MK 8591A-028

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

Rationale

With anticipation of lifelong treatment, long term tolerability and safety of antiretrovirals have become increasingly important for pediatric patients. Accumulating evidence shows simplified 2-drug regimens can achieve efficacy and improve tolerability comparable to that of 3-drug regimens. A 2-drug regimen could mean fewer potential DDIs, and a lesser likelihood of safety or tolerability issues compared to 3-drug regimens. DOR/ISL has the potential to be an ideal 2-drug regimen for adult and pediatric patients for the treatment of HIV-1

Primary Objectives

Primary Objectives:

• To evaluate the steady-state plasma pharmacokinetic profile of ISL and DOR as assessed by intensive pharmacokinetic sampling on Day 28 in the Intensive PK Cohort

• To evaluate the steady-state intracellular pharmacokinetic profile of ISL-triphosphate in peripheral blood mononuclear cells on Day 28 in the Intensive PK Cohort

• To evaluate the safety and tolerability of DOR/ISL as assessed by review of the accumulated safety data through Week 24

Secondary Objectives

Secondary Objectives:

• To evaluate the safety and tolerability of DOR/ISL as assessed by review of the accumulated safety data through study duration

• To evaluate the antiretroviral activity of DOR/ISL as assessed by the percentage of participants with the following at Weeks 24 and 48:

- HIV-1 RNA ≥50 copies/mL

- HIV-1 RNA <50 copies/mL

• To evaluate the immunologic effect of DOR/ISL as measured by change from baseline in CD4+ T-cell count at Weeks 24 and 48

• To evaluate the development of viral drug resistance to DOR or ISL in participants who receive DOR/ISL

Tertiary Objectives/ Exploratory

• To evaluate the pharmacokinetics of ISL and DOR as assessed by sparse pharmacokinetic sampling through Week 48

• To explore the relationship between genetic variation and response to the treatment(s) administered, and mechanisms of disease. Variation across the human genome may be analyzed for association with clinical data collected in this study

Endpoint/Outcome

1. Pharmacokinetic Endpoints:

• Plasma PK

PK samples collected for analysis of ISL and DOR plasma concentrations will be used to calculate the steady-state plasma AUC0-24 and Cmax, and C24 (for DOR only). These results will confirm that adequate exposures of ISL and DOR are achieved in adolescents ≥12 to <18 years of age weighing ≥35 kg and will support dosing recommendations in the pediatric population. As DOR/ISL is anticipated to be chronically dosed, steady-state PK endpoints are the most appropriate endpoints. Intensive plasma PK samples will be collected from the Intensive PK Cohort participants. In addition to these results, data from sparse plasma PK sampling collected from all participants will be used in population PK models for ISL and DOR levels.

• PBMC PK

PBMC PK samples collected from the Intensive PK Cohort participants (Section 8.6) will be used to evaluate intracellular ISL-TP levels, the active anabolite resulting from ISL dosing. Intracellular PBMC trough levels (C24) are a better predictor of efficacy than the exposure (AUC) and can be used along with in vitro potency values to predict efficacy against both wild-type virus and mutant variants.

2. Safety Endpoints

Safety evaluations will include physical examinations (including vital signs) and laboratory tests (haematology, chemistry, and urinalysis). AEs will be evaluated at each visit and assessed according to the study guidelines. Participants may be asked to return for unscheduled visits to perform additional safety monitoring. Efficacy Endpoints The key efficacy endpoint in this study is plasma HIV-1 RNA ≥50 copies/mL. Eligible participants in the adolescent population being studied are virologically suppressed, with HIV-1 RNA

3. Efficacy Endpoints

The key efficacy endpoint in this study is plasma HIV-1 RNA ≥50 copies/mL. Eligible participants in the adolescent population being studied are virologically suppressed, with HIV-1 RNA <50 copies/mL at baseline. The assessment of interest is the percentage of participants who are unable to maintain virologic suppression after switching to a new antiretroviral regimen. Clinical studies of antiretroviral agents in multiple drug classes have demonstrated that virologic suppression of HIV-1 RNA to <50 copies/mL reflects a clinically relevant standard used across development programs for antiretroviral therapies and in clinical practice [Vandenhende, M. A., et al 2015]. Suppressing HIV-1 RNA to <50 copies/mL preserves the immune system and minimizes the risk of opportunistic infections and disease progression. e

Study Population

Adolescent participants with HIV-1 who are ≥12 to <18 years of age, weighing ≥35 kg, and have been virologically suppressed for ≥3 months on any stable oral 2-drug or 3-drug cART (± PK booster) and Treatment Naïve, will be enrolled in this study.

Investigators

Prof Lee Fairlie (Principal Investigator)

Dr Faeezah Pate

Dr Elizea Horne

Latest Update: 17 August 2021

For more about MK 8591A-028 please email rhicomms@wrhi.ac.za