Merck's Two-Drug HIV Regimen (Islatravir + Doravirine) Demonstrates Efficacy Comparable to Three-Drug Delstrigo with Improved Safety Profile

July 08, 2020 News /BioValleyBIOON/ -- Merck & Co. recently at the 23rd International AIDS Conference (AIDS 2020) virtualMeetingPhase IIb was published onClinical TrialsNew analysis data from (NCT03272347). The study is being conducted in HIV-1-infected individuals who have not previously received antiretroviral (ARV) therapy, and it is evaluating the efficacy and safety of the investigational oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (formerly MK-8591) in combination with doravirine (trade name: Pifeltro; generic name: doravirine).

The first subanalysis further characterized the tolerability and safety of islatravir at three dose levels (0.25, 0.75, and 2.25 mg) in combination with doravirine (100 mg) over 48 weeks of treatment. The second subanalysis demonstrated that patients initiating therapy with islatravir and doravirine in combination with lamivudine (3TC) maintained antiviral activity (HIV-1 RNA <50 copies/mL) at Week 48, with a low incidence of protocol-defined virologic failure (PDVF), comparable to that observed with the triple-combination regimen Delstrigo (doravirine/3TC/TDF).

The 48-week analysis data reinforce the efficacy and safety of islatravir in combination with doravirine as a two-drug regimen (2DR) for the treatment of HIV-infected individuals. Currently, MSD is conducting Phase III clinical programs to further evaluate this regimen.

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

Delstrigo is a three-in-one combination medication composed of fixed-dose novel NNRTI doravirine (DOR, 100 mg) with lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg). This drug is a once-daily tablet, serving as a complete treatment regimen for adult patients infected with HIV-1, specifically: (1) for patients with no prior history of ARV treatment; (2) for patients who have achieved virologic suppression (HIV-1 RNA <50 copies/mL) on a stable ARV regimen, have no history of treatment failure, and have no known resistance-associated substitution mutations related to each component of Delstrigo (doravirine, 3TC, TDF), replacing their current ARV regimen. The Delstrigo drug label contains a black box warning indicating the risk of acute exacerbation of hepatitis B virus (HBV) infection after treatment.

In this international, multicenterClinical TrialsAmong treatment-naïve adults with HIV-1 infection, participants were randomly assigned (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 combined with doravirine (100 mg) and lamivudine (3TC; 300 mg), or Delstrigo (n=31). After at least 24 weeks of treatment, participants in the three islatravir groups who achieved virologic suppression (HIV-1 RNA <50 copies/mL) and did not meet the criteria for protocol-defined virologic failure (PDVF) switched to a two-drug regimen (2DR) consisting of islatravir at the same dose plus doravirine (100 mg), without 3TC.

At Week 48, the incidence of drug-related adverse events was lower in the islatravir treatment group (7.8%) than in the Delstrigo group (19.4%). From Week 0 to Week 48, the incidence of drug-related adverse events was similar across all islatravir groups (0.25 mg–0.0%; 0.75 mg–10.0%; 2.25 mg–12.9%), indicating no dose-dependent differences in the safety profile of islatravir. The incidence of drug-related adverse events was higher during the first 24 weeks of the trial (0.25 mg–0.0%; 0.75 mg–10.0%; 2.25 mg–6.5%; Delstrigo–19.4%) than during the second 24 weeks (0.25 mg–0.0%; 0.75 mg–3.3%; 2.25 mg–7.4%; Delstrigo–3.6%). The most commonly reported adverse events in the Delstrigo group (reported by >10% of participants) were diarrhea (16.1%), bronchitis (12.9%), and syphilis (12.9%). In the islatravir treatment groups, the most commonly reported adverse events (reported by >10% of participants) were: for the 0.25 mg dose, sinusitis, extremity pain, and headache (10.3%, 10.3%, and 13.8%, respectively); for the 0.75 mg dose, diarrhea, nausea, bronchitis, nasopharyngitis, syphilis, and vitamin D deficiency (13.3%, 13.3%, 13.3%, 13.3%, 10.0%, and 13.3%, respectively); and for the 2.25 mg dose, arthralgia and headache (12.9% and 12.9%, respectively). Most adverse events were mild and did not lead to study discontinuation. Two participants in the islatravir treatment groups (both in the 2.25 mg group) discontinued treatment due to adverse events. One participant in the Delstrigo group discontinued treatment due to a serious adverse event considered to be drug-related.

