Volume 3 • Issue 1 • 1000138 Open Access Research article J AIDS Clinic Res ISSN:2155-6113 JAR an open access journal Cahn et al., J AIDS Clinic Res 2012, 3:1 http://dx.doi.org/10.4172/2155-6113.1000138 AIDS & Clinical Research Preclinical and First-In-Human Phase I Clinical Evaluation of Stampidine, a Potent Anti-HIV Pharmaceutical Drug Candidate Pedro Cahn 1,2,3 *, Maria Jose Rolon 2 , Ana Mirta Gun 2 , Ines Ferrari 4 , Ilker Dibirdik 5,6 , Sanjive Qazi 5,6 , Osmond D’Cruz 5,6,8 , Kazim Sahin 7 and Fatih Uckun 6,8,9 * 1 Department of Medicine, Buenos Aires University Medical School, Buenos Aires, Argentina 2 Infectious Diseases Unit, Hospital Juan A. Fernández, Buenos Aires, Argentina 3 Fundación Huesped,m Buenos Aires, Argentina 4 Laboratorio de Bioequivalencia y Biologia Molecular, Universidad Barceló. French 2464 – Ciudad Autonoma de Buenos Aires, Argentina 5 Paradigm Pharmaceuticals, St. Paul, Minnesota 55455, Drug Discovery Program, USA 6 Parker Hughes Institute, St. Paul, MN 55455, USA 7 Faculty of Veterinary Science and Department of Nutrition, Firat University, Elazig, Turkey 8 Developmental Therapeutics Program, Children’s Hospital Los Angeles, Children’s Center for Cancer and Blood Diseases, Los Angeles, CA 90027, USA 9 Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA *Corresponding authors: Fatih M. Uckun, M.D., Ph.D., Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, MS#57, Los Angeles, California 90027-0367, USA, Tel: (323)-361-4328; Fax: 323-361-876; E-mail: fmuckun@chla.usc.edu Pedro Cahn, M.D, Ph.D., Fundación Huesped, Angel Peluffo 3932 (C1202ABB) Buenos Aires, Argentina, E-mail: pcahn@huesped.org.ar Received December 22, 2011; Accepted January 20, 2012; Published January 24, 2012 Citation: Cahn P, Rolon MJ, Gun AM, Ferrari I, Dibirdik I, et al. (2012) Preclinical and First-In-Human Phase I Clinical Evaluation of Stampidine, a Potent Anti-HIV Pharmaceutical Drug Candidate. J AIDS Clinic Res 3:138. doi:10.4172/2155- 6113.1000138 Copyright: © 2012 Cahn P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Human immunodefciency virus type 1 (HIV-1) infection remains a global health concern afecting millions of individuals worldwide [1,2]. Combination antiretroviral therapy has become the standard of care for patients with HIV infection [3,4]. Antiretroviral (ARV) treatment regimens employing combinations of drugs from at least two of the three classes of ARV therapy, namely nucleoside analogue RT inhibitors (NRTI), non-nucleoside analogue RT inhibitors (NNRTI), and protease inhibitors, exhibit a potent and sustained antiviral efect and confer consistent long-term viral suppression in patients with HIV infection [3,4]. However, each of these drugs can select for drug-resistant viruses and the emergence of antiviral drug resistance limits their clinical beneft [5-8]. Acquired resistance to ARV agents hampers the long- term success of contemporary highly active antiretroviral therapy (HAART) regimens [5-8]. Likewise, pre-exposure prophylaxis (PrEP), an evolving new approach to HIV prevention in which ARV agents are used prior to potential HIV exposure in an attempt to reduce the likelihood of HIV infection post exposure in the context of unprotected heterosexual intercourse [9-13], has had limited success due to ARV resistance [14-19]. Notably, TDF, one of the PrEP arms of VOICE study, an NIH funded HIV prevention trial of the Microbicide Trials Network involving more than 5,000 women in Africa and evaluating oral PrEP agents TDF and Truvada (TDF/FTC), a vaginal microbicide gel formulation of TDF, and combinations thereof, has been discontinued based on the interim review of the data by the NIAID Prevention Trials DSMB demonstrating that oral TDF did not reduce HIV infection in participants receiving it [18]. Likewise, FEM-PrEP, a large PrEP trial of Truvada could not demonstrate efcacy in preventing HIV acquisition in women and was recently closed for futility [19]. Terefore, there is an urgent need for potent anti-HIV agents that are active against ARV- resistant HIV strains. Stampidine (5’-[4-bromophenyl methoxylaninylphosphate]-2’,3’- didehydro-3’-deoxythymidine) (CAS 217178-62-6), is a rationally designed novel aryl phosphate derivative of stavudine (STV)/ d4T (CAS 3056-17-5) that is being developed as a promising new drug candidate against ARV-resistant HIV [20,21]. NRTI form the backbone of contemporary combination ARV therapy regimens. Te 5’-triphosphates of the NRTI family, which are generated intracellularly by the action of nucleoside and nucleotide kinases, are capable of competing with the natural deoxynucleoside triphosphates for binding to the RT primer:template complex and represent the biologically active form of NRTI responsible for their anti-HIV activity [22]. Te rate- limiting step for the generation of the bioactive NRTI triphosphates is the conversion of the NRTI to their monophosphate derivatives. Stampidine was developed in an attempt to overcome the dependence 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 profle 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 GMP- grade 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 profle of Stampidine warrants its further development as a new anti-HIV drug candidate.