CROI 2016 Abstract eBook

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Oral Abstracts

97 HIV-1 Combinectin BMS-986197: A Long-Acting Inhibitor With Multiple Modes of Action Mark Krystal 1 ; DavidWensel 2 ;Yongnian Sun 1 ; Jonathan Davis 2 ; Zhufang Li 1 ;Thomas McDonagh 2 ; Sharon Zhang 1 ; Matt Soars 1 ; Mark Cockett 1 ; for the CombinectinWorking Group 1 Bristol-Myers Squibb, Wallingford, CT, USA; 2 Bristol-Myers Squibb, Waltham, MA, USA Background: Long-acting antiretrovirals could provide a useful alternative to daily oral therapy for HIV-1 infected individuals. However, the need for combination therapy and the potential for multiple IV/IM injections or tolerability issues may create roadblocks to this type of therapy. Adnectins are small proteins derived from the 10 th type III domain of the human fibronectin protein that possess modifiable binding loops akin to the complementarity determining region of an antibody. Using Adnectins, we have developed the Combinectin inhibitor BMS-986197, a long-acting biologic with 3 independent and synergistic modes of HIV entry inhibition that potentially could be self-administered as a long- acting subcutaneous injection. Methods: Adnectins targeting CD4 and a region of gp41 were isolated and optimized for antiviral potency and biophysical characteristics. The anti-gp41 Adnectin was joined at its amino terminus to the anti-CD4 Adnectin via a peptide linker. A third inhibitor, an alpha-helical peptide fusion inhibitor, was linked to the carboxy end of the anti-gp41 Adnectin via another linker. Finally, a human serum albumin (HSA) molecule was attached to amino terminus of the anti-CD4 Adnectin to optimize in vivo PK. Results: The EC 50 s of the isolated anti-CD4 Adnectin, anti-gp41 Adnectin, and fusion inhibitor peptide were 8.5 nM, 5.4 nM, and 0.4 nM, respectively. Various synergies were obtained through linking all three inhibitors into a single molecule. Optimally combining the two Adnectins increased potency over 100-fold to ~30 pM. Addition of the fusion inhibitor peptide resulted in an increased resistance barrier compared to the separate components, as virus resistant to any one of the three components did not affect the potency of BMS-986197. Addition of HSA to the amino terminus decreased potency to 0.27 nM, but improved PK, as subcutaneous dosing in a cynomologous monkey model produced a t 1/2 of 30 h. BMS-986197 has the biophysical characteristics and expression levels in stable cell lines compatible for further drug development, with a projected weekly subcutaneous human dose. Conclusions: BMS-986197 is a novel recombinant biologic molecule containing three independent HIV inhibitors that has been developed as a potential single long-acting regimen for HIV-1. This molecule has the biophysical characteristics amenable for a self-administered subcutaneous weekly injection. 98 Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis Jay Grobler 1 ; Evan Friedman 2 ; Stephanie E. Barrett 1 ; Sandra L.Wood 1 ;Wendy Ankrom 1 ; Kerry L. Fillgrove 1 ; Ming-Tain Lai 1 ; Marian Gindy 1 ; Marian Iwamoto 3 ; Daria J. Hazuda 1 ; for the MK-8591 Early DevelopmentTeam 1 Merck & Co, Inc, West Point, PA, USA; 2 Merck & Co, Inc, Rahway, NJ, USA; 3 Merck & Co, Inc, Kenilworth, NJ, USA Background: The potential to enhance adherence with less frequent dosing would represent a major advance for the treatment and prevention of HIV. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with sub-nM potency that is in early stage clinical development. The phosphorylated anabolites of MK-8591, including the active triphosphate (MK-8591-TP), exhibit protracted intracellular persistence in human PBMCs and macrophages, protecting cells from infection in the absence of continued exposure in vitro. The potency, pharmacokinetic, and physical properties of MK-8591 are ideal for extended duration dosing. Methods: MK-8591 efficacy was evaluated in a SIVmac251-infected rhesus macaques dosed once weekly (QW) with 1.3 to 18.2 mg/kg. Doses were chosen on the basis of rhesus PK and intracellular NTP levels designed to match levels associated with antiviral efficacy in PBMCs. Plasma viral loads and MK-8591 concentrations (measured pre-dose through day 42) were used to a develop a PK/PD model and select ph1 doses for evaluation as QW oral dose in healthy subjects and enable dose selection for the development of long-acting parenteral formulations. Results: Baseline SIV viral loads in monkeys ranged from 10 6 to 10 8 copies per ml. After administration of QW doses of 3.9 to 18.2 mg/kg MK-8591, monkeys with viral loads < 10 8 exhibited near maximal 2-log drops in viral loads and maintained suppression of viremia for at least 7days. MK-8591-TP concentrations of ≥0.53 pmol/10 6 PBMCs were associated with QW efficacy. In healthy volunteers, single doses of 10 mg and greater were able to achieve these levels of MK-8591-TP for at least 7 days, suggesting the potential for QW antiviral efficacy at a low dose. Finally, long-acting parenteral formulations of MK-8591 exhibited continuous, extended-duration drug release in rodents with MK-8591 plasma levels comparable to those achieved in rhesus and humans and duration of release exceeding 6 months. Conclusions: The antiviral efficacy in an SIV rhesus macaque model when dosed QW together with the human PK data, suggest the potential for MK-8591 QW oral dosing in the clinic and a low dose compatible with delivery via long-acting formulations. MK-8591 QW oral and long-acting parenteral formulations with potential for six months or longer duration would represent a potential paradigm shift as a single agent for prevention of HIV infection or as a component of an extended dosing regimen for HIV treatment.

Oral Abstracts

37

CROI 2016

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