Early Neutralizing Antibodies in Infants Living With HIV to Enhance Their Life (ENABLE 1)

A Phase 1/2 Trial Evaluating the Safety, Pharmacokinetics, and Antiviral Activity of Subcutaneous ePGT121v1-LS, Added to Standard Antiretroviral Therapy in Infants Living With HIV

The goal of this clinical trial is to learn if subcutaneous ePGT121v1-LS added to standard antiretroviral therapy (ART) is safe and helps improve HIV viral suppression in infants living with HIV in South Africa. The study will also learn how the body processes ePGT121v1-LS and whether caregivers and health workers find this treatment approach acceptable.

The main questions it aims to answer are:

• Is ePGT121v1-LS safe and well tolerated in infants living with HIV?
• Does adding ePGT121v1-LS to standard ART increase the number of infants who achieve HIV viral suppression by week 48?
• How long does it take participants receiving ePGT121v1-LS to achieve viral suppression compared with standard treatment alone?
• How does ePGT121v1-LS behave in the body after repeated subcutaneous injections?

Researchers will compare infants receiving ePGT121v1-LS plus ART to infants receiving standard ART plus placebo (saline) to see if ePGT121v1-LS improves HIV viral suppression.

Participants will:

• Continue taking standard oral ART.
• Receive 4 subcutaneous injections of ePGT121v1-LS or placebo every 12 weeks.
• Attend regular clinic visits for safety checks, blood tests, and HIV viral load monitoring.
• Have follow-up visits for 48 weeks.
• Participate in evaluations of treatment adherence and acceptability from the perspective of caregivers and health workers.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV -1 Infection
• Intervention / Treatment: Drug: Broadly neutralizing antibody (bNAb) ePGT121v1-LS; Drug: Saline (0.9% NaCl)

Detailed Description

This Phase 1/2 clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of subcutaneous (SC) ePGT121v1-LS administered as adjunctive therapy to standard antiretroviral therapy (ART) in infants living with HIV (ILHIV) in South Africa.

Although early ART initiation has significantly improved survival among infants with HIV, achieving sustained virological suppression during infancy remains challenging because of factors including limited pediatric formulations, adherence difficulties, high baseline viral loads, and treatment interruptions. Novel long-acting therapeutic strategies that simplify treatment delivery and enhance antiviral activity may improve outcomes in this vulnerable population.

Broadly neutralizing antibodies (bNAbs) have shown antiviral activity in adults and children living with HIV and may provide additional benefits through prolonged antiviral coverage and immunomodulatory effects. ePGT121v1-LS is a long-acting bNAb directed against the V3 glycan supersite of the HIV-1 envelope. The LS mutation extends antibody half-life and supports infrequent dosing schedules using SC administration.

This study includes an initial safety lead-in phase followed by a randomized placebo-controlled phase evaluating ePGT121v1-LS in combination with standard ART. The trial will assess the safety profile and tolerability of repeated SC administrations and will characterize pharmacokinetic parameters following serial dosing in infants. In addition, the study will evaluate the antiviral effect of ePGT121v1-LS intensification therapy on HIV viral suppression during the first 48 weeks of follow-up.

Exploratory analyses will further assess virological, immunological, and reservoir-related outcomes, including HIV-1 DNA dynamics, viral diversity, neutralization sensitivity, anti-drug antibodies, and immune responses associated with bNAb exposure. Qualitative assessments will also evaluate the acceptability and feasibility of SC bNAb administration from the perspective of caregivers, healthcare workers, and stakeholders.

The results of this study are intended to inform the development of future pediatric trials evaluating long-acting bNAb-based therapeutic strategies for infants living with HIV.

• Study Type: Interventional
• Enrollment (Estimated): 87
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Alfredo Tagarro, PhD; Phone Number: +34606194888; Email: alfredo.tagarro@salud.madrid.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants from 1 to 365 days old at the time of enrolment.
• Living with HIV-1, diagnosed with an approved assay detecting HIV nucleic acids in blood.
• Weight > 2.5 kg at enrolment.
• ART-naïve or ≤ 30 days of triple ART at screening (not including prophylaxis in HIV-exposed).
• Clinically stable and can be managed as outpatient (participants identified in-hospital can start the trial at their first routine visit).
• Parent or legal guardian able to provide Informed consent (IC).

Exclusion Criteria:

• Participation in other concurrent research studies that, in the opinion of the principal investigator and central team, would interfere with the objectives of this study.
• Previous receipt of bNAbs against HIV.
• Serious Adverse Reactions (SARs) to the investigational medicinal product (IMP) or its components.
• Intravenous (IV) immunoglobulins received within 90 days before IMP administration.
• Any clinically significant acute or chronic illness or condition at screening that, in the opinion of the principal investigator/designee, renders the participant unfit to participate in the study or jeopardizes the safety or rights of the participant. Including, but not restricted to:
• Evidence of active tuberculosis (TB) disease at the time of enrolment.
• Life-threatening condition associated with a high risk of death within 30 days of enrolment, as determined by the study clinician.
• Severe acute malnutrition with complications.
• Severe neurological illness.
• Hemodynamically significant severe congenital heart disease.
• Active malignancies.
• Life-threatening bleeding disorder.
• Use of systemic immunosuppressive drugs within 30 days before first IMP administration. Not exclusionary: nasal steroid spray, inhaled steroids, topical steroids, a single course of oral/parenteral prednisone or equivalent at 2 mg/kg/day, and length of therapy <14 days.
• Unwillingness to have blood drawn
• Unable to receive SC medications.
• Chronic or recurrent urticaria or any other chronic dermatological condition that may be confused with local Adverse Reactions (ARs).

