BioMarin’s PKU Gene Therapy On Hold Pending New Studies


The company also announced that the phase 3 study of val-rox has completed enrollment.

BioMarin’s PHEARLESS study (NCT04480567) of BMN-307 for the potential treatment of phenylketonuria (PKU) will likely be on clinical hold for several quarters, as the FDA has requested additional studies of the therapy.1

"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," Hank Fuchs, MD, president, worldwide research and development, BioMarin, said in a statement. "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. We remain grateful to all of the participants and investigators in our gene therapy studies, as well as for the support from patient advocacy groups."

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.

The phase 1/2 PHEARLESS study was previously placed on hold after 6 of 7 mice treated with the highest dose (2 x1014 vg/kg) of the investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy had tumors on liver necropsy 52 weeks after dosing, as well as evidence that portions of the adeno-associated virus (AAV) vector had integrated into the genome.2

READ MORE: LogicBio’s Methylmalonic Acidemia Gene-Editing Therapy Program Placed on Clinical Hold

The mice may have been predisposed to develop such malignancies, as they bore 2 germline mutations for the study: a mutation to eliminate the PAH gene to model PKU and a second to render the mice immunodeficient. At 24 weeks posttreatment, no lesions were observed in any mice. Of the 6 mice that developed tumors seen at 52 weeks, 5 had adenomas and one had a hepatocellular carcinoma (HCC).

The 2 x 1014 vg/kg dose the mice were treated with is higher than the 2 x 1013 vg/kg and 6 x 1013 vg/kg doses that humans have been treated with so far in the PHEARLESS study. BioMarin continues to monitor liver health closely in these participants following the clinical hold and pause in enrollment.

"More than 3000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence. Acknowledging the complexity of the issue as highlighted in this week's FDA discussion, integrational mutagenesis and resultant cancer formation has been observed in mice using other AAV vectors. Therefore, we plan to investigate these findings," Fuchs said in a previous statement.2

BioMarin also announced that the phase 3 GENEr8 (270-303) study of valoctocogeneroxaparvovec (val-rox) has completed enrollment.1 The AAV5 gene therapy is being evaluated in combination with prophylactic corticosteroids in people with severe hemophilia A and 52-week data from the study is expected in the first half of 2023.

1. BioMarin Provides Updates on Progress in Gene Therapy Programs. News release. Biomarin. Feburary 17, 2022.
2. U.S. FDA Placed a Clinical Hold on BMN 307 Phearless Phase 1/2 Gene Therapy Study in Adults with PKU Based on Interim Pre-clinical Study Findings. News release. BioMarin Pharmaceuticals. September 5, 2021.
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