In this study, PDVF was defined as virologic rebound (HIV-1 RNA ≥50 copies/mL at any time during the study after initial response; or, at any time during the study, a confirmed increase of >1 log in HIV-1 RNA from the nadir HIV-1 RNA level after a >1 log decline from baseline) or non-response (HIV-1 RNA ≥200 copies/mL at any time from Week 24 to Week 48, with confirmed HIV-1 RNA ≥50 copies/mL at Week 48); PDVF must be confirmed by an additional HIV-1 RNA measurement within two weeks.

At Week 48, the incidence of PDVF was low, and all participants who discontinued treatment due to PDVF had HIV-1 RNA levels below the clinically significant threshold of 200 copies/mL. The observed low-level viremia was comparable to levels detected in other studies involving previously untreated patients. At Week 48, virologic suppression (HIV-1 RNA <50 copies/mL) was achieved by 89.7% (26/29), 90.0% (27/30), and 77.4% (24/31) of patients in the 0.25 mg, 0.75 mg, and 2.25 mg islatravir groups, respectively, compared with 83.9% (26/31) in the Delstrigo group. Six patients met the criteria for PDVF: two each in the 0.25 mg and 0.75 mg islatravir groups, one non-responder in the 2.25 mg islatravir group, and one case of viral rebound in the Delstrigo group. All confirmed HIV-1 RNA levels were <80 copies/mL, and none met the criteria for resistance testing (>400 copies/mL). Despite switching to new regimens, low-level viremia (HIV-1 RNA <200 copies/mL) persisted in three of the six patients (one each from the 0.25 mg and 0.75 mg islatravir groups, and one from the Delstrigo group) at the assessment 42 days after discontinuation.

The Phase III DRIVE-SHIFT study was a multicenter, open-label, randomized, active-controlled, non-inferiority Phase III trial that enrolled 670 HIV-1-infected adults who had achieved virologic suppression for at least 6 months on an antiretroviral regimen (baseline regimen). The study evaluated the non-inferiority of switching from the baseline regimen to Delstrigo versus continuing the baseline regimen. Patients were randomized into two groups: (1) the Immediate Switch Group (ISG, n=447), which switched to Delstrigo treatment on Day 0; and (2) the Delayed Switch Group (DSG, n=223), which switched to Delstrigo treatment after Week 24. The primary endpoint was the rate of virologic suppression. The primary comparison was between the virologic suppression rate in the Delstrigo ISG at Week 48 and that in the baseline regimen DSG at Week 24, followed by a comparison of the virologic suppression rates between the Delstrigo ISG and the baseline regimen DSG at Week 24.

Post-hoc analysis of the study revealed new findings indicating that weight changes in patients switching to Delstrigo were similar to the average changes observed in HIV-negative adults in the United States. After two years of switching to Delstrigo, patients in the ISG group gained 1.4 kg (95% CI: 0.8–1.9), and those in the DSG group gained 1.2 kg (95% CI: 0.4–2.0). The results of the DRIVE-SHIFT study were first presented at the IDWeek 2018 conference.

In individuals with HIV, initiation of certain types of antiretroviral (ARV) therapy is associated with weight gain. A post hoc analysis of weight changes from the DRIVE-SHIFT study indicated that weight changes associated with Delstrigo were comparable to the average annual weight gain observed in the general adult population. (Bioon.com)

Original Source:Merck Announces New Analyses Showing Additional Safety and Efficacy Data for Investigational Islatravir in Combination with Doravirine in Adults with HIV-1 Infection