Drug information

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Pronounce:
Other Names:
EFdA, ISL, MK-8591
Drug Class:
Nucleoside Reverse Transcriptase Translocation Inhibitors
Molecular Formula:

C12 H12 F N5 O3

Registry Number:
865363-93-5 (CAS)
Chemical Name:

4'-Ethynyl-2-fluoro-2'-deoxyadenosine

Chemical Class:
Purine Nucleosides
Organization:
Merck Sharp & Dohme Corp.
Phase of Development:

Islatravir is in Phase 3 development for HIV treatment. It is being studied as a single-drug capsule and as part of a fixed-dose combination containing doravirine and islatravir (DOR/ISL). Islatravir is also being developed for HIV prevention.

Chemical Image: (Click to enlarge)

Islatravir

Molecular Weight: 293.2568

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Treatment Action Group Pipeline Report 2020,3 and ClinicalTrials.gov4,5)

Pharmacology

Pharmacology

Mechanism of Action: Nucleoside reverse transcriptase translocation inhibitor (NRTTI). Islatravir (ISL), a deoxyadenosine analog, belongs to a new class of ARV drugs called NRTTIs. It has potent activity against HIV-1 and is also active against HIV-2 and multidrug-resistant HIV strains.6,7

Intracellularly, ISL is converted to its active triphosphate form (ISL-TP). ISL-TP inhibits HIV reverse transcriptase (RT) through multiple modes of action. Primarily, ISL-TP functions as an immediate chain terminator—after ISL is incorporated into viral DNA, it blocks RT translocation and prevents nucleotide attachment onto the viral DNA chain. In instances where RT translocation does occur and additional nucleotides are allowed to incorporate onto the viral DNA chain, ISL-TP can act as a delayed chain terminator by causing structural changes to the viral chain. Furthermore, ISL can be misincorporated by RT, resulting in mismatched primers that cannot be extended or excised.6–9

Half-life (T½): In a Phase 1b trial (NCT02217904) evaluating single oral doses of ISL in treatment-naive adults, the intracellular half-life of ISL-TP ranged from 78.5 to 128 hours.10

Metabolism/Elimination: ISL is intracellularly metabolized to the active triphosphate ISL-TP.8 In vitro, islatravir does not interact with CYP enzymes.11

Resistance: A Phase 2b trial (NCT03272347) evaluated three doses of ISL that were administered in combination with doravirine (DOR). By Week 48, five participants who received ISL plus DOR had experienced protocol-defined virologic failure; however, all of these participants had HIV-1 RNA <80 copies/mL, and none met the criteria for resistance testing.12

Select Clinical Trials

Select Clinical Trials


Islatravir for HIV treatment

Study Identifiers: MK-8591-011; NCT03272347
Sponsor: Merck Sharp & Dohme Corp.
Phase: 2b
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a regimen that consists of ISL (at three different dose levels) plus DOR and 3TC over 24 weeks. After 24 weeks, investigators will evaluate the safety and efficacy of ISL (at three different dose levels) plus DOR. In both cases, the active comparator group will receive DOR/3TC/TDF.
Study Population:
  • Participants are treatment-naive adults with HIV.
  • Participants have HIV RNA ≥1,000 copies/mL and CD4 counts ≥200 cells/mm3.
  • Participants have no known resistance to ARV drugs.12–14
Selected Study Results:


Study Identifiers: MK-8591A-017; NCT04223778
Sponsor: Merck Sharp & Dohme Corp.
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label trial is to evaluate the safety and efficacy of a switch from a current ART regimen to a fixed-dose combination (FDC) containing DOR/ISL.
Study Population:

  • Participants are adults with HIV who have been receiving a continuous, stable 2- or 3-drug ART regimen for at least the past 3 months.
  • Participants have had viral suppression on ART with HIV RNA <50 copies/mL for at least the past 3 months.
  • Participants have no history of virologic treatment failure on any past or current ART regimen.15


Study Identifiers: MK-8591A-018; NCT04223791
Sponsor: Merck Sharp & Dohme Corp.
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of a switch from bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF; Biktarvy) to an FDC containing DOR/ISL.
Study Population:

  • Participants are adults with HIV who have been receiving Biktarvy for at least the past 3 months.
  • Participants have had viral suppression on Biktarvy with HIV RNA <50 copies/mL for at least the past 3 months.
  • Participants have no history of virologic treatment failure on any past or current ART regimen.16


Study Identifiers: MK-8591A-019; NCT04233216
Sponsor: Merck Sharp & Dohme Corp.
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of ISL, DOR, and an FDC containing DOR/ISL, each compared to placebo.
Study Population:

  • Participants are heavily treatment–experienced children and adults with HIV who have been receiving the same ART regimen for at least the past 3 months.
  • Participants have resistance to at least one drug within three different ARV drug classes (NRTI, NNRTI, and one other class) and have limited treatment options available to form a viable ART regimen.4


