2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-pheEDIT: A Phase 1, Open-Label, Dose-Escalation Safety and Efficacy Gene Editing Study Evaluating HMI-103 in Adults with Classical PKU

Pdf Summary

HMI-103 is a gene editing therapy being evaluated for the treatment of classical phenylketonuria (PKU) due to phenylalanine hydroxylase (PAH) deficiency. PKU is a rare genetic disorder that leads to neurological impairment if left untreated. Current treatments, such as a phenylalanine-restricted diet, do not address the underlying cause of the disease.<br /><br />HMI-103 works by introducing functional copies of the PAH gene into hepatocytes, liver cells responsible for phenylalanine metabolism. It does this through non-nuclease-based AAV-mediated homologous recombination, a high-fidelity DNA repair process.<br /><br />Preclinical studies have shown that HMI-103 can integrate into the PAH locus in both mouse and human models, resulting in sustained reduction of phenylalanine levels. It has also been shown to have a favorable safety profile in animal studies, with no adverse findings or germline transmission observed.<br /><br />The pheEDIT clinical trial is an ongoing Phase 1 study evaluating the safety and efficacy of HMI-103 in adults with classical PKU. Eligible participants are adults aged 18-55 with uncontrolled PKU despite dietary management. The trial aims to assess the incidence and severity of treatment-emergent adverse events and measure the change in plasma phenylalanine concentrations.<br /><br />The trial design includes three dose cohorts, with up to three participants in each cohort. The primary endpoints of the study include the incidence and severity of adverse events and the change in phenylalanine levels after treatment with HMI-103.<br /><br />If positive safety and efficacy results are observed in adult participants, future studies may include enrollment of younger patients. HMI-103 has received Fast Track designation from the FDA, indicating its potential to address an unmet medical need for patients with PKU.<br /><br />The use of a prophylactic immunosuppressive regimen aims to minimize the potential for an immune response to HMI-103. Follow-up studies are also planned to evaluate the long-term safety and durability of efficacy of the therapy.<br /><br />HMI-103 has shown promising preclinical efficacy and safety data, and the ongoing pheEDIT clinical trial aims to further evaluate its potential as a one-time treatment for PKU.

Asset Subtitle

Submitter Only - Michael Blum, MBA; Presenting Author - Gerry Shioshita, PharmD;

Meta Tag

Counseling

Education

Enzyme Replacement Therapy

Metabolic Disorder

Presenting Author Gerry Shioshita, PharmD

Submitter Only Michael Blum, MBA

Keywords

HMI-103

gene editing therapy

classical phenylketonuria

PKU

phenylalanine hydroxylase deficiency

hepatocytes

AAV-mediated homologous recombination

pheEDIT clinical trial

safety and efficacy

plasma phenylalanine concentrations