Expanded Use Of ISENTRESS® (raltegravir) In Combination Therapy For Adult Patients With HIV-1 Infection

Main Category: HIV / AIDS
Also Included In: Regulatory Affairs / Drug Approvals;  Clinical Trials / Drug Trials;  Pharma Industry / Biotech Industry
Article Date: 01 Aug 2009 - 1:00 PDT

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Merck & Co., Inc. announced that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for ISENTRESS®. The broadened indication now includes use in the treatment of adult patients starting HIV-1 therapy for the first time (treatment-naïve), as well as in treatment-experienced adult patients. ISENTRESS is used in combination with other antiretroviral (ARV) medicines for the treatment of HIV-1 infection in adult patients. The indication for ISENTRESS is based on analyses of plasma HIV-1 RNA levels through 48 weeks in three double-blind controlled studies. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRT, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naïve adults. The safety and efficacy of ISENTRESS have not been established in pediatric patients. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

"Having a therapeutic option like ISENTRESS, with an efficacy and safety profile established through clinical studies up to 48 weeks, as part of a regimen with other anti-HIV medicines is a significant step forward for adult patients starting HIV therapy," said Dr. Daniel S. Berger, clinical associate professor at the College of Medicine, University of Illinois at Chicago and medical director of NorthStar Medical Center. "As clinicians, we believe in individualizing treatment regimens for adults with HIV because of the complexity of the disease. The new indication for ISENTRESS gives us an additional treatment option for patients starting therapy for the first time."

Treatment-naive indication supported by a double-blind controlled study of ISENTRESS The treatment-naïve indication for ISENTRESS was based on analyses of 563 treatment-naïve, HIV-1 infected patients through 48 weeks in an ongoing, multi-center, double-blind, randomized, active-controlled, Phase III study called STARTMRK. Patients in the study received either 400 mg ISENTRESS administered orally twice daily or 600 mg efavirenz, one of the leading ARVs prescribed for treatment-naïve patients, dosed orally once daily. ISENTRESS and efavirenz were administered in combination with tenofovir/emtricitabine. Patients who entered the study were required to have HIV viral loads greater than 5000 copies/mL. At baseline, geometric mean HIV RNA levels for patients on the regimen including ISENTRESS was 103,205 copies/mL (n=281) and for the efavirenz regimen was 106,215 copies/mL (n=282). Mean baseline CD4 cell counts were 219 and 217 cells/mm³ for the groups receiving ISENTRESS and efavirenz, respectively.

In the study, the ISENTRESS-based regimen was as effective as the efavirenz-based regimen at reducing HIV-1 viral load to undetectable levels. Additionally, patients treated with the ISENTRESS-based regimen had a greater increase in CD4 cell counts compared to patients receiving efavirenz-based therapy. Patients taking ISENTRESS had a low incidence of adverse experiences (AEs) and experienced less effects on lipid levels than patients on the efavirenz-based regimen. The most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical adverse experience (AE) of moderate or severe intensity in treatment-naïve patients receiving ISENTRESS and at a higher incidence compared to efavirenz was insomnia (four percent versus three percent).

Suppression of viral load and increase in CD4 cell counts durable through 48 weeks In the STARTMRK trial, ISENTRESS reduced HIV-1 viral load to undetectable levels (less than 50 copies/mL) at a rate comparable to efavirenz (87 percent for ISENTRESS versus 82 percent for efavirenz); the difference in viral load reduction between the two treatment groups was 4.7 percent (95 percent CI; -1.3 percent, 10.6 percent) through 48 weeks. There were greater average increases in CD4 cell counts (176 cells/mm³ for ISENTRESS versus 150 cells/mm³ for efavirenz); the difference in mean CD4 cell count change from baseline between the two treatment groups was 25.8 (95 percent CI; 5.0, 46.5) through 48 weeks.

These efficacy results were supported by the 96-week analysis of a randomized, double-blind, controlled, dose-ranging trial, Protocol 004, in ARV treatment-naïve HIV-1 infected adult subjects comparing ISENTRESS to efavirenz, both in combination with tenofovir and lamivudine.

Impact on lipids

Results from STARTMRK showed that ISENTRESS in combination therapy had less effects on lipid levels than efavirenz-based therapy for treatment-naïve patients.

Efficacy and safety of ISENTRESS in treatment-experienced patients through 48 weeks The use of ISENTRESS in treatment-experienced patients was supported by two identical ongoing multi-center, double-blind, randomized, placebo-controlled Phase III studies (BENCHMRK-1 and BENCHMRK-2). In these studies, 699 treatment-experienced patients with triple class resistant HIV who were failing ARV therapies received ISENTRESS 400 mg orally twice daily in combination with optimized background therapy (OBT) or received placebo 400 mg orally twice daily plus OBT. Patients who entered the study were 16 years or older with documented resistance to at least one drug in each of the three oral classes of ARVs (NNRT, NRTI, PI).

In a pooled analysis of BENCHMRK-1 and BENCHMRK-2, ISENTRESS plus OBT suppressed viral load to below 50 copies/mL in 60 percent of patients (277 out of 462) compared to 31 percent of patients (73 out of 237) who received placebo plus OBT. ISENTRESS plus OBT increased CD4 cell counts from baseline by 106 cells/mm³ compared to 44 cells/mm³ for patients receiving placebo plus OBT. ISENTRESS plus OBT maintained suppression of HIV RNA levels below 400 copies/mL in 72 percent of patients (332 out of 462) compared to 37 percent of patients (88 out of 237) receiving placebo plus OBT.

The most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical AEs of moderate or severe intensity in treatment-experienced patients receiving ISENTRESS and at a higher rate compared to placebo were headache (rate of three versus one, per 100 patient years), nausea (rate of two versus one, per 100 patient years), asthenia/weakness (rate of two versus one, per 100 patient years) and fatigue (rate of two versus one, per 100 patient years).

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

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

Dosing and administration

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. The dose of ISENTRESS should be increased during coadmistration with rifampin to 800 mg twice daily.

Drug interactions

Coadmistration with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may reduce plasma concentrations of ISENTRESS. Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other ARV agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes.

One million Americans living with HIV and AIDS

"HIV continues to grow at pandemic proportions with over 55,000 new cases reported in the U.S. each year. Blacks and Hispanics in particular, are disproportionally affected by the disease," said Phill Wilson, founder and executive director of the Black AIDS Institute. "The availability of additional treatment options for HIV-1 patients, including those beginning treatment or those experiencing resistance to other treatments, is encouraging news for the more than one million Americans currently living with HIV and AIDS."

About ISENTRESS

ISENTRESS is the first medicine to be approved in a class of ARV drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process protease and reverse transcriptase but ISENTRESS is the only approved drug that inhibits the integrase enzyme.

ISENTRESS is now approved in more than 80 countries worldwide for treatment-experienced adult patients. Merck is continuing to move forward with filings in additional countries around the world for use of ISENTRESS in both treatment-experienced and treatment-naïve patients.

Patient assistance programs in the U.S

Merck is launching a co-pay assistance program in August in the U.S. for eligible patients on ISENTRESS who are commercially insured and have co-pays or coinsurance above $30 up to a maximum of $400 per month. With this program eligible patients can receive savings off their out-of-pocket costs for up to one year.

In addition, for eligible patients with HIV, Merck provides patient assistance to ensure access to ISENTRESS through a program called SUPPORT™. The SUPPORT Program helps patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues. The Program can also provide patient assistance which may provide ISENTRESS free of charge to eligible patients.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

ISENTRESS® is a registered trademark of Merck & Co., Inc.

Source: Merck

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