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03/06/2014

Antiretrovirals in the Pipeline: CROI 2014


The antiretroviral (ARV) armamentarium is currently stocked with many potent and tolerable agents with varying mechanisms of action. Still, there are some patients who have experienced treatment failure or unacceptable adverse events (AEs) with many approved drugs for whom alternate therapies would be desirable. Several drugs in development were highlighted in presentations at CROI 2104.

A Novel Attachment Inhibitor. BMS 663068 (068) is the prodrug of an HIV attachment inhibitor with a novel mechanism of action. It binds to HIV envelope protein gp120 to prevent the conformational changes needed to expose the CD4 binding site. This mechanism is different from CCR5 inhibitors. The drug has intrinsic activity against most but not all HIV strains. Lalezari et al [1] reported results of a randomized, phase 2b trial comparing 4 doses of 068 and atazanavir/ritonavir, each given with tenofovir DF plus raltegravir. Eligible participants were treatment-experienced, on or off ART, with HIV-RNA levels >1,000 and HIV isolates susceptible to all study drugs. Based on earlier studies, susceptibility criteria included an IC50 <100nM in a phenotypic assay using the active form of 068. Five percent of those screened were ineligible due to resistance to the active form of 068. Fifty participants enrolled in each arm; 10 in each 068 arm received 7 days of monotherapy prior to adding background ARVs. Three doses of 068, 600 mg qd, 1200 mg qd and 800 mg bid, produced similar viral load reductions during monotherapy ranging from -1.22 to -1.47 logs. The fourth dose, 400 bid, was less active. At 24 weeks, 69-80% achieved a viral load <400 and 16-26% reached a viral load <50, with no apparent relation between virologic success and dose of 068 or IC50 of the activity drug. Similar increases in CD4 were seen with all doses of 068 and atazanavir. Grade 2-4 AEs were fewer with 068 than with atazanavir. There were 15 serious AEs reported but none were felt to be 068-related and no participant discontinued for 068-related AEs. This novel attachment inhibitor has promising activity and safety. Further development is planned. An important unanswered question is whether clinical use of this drug should be preceded by a specialized phenotypic assay to document susceptibility, a requirement that has blunted the uptake of CCR-5 inhibitors.

A New NNRTI. The NNRTI class of ARVs has been widely and successfully used in clinical practice, yet no currently approved NNRTI has idea features. Efavirenz (EFV) has frequent although usually transient neuropsychiatric AEs. Rilpivirine is somewhat less potent. Etravirine is active in many EFV-experienced patients but its role in initial therapy has not been adequately defined. All NNRTIs have a low genetic barrier to resistance. Doravirine (MK-1439) is an investigational NNRTI that appears to have many favorable features. Morales-Ramirez et al [2] reported results of a randomized, phase 2b study of 4 doses (25, 50, 100, 200 mg daily) of MK-1439 or efavirenz, each combined with tenofovir DF/emtricitabine, in 208 treatment-naive patients. At 24 weeks, 76% in the combined MK-1439 arms and 64% on EFV achieved a viral load <40 copies/mL, with no apparent relation between virologic success and dose of MK-1439. Using the threshold of <200 copies/mL, 89% on MK-1439 responded with no apparent differences between those above or below 100,000 copies at baseline. As might be expected with only 24 weeks of treatment, lower responses were seen at high viral loads when the <40 copy threshold was used. CD4 increases were similar in all arms. Dizziness and nightmares, but not abnormal dreams, were reported more commonly with EFV. Grade 1 increases in cholesterol, AST, ALT, alkaline phosphatase and lipase appeared to be less with MK-1439. Resistance data was not presented but previous in vitro studies suggested this drug has a unique pathway to resistance that does not overlap those of current NNRTIs. MK-1439 appears to have many desirable features that could improve upon those of currently licensed NNRTIs. Further large scale studies are warranted to confirm these preliminary results reported at CROI 2014.

References:
1. Lalezari J, Latiff GH, Brinson C, et al. Attachment Inhibitor Prodrug BMS-663068 in ARV-Experienced Subjects: Week 24 Analysis. Abstract 86, CROI 2014, Boston, MA, March 3-6, 2014.
2. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety and Antiviral Effect of MK-1439, A Novel NNRTI (+FTC/TDF) in ART-Naive HIV-Infected Patients. Abstract 92LB, CROI 2014, Boston, MA, March 3-6, 2014.


Source: Reporting from Boston for PRN News: David H Shepp, MD