The novel non-nucleoside reverse transcriptase inhibitor (NNRTI) MK-1439 exhibited good activity against a variety of HIV subtypes and maintained its potency against most common NNRTI-resistant viruses, researchers reported at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) this month in San Francisco.

NNRTIs are generally well-tolerated antiretroviral drugs, but emergence of resistance and cross-resistance can limit their effectiveness. In addition to a favorable resistance profile, researchers are looking for NNRTI candidates that have few drug-drug interactions, are well-tolerated, can be taken once-daily without food requirements, and can be combined into coformulations.

Ming-Tain Lai and colleagues from Merckcharacterized the antiviral activity and resistance profile of the next-generation NNRTI MK-1439 in laboratory studies.

Results

• MK-1439 demonstrated good potency in vitro against a panel of nearly 100 HIV isolates from different subtypes.
  
  
• MK-1439 inhibited reverse transcriptase activity of wild-type HIV-1 and viruses with the K103N and Y181C, and dual K103N/Y181C NNRTI resistance mutations, with less than a 3-fold potency shift.
  
  
• MK-1439 was less active against virus strains with Y188L and triple mutations.
  
  
• MK-1439's activity against a broad range of NNRTI-resistant viruses was superior to that of efavirenz (Sustiva, also in the Atripla combination pill), and comparable to those of etravirine (Intelence) and rilpivirine (Edurant, also in the Complera coformulation).
  
  
• MK-1493 had a distinct resistance mutation development pathway, with identified new mutations F227C, L234I, V106A, and V108I identified in breakthrough virus.
  
  
• MK-1439 's 76% protein binding was lower than that of efavirenz, etravirine, and rilpivirine (all > 99%), but comparable to that of nevirapine (Viramune) at 62%.
  
  
• The new drug appeared to have low potential for drug-drug interactions.
  
  
• Though mainly metabolized by the CYP3A enzyme in the liver, MK-1439 was not a CYP3A inducer or a P450 inhibitor.
  
  
• MK-1439 did not show cytotoxicity (ability to kill or damage cells) in 10 different in vitro cell types.
  
  
• MK-1439 had low potential for "off-target activity," suggesting it may cause fewer side effects including central nervous system effects associated with efavirenz.
  
  

Based on these studies, the researchers concluded that MK-1439 warrants further development and that preclinical data support low once-daily dosing.

Lai said that a Phase 2a study has been done (though he did not reveal the findings) and investigators are ready to launch a Phase 2b trial comparing MK-1439 versus efavirenz, both combined with tenofovir/emtricitabine (the drugs in Truvada), in treatment-naive individuals.

By Liz Highleyman

Reference

M Lai, M Feng, M Lu, D Hazuda, et al. Antiviral Activity andin vitro Mutation Development Pathways of MK-1439: A Novel Non-Nucleoside Reverse Transcriptase Inhibitor. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-551.