Merck's ISENTRESS (raltegravir) in Combination Therapy Demonstrated Efficacy in a Phase II Study Extending to Nearly Five Years in Previously Untreated Adults with HIV-1

ROME--(BUSINESS WIRE)--Jul 18, 2011 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced final results from a Phase II clinical study, extending out to 240 weeks, of its integrase inhibitor ISENTRESS® (raltegravir) Tablets in combination therapy in previously untreated (treatment-naïve) adult HIV-1-infected patients. The regimen containing ISENTRESS showed efficacy similar to the regimen containing efavirenz at suppressing HIV-1 viral load to undetectable levels (less than 50 copies/mL) and at improving CD4 counts in treatment-naïve adult patients. Data also showed that ISENTRESS in combination therapy resulted in fewer reported drug-related adverse events (AEs) than efavirenz, and showed a modest impact on low-density lipoprotein (LDL) cholesterol and triglycerides. These 240-week results will be presented on July 20th at the 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Rome.

“In this Phase II study, ISENTRESS demonstrated comparable efficacy and tolerability to efavirenz at 240 weeks in treatment-naïve adult patients with HIV-1,” said primary investigator Dr. Eduardo Gotuzzo, professor of medicine, infectious diseases and tropical medicine, Universidad Peruana Cayetano Heredia, Lima, Peru, who presented the data. “Because physicians consider many factors when selecting antiretroviral therapy for adult HIV-1 patients new to treatment, the results seen in this Phase II study with ISENTRESS in combination therapy showing a modest impact on LDL and triglycerides provide important insights.”

ISENTRESS is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults. The label for ISENTRESS is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled Phase III clinical 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 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.

Protocol 004 study design

In this completed multicenter, double-blind, randomized, active-controlled Phase II study, 198 previously untreated HIV-1-infected adult patients received either 400 mg ISENTRESS orally twice daily (n=160) or 600 mg efavirenz orally once daily (n=38), each in combination with tenofovir/lamivudine (TDF/3TC), beginning at week 48. During the first 48 weeks of the study, patients receiving ISENTRESS were randomized to one of four dose regimens (100, 200, 400 and 600 mg twice daily). After which, all patients taking a regimen including ISENTRESS received the 400 mg dose twice daily. The study's primary endpoints were reductions in HIV-1 viral load to less than 50 copies/mL and an evaluation of safety and tolerability. Secondary endpoints included ARV activity as measured by the proportion of patients achieving HIV-1 viral load to less than 400 copies/mL and change from baseline in CD4 cell count at week 240. The evaluation of total cholesterol, LDL cholesterol and triglycerides were exploratory analyses.

The data reported at IAS 2011 represent final 240-week results from this Phase II trial.

Patients who entered the study were required to have HIV-1 viral loads greater than 5,000 copies/mL. At baseline, the geometric mean HIV-1 viral load level for patients on the regimen including ISENTRESS was 55,266 copies/mL (n=160) and 67,554 copies/mL (n=38) for the regimen with efavirenz. Mean baseline CD4 cell counts were 305 cells/mm3 and 280 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively.

ISENTRESS in combination therapy maintained viral load suppression and increased CD4 cell counts at 240 weeks of treatment in previously untreated adult patients with HIV-1

At week 240 of this study, the regimen containing ISENTRESS suppressed HIV-1 viral load levels to below 50 copies/mL in 68.8 percent of patients compared to 63.2 percent of patients on the regimen containing efavirenz (95 percent CI).

Additionally, 71.9 percent of patients on the regimen containing ISENTRESS and 65.8 percent of patients on the regimen containing efavirenz maintained HIV-1 viral load suppression below 400 copies/mL (95 percent CI).

Patients on the regimen containing ISENTRESS experienced an increase from baseline in mean CD4 cell count of 301.7 cells/mm3 compared to 275.6 cells/mm3 for patients on the regimen containing efavirenz.

Tolerability profile

Cumulative rates of drug-related clinical AEs at 240 weeks were lower in the regimen containing ISENTRESS versus the regimen containing efavirenz (55 percent vs. 76 percent, respectively).

Additionally, the most commonly reported AEs from the study in the regimens containing ISENTRESS and efavirenz, respectively, were diarrhea (6.9 percent vs. 10.5 percent), nausea (12.5 vs. 10.5 percent), dizziness (8.1 vs. 26.3 percent), headache (8.8 vs. 23.7 percent), abnormal dreams (6.9 percent vs. 18.4 percent), insomnia (8.1 percent vs. 13.2 percent) and nightmares (0.0 percent vs. 10.5 percent).

Exploratory analyses on lipids

Exploratory analyses in this Phase II study included the change in serum lipids.

 
Serum Lipid Level Mean Changes from Baseline (mg/dL) at Week 240

 

                 
        ISENTRESS   Efavirenz   P Value
        Baseline
mean

 

  Mean
change

 

  Baseline
mean

 

  Mean
change

 

   
Cholesterol       165.9   11.7   172.9   26.4   P=0.014
LDL-Cholesterol       104.6   2.1   111.6   7.4   P=0.302
HDL-Cholesterol       38.0   7.4   38.9   14.2   P=0.024
Triglycerides       129.5   4.5   113.4   23.1   P=0.213
Total: HDL Ratio       4.6   -0.5   4.6   -0.6   P=0.722
                         
Additional ISENTRESS data presented at IAS 2011

Poster presentations

 

  • Impact of Treatment Failure with Three Traditional Antiretroviral (ARV) Classes of Drugs on Healthcare Resource Utilisation in Latin America (INFORM-LA study) (MOPE 222)
  • Exploratory Analysis in the BENCHMRK Studies at Wk 192: Late Outcomes Based on Early Virologic Responses (MOPE 225)

In addition, 12 studies evaluating ISENTRESS clinical data from the Merck Investigator Studies Program (MISP) were presented at the conference.

About ISENTRESS

ISENTRESS is Merck's integrase inhibitor for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adult patients. 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 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 for use of ISENTRESS.

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 during the initial phase of treatment immune reconstitution syndrome can occur, which may necessitate further evaluation and treatment. Monitor for immune reconstitution syndrome.

Grade 2-4 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.

The most common adverse reactions of moderate to severe intensity* greater than or equal to 2 percent that occurred at a higher rate than the comparator were insomnia in treatment-naïve patients and headache in treatment-experienced patients.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS and darunavir/ritonavir compared to patients receiving ISENTRESS without darunavir/ritonair 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.

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

*Intensities were defined as follows: Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).

Dosing and administration

For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food.

Drug interactions

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 should be increased during coadministration with rifampin. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine and darunavir/ritonavir. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

About Merck

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 www.merck.com.

Forward-Looking Statement

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 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; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally 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 2010 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).

Please see full prescribing information for ISENTRESS® (raltegravir) Tablets at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf, and patient information for ISENTRESS® (raltegravir) Tablets at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.

 

Contact: Merck
Media:
Pam Eisele, 908-423-5024
Robert Consalvo, 908-423-6595
or
Investor:
Carol Ferguson, 908-423-4465

 

 

Posted: July 2011

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