Any social or medical condition in the caregivers that, in the judgement of the investigator, would interfere with protocol adherence, completion of the trial or assessment of safety.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (saline); 4 injections of saline, separated 12 weeks, plus antiretroviral treatment.	Drug: Saline (0.9% NaCl); Administration of subcutaneous saline, 4 doses, separate 12 weeks away.
Active Comparator: ePGT121v1-LS; 4 injections of the bNAb ePGT121v1-LS, separated 12 weeks, plus antiretroviral treatment.	Drug: Broadly neutralizing antibody (bNAb) ePGT121v1-LS; Administration of subcutaneous ePGT121v1LS, 4 doses, separate 12 weeks away.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Serious adverse events)	Proportion of participants experiencing SAEs throughout the whole trial.	48 weeks
Time to virological suppression	• Time to first virological suppression, defined as the time from randomization to the first post-baseline measurement of plasma HIV-1 RNA < 40 copies/mL.	48 weeks
Tolerability of the treatment (participants who discontinue)	• Proportion of participants who discontinue due to toxicity or tolerability issues.	48 weeks
Tolerability of the injection	• Median score of pain assessment scale after administration of bNAb (FLACC scale).	1 hour
Virological suppression (snapshot)	• Proportion of infants achieving virological suppression (plasma HIV-1 RNA < 40 copies/mL) at week 48, as well as over the 48 week follow-up period.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to sustained virological suppression	Time from randomization to the first scheduled post-baseline visit at which HIV-1 RNA is < 40 copies/mL, provided that all subsequent scheduled HIV-1 RNA measurements through week 48 also remain < 40 copies/mL.	48 weeks
Longitudinal virological response	Proportion of participants with HIV-1 RNA < 40 copies/mL at weeks 12, 24, 36, and 48 will be recorded as the endpoint and log change in plasma HIV-1 RNA levels relative to baseline and subsequent pre-dose measurements.	48 weeks
Acceptability	The acceptability will be assessed through a series of qualitative interviews and limited quantitative assessments.	48 weeks
Adverse events	Number of and proportion of participants with solicited adverse event (AEs) and laboratory-related AEs.	48 weeks
PK profile of ePGT121v1-LS	Half-life	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality and number of hospitalizations.	All-cause mortality and number of hospitalizations.	48 weeks
Clinical features at baseline and during follow-up	This exploratory objective will include a comprehensive evaluation of different clinical parameters such as demographics (age, gestational age, weight, Prevention of Mother-To-Child Transmission (PMTCT) interventions), HIV disease severity (VL, CD4+ T-cell count/percentage), nutritional status, comorbidities (infectious and non-infectious), and ART (time to initiation, adherence during follow-up).	48 weeks
HIV-1 DNA	The concentration of intact and defective HIV-1 proviral DNA, expressed as copies per million of peripheral blood mononuclear cells (PBMCs), measured by intact proviral DNA assay (IPDA) and quantified at baseline and week 48	48 weeks
Anti-drug antibodies (ADAs)	The titers of ADAs will be quantified at baseline and week 48 to assess whether the development of host antibodies (anti-bNAbs) contributes to virological failure among infants who experience viral rebound by week 48, compared to infants with virological suppression at week 48.	48 weeks
Neutralizing Activity	Neutralization titers will be calculated as IC50 (50% inhibitory concentration) and IC80 (80% inhibitory concentration) by TZM-bl luciferase reporter assay. In vitro susceptibility of env-pseudotyped viruses derived from all participants at baseline and from those experiencing breakthrough viremia at week 48 will be used to establish whether in vitro susceptibility predicts virological success	48 weeks
Immunophenotype	Cellular immunophenotype will be measured using AIM-ICS flow cytometry to determine the activation status and cytokine production of T-cells and NK cells.	48 weeks
HIV-1 Env Diversity	Comprehensive single-genome sequencing (SGS) of HIV-1 breakthrough and pre-treatment sequences to identify acquired mutations that might be associated with viral escape and phenotypic resistance to bNAb therapy in infants that do not achieve viral suppression by week 48. Additionally, these sequences will be compared to the baseline profiles of infants who did achieve suppression to identify potential genotypic predictors of treatment success or failure.	48 weeks

Collaborators and Investigators

• Sponsor: Hospital Universitario 12 de Octubre
• Collaborators: International AIDS Vaccine Initiative; University of Stellenbosch; University of Witwatersrand, South Africa; PENTA Foundation; Africa Health Research Institute; Faculty of Medical Sciences, Radboud University of Medical Center; Servicio Madrileño de Salud (SERMAS); Enhancing Care Foundation

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 9, 2026
• First Submitted That Met QC Criteria: June 12, 2026
• First Posted (Actual): June 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: safety; HIV; children; infant; viral load; broadly neutralizing antibody; ePGT121v1-LS
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Antibodies, Neutralizing; Sodium Chloride; Broadly Neutralizing Antibodies
• Other Study ID Numbers: 101190620_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The individual de-identified participant data (including data dictionary), statistical code, and any other materials will be accessible after the end of the project in an open repository upon request.
• IPD Sharing Time Frame: The individual de-identified participant data (including data dictionary), statistical code, and any other materials will be accessible after the end of the project in an open repository upon request.
• IPD Sharing Access Criteria: Upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No