HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Researchers
Present Pre-clinical Data on 2 New Investigational NNRTIs
While
novel classes of antiretroviral agents garnered the most attention at the 14th
Conference on Retroviruses and Opportunistic Infections last month in Los
Angeles, encouraging data were also presented on new candidates within existing
classes.
Among
these were 2 investigational non-nucleoside reverse transcriptase inhibitors (NNRTIs)
being developed Idenix Pharmaceuticals, known as IDX12899 and IDX12989.
The
researchers noted that new NNRTIs that provide more durable suppression of HIV
replication with improved tolerability could prove clinically useful, especially
those that have activity against drug-resistant virus.
Investigators performed
enzyme and cell-based assays using a spectrum of wild type HIV-1 subtypes and
a panel of strains with various single and multiple NNRTI-resistance mutations.
They analyzed barriers to resistance and selection of in vitro resistance mutations
by phenotypic and genotypic
analyses.
In addition, the oral absorption, metabolism, and pharmacokinetics
of the compounds were studied in rats, rabbits, dogs, and monkeys.
Results
•
Both IDX12899 and IDX12989 demonstrated activity against a broad panel of wild
type HIV-1 isolates at nanomolar or sub-nanomolar concentrations.
•Antiviral
potency was retained against HIV isolates containing various single and double
NNRTI-resistance mutations, including those associated with high-level resistance
to efavirenz (Sustiva).
•
Both IDX12899 and IDX12989
demonstrated a higher barrier to resistance than efavirenz.
•
Oral absorption in
monkeys was around 60% for both IDX12899 and IDX12989, and plasma drug levels
significantly exceeded 90% effective concentrations 24 hours after dosing.
•
No adverse effects
were observed in rats or monkeys receiving doses up to 1000 mg/kg.
•
IDX12899 and IDX12989
were found to be weak-to-moderate inducers of the cytochrome P450 3A4 isoenzyme.
•
The IDX NNRTI[s] are
potent inhibitors of wild-type and resistant HIV-1 and demonstrate superior barriers
to resistance development compared to efavirenz," the researchers concluded.
"Extrapolation from animal data supports the potential for once-daily dosing
in humans."
Below
is the text of an Idenix press release announcing the findings:
IDX12899
and IDX12989, Novel NNRTI with Potent Anti-HIV Activity, Enhanced Barrier to Resistance
and Favorable Pharmacokinetic Profile
Preclinical
Data From Two Novel Idenix Compounds for the Treatment of HIV Presented at Conference
on Retroviruses and Opportunistic Infections
CAMBRIDGE,
Mass., March 1, 2007 -- PR Newswire-FirstCall via COMTEX News -- Idenix Pharmaceuticals,
Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery, development
and commercialization of drugs for the treatment of human viral and other infectious
diseases, announced today that preclinical data from two novel non-nucleoside
reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency
virus type 1 (HIV-1) infection, IDX899 and IDX989, demonstrated potent and selective
activity in vitro. These data were presented today by Dr. Douglas Richman at the
14th Conference on Retroviruses and Opportunistic Infections (CROI) in Los Angeles.
"NNRTIs are a critical part of combination antiviral regimens for the
treatment of patients with HIV-1 infection," said Dr. Douglas Richman, Professor
of Pathology and Medicine, University of California San Diego, and Director of
the UCSD Center for AIDS Research. "However, rapid emergence of NNRTI-resistant
virus remains a challenge of therapy today. New treatments are needed that offer
an enhanced resistance threshold with potential for once-a- day oral dosing for
HIV-1 infected individuals. These preclinical data are encouraging and I look
forward to the further evaluation of this program in clinical testing."
Preclinical
data for IDX899 and IDX989 demonstrated activity against a broad panel of wild-type
HIV-1 isolates. Potency was retained against panels of clinical isolates containing
various single and double NNRTI mutations. Both compounds exhibited good oral
bioavailability with a favorable pharmacokinetic profile. A favorable toxicology
profile was also reported as genotoxicity studies were negative and no major adverse
effects were observed in acute toxicity studies. IDX899 and IDX989 showed inhibition
of CYP450 3A4, 2C8 and 2C9.
Preliminary
clinical evaluation of both Idenix compounds has been conducted under an exploratory
Investigational New Drug (IND) application. A lead candidate, IDX899, has been
selected for further clinical development based on its overall profile and IDX989
will remain a back-up candidate.
About Idenix
Idenix
Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical
company engaged in the discovery, development and commercialization of drugs for
the treatment of human viral and other infectious diseases. Idenix's current focus
is on the treatment of infections caused by hepatitis B virus, hepatitis C virus
and HIV. For further information about Idenix, please refer to http://www.idenix.com.
03/23/07
References
D
Richman, C Dousson, R Storer, and others. IDX12899 and IDX12989, Novel NNRTI with
Potent Anti-HIV Activity, Enhanced Barrier to Resistance and Favorable Pharmacokinetic
Profile. 14th Conference on Retroviruses and Opportunistic Infections; February
25-28, 2007; Los Angeles, California. Abstract 489 (poster).
Idenix
Pharmaceuticals (via PR Newswire). IDX12899 and IDX12989, Novel NNRTI with Potent
Anti-HIV Activity, Enhanced Barrier to Resistance and Favorable Pharmacokinetic
Profile. Press release. March 1, 2007.
