Stampidine: A Novel Broad-Spectrum Antiviral Agent

Period of Performance: 04/15/2003 - 10/14/2004

$100K

Phase 1 SBIR

Recipient Firm

Paradigm Pharmaceuticals, LLC
Roseville, MN 55113
Principal Investigator

Abstract

DESCRIPTION (provided by applicant): Stampidine [STAMP], [STV-5'-[p-bromophenyl methoxyalaninyl phosphate] is a novel aryl phosphate derivative of Stavudine (STV/d4T), a pyrimidine nucleoside analogue used in the treatment of HIV infection. STAMP was a potent inhibitor of drug-resistant HIV- 1 strains with genotypic and phenotypic drug resistance. STAMP was 100-fold more potent than STV/d4T and 2-fold more potent than zidovudine (ZDV/AZT) against 9 clinical HIV-1 isolates of non-B envelope subtype. STAMP inhibited the in vitro replication of 20 genotypically and phenotypically nucleoside analogue-resistant (NRTI) and 6 nonnucleoside inhibitor (NNRTI)-resistant HIV-I isolates tested at subnanomolar to low nanomolar concentrations. Orally administered STAMP exhibited significant and dose-dependent in vivo anti-HIV activity against the NRTI-resistant clinical HIV-1 isolate, BR/92/019 in Hu-PBL-SCID mice. Pharmacokinetic and toxicity studies of STAMP conducted in mice, rats, cats, and dogs following oral administration of formulated GMP-grade STAMP (25-100 mg/kg/day) as hard gelatin capsules showed favorable pharmacokinetics. STAMP therapy was not associated with any clinical or laboratory evidence of toxicity at dose levels as high as 500 mg/kg. Therapeutic concentrations of STAMP >4-logs higher than its IC50 value was achieved after oral administration in dogs and cats at the 50 or 100 mg/kg dose levels. The documented in vitro potency of STAMP against primary clinical HIV-1 isolates with genotypic and/or phenotypic NRTI- or NNRTI-resistance as well as non-B envelope subtype together with its in vivo anti-HIV activity in HIV-infected Hu-PBL SCID mice and favorable pharmacokinetics in dogs and cats warrants the further development of this promising new NRTI compound for possible clinical use in both treatment naive and treatment experienced HIV-1 infected persons. We are now proposing studies aimed at evaluating the safety and efficacy of STAMP against the feline immunodeficiency virus (FIV) infection in domestic cats, an established model for HIV-1 infection in man. The goals of this Phase I proposal are: (i) To evaluate the anti-retroviral activity of STAMP in chronically FIV-infected cats; and (ii) To evaluate the toxicity profile of STAMP in domestic cats. We will test our hypothesis that oral treatment of FIV-infected cats with STAMP can lead to therapeutic response without side effects. The further development of STAMP may provide important data for possible clinical use in both treatment naive and treatment experienced HIV-1 infected persons.