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.
