Author: Leslie Geer ; R. Karl Malcolm ; Thomas J. Ketas ; Susan M. Fetherston ; Sylvain Blois ; Paolo La Colla ; Ronald S. Veazey ; Laurie Goldman ; John P. Moore ; Per Johan Klasse ; Diarmaid J. Murphy

OBJECTIVESThe non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques.METHODSIn vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks.RESULTSSEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037).CONCLUSIONSAn MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1.

01 Sep 2011·AIDS Research and Human RetrovirusesQ4 · MEDICINE

Topical Nonnucleoside Reverse Transcriptase Inhibitor MC 1220 Partially Prevents Vaginal RT-SHIV Infection of Macaques

Q4 · MEDICINE

Article

Author: La Colla, Paolo ; Storer, Richard ; Stahl-Hennig, Christiane ; Parsy, Christophe ; Antimisiaris, Sophia ; Schultheiss, Tina ; Stolte-Leeb, Nicole ; Loddo, Roberta ; Sauermann, Ulrike ; Franz, Monika ; Mourtas, Spyridon

The availability of an effective vaginal microbicide would be a major step toward containment of HIV transmission as well as allowing women self-protection against HIV infection. Here we evaluated the efficacy of vaginal application of the potent nonnucleoside reverse transcriptase inhibitor (NNRTI) MC 1220 against vaginal challenge of macaques with RT-SHIV, a chimeric simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT) gene of HIV-1. Challenge infection of monkeys with RT-SHIV currently represents the only nonhuman primate model available to test the anti-HIV-1 effects of NNRTIs. Two different gel formulations containing different MC 1220 concentrations were evaluated for efficacy in female rhesus macaques exposed to RT-SHIV. Five groups of five animals each were treated with two different gel compositions containing no drug, 0.1% or 0.5% MC 1220, followed by vaginal RT-SHIV challenge 30 min later. One animal in each group treated with the low concentration of MC 1220 as well as one control animal remained uninfected after vaginal challenge. By contrast, three of the animals receiving 0.5% MC 1220 remained uninfected, suggesting a threshold of the drug. Despite being negative for plasma viral RNA and absence of seroconversion, almost all uninfected animals exhibited SIV-specific T cells, either in the periphery or in lymph nodes draining the portal of virus entry. Our results make MC 1220 a promising compound for further development as a topical microbicide and warrant additional testing with improved formulation, long-lasting vaginal delivery systems, or even combinations with other inhibitors.

08 Nov 2010·ChemMedChemQ3 · MEDICINE

A Novel Synthetic Route for the Anti‐HIV Drug MC‐1220 and its Analogues

Q3 · MEDICINE

Article

Author: Yasser M. A. Loksha ; Paolo La Colla ; Roberta Loddo ; Daniel Globisch ; Gabriella Collu ; Erik Bjerregaard Pedersen

A new route for the synthesis of the lead compound MC-1220 (I) and its analogs by reduction in 4 steps is presented.Although anti-HIV-1 activities were observed for MC-1220 analogs, in all cases the were lower than that of the lead compound MC-1220.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	US	Idenix Pharmaceuticals LLC	-
HIV Infections	Preclinical	FR	Idenix Pharmaceuticals LLC	-
HIV Infections	Preclinical	IT	Universita degli Studi di Roma "Foro Italico"	-
HIV Infections	Preclinical	IT	University of Cagliari	-

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