Study Identifiers: MK-8591A-020; NCT04233879
Sponsor: Merck Sharp & Dohme Corp.
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this trial is to evaluate the safety and efficacy of an FDC containing DOR/ISL versus Biktarvy.
Study Population:

  • Participants are treatment-naive adults with HIV.
  • Participants have no known resistance to any approved HIV-1 reverse transcriptase inhibitor or any study intervention.17

A Phase 2 trial (NCT04295772) will evaluate DOR/ISL as an HIV treatment in adolescents who are virologically suppressed on ART. See the ClinicalTrials.gov record for this study’s status.18


Islatravir for HIV prevention

Study Identifiers: MK-8591-016; NCT04003103
Sponsor: Merck Sharp & Dohme Corp.
Phase: 2a
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of two different doses of oral ISL administered once monthly to participants who have a low risk of acquiring HIV.
Study Population:

  • Participants are adults without HIV who have a low risk of acquiring HIV.5

A Phase 1 trial that evaluated an islatravir-eluting implant for HIV pre-exposure prophylaxis has also been completed.19

Adverse Events

Adverse Events

In the MK-8591-011 study (NCT03272347), 90 participants received ISL (in doses of 0.25 mg, 0.75 mg, or 2.25 mg) plus DOR and 3TC and 31 participants received DOR/3TC/TDF for 24 weeks. After 24 weeks, eligible participants who were receiving ISL, DOR, and 3TC switched to a regimen of ISL plus DOR. The Week 48 analysis found that 73.3% of participants who received any dose of ISL and 77.4% of participants who received DOR/3TC/TDF experienced at least one adverse event (AE). Drug-related AEs occurred in 7.8% of participants who received ISL and 19.4% of participants who received DOR/3TC/TDF. Two participants who received the 2.25-mg dose of ISL discontinued treatment because of an AE; one participant experienced diarrhea, nausea, and vomiting, and one participant had HBV reactivation. Across all treatment groups, headache, diarrhea, and nausea were the most common AEs. Headache was more common in the combined ISL groups (11.1%) than in the DOR/3TC/TDF group (6.5%), and diarrhea was more common in the DOR/3TC/TDF group (16.1%) than in the combined ISL groups (6.7%). Most of the cases of headache and diarrhea were mild, transient, and unrelated to treatment.14, 20

Drug Interactions

Drug Interactions

In vitro, ISL does not interact with renal or hepatic drug transporters or CYP enzymes.11

During a drug-drug interaction study in adults who did not have HIV, the coadministration of ISL and DOR did not affect the pharmacokinetics of either drug.11 In addition, a two-way interaction study in participants who did not have HIV found that ISL does not appear to have any significant pharmacokinetic interaction with dolutegravir plus TDF.21

The pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) were not affected when an oral contraceptive that contained these drugs was coadministered with ISL. This suggests that hormonal contraceptives that contain LNG or EE can be used in individuals who are taking ISL.22

