CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Day 1 baseline samples were sensitive to GSK'254 with IC 50 values ranging from 0.39 – 18.4nM. No on-treatment week 4 samples had greater than a 4-fold shift in IC 50 compared to day 1 baseline samples. Two samples with low infectivity are continuing to be explored. No sample from any participant that met PDVF criteria resulted in phenotypic resistance. The MI resistance associated mutation A364V was not detected in any sample with data at the level of sensitivity for the NGS assay. Conclusions: In vitro analysis of GSK'254 predicted activity against a broad array of gag polymorphisms, including those hindering prior MI class compounds. Clinical data from the DOMINO study supported the efficacy of this novel MI, GSK'254, as no virus tested from the study demonstrated a decrease in potency to GSK'254 at baseline, through week 4 on treatment, or at any time of protocol defined virologic failure. The clinical durability observed for GSK'254 in this study suggests a sufficient genetic barrier without emergence of resistance. Overall, these data provide clinical evidence that newer MI class compounds offer future options for HIV-1 treatment without the issue of gag polymorphisms observed with prior MI compounds. Finally, the learnings from this Phase 2b study will support the development of future MI compounds in the ViiV pipeline Structure-Guided Optimization of InSTIs to Increase Antiviral Potencies Against HIV-1 IN Mutants Steven Smith , Xue Zhi Zhao, Stephen Hughes, Terrence R. Burke National Cancer Institute, Frederick, MD, USA Background: There are at least four distinct resistance pathways that emerge against second-generation INSTIs: G118R, G140A/S + Q148H/K/R, N155H, and R263K. Although it is critical to develop INSTIs that retain potency against all four resistance pathways, an important aspect of our research has been directed at overcoming resistance associated with G140S/Q148H mutants, a pathway common in PLWH who have undergone virological failure. We are using combinations of our most promising compounds to develop new INSTIs with improved antiviral potencies against the IN G140S/Q148H mutants. Methods: Compound AK-01 was generated by combining some of the best structural features of our previous compounds 4d and 5j to produce a naphthyridine scaffold with modifications at the 4' and 5' positions. Single round infectivity assays were used to measure EC 50 values against a panel of clinically relevant IN mutants. We compared the antiviral potencies of AK-01 with the potencies of parent compounds, 4d, 5j, another naphthyridine-based prototype INSTI (4a), and FDA-approved second-generation INSTIs. Results: AK-01 exhibited high antiviral potencies against WT HIV-1 (1.2 ± 0.4 nM) and several well-characterized IN mutants (G118R = 3.8 ± 0.7, N155H = 2.3 ± 0.2 nM, and R263K = 2.8 ± 0.6 nM). Importantly, AK-01 showed only a modest loss in potency against the key IN mutant G140S/Q148H (17.9 ± 4.2 nM). However, there was a more pronounced loss of antiviral potency when AK-01 was challenged with some other well-known IN double and triple mutants. Conclusion: Although AK-01 is not a fully optimized compound, our results show that combining structural modifications of promising naphthyridine based INSTIs can be used to produce new compounds that are effective against some of the known drug-resistant mutants. Importantly, AK-01 had an improved antiviral profile when compared to cabotegravir. We are currently using the available structural and virological data to design and evaluate additional INSTIs. Preclinical Characterization of GS-5894, a Potent NNRTI With Once Weekly Oral Dosing Potential Eric Lansdon 1 , Andrew Mulato 1 , Petr Jansa 1 , Gary Lee 1 , George Stepan 1 , Mike Matles 1 , Kelly Wang 1 , Carmen Ip 1 , Julie Fogarty 1 , Dan Soohoo 1 , Bernard Murray 1 , Stephen Yant 1 , Zlatko Janeba 2 , Richard L. Mackman 1 , Tomas Cihlar 1 1 Gilead Sciences, Inc, Foster City, CA, USA, 2 Institute of Organic Chemistry and Biochemistry of the CAS, Prague, Czech Republic Background: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) target an allosteric binding pocket near the polymerase active site of HIV-1 reverse transcriptase (RT) to prevent viral replication. To date, all approved NNRTIs must be dosed once-daily as part of a highly active antiretroviral regimen. Due to their physiochemical properties such as low solubility and high logD, NNRTIs are good candidates for long-acting regimens. Here we describe a novel and potent NNRTI with metabolic stability supportive of once-weekly (QW) oral dosing for the treatment of HIV-1 infection. Methods: Antiviral activity against IIIB WT virus and drug resistant variants was measured in cytopathic assays using the MT-2 and MT-4 T-cell lines. Cross

