Chemistry:Islatravir
Islatravir (ISL) is an antiretroviral drug used, in fixed-dose combination with doravirine, as a switch regimen for the treatment of HIV-1 infection in adults. The combination, marketed as Idvynso, was approved by the FDA in April 2026.[1][2] It is classified as a nucleoside reverse transcriptase translocation inhibitor (NRTTI).
Medical uses
The fixed-dose combination of doravirine and islatravir is indicated as a complete regimen for the treatment of HIV-1 infection in adults, to replace current antiretroviral therapy in those who are virologically suppressed, defined as HIV-1 RNA less than 50 copies/mL, on a stable antiretroviral regimen, with no history of virologic treatment failure and no known substitutions associated with resistance to doravirine.[1]
History
In 2021, the FDA placed clinical holds on several studies of islatravir after decreases in total lymphocyte and CD4+ T-cell counts were observed in some participants receiving the drug.[3]
Development was subsequently resumed using a lower-dose once-daily oral regimen combining doravirine with islatravir, while development of once-monthly oral islatravir for pre-exposure prophylaxis (PrEP) was discontinued.[4]
In April 2026, the lower-dose doravirine/islatravir combination was approved by the FDA as Idvynso.[2]
Biological activity
Islatravir was originally described as a 4′-modified nucleoside analogue active against drug-resistant HIV-1 variants.[5]
Islatravir has potent activity against HIV-1 in vitro and in animal models, including humanized mice and non-human primates.[6][7] It demonstrates high potency against both wild-type and drug-resistant HIV-1 strains and has a high genetic barrier to resistance.[8]
Mechanism of action
Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Like other nucleoside reverse transcriptase inhibitors, it must first be converted inside cells to an active triphosphate metabolite, islatravir triphosphate (ISL-TP). HIV-1 reverse transcriptase (RT) then incorporates ISL-TP into nascent viral DNA in place of deoxyadenosine triphosphate.[6][9]
Islatravir differs from conventional nucleoside and nucleotide reverse transcriptase inhibitors in that it retains a 3′-hydroxyl group. Despite this, its incorporation usually prevents efficient continuation of DNA synthesis. The main mechanism is defective translocation: after islatravir is incorporated at the primer terminus, RT has difficulty moving the primer from the pre-translocation nucleotide-binding site (N-site) to the post-translocation primer site (P-site), thereby preventing addition of the next nucleotide.[10]
Depending on the template sequence, islatravir can act as either an immediate or a delayed chain terminator. If translocation is blocked immediately after incorporation, DNA synthesis stops at that point. If translocation occurs, RT may add one more nucleotide, but further elongation is then blocked because the islatravir-containing primer terminus becomes distorted, creating steric clashes with the incoming nucleotide in the polymerase active site.[6][11]
Structural studies indicate that this behavior is largely explained by the 4′-ethynyl group of islatravir. The group fits into a conserved hydrophobic pocket in the polymerase active site of RT, forming interactions with amino acid residues. These interactions stabilize the pre-translocation complex and make the post-translocation state less favorable.[11][12]
RT can also misincorporate islatravir opposite non-canonical template bases. The resulting mismatched primer termini are inefficiently extended and are relatively resistant to phosphorolytic excision. These additional mechanisms, together with impaired translocation, contribute to the high potency of islatravir against wild-type and drug-resistant HIV-1 variants.[6][5]
Research
A once-weekly oral regimen combining islatravir with the capsid inhibitor lenacapavir is in Phase 3 clinical development as a potential long-acting treatment option for HIV-1 infection. In 2024, Phase 2 data indicated that switching to the islatravir/lenacapavir regimen maintained viral suppression in adults with HIV-1.[13][14][15]
Islatravir is also being studied in combination with the investigational non-nucleoside reverse transcriptase inhibitor ulonivirine (MK-8507) as a once-weekly oral regimen in Phase 2b trials.[14]
References
- ↑ 1.0 1.1 "Idvynso prescribing information". U.S. Food and Drug Administration. April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/216964Orig1s000lbl.pdf.
- ↑ 2.0 2.1 "NDA 216964 approval letter". U.S. Food and Drug Administration. 20 April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/216964Orig1s000ltr.pdf.
- ↑ "Merck restarts islatravir HIV treatment studies, but abandons monthly PrEP". 23 September 2022. https://www.aidsmap.com/news/sep-2022/merck-restarts-islatravir-hiv-treatment-studies-abandons-monthly-prep.
- ↑ "Merck to Initiate New Phase 3 Clinical Program with Lower Dose of Daily Oral Islatravir in Combination with Doravirine". 20 September 2022. https://www.merck.com/news/merck-to-initiate-new-phase-3-clinical-program-with-lower-dose-of-daily-oral-islatravir-in-combination-with-doravirine-for-treatment-of-people-with-hiv-1-infection/.
- ↑ 5.0 5.1 "2'-deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants". The International Journal of Biochemistry & Cell Biology 40 (11): 2410–2420. 2008. doi:10.1016/j.biocel.2008.04.007. PMID 18487070.
- ↑ 6.0 6.1 6.2 6.3 "4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms". The Journal of Biological Chemistry 289 (35): 24533–24548. August 2014. doi:10.1074/jbc.M114.562694. PMID 24970894.
- ↑ "Oral administration of the nucleoside EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaque". Antimicrobial Agents and Chemotherapy 59 (7): 4190–4198. July 2015. doi:10.1128/AAC.05036-14. PMID 25941222.
- ↑ "The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase". Cell Chemical Biology 25 (10): 1268–1278.e3. October 2018. doi:10.1016/j.chembiol.2018.07.014. PMID 30174310.
- ↑ "4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor". Current Opinion in HIV and AIDS 13 (4): 294–299. July 2018. doi:10.1097/COH.0000000000000467. PMID 29697468.
- ↑ "Low-dose tamoxifen in the treatment of breast ductal intraepithelial neoplasia: results of a large observational study". Annals of Oncology 21 (5): 949–954. May 2010. doi:10.1074/jbc.M109.036616. PMID 19858087.
- ↑ 11.0 11.1 "Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)". Proceedings of the National Academy of Sciences of the United States of America 113 (33): 9274–9279. August 2016. doi:10.1073/pnas.1605223113. PMID 27489345. Bibcode: 2016PNAS..113.9274S.
- ↑ "DICER1 Is Essential for Self-Renewal of Human Embryonic Stem Cells". Stem Cell Reports 11 (3): 616–625. September 2018. doi:10.1016/j.chembiol.2018.07.014. PMID 30146489.
- ↑ "Islatravir plus lenacapavir could be the first once-weekly oral HIV treatment". 6 March 2024. https://www.aidsmap.com/news/mar-2024/islatravir-plus-lenacapavir-could-be-first-once-weekly-oral-hiv-treatment.
- ↑ 14.0 14.1 "FDA Approves Merck's Once-Daily IDVYNSO". Merck. 21 April 2026. https://www.merck.com/news/fda-approves-mercks-once-daily-idvynso-doravirine-islatravir/.
- ↑ "Gilead and Merck announce Phase 2 data showing a treatment switch to an investigational oral once-weekly combination regimen of islatravir and lenacapavir maintained viral suppression in adults with HIV". Gilead Sciences. 6 March 2024. https://www.gilead.com/news/news-details/2024/gilead-and-merck-announce-phase-2-data-showing-a-treatment-switch-to-an-investigational-oral-once-weekly-combination-regimen-of-islatravir-and-lenacapavir-maintained-viral-suppression-in-adu.
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