FDA Committee Recommends Approval of First Integrase Inhibitor, Raltegravir (Isentress, MK-0518)

By Liz Highleyman

On September 5, an advisory committee of the U.S. Food and Drug Administration (FDA) unanimously voted in favor of approval for Merck and Company's raltegravir (Isentress, formerly MK-0518), the first integrase inhibitor to be considered for approval.

Integrase inhibitors work by preventing HIV from inserting its genetic material into host cells, thereby halting viral replication. Because integrase inhibitors work by a different mechanism than currently approved anti-HIV drugs, they are likely to work against virus that has developed resistance to other drug classes.

The full FDA is not required to accept the Antiviral Drugs Advisory Committee's recommendation, but usually does so. Coming close on the heels of the approval in August of the first CCR5 antagonist -- Pfizer's maraviroc (Selzentry) -- the approval of raltegravir would mark the first time two new classes of antiretroviral drugs have come on the market in such a short time. The agency is expected to make a decision by mid-October.

The availability of 2 new drug classes is particularly beneficial for highly treatment-experienced individuals who have HIV that has developed resistance to the three major existing drug classes. While adding a single novel drug may be enough to suppress the virus (at least temporarily), the chances of doing so are better if more than one new type of drug can be started at the same time, and this also reduces the risk of developing resistance to the new agents.

The FDA committee recommended that raltegravir be approved for use in combination therapy by treatment-experienced HIV patients. It was not recommended or treatment-naive individuals, though it has been studied in this population.

The committee's recommendation was based on an extensive review of raltegravir's virological and immunological efficacy and side effects profile. The FDA released its background material on the drug in advance of Wednesday's meeting. The full 160-page briefing document is available on the FDA's web site at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-01-Merck.pdf.

As previously reported, data presented at the 14th Conference on Retroviruses and Opportunistic Infections in Los Angeles this past February (and published in the April 14, 2007 issue of The Lancet showed that after 24 weeks, treatment-experienced patients in the BENCHMRK 1 and 2 studies who added raltegravir to an optimized background regimen were about twice as likely as those who added placebo to achieve a viral load below 50 copies/mL (about 65% vs about 35%).

Raltegravir was also found to cross blood-brain barrier -- meaning that it may attack HIV in the central nervous system -- and the blood-placenta barrier.

An extensive safety review indicated that patients taking raltegravir were more likely to experience skin rashes and elevated creatinine than those taking placebo, but rates of severe adverse events were similar overall. While liver toxicity is a concern with many antiretroviral drugs, rates of elevated liver enzymes were similar in patients taking raltegravir and placebo.

Cancer is also a concern, since more malignancies were reported in the raltegravir arm compared with the placebo arm in previous studies. However, FDA reviewers suggested that this imbalance may reflect an unusually low rate of cancer in the placebo group.

Merck plans to implement a program to monitor the incidence of cancer and other adverse events, including pregnancy outcomes, as well as development of drug resistance in patients taking raltegravir.

Below is an excerpt from Merck's press release announcing the committee's recommendation:

FDA Advisory Committee Unanimously Recommends Accelerated Approval of ISENTRESS (raltegravir), Merck's Investigational Oral Integrase Inhibitor, for Treatment of HIV

WHITEHOUSE STATION, N.J., Sept. 5, 2007 -- Merck & Co., Inc. announced today that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) voted unanimously to recommend accelerated FDA approval of ISENTRESS (raltegravir) in combination with other antiretroviral therapy (ART) for the treatment of HIV infection in treatment-experienced patients with ongoing viral replication despite existing therapy.

If approved, ISENTRESS would be the first in a new class of antiretroviral agents called integrase inhibitors available for the treatment of HIV. The FDA is not bound by the committee's recommendation but takes its advice into consideration when reviewing investigational medicines.

The FDA granted ISENTRESS priority review status, a designation for investigational products that address unmet medical needs. Under the priority review designation, the FDA is expected to review and act on the New Drug Application for ISENTRESS within six months of submission. Merck anticipates FDA action by mid-October.

"ISENTRESS is an important example of our ongoing commitment to HIV research," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Despite the availability of various treatment options, the HIV epidemic continues, so there remains a need for new therapeutic approaches. This positive recommendation signals an important step forward for the treatment of patients living with HIV."

In addition to the FDA regulatory application, Merck is also moving forward with regulatory filings in countries outside of the United States.

The advisory committee's recommendation was based on review of efficacy and safety results from studies with ISENTRESS used in combination with optimized background therapy in treatment-experienced HIV-infected patients who had failed antiretroviral therapies, and who had HIV resistant to at least one drug in each of three classes of oral ARTs.

About ISENTRESS

ISENTRESS works to inhibit the insertion of HIV DNA into human DNA by the viral integrase enzyme. Inhibiting integrase from performing this essential function blocks the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV replication process -- protease and reverse transcriptase -- but currently no approved drugs that inhibit integrase.

For more information, visit www.merck.com.

09/07/07

Sources

Merck and Company. ISENTRESS (raltegravir) 400 mg For Treatment of HIV (NDA 22-145). Briefing document. August 6, 2007. Available at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-01-Merck.pdf.

Merck and Company. FDA Advisory Committee Unanimously Recommends Accelerated Approval of ISENTRESS (raltegravir), Merck's Investigational Oral Integrase Inhibitor, for Treatment of HIV. Press release. September 7, 2007.

D Cooper, J Gatell, J Rockstroh, and others. Results from BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, February 25-28, 2007. Abstract 105aLB.

R Steigbigel, P Kumar, J Eron, and others. Results from BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, February 25-28, 2007. Abstract 105bLB.

B Grinsztejn, N Bach-Yen, C Katlama, and others. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomized controlled trial. The Lancet 369(9569): 1261-1269. April 14, 2007.