resistance was assessed against a Monogram panel of HIV-1 reporter viruses containing NNRTI resistance-associated mutations. Mutations that emerged under selective drug pressure were identified by dose-escalation and fixed-drug concentration resistance selections. Compound binding to rat, dog and human plasma was measured by equilibrium dialysis. Predicted clearance (CL) was measured by metabolic stability in human hepatocytes. Additional oral and intravenous pharmacokinetic studies were conducted in rat and dog. Results: GS-5894 is a potent and selective inhibitor of HIV-1 replication in the MT-4 T-cell line, in primary human CD4+ T lymphocytes, and in monocyte derived macrophages, with EC 50 and selectivity index (CC 50 /EC 50 ) values ranging from 1.5 to 4.2 nM and 5,152 to >66,000, respectively. The antiviral activity of GS-5894 against a panel of 32 NNRTI-resistant reporter HIV-1 variants derived from treatment-experienced people with HIV (PWH) was superior to that of other marketed NNRTIs. GS-5894 dose escalating resistance selections resulted in the emergence of an HIV-1 triple RT variant (I125V+E138K+P236T) that was cross-resistant to EFV and RPV. GS-5894 is tightly bound to plasma across species though the human binding-adjusted EC95 is 122 nM. The human predicted CL for GS-5894 (uncorrected for plasma binding) is 0.17 L/h/kg. GS-5894 has oral bioavailabilities of 34% and 31% (dosed as a solution), and mean-residence times of 2.9 and 23 hours in rat and dog, respectively. Conclusion: GS-5894 is a novel and potent NNRTI with an improved resistance profile compared to other NNRTIs. Given the high plasma binding and low predicted metabolic clearance, GS-5894 has the potential for once-weekly oral dosing in PWH for the treatment of HIV-1 infection. Discovery of GS-9770: A Novel Unboosted Once Daily Oral HIV Protease Inhibitor Xiaochun Han , Ron Aoyama, Jacob Cha, Aesop Cho, Ana Z. Gonzalez, Salman Jabri, Michael Lee, Albert C. Liclican, Ryan McFadden, Andrew Mulato, Zach E. Newby, Jie Xu, Johannes Voigt, Lianhong Xu, Hong Yang Gilead Sciences, Inc, Foster City, CA, USA Background: HIV protease was one of the first biochemical targets identified to inhibit HIV replication. Nine HIV-protease inhibitors (PIs) have been approved since the first, saquinavir, in 1995. The latest generation showing high efficacy and barrier to resistance. However, these agents have poor metabolic stability and a short human half-life on their own. As a result, HIV-PIs need to be co-administered with a CYP-inhibitor or pharmacokinetic (PK) booster, such as Cobicistat, to extend their half-life long enough to achieve daily oral dosing, hampering their broad utility. Methods: To meet this need, it was our goal to discover a novel HIV-PI that could be administered without the need of a PK booster. Attributing the poor metabolic stability of known HIV protease inhibitors to their peptidomimetic nature and inspired by the guanidine scaffold which was used in the discovery of non-peptidomimetic, and unboosted, β-secretase 1 (BACE1) inhibitors, we selected an iminohydantoin pharmacophore to initiate a structure-enabled optimization to GS-9770. Results: GS-9770 is exquisitely potent (Ki = 0.14 nM, EC 50 = 7 nM) and metabolically stable (3H hLM pred CL = 0.09 L/h/kg). Pre-clinical in vivo PK studies showed that GS-9770 had good oral bioavailability (46 – 100 %) and long half-life (7 – 12 hours). Conclusion: Both in vitro and in vivo data of GS-9770 support its unboosted, once daily oral administration. This poster will walk audience through our medicinal chemistry efforts with structure-based drug design approach towards GS-9770. Discovery of MK-8527: A Long-Acting HIV-1 Nucleoside Reverse Transcriptase Translocation Inhibitor Izzat Raheem, Kerry Fillgrove, Gregory O'Donnell, Jonathan Patteson, Shih Lin Goh, Carolyn Bahnck-Teets, Qian Huang, Ernest Asante-Appiah, Min Xu, Steve S. Carroll, Jay A. Grobler, Jeffrey Hale, Ming-Tain Lai, Vinay Girijavallabhan, Tracy L Diamond Merck & Co, Inc, Rahway, NJ, USA Background: Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) such as islatravir (ISL) are potent inhibitors of HIV-1 replication. We have invented a novel NRTTI with antiviral potency and pharmacokinetics (PK) suitable for less-frequent-than-daily dosing, an attractive profile for HIV pre-exposure prophylaxis. MK-8527 is a 7-deaza-deoxyadenosine analog and is phosphorylated intracellularly to its active triphosphate (TP) form, which is a potent inhibitor of HIV-1 replication.

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