EACS2023: 697 Investigational studies to understand the decreases in lymphocytes seen clinically with Islatravir (ISL) and enabling the initiation of new clinical trials J.A. Lebron , Z. Sobol , J. Barnum , T.L. Diamond , D. Ma , B. Bhatt , N. Li , Z. Wang , B.-L. Wan , F. Li , M. Korrapati , Y. Li , Q. Huang , K. Fillgrove , Q. Xu , A.G. Aslamkhan , L. Liu , M. Moslow , R. Staupe , J.Y. Phuah , N. Thambi , K.A. Vora , R. Vargo , E. Asante-Appiah , S. Ferry-Martin Merck, Sharp & Dohme, Nonclinical Drug Safety, Rahway, United States, Merck, Sharp & Dohme, Discovery Biology, Rahway, United States, Merck, Sharp & Dohme, Discovery BioAnalytical, Rahway, United States, Merck, Sharp & Dohme, ADME, Rahway, United States, Merck, Sharp & Dohme, Quantitative Pharmacology & Pharmacokinetics, Rahway, United States General data Abstract category: Antiretroviral drugs preclinical Abstract body Purpose: ISL is an inhibitor of HIV-1 replication. Its active form (ISL-triphosphate; ISL-TP) preferentially accumulates in lymphocytes. During Phase 2/3 clinical trials, ISL-related decreased lymphocytes were observed at doses (e.g., ≥0.75 mg QD) corresponding to ISL-TP concentrations ≥35 µM, but not at doses associated with an ISL-TP concentration of 9 µM. Studies were conducted to investigate possible mechanisms for these lymphocyte decreases. Method: In vitro effects of ISL and several HIV NRTIs on TK6 cells (lymphoblast cell-line) population doubling and mitochondrial DNA content were evaluated. In vitro effects of ISL on human PBMC cytotoxicity, activation, and function were also assessed. ISL‑TP was evaluated for its ability to inhibit human DNA polymerases α, β, and γ. Additionally, ISL was evaluated in a 10-week immunophenotyping study in mice. Results: In TK6 cells, ISL and most NRTIs resulted in population growth inhibition at similar triphosphate concentrations. ISL-TP concentrations that resulted in cytotoxicity in TK6 cells and human PBMCs were comparable. ISL-TP weakly inhibited DNA polymerase α. Consistent with the lack of inhibition of polymerase γ, ISL did not impact mitochondrial DNA content. In mice, decreased lymphocyte counts were observed at ISL-TP PBMC levels associated with lymphocyte decreases in humans. Additionally, effects on B and/or T cell activation in splenocytes from mice dosed with ISL were observed at ISL-TP levels that greatly exceed those achieved at the clinical dose without lymphocyte effects. Conclusions: Preferential accumulation of high ISL-TP concentrations in lymphocytes can lead to cytotoxicity, possibly through DNA polymerase α inhibition as a contributing factor. These effects are shared with several marketed NRTIs, at similarly high triphosphate levels. Mitochondrial toxicity is not a contributing mechanism. These investigations, together with clinical and modelling data, identified an ISL-TP threshold (9 µM), and subsequently ISL QD and QW clinical doses, below which decreases in lymphocytes are not expected. General conditions 1. I confirm that I previewed this abstract and that all information is correct. I accept that the content of this abstract cannot be modified or corrected after the submission deadline and I am aware that it will be published exactly as submitted.: Yes 2. I confirm that the submission of the abstract constitutes my consent to publication (e.g. conference website, programmes, other promotions, etc.). : Yes 3. I herewith confirm that the contact details saved in this system are those of the corresponding author, who will be notified about the status of the abstract. The corresponding author is responsible for informing the other authors about the status of the abstract.: Yes 4. I agree that all data provided may be used (saved, stored, processed, transmitted and deleted) in compliance with the privacy policy to provide the services described.: Yes 1 1 1 2 2 1 1 1 3 3 1 2 2 4 1 1 1 2 2 2 2 2 5 2 1 1 2 3 4 5 80 19TH EUROPEAN AIDS CONFERENCE | WARSAW 2023
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