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FDA Places Hold on Homology PKU Gene Therapy Trial

February 22, 2022

Homology Medicines reported that the U.S. Food and Drug Administration notified the company that its pheNIX gene therapy trial of HMI-102 in adults with phenylketonuria has been placed on clinical hold due to the need to modify risk mitigation measures in the study in response to observations of elevated liver function tests.

Photo: Arthur Tzianabos, president and CEO of Homology Medicines

The hold came just hours after BioMarin Pharmaceutical said it had received additional requests from FDA for information needed to resolve the clinical hold of its PKU gene therapy, which was placed on hold in September 2021. That hold was put in place based on a preclinical, non-GLP pharmacology study in mice to understand the durability of the gene therapy activity in mice bearing two germline mutations that may predispose the mice to the development of cancerous tumors. When the hold was issued, BioMarin noted that to date there have been no reports of cancer emerging in a patient dosed with an AAV gene therapy. 

PKU, or phenylalanine hydroxylase (PAH) deficiency, is a rare genetic disorder caused by a deficiency of the enzyme PAH. This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems, and psychiatric symptoms. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU under the age of 40 in countries with newborn screening programs are diagnosed at birth and treatment is implemented soon after.

PKU can be managed with a severe Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, it is difficult for most patients to adhere to the life-long strict diet to the extent needed to achieve adequate control of blood Phe levels. Dietary control of Phe in childhood can prevent major developmental neurological toxicities, but poor control of Phe in adolescence and adulthood is associated with a range of neurocognitive disabilities with significant functional impact.

Homology expects to receive an official clinical hold letter within 30 days and plans to provide an update pending further clarity from the FDA.

“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,” said Arthur Tzianabos, president and CEO of Homology Medicines. “We plan to provide next steps once we have more information following our FDA interactions.”

Homology has two ongoing clinical programs, the pheEDIT gene editing trial of HMI-103 for PKU and the juMPStart gene therapy trial of HMI-203 for Hunter syndrome, with program updates expected by the end of this year.

Author: Rare Daily Staff

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