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced: Islatravir. https://chem.nlm.nih.gov/chemidplus/rn/865363-93-5. Accessed August 24, 2020
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed August 24, 2020
  3. Jefferys R. The antiretroviral therapy pipeline 2020. Treatment Action Group Pipeline Report 2020. https://www.treatmentactiongroup.org/wp-content/uploads/2020/07/pipeline_ARV_2020.pdf. Accessed August 24, 2020
  4. Merck Sharp & Dohme Corp. A Phase 3, randomized, clinical study in HIV-1-infected heavily treatment-experienced participants evaluating the antiretroviral activity of blinded islatravir (ISL), doravirine (DOR), and doravirine/islatravir (DOR/ISL), each compared to placebo, and the antiretroviral activity, safety, and tolerability of open-label DOR/ISL. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2020. NLM Identifier: NCT04233216. https://www.clinicaltrials.gov/ct2/show/NCT04233216. Accessed August 24, 2020
  5. Merck Sharp & Dohme Corp. A Phase 2a, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral MK-8591 once-monthly in participants at low-risk for HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 27, 2019. NLM Identifier: NCT04003103. https://clinicaltrials.gov/ct2/show/NCT04003103. Accessed August 24, 2020
  6. Michailidis E, Huber AD, Ryan EM, et al. 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms. J Biol Chem. 2014;289(35):24533-24548. doi:10.1074/jbc.M114.562694
  7. Grobler J. Efficacy of MK-8591 against diverse HIV-1 subtypes and NRTI-resistant clinical isolates. Webcast presented at: International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 28-31, 2018; Glasgow, United Kingdom. https://vimeo.com/298576925. Accessed August 24, 2020
  8. Michailidis E, Marchand B, Kodama EN, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by 4′-ethynyl-2-fluoro-2′-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. J Biol Chem. 2009;284(51):35681-35691. doi:10.1074/jbc.M109.036616
  9. Markowitz M, Sarafianos SG. EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine, MK-8591): a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS. 2018;13(4):294-299. doi:10.1097/COH.0000000000000467
  10. Schürmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV. 2020;7(3):e164-e172. doi:10.1016/S2352-3018(19)30372-8
  11. Matthews R, Rudd D, Fillgrove K, et al. 546. No difference in MK-8591 and doravirine pharmacokinetics after co-administration. Open Forum Infect Dis. 2018;5(Suppl 1):S203. doi:10.1093/ofid/ofy210.554
  12. Molina JM, Yazdanpanah Y, Afani Saud A, et al. Islatravir (ISL, MK-8591) at doses of 0.25 to 2.25 mg QD, in combination with doravirine maintains viral suppression through 48 weeks in adults with HIV-1 infection. Slides presented at: IAS Conference on HIV Science; July 21-24, 2019; Mexico City, Mexico. http://programme.ias2019.org/PAGMaterial/PPT/1878_4152/2019 IAS Presentation Molina MK-8591-011 48 wk FINAL 7-24-19 LOCKED.pptx. Accessed August 24, 2020
  13. Molina J-M, Yazdanpanah Y, Afani Saud A, et al. Tolerability, safety, and efficacy of islatravir (MK-8591) at doses of 0.25 to 2.25 mg QD, in combination with doravirine and lamivudine through 24 weeks in treatment-naive adults with HIV-1 infection. IAS Conference on HIV Science; July 21-24, 2019; Mexico City, Mexico. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2019. http://www.natap.org/2019/IAS/IAS_15.htm. Accessed August 24, 2020
  14. Merck Sharp & Dohme Corp. A Phase 2B, randomized, double-blind, active-comparator-controlled, dose-ranging clinical trial to evaluate the safety, tolerability, antiretroviral activity, and pharmacokinetics of MK-8591 given in combination with doravirine (DOR) and lamivudine (3TC) in HIV-1-infected treatment-naive adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 1, 2017. NLM Identifier: NCT03272347. https://clinicaltrials.gov/ct2/show/NCT03272347. Accessed August 24, 2020
  15. Merck Sharp & Dohme Corp. A Phase 3 randomized, active-controlled, open-label clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV-1 virologically suppressed on antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2020. NLM Identifier: NCT04223778. https://www.clinicaltrials.gov/ct2/show/record/NCT04223778. Accessed August 24, 2020
  16. Merck Sharp & Dohme Corp. A Phase 3, randomized, active-controlled, double-blind clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once-daily in participants with HIV- 1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2020. NLM Identifier: NCT04223791. https://www.clinicaltrials.gov/ct2/show/NCT04223791. Accessed August 24, 2020
  17. Merck Sharp & Dohme Corp. A Phase 3 randomized, active-controlled, double-blind clinical study to evaluate the antiretroviral activity, safety, and tolerability of doravirine/islatravir once-daily in HIV-1 infected treatment-naïve participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2020. NLM Identifier: NCT04233879. https://www.clinicaltrials.gov/ct2/show/NCT04233879. Accessed August 24, 2020
  18. Merck Sharp & Dohme Corp. A Phase 2 clinical study to evaluate the pharmacokinetics, safety, and efficacy of doravirine/islatravir in adolescents with HIV-1 infection who are virologically suppressed, are ≥12 to <18 years of age, and weigh ≥35 kg. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2020. NLM Identifier: NCT04295772. https://www.clinicaltrials.gov/ct2/show/NCT04295772. Accessed August 24, 2020
  19. Matthews RP, Barrett SE, Patel M, et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. Abstract presented at: IAS Conference on HIV Science; July 21-24, 2019; Mexico City, Mexico. Abstract TUAC0401LB. http://programme.ias2019.org/Abstract/Abstract/4843. Accessed August 24, 2020
  20. DeJesus E, Molina J-M, Yazdanpanah Y, et al. Islatravir (ISL, MK-8591) safety analysis through Week 48 from a Phase 2 trial in treatment naive adults with HIV-1 infection. Slides presented at: International AIDS Conference; July 6-10, 2020. https://go.aws/2Ak3eKp. Accessed August 24, 2020
  21. Jackson Rudd D, Zhang S, Fillgrove KL, et al. Pharmacokinetics of MK-8591, dolutegravir and tenofovir disoproxil fumarate are not altered after coadministration when compared to single agent administration. International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 28-31, 2018; Glasgow, United Kingdom. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2018. http://www.natap.org/2018/GLASGOW/GLASGOW_67.htm. Accessed August 24, 2020
  22. Ankrom W, Jonathan D, Rudd D, et al. MK-8591 does not alter the pharmacokinetics of the oral contraceptives ethinyl estradiol and levonorgestrel. Abstract presented at: ID Week 2018; October 3-7, 2018; San Francisco, CA. Abstract 551. https://idsa.confex.com/idsa/2018/webprogram/Paper71806.html. Accessed August 24, 2020

Last Reviewed: August 24, 2020