next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI),
MK-1439, demonstrated robust antiretroviral activity and good tolerability as
monotherapy in a small phase Ib clinical study, researchers reported yesterday
at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
NNRTIs are generally well tolerated and are well-suited for first-line
HIV treatment, but as a class these drugs are susceptible to resistance. Pre-clinical
studies showed that MK-1439 has enhanced activity against HIV strains with
certain other common NNRTI resistance mutations (including K103N and Y181C).
Unlike the widely used NNRTI efavirenz (Sustiva
or Stocrin), it appears to have low
potential for central nervous system (CNS) toxicity.
Matt Anderson from
Merck and colleagues evaluated MK-1439 in a double-blind, placebo-controlled
trial at a single site in Berlin. The researchers looked at drug safety, tolerability,
antiviral activity, pharmacokinetics and emergence of viral resistance.
This study was the
first to test multiple doses of MK-1439 in HIV-positive people. Prior research
showed acceptable safety and pharmacokinetics in HIV-negative volunteers (also
reported at CROI, poster 527) and in HIV-positive people given single doses up
included 18 previously untreated people with HIV. Although both men and women
were eligible, only men sought to enrol in the trial. Ages ranged from 23 to 45
years. At study entry they had at CD4 cell counts of at least 200 cells/mm3
and normal biochemistry and blood lab results. People with hepatitis B or C
co-infection were excluded.
Participants were evenly
randomised to receive 25mg or 200mg once-daily MK-1439 or placebo as
monotherapy for seven days. After completion of dosing, participants were
started on standard combination antiretroviral therapy for ten more days so
that residual MK-1439 would not promote development of resistance in the
absence of other antiretrovirals.
MK-1439 showed potent
antiviral activity. Viral load levels fell steadily for people taking either
dose of MK-1439, whilst remaining stable for placebo recipients. At day seven of
treatment, HIV RNA declines were similar in the 25mg and 200mg dose arms, at
1.37log10 and 1.26 log10, respectively. No participants showed
evidence of viral breakthrough after one week of monotherapy.
pharmacokinetic parameters were similar to those previously seen in
HIV-negative volunteers taking the same doses. Drug levels reached a steady
state after three to five days, exposures exceeded the level needed for viral
inhibition, and the average effective half-life in the body was 10 to 16 hours.
MK-1439 continued to appear safe and well tolerated. Although about
three-quarters of participants experienced adverse events, these
were mostly mild-to-moderate in intensity and resolved after the end of
treatment. No significant skin rash, CNS events or laboratory abnormalities
Only three events
were considered potentially related to the drug (night sweats, headache, and
loss of appetite). The single serious adverse event – increased liver
enzymes in a person with acute hepatitis C – was judged to be
probably unrelated to the study drug.
generally well tolerated with no clinically significant trends or signals
apparent in vital sign measurements, laboratory findings, or ECGs," the
researchers concluded. "Similarly
robust antiviral activity against HIV-1 was observed with 25 and 200mg QD [once-daily]
Anderson said that a phase IIb clinical trial is currently enrolling to
compare MK-1439 and efavirenz, both with tenofovir/emtricitabine (the drugs in Truvada). More details are available at www.clinicaltrials.gov/ct2/show/NCT01632345.