Merck's Two-Drug HIV Regimen Islatravir/Doravirine Shows Non-Inferior Efficacy to Delstrigo at 144 Weeks in Phase 2b Trial
Oct 28, 2021 02:21
CST Updated
02:21
MSD
Pharmaceutical R&D and Manufacturer
October 27, 2021 /BioonBIOON/ -- Merck & Co. recently at the 18th European AIDSConferenceAt (EACS 2021), 144-week data from a Phase 2b dose-ranging study (NCT03272347) were presented. This studyconducted in HIV-1-infected adults who had not previously received antiretroviral therapy (treatment-naive), currentlyComparison of the two-drug regimen of islatravir and doravirine (islatravir/doravirine, ISL/DOR) and the three-in-one fixed-dose combination single tablet Delstrigo (Chinese trade name: Desizhuo, generic name: doravirine/lamivudine/tenofovir disoproxil fumarate tablets, DOR/3TC/TDF)antiretroviral activity, tolerability, and safety.
Week 144 data show: measured by the proportion of patients achieving HIV-1 RNA levels <50 copies/mL (c/mL),Efficacy of ISL/DOR in Maintaining Viral Suppression Is Similar to That of DOR/3TC/TDF. The data further characterize the tolerability and safety of the ISL/DOR dual-drug regimen. The 144-week data serve as a follow-up to the 96-week results and safety data. In the 0.75 mg dose group (the selected Phase 3 dose), the 144-week results were consistent with the 96-week results.
islatravir (Islatravir, ISL) is an investigational drug by MSDNovel Oral Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI), for use in combination with other antiretroviral drugs for the treatment of HIV-1-infected individuals. Doravirine (DOR) has been approved for use in combination with other antiretroviral drugs for the treatment of HIV-1-infected adults: as a single agent (Pifeltro) and as a component of a single-tablet regimen (Delstrigo; DOR/3TC/TDF).
Recently, MSD announced positive top-line results from two pivotal Phase III trials. These two Phase III trialsConducted in HIV-1-infected adults who have achieved virologic suppression while receiving different antiretroviral therapy (ART) regimens (ILLUMINATE SWITCH A trial) or Gilead’s three-drug combination Biktarvy (BIC/FTC/TAF; ILLUMINATE SWITCH B trial)., evaluated the efficacy and safety of a once-daily oral fixed-dose doravirine/islatravir (DOR/ISL) combination tablet. The results showed that at Week 48 of treatment, both trials met the primary efficacy endpoint (proportion of patients with HIV-1 RNA levels ≥50 copies/mL):`Confirm`Antiviral efficacy was comparable between DOR/ISL and ART, and between DOR/ISL and Biktarvy.. To date, the safety and tolerability profile of DOR/ISL during the trial was consistent with that previously reported in the Phase 2 study.
Chemical structure of islatravir (MK-8591) (Image source: medchemexpress.cn)
Phase 2b Presented at the EACS 2021 ConferenceClinical TrialIn trial (NCT03272347), treatment-naive adults with HIV-1 were randomized (1:1:1) to 4 once-daily oral treatment arms: islatravir 0.25 mg (n=29), 0.75 mg (n=30), or 2.25 mg (n=31) in combination with doravirine (100 mg) and 3TC (300 mg), compared with DOR/3TC/TDF (n=31) (Part 1). After at least 24 weeks of treatment, patients in the islatravir treatment arms with HIV-1 RNA <50 copies/mL were switched to a two-drug regimen consisting of islatravir and doravirine, without 3TC (Part 2). Between weeks 60 and 84, patients in the islatravir arms transitioned to treatment with 0.75 mg islatravir (the Phase 3 selected dose) and doravirine, and continued combination therapy through week 144 (Part 3). At week 144, patients will receive the selected dose of islatravir in a fixed-dose combination with doravirine as open-label therapy until the end of the study at week 192 (Part 4).
At Week 144, as measured by the proportion of patients achieving HIV-1 RNA levels <50 copies/mL,At all dose levels, islatravir + doravirine maintained virologic suppression: 72.4% (n=21/29), 83.3% (n=25/30), and 61.3% (n=19/31) of patients in the 0.25 mg, 0.75 mg, and 2.25 mg dose groups, respectively, maintained virologic suppression.。Overall,In the islatravir + doravirine combination group, 72.2% (n=65/90) of patients achieved HIV-RNA levels <50 copies/mL, similar to 77.4% (n=24/31) in the DOR/3TC/TDF group.Within 144 weeks, 7 patients met the criteria for protocol-defined virologic failure (PDVF) (confirmed HIV-1 RNA ≥50 copies/mL) and discontinued treatment; all patients had HIV-1 RNA levels <80 copies/mL. No patients met the criteria for clinically significant confirmed viremia (HIV-1 RNA ≥200 copies/mL) or viral resistance analysis.
Regarding safety, at week 144, the proportion of patients experiencing at least one adverse event (AE) was similar between the islatravir + doravirine group and the DOR/3TC/TDF group. At week 144, 89.7% (n=26/29), 90.0% (n=27/30), and 77.4% (n=24/31) of patients in the 0.25 mg, 0.75 mg, and 2.25 mg islatravir + doravirine groups, respectively, experienced adverse events. Additionally, 85.6% (n=77/90) of patients in the pooled islatravir + doravirine group experienced adverse events, compared with 87.1% (n=27/31) in the DOR/3TC/TDF group.
the most common drug-related adverse events in the islatravir + doravirine group compared with the DOR/3TC/TDF groupAdverse Reactionswere diarrhea (1.1% [n=1/90] vs 12.9% [n=4/31]), nausea (3.3% [n=3/90] vs 9.7% [n=3/31]), headache (2.2% [n=2/90] vs 3.2% [n=1/31]), and abnormal dreams (2.2% [n=2/90] vs 0% [n=0/31]). After Week 48, no additional patients in the islatravir + doravirine group reported drug-related adverse events. The discontinuation rate due to drug-related adverse events was 2.2% (n=2/90) in the islatravir + doravirine group and 3.2% (n=1/31) in the DOR/3TC/TDF group, all occurring prior to Week 48. There were no deaths or serious drug-related adverse events in the islatravir + doravirine group. (Bioon.com)