August 17, 2006

IAC: Data, Access for Integrase Inhibitor

August 17, 2006 (AIDSmeds)—Preliminary results from an ongoing clinical trial of MK-0518, Merck's experimental integrase inhibitor, suggest that it has comparable anti-HIV activity to Sustiva® (efavirenz) after 24 weeks of treatment. The new data were reported today at the International AIDS Conference (IAC) in Toronto by Martin Markowitz, MD, of the Aaron Diamond AIDS Research Center in New York, and were accompanied by an announcement from Merck that an expanded access program for the drug will be started within the next few months.

MK-0518 is one of two integrase inhibitors currently in phase II clinical trials. The other agent is Gilead Sciences' GS-9137.

Integrase inhibitors block a middle step in HIV's lifecycle. After HIV has entered a CD4 cell and its RNA has been reverse transcribed to viral DNA, it must then be integrated into the CD4 cell's DNA. The HIV DNA can then hijack the CD4 cell, turning it into a viral factory. MK-0518 blocks the viral DNA integration, hence its classification as an integrase inhibitor.

The new data comes from a two-part clinical trial of MK-0518.  The first part of the study, reported in November 2005, evaluated different doses of MK-0518 given as monotherapy (without other HIV drugs): 100mg, 200mg, 400mg, or 600mg taken twice a day. 

Dr. Markowitz's presentation focused on the research conducted in the second part of the study.  It enrolled 198 HIV-positive people starting treatment for the first time – and included 30 participants enrolled in part one of the study – to receive either MK-0518 at one of the six doses explored in part one of the study or Sustiva.  All patients in the study also received Viread® (tenofovir) and Epivir® (lamivudine).

The study will maintain patients on treatment for 48 weeks.

Upon entering the study, average viral loads in the various treatment groups ranged from approximately 43,000 to 68,000. After 24 weeks of therapy, 85% to 95% of patients taking the MK-0518 regimen saw their viral loads reduced to less than 50, regardless of which dosing group they were in. In the Sustiva group, approximately 92% of patients experienced viral load reductions to less than 50. The differences between the various MK-0518 dosing groups and the Sustiva group were not statistically significant, meaning that the variations could have been due to chance. 

CD4 cell counts, ranging from 271 to 314 at the start of the study, increased in all patients after 24 weeks or treatment. Among patients in the MK-0518 groups, CD4 counts increased by 139 to 175 cells. In the Sustiva group, CD4 counts increased by 112 cells. As with the viral load results, these differences were not statistically significant.

Dr. Markowitz reported that, thus far, treatment with MK-0518 or Sustiva seems to be well tolerated. Nausea, dizziness, and headache appear to be the most frequently reported side effects. The only possible treatment-related toxicity of concern was a patient in the 600mg MK-0518 group who discontinued therapy due to significantly increased liver enzymes.

Expanded Access Program Announced

The expanded access program (EAP) with MK-0518, announced today by Merck, will essentially be an open-label study of the drug. It will continue until approximately three months after MK-0518 has been approved by the U.S. Food and Drug Administration and made available through pharmacies.

To be eligible to participate in the EAP, which will essentially provide the drug, free of charge, to patients in need, candidates must be HIV-positive, at least 16 years of age, have limited or no treatment options available to them due to resistance or intolerance to multiple HIV regimens, are not achieving adequate viral load reductions on a current regimen, and are at risk of serious disease progression.

Patients in the EAP will receive open-label MK-0518 400mg twice daily. It will need to be combined with a drug regimen selected by patients and their health care providers (Merck will not pay for the medications being combined with MK-0518 in the EAP). The program will be managed by a clinical research organization (CRO). The CRO will collect all case report information including serious side effects.

According to Merck, the EAP will be started in the United States within the next few months; no specific date was announced. Once the EAP is open to enrollment, information will be posted immediately as an AIDSmeds.com news story and will be listed in the MK-0518 lesson on this site.