FDA Approves New Labeling for ISENTRESS® (raltegravir) to Include 156-Week Data Demonstrating Long-Term Efficacy, Safety and Tolerability with ISENTRESS in Combination Therapy in Previously Untreated Adult Patients Infected with HIV-1
May 21, 2012 7:00 am ET
Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) approved a labeling update for ISENTRESS® (raltegravir) Film-coated Tablets to include 156-week data from the STARTMRK study with ISENTRESS in combination therapy compared to efavirenz in combination therapy in previously untreated (treatment-naïve) adult HIV-1-infected patients. The analyses showed that the regimen containing ISENTRESS demonstrated long-term viral suppression, a greater immunologic response and a proven safety and tolerability profile at 156 weeks.ISENTRESS is the first and only integrase inhibitor indicated for the treatment of HIV-1 in adult treatment-experienced and treatment-naïve patients as part of a combination treatment regimen.
ISENTRESS is 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 156 weeks.
The use of other active agents with ISENTRESS 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 treatment, immune reconstitution syndrome may occur. (See Important Selected Safety Information below.)
“As the continuum of HIV care continues to evolve, ISENTRESS remains an important treatment option for adult patients with HIV-1,” said Jürgen Rockstroh, M.D., University of Bonn, Bonn-Venusberg, Germany. “Physicians now have new information about a regimen that includes long-term efficacy and tolerability of ISENTRESS, out to three years in treatment-naïve adult HIV-1 patients.”
STARTMRK study design
In this ongoing, multi-center, double-blind, randomized, active-controlled, Phase III non-inferiority study,563 previously untreated HIV-1 infected adult patients with HIV-1 RNA greater than 5000 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 and the evaluation of safety and tolerability 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, less than 400 copies/mL, and change from baseline in CD4-cell count, as well as safety.The 156-week data reported in the updated label for ISENTRESS represent three-year results from a planned five-year study.
Long-term efficacy of ISENTRESS (raltegravir) in treatment-naïve adult patients with HIV-1 through three years
In the STARTMRK trial, the regimen containing ISENTRESS was as effective as the regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL). At study entry, the mean baseline plasma HIV-1 RNA for patients on a regimen containing ISENTRESS was 103,205 copies/mL, and for patients on a regimen containing efavirenz was 106,215 copies/mL. Results for the 156-week analysis showed long-term viral suppression for patients on a regimen containing ISENTRESS of 76 percent and 68 percent for the regimen containing efavirenz [treatment difference of 7.4 percent of patients with 95 percent confidence interval (CI): -0.1%, 14.7%].
The regimen containing ISENTRESS demonstrated a greater immunologic response than the regimen containing efavirenz at 156 weeks. At study entry, patients on the regimen containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm3, and at 156 weeks experienced a mean change of 281 cells/mm3. Patients on the regimen containing efavirenz had a mean baseline CD4 cell count of 217 cells/mm3, and experienced a mean change of 241 cells/mm3 at 156 weeks.
Safety and tolerability profile of ISENTRESS (raltegravir) in treatment-naïve adult patients with HIV-1
Patients on the regimen containing ISENTRESS demonstrated a lower treatment discontinuation rate due to clinical adverse reactions versus patients on the regimen containing efavirenz at 156 weeks.Nearly 50 percent fewer patients on the regimen containing ISENTRESS discontinued treatment versus the regimen containing efavirenz, with discontinuation rates at 5 percent for patients on the regimen containing ISENTRESS versus 9 percent for patients on the regimen containing efavirenz.
In the STARTMRK trial, through 156 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) and fatigue (2 percent versus 3 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.
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 144, shown in the table below.
Lipid Values, Mean Change from Baseline at Week 144
|ISENTRESS 400 mg
Twice Daily + Emtricitabine (+) Tenofovir
N = 281
|Efavirenz 600 mg
At Bedtime + Emtricitabine (+) Tenofovir
N = 282
*Fasting (non-random) laboratory tests at week 144.
N = Number of subjects in the treatment group. The analysis is based on all available data.
If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis.
Important Selected Safety Information
ISENTRESS (raltegravir) does not cure HIV-1 infection or AIDS.
Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis.Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systematic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.
Health care providers should know that during the initial phase of treatment, immune reconstitution syndrome can occur, which may necessitate further evaluation and treatment. Monitor for immune reconstitution syndrome.
Coadministration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in reduced plasma concentrations of raltegravir. Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS for adults should be increased to 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.
Grade 2 to 4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.
Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS plus darunavir/ritonavir, compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug-related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
About ISENTRESS (raltegravir)
ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1 infection in adult patients and pediatric patients ages 2 years and older as part of combination HIV therapy.ISENTRESS is currently the only approved integrase inhibitor for the treatment of HIV-1.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 combination therapy in more than 45 countries for use in treatment-naïve adult patients with HIV-1 and in more than 90 countries for use in treatment-experienced adult patients with HIV-1. Merck is continuing to move forward with filings in additional countries around the world.
To assist patients taking ISENTRESS, Merck offers the SUPPORT™ program, which provides personal support and patient advocacy regarding individual reimbursement issues. For more information about the SUPPORT™ program, please visit www.merckhelps.com or call 1-800-850-3430.
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com and connect with us on Twitter, Facebook and YouTube.
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.
The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
ISENTRESS® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA
Please see Prescribing Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf and Patient Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.
Pam Eisele, 908-423-5024
Claire Mulhearn, 908-423-7425
Carol Ferguson, 908-423-4465