Ultrapotent Inhibitors of Wild-type and Multi-drug Resistant HIV

Emory University, Atlanta GA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT NIH guidelines for priority AIDS funding (NOT-OD-20-018) call for "next-generation therapies,,,that are longer acting,,,and less toxic", Our efforts over the past >15 years (R01AI076119, R37AI076119) resulted in the discovery of a novel mechanism of HIV inhibition that blocks viral replication by targeting the translocation step of HIV RT, Our studies on these nucleoside RT translocation inhibitors (NRTTIs, ~30 relevant papers), propelled the pre-clinical development of the prototype NRTTI 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) or islatravir (ISL), Merck Phase 1 and 2 clinical trials of ISL aimed at once-weekly oral dosing and once-yearly slow-release dosing, "Higher-dose" ISL regimens (0,75 mg/day) achieved robust virological suppression, albeit with a measurable decrease in T-cell count, whereas "lower-dose" ISL (0,25 mg/day) achieved unabated viral load suppression without decrease in T-cells, Lower-dose ISL clinical trials have resumed, although PrEP regimens are paused, Merck announced they "continue to believe in the potential of the NRTTI mechanism and are evaluating additional candidates with the goal of helping to address unmet needs in HIV prevention", Hence, while ISL is still in clinical trials, a second-generation NRTTI, MK-8527, was also introduced in Phase 1 clinical trials, They have provided a renewed letter of support expressing unwavering support for our continued collaborative efforts (ongoing for >10 years), Moreover, Merck is now collaborating with Emory University on a new Phase 3 clinical trial that will evaluate a once-daily oral combination of doravirine (DOR) and a "low-dose" of ISL (DOR/ISL, see additional collaborative letter of support), Phase 1 of this MERIT award aimed to understand the mechanisms of resistance and hypersusceptibility to ISL and other N RT ls used in the clinic towards the goal of optimizing combination treatments that reduce drug burden and have long-acting potential, Over the past ~3,5 years we used a multidisciplinary approach, including biochemical, structural, and virological experiments to effectively address the goals of phase 1, Results included nine manuscripts which are directly related to ISL studies (full details in progress report), As we described in our original MERIT award application, characterization of next-generation NRTTIs, such as MK-8527, would be a natural extension of our phase 1 studies, Furthermore, new information regarding dosing and toxicity has very recently become available from late stage ISL clinical trials, As phase 3 clinical trials of DOR/ISL proceed, including here at Emory University, potential additional information about novel resistance mutations may arise, This information may help the design of new antiviral combination strategies, Given their structural differences, we hypothesize that NRTTls have similar, yet distinct mechanisms of action, resistance, and hypersusceptibility, offering the opportunity for promising combinations with other drugs for future potent and less toxic regimens, Our leading expertise in NRTTls, strategic collaboration with Merck, and collaborative access to Emory clinical trial information will enable a productive and potentially transformative R37 extension that can swiftly pivot the strategic design of next-generation NRTTl-based regimens, We will pursue the following aims that align with the original scope of the 1st phase of the MERIT award: Aim 1, Characterize the mechanism of action (MOA) of next-generation NRTTls, Aim 2, Characterize the mechanism of resistance (MOR) of next-generation NRTTls and hypersusceptibility to drugs used in the clinic, Aim 3: Optimize next-generation NRTTl-based regimens by characterizing antiviral combinations, Aim 4, Thoroughly assess toxicity profiles of next-generation NRTTls, Our studies will help prioritize drug candidates based on MOA, MOR, hypersusceptibility, toxicity, and use in optimal combinations, thus advancing optimal solutions for use in clinical trials and future treatment strategies, The deliverables directly address one of the NI H's highest priorities for HIV/AIDS research: "develop the next generation of HIV therapies with improved safety and ease of use."