Biotech Values

[DewDiligence]

IDIX Reports PK Data for IDX320/IDX184/IDX375/NS5A

[While IDX184 has been getting most of the press lately, IDX320 is arguably IDIX’s most impressive drug candidate. The PK data reported here pertain to IDX320 as a standalone agent and to combinations of IDX320 with IDIX drugs from different classes. The most promising PK activity was seen with triplets consisting of IDX320 + IDX184 + one member of the set {IDX375, NS5A inhibitor}.

According to this PR, the IDX320 program will move forward with expedition: a PoC monotherapy trial of IDX320 in HCV patients will begin during 2Q10. Please see #msg-45598790 for background on the rationale for the IDX320 program.]

http://finance.yahoo.com/news/Idenix-Pharmaceuticals-prnews-587408156.html/print?x=0

›Friday April 16, 2010, 2:00 am EDT

• IDX320 pharmacokinetic data in healthy volunteers suggest potential for once-daily dosing in HCV-infected patients

• Triple combinations of direct-acting antiviral agents demonstrate strong in vitro synergy against hepatitis C virus (HCV)

• Data were presented in three posters at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL)

CAMBRIDGE, Mass., April 16 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today reported promising in vitro data for IDX320, an HCV protease inhibitor, demonstrating potent and selective antiviral activity in multiple genotypes, or strains, of the virus. The favorable pharmacokinetic profile defined in preclinical studies was confirmed by interim Phase I clinical data in healthy volunteers.

Additional data presented demonstrated that a combination of three Idenix drug candidates, including IDX320, with different mechanisms of action produced strong synergy in vitro. These data support the evaluation of direct-acting antiviral (DAA) combination regimens for the treatment of HCV.

"We are excited about the preclinical and first-in-man data presented today from the IDX320 program. With the in vitro potency and favorable pharmacokinetic profile seen to date combined with the potential for once-daily dosing and multi-genotypic coverage, we believe IDX320 could offer improvements over other protease inhibitors currently in development," said David Standring, Ph.D., Idenix's executive vice president, biology. "The Phase I single and multiple ascending dose clinical study in healthy volunteers is now complete, and we look forward to advancing IDX320 into a three-day proof-of-concept study expected to begin in the second quarter."

"The in vitro combination data presented today continue to support our belief that the future of HCV treatment will be a combination of direct-acting antivirals from different drug classes. We are pursuing a drug development strategy to achieve that goal," said Jean-Pierre Sommadossi, Ph.D., chief executive officer of Idenix.

IDX320 is a potent inhibitor of NS3/4A proteases from genotypes 1a, 1b, 2a and 4a (IC(50) values from 0.8 to 1.9 nM), as well as from genotype 3a (IC(50)=23 nM). IDX320 did not inhibit nine tested cellular proteases (IC(50) > 10 micromolars) in vitro, suggesting high selectivity [i.e. the lack of off-target effects on host proteases]. IDX320 bound tightly to the HCV protease enzyme with a long dissociation half-life (> 9 hours).

The signature mutation observed in vitro was D168V, consistent with other macrocyclic inhibitors. This mutation had reduced replication fitness and was susceptible to treatment with interferon as well as other classes of DAAs [i.e. not likely to cause viral breakthrough when IDX320 is used in combination therapy]. Additionally, IDX320 retained activity against mutations that produce resistance to other protease inhibitors in clinical development. (Lallos, et al, "In Vitro Antiviral Activity of IDX320, a Novel and Potent Macrocyclic HCV Protease Inhibitor", Poster #768.)

After single 2 mg/kg oral doses of IDX320 in two animal species, favorable bioavailability and a long plasma half-life were observed, with substantial plasma concentrations 24 hours post dose. These preclinical data were confirmed in orally-dosed healthy volunteers (n=6) receiving a single 200 mg tablet.

Further, no significant in vitro inhibition of human drug metabolizing enzymes, CYP450s and UGT1A1, by IDX320 suggests low potential for drug-drug interactions in patients. (Good, et al, "Preclinical Pharmacokinetic Profile of IDX320, a Novel and Potent HCV Protease Inhibitor", Poster #750).

Double and triple combination in vitro studies of Idenix's HCV direct-acting antiviral drug candidates from different HCV drug classes, including IDX184 (a nucleotide inhibitor), IDX320 (a protease inhibitor), IDX375 (a non-nucleoside inhibitor) and a prototype Idenix NS5A inhibitor, were reported. Data demonstrated that double combinations (IDX320 with IDX184, IDX375 or NS5A inhibitor) resulted in additive to mildly synergistic effects after 3 days of treatment in vitro. Furthermore, triple combinations, especially those including agents from three different HCV drug classes (IDX184/IDX320/IDX375 or IDX184/IDX320/NS5A inhibitor), demonstrated the strongest synergy in vitro [note that IDX184 and IDX320 are in both of these triplets]. Similar results were observed over 14-days of treatment with no evidence of viral breakthrough or cellular cytotoxicity. (La Colla, et al, "A Triple Combination of Direct-Acting Antiviral Agents Demonstrates Robust Anti-HCV Activity In Vitro", Poster #769.)‹