RARE Daily

BioMarin Says its Experimental PKU Gene Therapy Could Be on Hold for Several Quarters

February 18, 2022

BioMarin Pharmaceutical said the company received additional requests from the U.S. Food and Drug Administration for information needed to resolve the clinical hold of the PHEARLESS phase 1/2 study of BMN 307, an AAV5-human phenylalanine hydroxylase (hPAH) gene therapy being studied in adults with phenylketonuria, which was placed on hold in September 2021.

Photo: Hank Fuchs, president, worldwide research and development at BioMarin

The FDA has requested data from additional non-clinical studies to assess the theoretical oncogenic risk to human study participants, which the company said is expected to take several quarters. 

“As leaders in the development of gene therapies, a novel treatment modality, it is our responsibility to answer new questions that arise for the benefit of patients, physicians, regulatory bodies, and for the field in general.  Patient safety is our utmost priority,” said Hank Fuchs, president, worldwide research and development at BioMarin.  “With new technologies in healthcare, we anticipate that both health authorities and developers will seek to characterize and evaluate potential safety-related signals to enable a more comprehensive assessment of these potential risks to patients.” advocacy groups.”

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.

The original hold was placed based on a preclinical, non-GLP pharmacology study in mice to understand the durability of BMN 307 activity in mice bearing two germline mutations, which may predispose the mice to the development of cancerous tumors. One mutation eliminated the PAH gene that’s missing in PKU and the second rendered the animals immunodeficient. Of 63 animals treated, six of seven animals administered BMN 307 at the highest dose group (2e14 Vg/kg) had tumors on liver necropsy 52 weeks after dosing with evidence for integration of portions of AAV vector into the genome.

But BioMarin had not dosed any humans with the highest dose of the gene therapy, and to date there have been no reports of cancer emerging in a patient dosed with an AAV gene therapy, noted Fuchs in September, when the hold was originally issued. 

Author: Rare Daily Staff

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