Merck Presents New Pharmacokinetic Data on ISENTRESS® (raltegravir) at 14th European AIDS Conference

Wed Oct 16, 2013 8:30am EDT

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Merck Presents New Pharmacokinetic Data on ISENTRESS® (raltegravir) at 14th European AIDS Conference

Company Confirms Development Program for Investigational Once Daily (QD) Dosing Regimen of ISENTRESS

Merck (NYSE:MRK), known as MSD outside the United States and Canada, is presenting pharmacokinetic data this week on investigational formulations of a once daily (QD) dose of ISENTRESS at the 14th European AIDS Conference (EACS), sponsored by the European AIDS Clinical Society. The meeting is currently taking place in Brussels, Belgium, Oct. 16-19, 2013. The poster presentation A Single Dose Food Effect Study of Raltegravir Formulations (Poster #PE10/17) will be presented Thursday, Oct. 17, and Friday, Oct. 18, from 12:00 p.m. to 2:00 p.m. CET. Based on the results of this study and other data, Merck plans to initiate a Phase III clinical study on a once daily dosing regimen of ISENTRESS in early 2014, pending review by regulatory agencies. ISENTRESS is administered twice daily, in accordance with the approved Prescribing Information.

“We previously studied once daily ISENTRESS in a combination regimen and in that study, the once daily formulation did not meet the non-inferiority endpoint compared to twice daily ISENTRESS,” said Jeff Chodakewitz, M.D., vice president, global clinical development, infectious disease & vaccines, Merck Research Laboratories. “The data we are presenting at the European AIDS Clinical Society conference, as well as other currently available data, provide a strong scientific basis to continue our investigational work toward a once daily dosing regimen.”

The primary endpoint of the previous Phase III trial (QDMRK) was non-inferiority of the once daily 800 mg dose in a combination regimen compared to the twice daily 400 mg dose in combination. The endpoint was not met, as the once daily dose studied was inferior to the twice daily dose. Results showed that at 48 weeks, 83 percent of treatment-naïve adult HIV-1 infected patients achieved viral suppression with the dosing regimen of 800 mg ISENTRESS (raltegravir) once daily, compared with 89 percent of patients treated with ISENTRESS 400 mg twice daily. Thus, non-inferiority was not met in the QDMRK trial. The safety and tolerability profiles of the two regimens were generally similar in the study and similar to the Prescribing Information for ISENTRESS. The study was concluded in 2010, and the results were presented at the 2011 Conference on Retroviruses and Opportunistic Infections (CROI) as well as published in The Lancet.

The Single Dose Food Effect Study of Raltegravir Formulations presented at EACS was an open-label, randomized, two cohort, three period, three treatment, six sequence, crossover study in 36 healthy subjects. The study evaluated the single dose pharmacokinetics and food effect of two different formulations of raltegravir, both given in a single 1200 mg dose at fasted, low-fat fed, and high-fat fed states. The results indicated that both formulations have the potential to be investigated further for once daily use in a clinical study, but showed that the pharmacokinetics of the reformulated version of raltegravir were less affected by food.

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 is associated with a greater likelihood of treatment response.

Important Selected Safety Information

ISENTRESS 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 systemic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Co-administration of ISENTRESS (raltegravir) with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT1A1) 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.

The most commonly reported (≥2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-naïve adult patients receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs 5%), nausea (3% vs 4 %), fatigue (2% vs 3%), and dizziness (2% vs 6%), respectively. 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).

Grade 2 to 4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS (raltegravir). 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 and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

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.

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.

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 and weighing at least 10 kg as part of combination HIV therapy. 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. ISENTRESS (raltegravir) is now approved in combination therapy in more than 76 countries for use in treatment-naïve adult patients with HIV-1 and in more than 110 countries for use in treatment-experienced adult patients with HIV-1. ISENTRESS, in combination therapy, for use in pediatric patients with HIV-1 has also been approved for use in 33 countries. 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.

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 and connect with us on Twitter, Facebook and YouTube.

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. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent 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 2012 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 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.

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