16th International AIDS Conference


Toronto, Canada - August 13 - 18, 2006

NEXT GENERATION FUSION INHIBITOR CANDIDATES TRI-1144 AND TRI-999 HAVE IMPROVED PHARMACOKINETICS: PROGRESS TOWARDS ONCE/WEEK DOSING

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0303

Delmedico M.1, Bray B.1, Cammack N.2, Di J.1, Heilman D.1, Silinski P.1, Webb S.1, Wring S.1, Greenberg M.1
1 Trimeris, Inc., Research & Development, Morrisville, United States, 2 Roche Palo Alto, Viral Diseases, Palo Alto, United States

BACKGROUND: Enfuvirtide (ENF, Fuzeon™), the first approved HIV entry inhibitor, is administered by SC injection twice/day and is an important therapeutic option for treatment-experienced patients. The Next Generation Fusion Inhibitor (NGFI) goal is to improve upon ENF efficacy while decreasing injection frequency to once/week. Two NGFI peptide candidates, TRI-1144 and TRI-999, demonstrate substantial improvements in potency, genetic barrier to resistance and pharmacokinetics. These peptides have been evaluated in sustained-release formulations.

METHODS: TRI-1144 and TRI-999 are derived from the gp41 HR2 domain. TRI-1144 incorporates amino acid changes which stabilize helical structure. TRI-999 retains wild-type sequence and is conjugated with a linker-fatty acid. Antiviral potency was evaluated in a cMAGI assay. Several sustained-release formulation approaches have been evaluated, including microspheres and gels, and others. In vitro release profiles were measured using UV absorbance methods. In vivo release profiles were obtained in rodents and monkeys with LC-MS detection.

RESULTS: TRI-1144 and TRI-999 have IC50's against fusion inhibitor-sensitive clinical isolates of 7 and 1 nM, have geometric mean IC50's against a panel of peptide fusion inhibitor resistant isolates that are 150 and 250-fold lower than ENF, and have pharmacokinetic clearance values that are 4- and 6-fold slower than ENF, respectively. In vitro release profiles of these peptides in sustained-release formulations demonstrate steady release of 90% of peptide at times greater than 1 week. Preliminary in vivo release profiles of early formulations of these peptides in monkeys provide evidence for release at times greater than 1 week.

CONCLUSIONS: TRI-1144 and TRI-999 demonstrate:

  1. Potent in vitro antiviral activity,
  2. High genetic barrier to generation of in vitro resistance and
  3. Slow clearance properties in monkeys. Current progress in developing a sustained release formulation provides evidence that extended-release of NGFI peptides is achievable. Work continues towards identification of refined formulations that will provide a patient friendly, once-a-week delivery.

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2006-08-13
ThAa0303

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