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  52nd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 9-12, 2012, San Francisco
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MK-1439, a New NNRTI, Has Good Resistance Profile in Cell Studies
  52nd ICAAC, September 9-12, 2012, San Francisco

ICAAC: Antiviral Activity and In Vitro Mutation Development Pathways of MK-1439: A Novel Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) - (09/10/12)

Mark Mascolini

MK-1439, an investigational nonnucleoside (NNRTI), had good activity against an array of viruses bearing classical NNRTI mutations [1]. At high concentrations the new NNRTI selected a rilpivirine-associated mutation.

When tested against recombinant wild-type (nonmutant) virus and virus bearing the classic NNRTI mutations K103N and Y181C, MK-1439 inhibited RNA-dependent DNA polymerization at 50% inhibitory concentrations (IC50s) of 12, 9.7, and 9.7 nM.

Against wild-type virus, K103N, Y181C, and K103N/Y181C in the presence of 10% normal human serum, MK-1439 had 95% effective concentrations (EC95s) of 11, 13, 16, and 31 nM. Against wild-type virus, K103N, Y181C, and K103N/Y181C in the presence of 50% serum, EC95s were 20, 43, 27, and 55 nM. In comparison, EC95s for etravirine against K103N, Y181C, and K103N/Y181C were 41, 225, and 624 nM, and EC95s for rilpivirine were 44, 117, and 374 nM.

When tested against 93 clinical isolates representing 10 HIV-1 subtypes, MK-1439 showed similar activity against all isolates. The experimental antiretroviral exhibited better activity than efavirenz against 96 clinical isolates resistant to current NNRTIs; MK-1439 activity was comparable to that of the newer NNRTIs etravirine and rilpivirine. In these experiments, viruses that mounted significant resistance against MK-1439 were those harboring the Y188L mutation (associated with resistance to efavirenz and nevirapine) and triple mutations. Y188L had more than 100-fold resistance to MK-1439.

In resistance selection studies, MK-1439 at low concentrations selected V108I and V106A, both associated with resistance to efavirenz and nevirapine. At high concentrations, MK-1439 selected F227C, a mutation associated with resistance to rilpivirine but not other licensed NNRTIs.

MK-1439 had less than a 3-fold loss in susceptibility to each of the three most frequently transmitted NNRTI mutations, K103N, Y181C, and G190A. Protein binding with MK-1439 (76%) was comparable to that of nevirapine (62%) and lower than that of efavirenz (99.6%), etravirine (99.9%), and rilpivirine (99.6%).

A dose-ranging trial will compare the safety and efficacy of MK-1439 and efavirenz, both with tenofovir/emtricitabine, in antiretroviral-naive people [2].


1. Lai M, Feng M, Lu M, et al. Antiviral activity and in vitro mutation development pathways of MK-1439: a novel non-nucleoside reverse transcriptase inhibitor. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-551.

2. Clinicaltrials.gov. A dose-ranging study to compare MK-1439 plus Truvada versus efavirenz plus Truvada in human immunodeficiency virus (HIV)-1 infected participants (MK-1439-007 AM5). http://clinicaltrials.gov/ct2/results?term=NCT01632345.