Healthcare Industry News:  integrase inhibitor 

Biopharmaceuticals HIV/AIDS

 News Release - February 9, 2006

Merck Announces Interim Results from Phase II Study of MK-0518, an Investigational Oral HIV Integrase Inhibitor

DENVER--(HSMN NewsFeed)--Feb. 9, 2006--Merck & Co., Inc.:
  • MK-0518, in Combination with Optimized Background Therapy (OBT), Provided Greater Viral Suppression vs. Placebo Plus OBT After 16 Weeks of Therapy in HIV Patients Infected with Highly Resistant Virus and Failing Multiple Therapies
  • After 16 Weeks of Therapy, MK-0518 plus OBT was Generally Well Tolerated with Tolerability Comparable to Placebo plus OBT
Interim results from a dose-ranging Phase II trial of MK-0518(i) (n=167) showed that the oral investigational medication at all three doses studied (200 mg, 400 mg, and 600 mg orally twice daily) in combination with optimized background therapy (OBT) had greater anti-retroviral activity than placebo with OBT. Study results also showed that MK-0518 in combination with OBT was generally well tolerated in these patients with advanced HIV infection who were failing anti-retroviral therapy (ART), who had viruses resistant to at least one drug of each of the three available classes of oral ARTs and who had limited active ARTs as options for treatment. The results were presented as a late breaker yesterday at the 13th Annual Conference on Retroviruses and Opportunistic Infections (CROI).

MK-0518 represents a new class of ART called integrase inhibitors that prevent the insertion of the HIV viral DNA into the human DNA genome*. Inhibiting integrase from performing this essential function blocks the ability of the virus to replicate and infect new cells.

"The efficacy of MK-0518 provides additional evidence that demonstrates the antiviral activity of HIV integrase inhibitors as a new and promising class of anti-retroviral agents," said Bach-Yen T. Nguyen, M.D., senior director, Infectious Diseases and Clinical Research, Merck Research Laboratories. "MK-0518, when used in combination with optimized background therapy, was generally well tolerated and significantly suppressed viral replication compared to placebo plus OBT in patients with complicated HIV treatment histories."

Study design

This multi-center, randomized, double-blinded, dose-ranging, placebo-controlled study compared MK-0518 plus OBT to placebo plus OBT in terms of reduction in HIV viral load, improvement in CD4 cell count and safety and tolerability. Patients received either MK-0518 200 mg, 400 mg, 600 mg or placebo, each dosed orally twice daily and in combination with OBT. Optimized background therapy was selected based on patient's prior treatment history and results from HIV resistance testing. Patients at study entry were infected with HIV that was resistant to one or more drugs in each of the three oral anti-retroviral drug classes (nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside RTIs (NNRTIs), and protease inhibitors (PI)), were receiving ART for more than three months and had HIV viral loads greater than 5,000 copies/mL and CD4 counts greater than 50 cells/mm3.

Study Results

Interim study results from a total of 167 enrolled patients showed that at week 16 the percent of patients achieving HIV RNA< 400 copies/mL ranged from 64 percent (18 out of 28 patients) to 84 percent (21 out of 25 patients) for MK-0518 plus OBT across all doses studied (200 mg, 400 mg, and 600 mg orally twice daily) versus 22 percent (six out of 27 patients) for placebo plus OBT.

Also, at week 16, the percent of patients achieving HIV RNA< 50 copies/mL ranged from 56 percent (15 out of 27 patients) to 72 percent (18 out of 25 patients) for MK-0518 plus OBT across all doses studied (200 mg, 400 mg, and 600 mg orally twice daily) versus 19 percent (five out of 27 patients) for placebo plus OBT.

The median duration for prior use of ARTs was approximately 10 years for all groups, mean baseline HIV viral load ranged from 4.6 to 4.8 log10 copies/mL and mean baseline CD4 cell counts ranged from 220 to 283 cells/mm3.

The regimen of MK-0518 plus OBT was generally well tolerated and comparable to the regimen of placebo plus OBT. The most commonly reported study therapy-related side effects (occurring in at least five percent or two patients in any treatment group) were diarrhea, nausea, fatigue, injection-site reaction, headache and itching.

Initial Phase II efficacy and tolerability results with MK-0518 as 10-day monotherapy in ART-naive (previously untreated) patients were presented at the European AIDS Clinical Society in November 2005.(ii)

"The results presented at CROI combined with those from the previously presented study in treatment-naive patients are compelling," said Robin Isaacs, M.D., executive director, Infectious Disease and HIV Vaccine Clinical Research, Merck Research Laboratories. "The Phase III studies (BENCHMRK-1 and -2) which are being initiated, and for which we are actively seeking patients, will provide greater insights into the efficacy and tolerability of MK-0518."

HIV resistance to drugs increases

It is estimated that up to 78 percent of patients who fail anti-retroviral drugs have developed resistance to more than one therapeutic class of these medicines and increased drug resistance has been noted even in drug-naive individuals. The proportion of treatment-naive patients who carry resistant virus has grown to more than 20 percent today from eight percent in 1999.

Despite the availability of drugs to treat HIV/AIDS, the epidemic continues. An estimated 40 million people are currently infected worldwide, and it is estimated that more than 4 million new infections occur worldwide annually. AIDS is one of the top causes of infectious diseases-related mortality worldwide, responsible for approximately three million deaths each year.

Merck's leadership in the effort to develop investigational treatments and a vaccine against HIV/AIDS has been underway for almost 20 years and continues today. Merck's research of HIV integrase inhibitors began in the early 1990's, and Merck was the first to demonstrate integrase strand transfer inhibition and to define the mechanism of action. Merck was also the first to demonstrate antiviral efficacy in vitro and in vivo.

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. For more information, visit

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 cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

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* Inside the host cell, reverse transcriptase makes viral DNA using viral RNA as a template. Integrase is one of three HIV enzymes (reverse transcriptase, protease and integrase) required by the virus to reproduce.

(i) MK-0518 is compatible with all ARTs and in preclinical evaluation was determined to have no genotoxicity in vitro or in vivo, is not a potent inhibitor or inducer of CYP3A4 (does not require ritonavir boosting) and is predominantly metabolized via glucuronidation (UGT1A1).

(ii) Morales-Ramirez JO, Teppler H, Kovacs C, Steigbigel RT, Cooper D, Liporace RL, Schwartz R, Wenning L, Zhao J, Gilde L, Isaacs R, Nguyen B-Y; Antiretroviral Effect of MK-0518, a Novel HIV-1 integrase inhibitor, in ART-Naive HIV-infected Patients. EACS presentation, Dublin, Ireland, November 2005.

Source: Merck

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