Evaluation of a Weekly Oral Islatravir/Lenacapavir Regimen Versus Standard Antiretroviral Therapy in Virologically Suppressed HIV-1 Patients

The primary objective of this Phase 3, randomized, open-label, active-controlled study is to evaluate the **efficacy** of switching to an oral weekly Islatravir/Lenacapavir (ISL/LEN) tablet regimen compared to continuing the standard of care in virologically suppressed individuals with **HIV-1 infection** at Week 48. This objective is clinically relevant as it aims to assess whether the new regimen can maintain viral suppression, which is crucial for long-term management of HIV-1 and improving patient adherence and quality of life.

Secondary objectives include:

• Evaluating the efficacy of switching to oral weekly ISL/LEN in virologically suppressed individuals with HIV at Weeks 48 and 96.
• Assessing the safety and tolerability of the oral weekly ISL/LEN regimen.

The clinical trial involves a total of **502 participants** diagnosed with **HIV-1 Infection**. The study population includes both male and female subjects, aged 18 years and older, who are virologically suppressed and receiving standard of care treatment. Participants were selected based on their ability to provide informed consent and maintain plasma HIV-1 RNA levels below 50 copies/mL for at least six months prior to screening. The trial includes individuals from a vulnerable population, and lifestyle considerations such as adherence to guideline-recommended antiretroviral therapy are relevant. Participants assigned female at birth and of childbearing potential must adhere to specified contraceptive methods. The trial aims to evaluate the efficacy of switching to an oral weekly ISL/LEN tablet regimen compared to continuing the standard of care over a 48-week period.

The clinical trial is designed to evaluate the efficacy of switching to an oral weekly regimen of **islatravir** and **lenacapavir** in individuals with **HIV-1 infection** who are virologically suppressed on standard care. This is a Phase 3, randomized, open-label, active-controlled study. The trial will span approximately five years, with an estimated recruitment start date of January 31, 2025, and an estimated end date of August 2, 2030. Participants will be randomly assigned to either continue their current antiretroviral therapy or switch to the investigational regimen. The primary endpoint is the proportion of participants with HIV-1 RNA levels of 50 copies/mL or more at Week 48, as determined by the US FDA-defined snapshot algorithm.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, virological suppression, and current treatment regimen. Participants must have HIV-1 RNA levels below 50 copies/mL for at least six months prior to screening. Follow-up visits will occur at regular intervals to assess virological response, safety, and any adverse events. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate long-term outcomes.

Participant involvement is expected to last up to 96 weeks, with conditions for early termination including significant protocol deviations, adverse events, or withdrawal of consent. The trial will also assess secondary endpoints, such as the proportion of participants with HIV-1 RNA levels below 50 copies/mL at Weeks 48 and 96, changes in CD4 T-cell counts, and the percentage of participants discontinuing the investigational regimen due to treatment-emergent adverse events. The trial aims to provide valuable insights into the potential benefits of the investigational regimen for maintaining virological suppression in individuals with HIV-1.

The clinical trial involves the evaluation of an oral weekly regimen of **Islatravir/Lenacapavir** in participants with HIV-1 who are virologically suppressed. The experimental medication, Islatravir/Lenacapavir, is administered in tablet form. The pharmaceutical form is specified as a tablet, and the route of administration is oral. The dosing schedule is weekly, with the maximum treatment period set at one week. The active substances in this formulation are **Lenacapavir** and **Islatravir**, both of which are chemically derived. The product is not a pediatric formulation and is classified as an antiretroviral medication.

In addition to the experimental treatment, the study includes several comparator treatments, which are standard-of-care antiretroviral therapies. These include combinations such as **Emtricitabine, Tenofovir Disoproxil Fumarate, Cobicistat, and Elvitegravir**; **Lamivudine and Dolutegravir**; and **Emtricitabine, Tenofovir Alafenamide, and Bictegravir**. Each of these comparator treatments is administered orally, with the pharmaceutical form being consistent across treatments as PHF00082MIG. The maximum treatment period for these comparator treatments is also one week, aligning with the experimental regimen. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Other comparator treatments include **Ritonavir**, **Raltegravir**, and **Rilpivirine**, each administered orally. The pharmaceutical form for Ritonavir is PHF00007MIG, while Raltegravir and Rilpivirine share the PHF00082MIG form. These treatments are also classified as antiretroviral medications and are not pediatric formulations. The trial aims to assess the efficacy of the experimental regimen compared to these standard-of-care therapies in maintaining virological suppression in participants with HIV-1.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to **HIV-1** RNA levels in participants. The primary endpoint is the proportion of participants with **HIV-1** RNA ≥ 50 copies/mL at Week 48, as determined by the United States Food and Drug Administration (FDA)-defined snapshot algorithm. Secondary endpoints include the proportion of participants with **HIV-1** RNA ≥ 50 copies/mL at Week 96, the proportion of participants with **HIV-1** RNA < 50 copies/mL at both Week 48 and Week 96, and changes from baseline in clusters of differentiation 4 (CD4) T-cell count at Week 48 and Week 96. Additionally, the percentage of participants discontinuing the ISL/LEN regimen due to treatment-emergent adverse events (TEAEs) will be monitored from the first dose date up to Week 96.

The efficacy parameters will be measured at specific time points, including baseline, Week 48, and Week 96. The FDA-defined snapshot algorithm will be utilized to determine the **HIV-1** RNA levels at these time points. Changes in CD4 T-cell counts will be assessed from baseline to Week 48 and Week 96 to evaluate the immunological response. The collection and analysis of these parameters will provide insights into the efficacy of switching to an oral weekly ISL/LEN tablet regimen compared to continuing the standard of care in virologically suppressed individuals with **HIV-1**.