Homology Medicines Joins Biomarin in Gene Therapy Clinical Hold

Homology Medicines is diving into crisis management mode after the FDA slapped its gene therapy program for phenylketonuria (PKU) with a clinical hold. The decision appears to be due to observed “elevated liver function” in tests, said the company. 

Prior to the hold, the company had expected data collection for the Phase 1/2 pheNIX gene therapy trial of HMI-102 to be wrapped up by mid-2022. 

“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,” stated Arthur Tzianabos, CEO of Homology Medicines.

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Treating PKU

PKU is an autosomal recessive disorder that occurs due to mutations in the phenylalanine hydroxylase (PAH) gene, which results in low levels of a protein that metabolizes phenylalanine (Phe). Inefficient breakdown of Phe leads to its toxic accumulation, causing damage to the heart and brain. 

The disease is typically managed by cutting down intake of food rich in Phe, such as red meat, seafood, eggs and dairy. A treatment called Kuvan (sapropterin dihydrochloride, BH4*2HCL) has been approved by the FDA to treat PKU alongside dietary measures. However, Kuvan is only suitable for a subpopulation of patients with PKU. 

Homology Medicines’ HMI-102 is designed to restore the body’s ability to metabolize Phe by inserting a functional copy of the PAH gene via the liver-targeting AAVHSC vector. 

The company initially presented positive data from the dose escalation portion of pheNIX, showing that HMI-102 markedly reduced Phe levels at two doses. 

Back then, the company had observed Grade 1 and 3 alanine aminotransferase (ALT) elevations in patients subjected to higher doses of HMI-102. ALT elevations, which are detected in the blood, are an indication for liver impairment. While the ALT elevations in the trial were treated with steroids, the FDA may have felt that possible liver damage justified the clinical hold on HMI-102.  

The news came shortly after Biomarin announced that the clinical hold on its own gene therapy for PKU, BMI-302, will take longer to resolve. The FDA has requested additional non-clinical data to assess the oncogenic risk of BMI-302 in human participants, which is expected to take several quarters. 

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Joy Lin

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