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

Schürmann, Dirk; Rudd, Deanne Jackson; Zhang, Saijuan; Lepeleire, Inge De; Robberechts, Martine; Friedman, Evan; Keicher, Christian; Hüser, Andreas; Hofmann, Jörg; Grobler, Jay A.; Stoch, S. Aubrey; Iwamoto, Marian; Matthews, Randolph P.

doi:10.1016/s2352-3018(19)30372-8

Cited by 66 publications

(83 citation statements)

References 19 publications

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“…Current LA ART undergoing clinical trials are once-weekly oral pills, and intramuscular and subcutaneous injectables. Islatravir, also known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor that suppresses plasma HIV-1 RNA by 1.2 log 10 copies per mL for at least 7 days after a single 0.5 mg oral pill in treatment-naïve PLWH (NCT02217904) [ 7 , 8 ]. Nanoformulations of cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor, are undergoing safety and efficacy testing comparing 4 week and 8 week intramuscular injections in the LATTE-2 study (NCT02120352) [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

et al. 2020

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HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues. The device was loaded with tenofovir alafenamide (TAF) and implanted in treatment-naïve simian HIV (SHIV)-positive nonhuman primates (NHP) for a month. We monitored intracellular tenofovir-diphosphate (TFV-DP) concentration in the target cells, peripheral blood mononuclear cells (PBMC). The concentrations of TFV-DP were maintained at a median of 391.0 fmol/106 cells (IQR, 243.0 to 509.0 fmol/106 cells) for the duration of the study. Further, we achieved drug penetration into lymphatic tissues, known for persistent HIV-1 replication. Moreover, we observed a first-phase viral load decay of −1.14 ± 0.81 log10 copies/mL (95% CI, −0.30 to −2.23 log10 copies/mL), similar to −1.08 log10 copies/mL decay observed in humans. Thus, LA TAF delivered from our nanofluidic implant had similar effects as oral TAF dosing with a lower dose, with potential as a platform for LA ART.

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Section: Introductionmentioning

confidence: 99%

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

et al. 2020

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“…Studies are under way to formulate CPT31 in a depot that could be used in such a context. Additionally, this formulation could be paired with other long-acting drugs, such as nanocrystals of cabotegravir (GSK744; GlaxoSmithKline) and/or rilpivirine (TMC278; Tibotec) ( 19 , 20 ), ibalizumab ( 21 ), or promising antibodies and small-molecule inhibitors (Merck’s islatravir/MK-8591 and Gilead’s GS-6207) in clinical development ( 22 , 23 ). To fully evaluate CPT31’s therapeutic potential, it will be important to evaluate its efficacy when administered with other antiretrovirals to identify optimal combinations.…”

Section: Discussionmentioning

confidence: 99%

Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d -peptide HIV entry inhibitor

Nishimura

Francis

Donau

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.

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“…Studies are underway to formulate CPT31 in a depot that could be used in such a context. Additionally, this formulation could be paired with other long-acting drugs, such as nanocrystals of cabotegravir (GSK744, GlaxoSmithKline) and/or rilpivirine (TMC278, Tibotec) (Orkin et al, 2020; Swindells et al, 2020), ibalizumab (Emu et al, 2018), or promising antibodies and small molecule inhibitors (Merck’s islatravir/MK-8591 and Gilead’s GS-6207) in clinical development (Coelho et al, 2019; Schurmann et al, 2020). To fully evaluate CPT31’s therapeutic potential, it will be important to evaluate its efficacy when administered with other antiretrovirals to identify optimal combinations.…”

Section: Discussionmentioning

confidence: 99%

Prevention and Treatment of SHIVAD8 Infection in Rhesus Macaques by a Potent D-peptide HIV Entry Inhibitor

Nishimura

Francis

Donau

et al. 2020

Preprint

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Cholesterol-PIE12-trimer (CPT31) is a potent D-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a SHIV macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ~2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising new candidate for HIV prevention and treatment.

show abstract

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

Cited by 66 publications

References 19 publications

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d -peptide HIV entry inhibitor

Prevention and Treatment of SHIVAD8 Infection in Rhesus Macaques by a Potent D-peptide HIV Entry Inhibitor

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