CRISPR Therapy Well Tolerated, Detectable in First 3 Participants With HIV


Excision plans to escalate the trial of EBT-101 to the second dose level in the fourth quarter of 2023.

EBT-101 (Excision Biotherapeutics) was well-tolerated and detectable in all participants with human immunodeficiency virus type 1 (HIV-1) treated so far in a phase 1/2 trial (NCT05144386).1

 Rachel M. Presti, MD, PhD

Rachel M. Presti, MD, PhD

Updated data from the first-in-human trial were presented at the 30th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT), held October 24-27 in Brussels, Belgium, by Rachel M. Presti, MD, PhD, Professor of Medicine, and medical director, Infectious Disease Clinical Research Unit, Washington University School of Medicine, St. Louis.1

“A major barrier to curing HIV is viral latency, which is defined as the persistence of integrated proviral DNA that is replication competent. Although antiretroviral therapy (ART) effectively suppresses viral replication and prevents disease progression to AIDS, long-term treatment with ART does not eliminate latent HIV and people living with HIV on suppressive ART have significant ART-related side effects and non-AIDS-related comorbidities and malignancies,” Presti and coauthors wrote.1

EBT-101 is a dual-guide CRISPR Cas9/gRNA multiplex, adeno-associated viral vector, investigational gene therapy targeting latent HIV-1 for genome editing. The therapy was shown to remove large sections of HIV proviral DNA in preclinical studies and was granted Fast Track designation by the FDA in 2023.

READ MORE: Verve’s Hypercholesterolemia Gene-Editing Therapy VERVE-101 Cleared for US Trial After Rocky Start

“Excision is dedicated to developing curative, CRISPR-based therapies for people with infectious disease,” Daniel Dornbusch, chief executive officer, Excision, said in a statement.2 “EBT-101 is a CRISPR-based gene therapy being tested as a potential functional cure for HIV. We believe that sharing this initial safety and biodistribution data is important for the HIV/AIDS community, the larger infectious disease community, and for gene therapies in development for other indications.”

The first 3 participants in cohort A at the first dose level were treated safely with no serious adverse events (AEs) or dose-limiting toxicities. There were 4 mild AEs possibly or definitely related to EBT-101 which resolved without intervention and 12 mild AEs.1 There were no infusion-related reactions, and no complement-mediated toxicity, or withdrawals during intravenous administration. Two participants had transient and reversible transaminase elevations. EBT-101 was detectable in blood at 4 weeks in every participant with peripheral exposure. There has been no evidence of horizontal transmission of gene vector shedding in 2 tissue compartments associated with male reproductive function. Excision plans to dose escalate to the 3.0x1012 vg/kg dose in the fourth quarter of 2023, with more data to come in 2024.1

“Establishing the safety and biodistribution of EBT-101 is an important first step in the clinical program. Treatment with EBT-101 resulted in no serious adverse events or dose limiting toxicities in the first three participants, and all reported adverse events were mild and reversible,” William Kennedy, MD, senior vice president, Clinical Development, Excision added.2 “Excision was also able to demonstrate positive biodistribution of the product candidate at this dose level. These initial observations provide important clinical data that support the advancement of the EBT-101-001 trial to the next dosing cohort.”

Clinical Takeaways

  1. EBT-101, an investigational gene therapy targeting latent HIV-1 using CRISPR-Cas9 technology, has been well-tolerated with mild adverse events in participants with HIV-1.
  2. EBT-101 gene therapy has demonstrated biodistribution with peripheral exposure in the first cohort of patients and is planned to advance to the next dosing cohort.
  3. The EBT-101-001 trial aims to evaluate the safety, efficacy, and long-term outcomes of EBT-101 therapy.

The EBT-101-001 single-ascending dose, open-label trial is evaluating the safety, efficacy, pharmacodynamics, and biodistribution of the EBT-101 therapy. Participants must be on stable HIV suppression on ART with CD4+ T cells > 500 cells/uL for at least 1 year and low anti-AAV9 neutralizing antibody titers. They receive 7 days of immunosuppression with dexamethasone starting 24 hours before IV EBT-101 administration. Participants will be followed up for 48 weeks posttreatment and will be assessed for sustained viral suppression off ART in an analytical treatment interruption starting at week 12 with weekly assessments for adverse events, HIV viral rebound, and changes in CD4+ T cell count. The long-term follow up study EBT-101-002 will follow EBT-101-001 for 15 years.

1. Presti R, Baxter J, Sivapalasingam S, Gordon J, Gordon TJ, Kennedy WP. First-in-human trial of systemic CRISPR-Cas9 multiplex gene therapy for functional cure of HIV. Presented at:
2. Excision BioTherapeutics presents positive interim clinical data from ongoing phase 1/2 trial of EBT-101 for the treatment of HIV at ESGCT 30th Annual Congress. News release. Excision Biotherapeutics. October 25, 2023.
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