Second Phenylketonuria Gene Therapy Study Put on Clinical Hold

The FDA has placed a clinical hold on Homology Medicines’ pheNIX trial (NCT03952156), which is investigating the gene therapy HMI-102 for the potential treatment of phenylketonuria (PKU) following elevated liver function test scores.1

Homology will have to modify the study’s risk mitigation measures to prevent any serious issues that may arise, although the company has not yet received a formal letter of clinical hold, so clearer directives by the FDA are forthcoming.

The pheNIX study is primarily assessing the safety of HMI-102 via treatment-related adverse events (AEs), liver function tests, electrocardiograms, and plasma Phe concentration in adults with classical PKU due to phenylalanine hydroxylase (PAH) deficiency. Participants receive a single intravenous administration of HMI-102 and are observed for 52 weeks plus an additional 4 years of follow-up to ensure stability.

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. 

In October 2021, Homology announced updated safety data from the trial that both doses were 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.2 At that time, the trial had been expanded to include a total of 13 clinical trial sites.

"This hold on our PKU gene therapy trial is based on clinical observations in the pheNIX study and does not relate to CMC/manufacturing capabilities or Homology's other clinical programs. We plan to provide next steps once we have more information following our FDA interactions," Arthur Tzianabos, PhD, president and chief executive officer, Homology, said in a statement.1

Unaffected by the clinical hold is Homology’s other trial in PKU, the pheEDIT trial of their gene-editing therapy HMI-103. HMI-103 uses the same viral vector as HMI-102, but unlike HMI-102, HMI-103 uses homologous recombination to insert a functional PAH gene into the genome of liver cells while also inactivating at least 1 of the mutated genes to induce PAH expression in liver cells and restore metabolism of Phe.2

The pheEDIT trial was initiated in October 2021 and plans to enroll up to 9 adult patients with PKU. Expanded enrollment is 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.

Homology’s clinical hold follows that of another gene therapy in the PKU space, BioMarin’s BMN-307 and its phase 1/2 PHEARLESS study (NCT04480567). The study seems likely to be on clinical hold for several quarters after previously being put on hold in September 2021 following tumor development in mice.3 The FDA has requested that BioMarin conduct additional nonclinical studies to evaluate the possible oncogenic risk of BMN-307 in humans. The company estimates this will take several quarters and will communicate next steps when available.