Merck's Two-Drug Regimen Islatravir/Doravirine Demonstrates Non-Inferior Efficacy to Delstrigo in Phase 2b First-Line HIV Treatment Trial

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On October 8, Merck presented 96-week data from the Phase 2b trial (NCT03272347) evaluating a two-drug regimen (2DR) of the novel oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir and Pifeltro (doravirine) in treatment-naïve (i.e., previously untreated) adults with HIV-1 infection at the 2020 International Conference on HIV Drug Therapy (HIV Glasgow 2020).

The results showed that the two-drug regimen (2DR) was comparable to the three-drug combination Delstrigo (doravirine/3TC/TDF) in terms of the proportion of patients maintaining virologic suppression (HIV-1 RNA <50 copies/mL), consistent with the 48-week results. Additional 96-week data revealed that the proportions of patients experiencing protocol-defined virologic failure (PDVF) were low in both the 2DR and Delstrigo treatment groups, and no patients in either group met the criteria for resistance testing.

In addition, MSD announced the results of the Phase 1/1b study of MK-8507, an investigational once-weekly oral non-nucleoside reverse transcriptase inhibitor (NNRTI). The data demonstrated that the antiviral potency and pharmacokinetic profile of MK-8507 support further evaluation of this agent as a once-weekly oral therapy, as part of combination antiretroviral (ARV) regimens, for the treatment of HIV-1 infection.

Chemical Structural Formula of Islatravir (MK-8591)(Image source: medchemexpress.cn)

Pifeltro (doravirine, 100 mg) is a novel, once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults, specifically: (1) for patients who are antiretroviral treatment-naïve; and (2) for patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen, have no history of treatment failure, and have no known doravirine resistance-associated substitutions, as a replacement for their current ARV regimen.

Delstrigo is a fixed-dose combination tablet comprising the novel non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR, 100 mg), lamivudine (3TC, 300 mg), and tenofovir disoproxil fumarate (TDF, 300 mg). Administered as a once-daily tablet, it serves as a complete regimen for the treatment of HIV-1 infection in adults, specifically indicated for: (1) antiretroviral (ARV)-treatment-naïve patients; and (2) patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen, have no history of treatment failure, and have no known resistance-associated substitutions to any component of Delstrigo (doravirine, 3TC, or TDF), as a replacement for their current ARV regimen. The prescribing information for Delstrigo includes a Boxed Warning regarding the risk of acute exacerbation of hepatitis B virus (HBV) infection following discontinuation of treatment.

Efficacy and Safety Data

In this international, multicenter clinical trial, treatment-naïve adults with HIV-1 infection were randomized (1:1:1:1) to four once-daily oral treatment regimens: islatravir 0.25 mg (n=29), 0.75 mg (n=30), or 2.25 mg (n=31), each in combination with doravirine (100 mg) and lamivudine (3TC; 300 mg), or Delstrigo (n=31). After at least 24 weeks of treatment, patients in the three islatravir groups who achieved virologic suppression (HIV-1 RNA <50 copies/mL) and did not meet the criteria for PDVF switched to a two-drug regimen (2DR) consisting of islatravir at the same original dose and doravirine (100 mg), without 3TC.

At Week 96, the islatravir plus doravirine regimen maintained virologic suppression (HIV-1 RNA <50 copies/mL) across all dose levels. Specifically, at Week 96 of treatment, virologic suppression was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of patients in the islatravir 0.25 mg, 0.75 mg, and 2.25 mg dose groups, respectively, compared with 80.6% (25/31) in the Delstrigo treatment group. The numerically lower rate of virologic suppression observed in the islatravir 2.25 mg dose group was primarily attributable to a higher discontinuation rate during the first 48 weeks of the study.

At Week 96, the proportion of patients experiencing drug-related adverse events (AEs) was lower in all islatravir dose groups (7.8%) compared with the Delstrigo treatment group (22.6%). Between Weeks 48 and 96, no additional drug-related serious adverse events were reported in any group. Based on these results, the 0.75-mg dose of islatravir will be used for further clinical development.

PDVF Analysis Results

The 96-week analysis showed a low incidence of PDVF. All patients who discontinued treatment due to PDVF had HIV-1 RNA levels <80 copies/mL, which is below the clinically significant threshold of 200 copies/mL. No patients met the criteria for resistance testing (HIV-1 RNA >400 copies/mL). PDVF was defined as confirmed virologic rebound with HIV-1 RNA ≥50 copies/mL after achieving virologic suppression, or lack of response to treatment with confirmed HIV-1 RNA ≥50 copies/mL.

At Week 96, a total of 7 patients met the criteria for PDVF and discontinued the trial. As previously mentioned, at Week 48, PDVF was confirmed in 6 patients, with an incidence rate of 5.6% (5/90; 4 cases of rebound, 1 case of non-response) across all islatravir treatment arms and 3.2% (1/31; 1 case of rebound) in the Delstrigo group. In the 2.25 mg islatravir dose group, only one patient discontinued treatment due to PDVF (rebound). No patients in any treatment arm met the criteria for resistance testing, as all patients meeting the PDVF definition had HIV-1 RNA levels <80 copies/mL. During the 42-day follow-up period, 3 of the 7 patients who discontinued treatment due to PDVF continued to exhibit low-level viremia after switching to a new regimen.

Renal Safety Analysis Results

The 96-week exploratory analysis revealed no renal safety concerns. Serum creatinine was measured at each study visit (including Day 1, Week 48, and Week 96). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation.

At Weeks 48 and 96, the median changes in serum creatinine and eGFR were minimal across all treatment groups. Two patients in the 0.25-mg islatravir group experienced increases in serum creatinine of ≥0.5 mg/dL from baseline, which resolved at the next study visit: one patient at Week 16 (1.7 mg/dL) and another patient at Week 60 (1.7 mg/dL) and Week 84 (1.9 mg/dL). No patients had an increase in serum creatinine of ≥1.0 mg/dL or a doubling of serum creatinine. A decrease in eGFR of >30% from baseline occurred in 12% (11/90) of patients in the islatravir treatment group and 16% (5/31) of patients in the Delstrigo group, and was transient in most cases.

In the islatravir treatment group, 4% (4/90) of patients experienced an eGFR <60 mL/min/1.73 m², three of whom had transient decreases (the fourth patient’s eGFR remained <60 mL/min/1.73 m² from baseline through Week 96). No clinically meaningful changes were observed in renal biomarkers, including urinary albumin, albumin-to-creatinine ratio, β-2 microglobulin-to-creatinine ratio, or retinol-binding protein-to-creatinine ratio. No dose–response relationship was observed for the renal effects of islatravir combined with doravirine, and no patients discontinued treatment due to renal adverse events.

Reference Source: Merck Announces Week 96 Data from Phase 2b Study Evaluating Islatravir in Combination With Doravirine in Adults With HIV-1 Infection

Original Title: Enhanced Safety! MSD’s Two-Drug Regimen Demonstrates Phase 2b Clinical Efficacy Comparable to the Triple-Combination Drug Delstrigo in First-Line HIV Treatment