Preclinical and First-In-Human Phase I Clinical Evaluation of Stampidine, a Potent Anti-HIV Pharmaceutical Drug Candidate

Abstract

The rationally designed novel anti-HIV drug candidate Stampidine exhibited (a) remarkable subnanomolar to low nanomolar in vitro ARV potency against genotypically and phenotypically NRTI-resistant primary clinical HIV isolates, non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 isolates, clinical non-B subtype HIV-1 isolates (subtypes A, C, F, and G) originating from South America, Asia, and sub-Saharan Africa with resistance to stavudine, adefovir and tenofovir, as well as recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance such as multiple TAMs plus M184V, multiple TAMs plus T69 insertion, and Q151 complex (b) favorable, safety profile in mice, rats, dogs, and cats, and (c) promising prophylactic in vivo anti-retroviral activity in Hu-PBL-SCID mice as well as therapeutic anti-retroviral activity in FIV-infected domestic cats. Notably, in a placebo-controlled Phase I study involving 30 therapy-naïve adult HIV-infected adult patients, formulated GMPgrade oral Stampidine capsules did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg. Taken together, the presented favorable preclinical and early clinical safety/activity profile of Stampidine warrants its further development as a new anti-HIV drug candidate. J o ur nal o f A ID S & Cli n ic a l R es earc h

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

“…Results from these studies involving oral dosing of stampidine did not show any dose-limiting toxicity at single dose levels of up to 25 mg/kg. 39 Beyond its potential in treating HIV-resistant strains, stampidine was also suggested as a promising candidate in the pre-exposure prophylaxis against HIV in heterosexual women as well as serodiscordant couples. 40 Thymectacin 35 is a phenyl L-alanine methyl ester ProTide of the therapeutic nucleoside brivudine (BVdU), which is used to treat herpes zoster (shingles).…”

Blocking HIV‐1 transmission in the female reproductive tract: from microbicide development to exploring local antiviral responses

“…Adding up, TFV modulation of proinflammatory cytokines (TNF-α, IL-2, IL-7, and IL-12p70) and activation of natural killer cells were associated with HIV-1 acquisition in women showing high systemic innate immune activation before infection. 41 Aside from TFV, a distinct new HIV anti-retroviral, stampidine, was evaluated recently in phase I clinical trial, and showed no toxicity at dosage ranging from 5 to 25 mg kg − 1 when taken daily as capsules, 42 which offers an alternative option of using anti-retrovirals as microbicide strategy. To overcome barriers to adherence, intravaginal ring (IVR 25 mg or IVR 200 mg) formulated with a non-nucleoside RT inhibitor (Dapivirine) has been developed.…”

Stampidine as a Potent Epigenetic Silencer of Host HIV Dependency Factor Genes in HIV-Infected Cells

“…Stampidine is a promising ARV drug candidate against HIV because of (a) its remarkable subnanomolar to low nanomolar in vitro anti-retroviral potency against genotypically and phenotypically NRTI-resistant primary clinical HIV isolates, non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 isolates, as well as clinical non-B subtype HIV-1 isolates (subtypes A, C, F, and G) originating from South America, Asia, and sub-Saharan Africa with resistance to stavudine, adefovir and tenofovir [28], (b) favorable pharmacokinetics profile in rodents, dogs, and cats with 25 mg/kg or 50 mg/kg tolerable dose levels yielding micromolar plasma concentrations of Stampidine in rodents, cats, and dogs, which are 1,000-fold higher than its in vitro IC 50 value against HIV [29,30], (c) favorable, safety profile in rodents, dogs, and cats [29,30], and (d) in vivo anti-retroviral activity in Hu-PBL-SCID mice as well as FIV-infected domestic cats [31]. In a recently completed placebo-controlled Phase I study involving 30 therapy-naïve adult HIV-infected adult patients, formulated cGMPgrade Stampidine [32] administered as a single oral bolus dose did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg, but it resulted in modest decreases in HIV load in 9 patients [33]. The favorable preclinical and early clinical safety/activity profile of Stampidine warrants its further development as a new anti-HIV drug candidate against ARV drug-resistant HIV strains.…”