Gene Editing Clinical Trial for PKU Announced


Homology is also developing a gene therapy, HMI-102, being evaluated in the phase 1/2 pheNIX trial.

Homology Medicines will initiate a phase 1 clinical trial, dubbed pheEDIT, of the gene editing therapy HMI-103 for the treatment of phenylketonuria (PKU).1

Homology’s investigational new drug application for the single-dose, in-vivo, nuclease-free gene therapy was accepted by the FDA based on promising preclinical data that demonstrated normalization of phenylalanine (Phe) blood levels and on-target integration to the PAH locus.2

“Today’s milestone is the culmination of our team’s tireless work to translate our gene editing technology from an academic discovery into a clinical program for people with PKU,” Albert Seymour, PhD, chief scientific officer, Homology Medicines, said in a statement.1 “Our positive preclinical data in the PKU model demonstrated phenotypic correction, and the precision of HMI-103 genome integration was confirmed in a humanized liver model, which showed no evidence of off-target mutations or unwanted on-target changes to the genome. These nonclinical data give us great confidence in initiating our Phase 1 pheEDIT trial, and we look forward to continuing to work with the PKU community on our clinical programs.”

The pheEDIT trial will enroll up to 9 adult patients with PKU, with plans to expand enrollment to pediatric patients pending positive safety and efficacy results. The trial will evaluate 3 doses of HMI-103, safety endpoints, and serum Phe changes. An 82-day screening will precede administration of the gene therapy. The first dosing will follow requisite Institutional Biosafety Committee and Institutional Review Board approvals at clinical sites.

READ MORE: PKU Gene Therapy Trial on Clinical Hold Following Tumor Development in Mice

HMI-103 is designed to induce PAH expression in liver cells and restore metabolism of Phe. It uses homologous recombination to insert a functional PAH gene into the genome while also inactivating at least 1 of the mutated genes. The gene is delivered via the AAVHSC15 vector.

Homology is also conducting the phase 2 pheNIX trial (NCT03952156) evaluating the gene therapy HMI-102 in adults with PKU. They announced updated safety data from the trial that both doses are well-tolerated with promising initial efficacy data including clinically meaningful reductions in Phe levels as well as increases in Tyr and reductions in the Phe-to-Tyr ratio.

The pheNIX trial has also been expanded to include a total of 13 clinical trial sites. Homology stated that enrollment is still slow due to the COVID-19 pandemic and they will announce more updates in mid-2022.

The HMI-102 gene therapy encodes the PAH gene which is delivered via the AAVHSC15 vector. The FDA previously granted the therapy fast track and orphan drug designations, while the EMA has granted the therapy orphan drug designation.

“We continue to be encouraged by the data from our pheNIX trial and to hasten enrollment, we have expanded our Medical Affairs, Clinical Development and Operations teams to support not only pheNIX, but now pheEDIT and our Hunter syndrome gene therapy trial expected this year,” Arthur Tzianabos, PhD, president and chief executive officer, Homology Medicines, added to the statement.1 “The flexibility of our technology platform enables us to develop gene therapy and gene editing product candidates as potential one-time treatments, and news today of our first trial that incorporates gene editing for PKU demonstrates our ability to employ both approaches in an effort to support the PKU community.”

1. Homology Medicines announces world’s first gene editing clinical trial for PKU. News release. Homology Medicines. October 12, 2021.
2. Benard L, Lamppu D, Prasad A, et al. HMI-103: An investigational gene editing vector for Phenylketonuria (PKU). Presented at: 2021 European Society for Gene & Cell Therapy Virtual Conference; October 19-22, 2021.
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