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Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial

Nature Medicine volume 27, pages 1712–1717 (2021)Cite this article

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Abstract

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.

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Fig. 1: Islatravir implant-site reactions.
Fig. 2: Pharmacokinetic concentration versus time.

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Data availability

MSD is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Although phase 1 trials in healthy volunteers are out of scope as per the MSD data sharing policy, an exception will be made in this case. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requesters. In line with data privacy legislation, submitters of approved requests must enter into a standard data sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and European Union or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requester and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data sharing agreement, MSD will either perform the proposed analyses and share the results with the requester or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requester can perform the proposed analyses.

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Acknowledgements

Funding for this research was provided by Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co. We thank the participants and clinical research staff who participated in this trial. MSD pharmacokinetics, pharmacodynamics and drug metabolism scientists (L. Sun, I. Xie, B. Lu, R. Valesky, M. Lyman, K. Fillgrove and M. Anderson) and early clinical scientists (V. Weissler and G. Chen) are acknowledged for their contribution to the study. Additional statistical support was provided by Y. Liu (MSD). Medical writing and/or editorial assistance was provided by Y.-M. Ching in accordance with good publication practice guidelines. This assistance was funded by MSD.

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Authors and Affiliations

  1. Merck & Co., Inc., Kenilworth, NJ, USA

    Randolph P. Matthews, Munjal Patel, Stephanie E. Barrett, Saijuan Zhang, Adrian Goodey, Ryan C. Vargo, Jay A. Grobler, S. Aubrey Stoch & Marian Iwamoto

  2. MSD Belgium, Brussels, Belgium

    Liesbeth Haspeslagh & Tom Reynders

  3. Ghent University Hospital, Ghent, Belgium

    Sylvie Rottey

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Contributions

R.P.M., M.P., J.A.G., S.E.B. and S.Z. conceived and designed the overall trial. The trial was overseen by R.P.M., S.R., L.H., T.R., S.A.S. and M.I. S.R. collected the clinical data. A.G. conducted the in vitro characterization. R.P.M., M.P. and S.Z. analyzed the data. R.P.M., M.P., S.Z., R.C.V. and M.I. interpreted the data. All authors had full access to the raw data, performed all the analyses, prepared the manuscript and were responsible for the decision to submit for publication. All authors vouch for the completeness and accuracy of the data.

Corresponding author

Correspondence to Randolph P. Matthews.

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Competing interests

R.P.M., M.P., S.E.B., L.H., T.R., S.Z., A.G., R.C.V., J.A.G., S.A.S. and M.I. were current or former employees of MSD when the study was conducted. S.R. declares no competing interests.

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Peer review information Nature Medicine thanks Douglas Richman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary Table 1, Fig. 1 and Study Protocol.

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Matthews, R.P., Patel, M., Barrett, S.E. et al. Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial. Nat Med 27, 1712–1717 (2021). https://doi.org/10.1038/s41591-021-01479-3

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