Unfortunately, clinical trials do not always proceed the way that drug developers – and patients – hope. For example, an ongoing Phase 1/2 clinical trial evaluating BMN 307, an investigational gene therapy, was recently halted by the FDA. According to XTalks, the FDA stopped the trial, which was evaluating the therapy for patients with phenylketonuria (PKU), due to potential safety issues discovered during preclinical tests.
So what exactly is BMN 307? According to drug developer BioMarin, BMN 307 is:
an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy designed to normalize blood phenylalanine (Phe) concentration levels in patients with PKU.
The treatment is delivered using an AAV vector. Prior to the placement of the clinical hold, the therapy was being evaluated in the Phase 1/2 Phearless clinical trial. However, BioMarin is no longer allowed to enroll any additional patients until further evaluation is done by the FDA.
The clinical hold follows preclinical data which highlighted a potential issue in mice models of PKU. When treated with high BMN 307 doses, 85.7% of the mice developed liver tumors within 1 year of treatment. Thus, the FDA became concerned that human patients treated with BMN 307 may also develop tumors.
However, BioMarin is hopeful that the clinical hold will soon be lifted. The company explains that only lower BMN 307 doses are being used within the clinical trial. In fact, all doses given to humans are lower than those used in the mice models. Additionally, out of all of the patients treated with gene therapy thus far, cancer has not been established as a side effect. Moving forward, BioMarin hopes to work with the FDA to resume testing and ensure patient health.
Phenylketonuria (PKU) is a rare genetic disorder and an inborn error of metabolism. Over 300 separate gene mutations have been linked to PKU. In each case, the mutations cause absent or deficient phenylalanine hydroxylase in the body. Normally, this enzyme helps process phenylalanine, an amino acid. In patients with PKU, the enzyme deficiency causes phenylalanine to accumulate in the body, causing a variety of health issues. Because phenylalanine is found in proteins and artificial sweeteners, many patients require a specialized PKU diet.
Typically, PKU is first diagnosed via newborn screening or within the first few months of life. Early diagnosis and treatment are crucial to avoid permanent intellectual disability. When symptoms appear, these include:
- Low birth weight
- Intellectual and developmental delays
- Microcephaly (abnormally small head size)
- Fair skin and eyes
- Skin rashes
- Musty breath, skin, and urine
- Heart defects
- Decreased bone strength