The next-generation HIV non-nucleoside reverse transcriptase inhibitor
(NNRTI) AIC292 showed good antiviral
activity, a high barrier to resistance and a favourable safety profile in laboratory
and animal studies presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last
week in Denver.
Researchers are especially eager to develop new antiretrovirals that
have a high barrier to resistance and low cross-resistance with existing drugs.
Given the effectiveness and good tolerability of existing medications, they
must also be simple to administer – ideally once-daily – and suitable for
combining in fixed-dose coformulations to minimise pill burden.
Holger Zimmerman from AiCuris in Wuppertal, Germany – a Bayer spin-off
focusing on infectious disease therapies – gave a late-breaker presentation on
AIC292, an NNRTI belonging to a novel chemical class known as diarylpyrazole-[imidazolidinone]-carboxamides.
In early laboratory studies,
AIC292 demonstrated potent and selective activity against various HIV-1 clinical
isolates with both CCR5 and CXCR4 tropism (using two different co-receptors to
In this analysis, AIC292 was evaluated in vitro using cell-based
assays against wild-type HIV (lacking resistance mutations) and multiple NNRTI-resistant
strains. It was also tested in combination with marketed antiretroviral drugs
from the nucleotide/nucleoside, NNRTI, protease inhibitor and integrase
In addition, AIC292 was studied in an in vivo model using mice with surgically implanted foam grafts
containing human cells. Toxicity studies were done in rats and dogs. Finally,
the first phase 1 clinical trial evaluated the new drug in 16 healthy
ACI292 showed good activity at low nanomolar concentrations against wild-type
HIV and viruses with a variety of NNRTI-resistance mutations, including the
highly prevalent K103N, Y181C and G190A substitutions. Tested against a panel
of viruses carrying double, triple or quadruple NNRTI-resistance mutations,
AIC292 worked better than currently approved drugs in its class. Zimmerman said
it "should be able to cover" those resistant viruses in clinical use.
Further, AIC292 proved highly active against HIV bearing the L100I
mutation, which is associated with resistance to the approved NNRTIs efavirenz
(Sustiva or Stocrin), etravirine (Intelence)
and rilpivirine (Edurant). Zimmerman
described these viruses as "hypersusceptible" to AIC292, adding that
the molecular mechanism for this is not yet known.
AIC292 also demonstrated a high barrier to resistance, remaining active
against wild-type and NNRTI-resistant HIV for more than a month when used as
monotherapy. At least two mutations are required to confer resistance, Zimmerman
When studied in combination with existing antiretrovirals, AIC292 showed
no antagonistic activity with any of the 21 tested drugs from all classes. On
the contrary, it demonstrated additive or slightly synergistic activity
(meaning the drugs work better together than their added individual effects would
predict) in all combinations.
In the mouse model, during five days of treatment, AIC292 again
demonstrated potent activity, with once-daily administration comparing
favourably to twice-daily dosing of efavirenz, etravirine or rilpivirine.
AIC292 appeared to be well-tolerated in different laboratory human cell
lines and in animals. "No noteworthy findings" were observed in
four-week toxicity studies in rats and dogs.
In the phase 1 trial, two groups of eight volunteers received either AIC292
at single ascending doses or placebo. The drug was shown to be safe and well-tolerated at doses up to 1400mg. There were "only a limited number of
adverse events" (not specified in the presentation), with no concerns
related to vital signs, electrocardiograms or laboratory safety parameters.
Looking at pharmacokinetics, AIC292 had protein-binding levels similar
to other NNRTIs. It did not inhibit major CYP450 enzymes involved in drug
metabolism, suggesting low potential for drug-drug interactions. Testing
against 68 different receptors showed low potential for "off-target
activity". In humans it had a half-life of about 20 hours, suggesting it
is suitable for once-daily administration.
"AIC292 represents a promising novel drug with the antiviral
properties of a next-generation NNRTI for the treatment of HIV-1
infection," the researchers concluded. "Preclinical data support
further clinical evaluation."