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NOVEL NON-CATALYTIC SITE INTEGRASE INHIBITOR WITH IMPROVED RESISTANCE PROFILE
Michael L. Mitchell1, Mini Balakrishnan1, Gediminas Brizgys1, Ruby Cai1, Eric Lansdon1, Andrew Mulato1, Mark Osier1, Jianhong Wang1, Helen Yu1, Roman Sakowicz1
1Gilead Scis, Inc, Foster City, CA, USA
Non-catalytic site integrase inhibitors (NCINIs) are a promising class of novel antiretrovirals (ARV). Here we describe the search for an NCINI with the potential for low-dose, unboosted once-daily oral dosing, potency against NCINI binding-pocket variants, a high barrier to resistance, and a favorable safety profile.
Novel NCINIs were evaluated against wild-type (WT) and integrase (IN) polymorphic variants of HIV-1, and DMPK properties. Resistance associated mutations were identified through dose-escalation resistance selection. Barrier to resistance was evaluated in a viral breakthrough assay at fixed drug concentrations. Interactions of NCINIs with WT and mutant catalytic core domains of IN were elucidated by X-ray crystallography. Pre-clinical toxicology was assessed in rats and cynomolgus monkeys.
GS-9695 was identified as an initial lead with excellent potency against WT HIV-1 (EC50: 1.2 ± 0.2 nM) and majority of IN polymorphic variants (fold shift: 0.2 to 4.7). However, GS-9695 resistance associated with the IN T174I mutation emerged rapidly in vitro. Subsequent NCINI compound optimization screened against the T174I mutant and lead to the identification of GS-9822 with similar antiviral potency (EC50: 3.0 ± 0.9 nM) and superior profile against IN polymorphic variants (fold shift: 0.4 to 1.3). Potent antiviral activity was observed against HIV-1 clinical isolates (mean EC50: 0.7 nM, range: 0.13 to 3.1 nM). GS-9822 had improved potency against the T174I mutant compared to GS-9695 (EC50: 143 vs 917 nM, respectively). Viral breakthrough assays also demonstrated a superior resistance profile for GS-9822 relative to GS-9695. GS-9822 but not GS-9695 maintained interactions with W131 in both wild-type and T174I mutant IN. GS-9822 had high in vitro metabolic stability and favorable oral pharmacokinetic profiles with low systemic clearance in rat, dog and monkeys. However, a key unexpected finding in cynomolgus monkey toxicology studies was a dose-dependent vacuolation of the urothelium of kidney, bladder and ureter.
GS-9822 is a novel, potent NCINI with a higher barrier to resistance relative to early prototype NCINIs, and a resistance profile orthogonal to existing antiretroviral agents. GS-9822 exhibited potential for once-daily oral dosing, making it suitable for combination with other ARVs. However, a unique and difficult-to-monitor urothelial toxicity observed in cynomolgus monkeys poses a formidable challenge for further development of GS-9822.