CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

HIV-2 compared with HIV-1 infected individuals (p=0.028, LRT). Finally, CD4+ T-cell levels at clinical AIDS was higher in HIV-2 compared with HIV-1 infected individuals (18.2% vs. 8.2%, p<0.001, 2-tailed Mann-Whitney U Test). Conclusion: Our results contradicts the common assumption that the majority of HIV-2 infected individuals remain long-term-non-progressors and suggest that, similar to HIV-1 infection, HIV-2 infection will result in disease development if followed long enough. This suggests that early treatment initiation would be beneficial also for HIV-2 infected individuals. 38 DISCOVERY OF NOVEL POTENT HIV CAPSID INHIBITORS WITH LONG-ACTING POTENTIAL Winston C. Tse , John O. Link, Andrew Mulato, Anita Niedziela-Majka, William Rowe, John R. Somoza, Armando G. Villasenor, Stephen R. Yant, Jennifer R. Zhang, Jim Zheng Gilead Scis, Inc, Foster City, CA, USA Background: While HIV capsid (CA) plays an essential role in multiple stages of the viral life cycle, it remains an unexplored target for antiretroviral (ARV) therapy. Here, we report the discovery of a novel class of exquisitely potent and metabolically stable HIV capsid inhibitors (CAIs) that exhibit pharmacokinetic (PK) profiles suitable for slow-release parenteral administration. Methods: In vitro CA binding and assembly assays, together with X-ray co-crystal structures of CAIs with cross-linked CA hexamers, were used to optimize compounds for high binding affinity to CA. Medicinal chemistry approaches were employed to optimize the antiretroviral activity and drug-like properties using a cytopathic antiviral assay in conjunction with extensive metabolism and pharmacokinetic profiling. CAI resistance-associated mutations were identified by in vitro resistance selections. CAI mode-of-action was defined by inhibitor time-of-addition, virion electron microscopy and viral DNA quantification. Results: GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in T cell lines (EC 50 = 0.24 nM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades in human PBMCs. Identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a CA hexamer and accelerate CA assembly in vitro. The identified CAIs maintain full activity against HIV-1 mutants resistant to licensed ARVs and select for HIV CA variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry CA functions. GS-CA1 shows high in vitro metabolic stability and favorable PK profiles in multiple preclinical species with low systemic drug clearances (0.08–0.33 L/ hr/kg) and long half-lives (7.2–18.7 hr). Low aqueous solubility provides for an extended-release preclinical PK profile following subcutaneous administration of a solid depot formulation. Conclusion: We have identified novel HIV-1 capsid inhibitors with uniquely potent antiviral activity and a favorable resistance profile orthogonal to existing ARVs. The high metabolic stability and low aqueous solubility of this new inhibitor class should enable the development of an extended-release parenteral formulation with the potential to be used as a novel long-acting antiretroviral treatment. 39 HUMAN CONFIRMATION OF ORAL DOSE REDUCTION POTENTIAL OF NANOPARTICLE ARV FORMULATIONS Andrew Owen 1 , Steve Rannard 1 , Akil Jackson 2 , Laura Dickinson 1 , Marco Giardiello 1 , Marco Siccardi 1 , Paul Domanico 3 , Melynda Watkins 3 , Yao Cheng 4 , Marta Boffito 5 1 Univ of Liverpool, Liverpool, UK, 2 Chelsea and Westminster Hosp, London, UK, 3 Clinton Hlth Access Initiative, Boston, MA, USA, 4 Med Patent Pool, Geneva, Switzerland, 5 Chelsea and Westminster NHS Fndn Trust, London, UK Background: Emulsion-templated spray drying to form solid drug nanoparticle (SDN) formulations of efavirenz (EFV) and lopinavir (LPV) previously showed preclinical potential for dose reduction while maintaining pharmacokinetics (PK). This study sought to confirm this in healthy volunteers after single dose and at steady state. Methods: Healthy volunteers (n=4) were consented and screened before receiving 50mg NANO-EFV OD over 21 days. A 72-hour PK profile was generated after the first dose, followed by steady-state PK profile after the final dose with 228-hour plasma decay. Single plasma concentration measurements were also made on days 7, 14, and 17. Safety (including physical examination with vital signs, ECG, urinalysis, laboratory testing) occurred at screening, day 1, 2, 14, 21 and at completion. Five volunteers were consented and screened before receiving 200mg NANO-LPV (boosted with 100mg Norvir) BID over 7 days. A 12-hour PK profile was generated after the first dose, followed by steady-state PK after the final dose with 56-hour decay. A single plasma concentration measurement was also made on day 3. Safety assessments occurred at screening, day 1 (pre morning and afternoon dose and 4 hours post afternoon dose), day 7, and at completion. PK was analysed through population-PK models, with the resulting models used to simulate (n=1000) bioequivalence with previously published clinical data. Results: Both nanoformulations proved to be well tolerated at the studied doses, with no grade 3-4 adverse events. For NANO-EFV, simulations predicted 300mg OD would provide bioequivalence to 600mg OD Sustiva for AUC 0-24 , C max , C 12 , but not C 24 (see table). Importantly, bioequivalence was missed at C 24 because concentrations were predicted to be higher than those for Sustiva. Similar simulations were made for 200mg NANO-EFV versus 400mg of the conventional formulation. For NANO-LPV, simulations predicted 200mg BID (with 100mg Norvir) would provide bioequivalence to BID Kaletra for AUC 0-12 , C max , and C 12 . Conclusion: These data confirm the potential for a 50% dose reduction while maintaining therapeutic exposure, using a novel approach to formation of SDNs. If confirmed in larger future studies, the approach has the potential for savings up to 243 million USD per year while also freeing up manufacturing capacity up to 930 tons per year.

Oral Abstracts

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CROI 2017