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  13th International Workshop on Clinical Pharmacology of HIV Therapy
Barcelona, Spain
April 16-18, 2012
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Good Virologic Response in 10-Day Study of Festinavir, a New NRTI
  13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Monotherapy with BMS-986001 (festinavir), an investigational nucleoside reverse transcriptase inhibitor (NRTI), lowered viral loads 10-fold or more in a placebo-controlled dose-ranging study that enrolled antiretroviral-experienced people [1]. Only 3 NRTI resistance mutations were detectable over the course of this study, despite NRTI experience in the study group, and all 3 people with these mutations had at least a 10-fold drop in viral load.
BMS-986001 is structurally similar to stavudine (d4T) but is a weak inhibitor of human DNA polymerase and is expected to have low mitochondrial toxicity [2]. This double-blind, placebo-controlled, multicenter study assigned 8 antiretroviral-experienced people to one of four dosing groups--100, 200, 300, or 600 mg once daily for 10 days. Two people in each group were assigned to placebo.
No one had taken antiretrovirals within the past 3 months. Everyone was between 26 and 67 years old and had a viral load above 5000 copies. Median CD4 count stood above 300 in all four study arms. No one had active HBV or HCV infection, an estimated glomerular filtration rate below 80 mL/min, or liver transaminases more than 2.5 times the upper limit of normal.
Bristol-Myers Squibb investigators measured BMS-986001 concentrations over 24 hours on days 1 and 10 and before dosing on days 3 and 5. They measured plasma viral load on day 1 (before dosing) and on days 3, 5, 11, 17, and 24. Standard genotypic resistance testing was performed on days 1 (before dosing), 11, and 17.
BMS-986001 was absorbed rapidly at all doses studied, with maximum concentration achieved 1 to 2 hours after dosing. Pharmacokinetic parameters were similar on day 1 and day 10 at all doses.
The experimental NRTI had a linear dose-response relationship. On day 11 the median viral load had dropped 0.97 log10 copies/mL (almost 10-fold) in the 100-mg group, 1.15 log in the 200-mg group, 1.28 log in the 300-mg group, and 1.15 log in the 600-mg group. Median gains in CD4 counts ranged from 71 to 178.5 across the four study groups.
A thymidine analog NRTI mutation could be detected on day 1 (before dosing) in 1 person as a mixed population (T215T/S) but could no longer be detected on day 11 or 17. Two people taking 300 mg of BMS-986001 had mixed-population thymidine analog mutations on day 17 (K70K/R and K219K/R) but not on days 1 or 11. All three of these people had more than a 10-fold drop in viral load on day 11. (The investigators did not probe for low-level resistance populations with a highly sensitive assay.)
A previous report noted four serious adverse events--sepsis, CMV viremia, and severe anxiety and paranoia--that emerged during the study, but none of these problems were judged to be related to BMS-986001 [2]. Two cases of abdominal pain and 1 case of chest pain were judged possibly related to BMS-986001 in the 100-mg group.
A placebo-controlled trial of BMS-986001 combined with efavirenz and lamivudine is recruiting antiretroviral-naive people [3].
1. Hwang C, Zhu L, Chan H, et al. Antiviral activity, exposure-response, and resistance analyses of monotherapy with the novel HIV NRTI BMS-986001 in ART-experienced subjects. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_06.
2. Thompson MA. New drugs, new strategies. Slide presentation. October 14, 2011. http://www.iasusa.org/keyslides/2011/HIV/fnewyork/2011FNY_Thompson.ppt.
3. Clinicaltrials.gov. Safety, efficacy and dose-response study of BMS-986001 in subjects with HIV-1 infection who are treatment-naive. http://www.clinicaltrials.gov/ct2/show/NCT01489046