PKU Gene Therapy Trial on Clinical Hold Following Tumor Development in Mice


Six of 7 mice treated with a new, higher dose of BMN-307 showed tumors in liver necropsy at 52 weeks post-treatment.

The FDA has placed a clinical hold on BioMarin’s phase 1/2 Phearless study (NCT04480567) of gene therapy BMN-307 for the treatment of phenylketonuria (PKU).1

The decision was made following preclinical data released by BioMarin that showed the development of serious adverse events (AEs) in mice. Data from the study revealed that 6 of 7 mice treated with the highest dose (2e14 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. 

"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," said Hank Fuchs, MD, president, worldwide research and development, BioMarin, in a statement.1

The mice bore 2 germline mutations for the purposes of the study, including a mutation to eliminate the PAH gene to model PKU and a second to render the mice immunodeficient, which may have made them predisposed to develop such malignancies. At 24 weeks post-treatment, 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).

READ MORE: FDA Lifts Clinical Hold on Novartis SMA Gene Therapy

“For patients who have already received lower doses of these vectors, we will continue to carefully evaluate and monitor their health. We are committed to understand and mitigate any risk of cancer causation,” Fuchs added.1

The 2e14 vg/kg dose the mice were treated with is higher than the 2e13 Vg/kg and 6e13 vg/kg doses that humans have been treated with so far in the Phearless clinical study, although BioMarin stated that they will monitor liver health closely in participants following the mice studies. Along with the clinical hold, further enrollment in the Phearless study has been paused and the company will communicate next steps at a later date.

With this new clinical hold, the Phearless trial joins a number of other gene therapy programs recently put on hold by the FDA. Earlier in September 2021, VBL Therapeutics announced a pause in recruitment for their phase 3 OVAL study (NCT03398655) of ofranergene obadenovec (VB-111) for the treatment of ovarian cancer.2

The pause is due to the pending completion of the Chemistry, Manufacturing, and Controls group’s technical review evaluating the variability of VB-111 manufactured between different source cites. Until the review is completed and new batches are cleared, the shortage of VB-111 supply necessitates the pause in recruitment.

In August 2021, the FDA also placed a clinical hold on Bluebird Bio’s elivaldogene autotemcel (eli-cel, Lenti-D™) for cerebral adrenoleukodystrophy following a Suspected Unexpected Serious Adverse Reaction of myelodysplastic syndrome thought to be mediated by the use of their lentiviral vector.3

“Given what we know, we remain confident that eli-cel can offer hope for patients and families impacted by this devastating disease who have very few treatment options. We are committed to working with regulators and physicians in order to resolve this hold as soon as possible and bring this important therapy to patients in need,” Nick Leschly, president and chief executive officer, bluebird bio, said in an update.3

Safety concerns surrounding gene therapies were the focus of a 2-day FDA Advisory Committee meeting last week, where experts convened to review key questions and provide recommendations on ideal animal models, study structure, and more to ensure the safety of gene therapy development going forward.

1. 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.
2. VBL Therapeutics provides update on OVAL, a phase 3 registration enabling study of VB-111 in ovarian cancer. News release. VBL Therapeutics. June 12, 2021.
3. bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021.
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