BioMarin Pharmaceutical has submitted a clinical trial application (CTA) to the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) to evaluate BMN 307 — its first investigational gene therapy for phenylketonuria (PKU) — in a Phase 1/2 trial.
“This clinical trial application marks the latest milestone in BioMarin’s 15-plus year commitment to the PKU community,” Hank Fuchs, MD, BioMarin’s president of worldwide research and development, said in a press release.
PKU is linked to more than 500 mutations in the PAH gene, which result in reduced levels of phenylalanine hydroxylase (PAH), an enzyme responsible for the breakdown of phenylalanine — an amino acid (the building blocks of proteins) obtained through the diet.
Deficient PAH levels lead to the toxic buildup of phenylalanine in the blood and organs, particularly the brain, where it can cause severe damage and intellectual disabilities.
Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase-pqpz), developed by BioMarin, are the only currently approved treatments for PKU. They control phenylalanine levels by boosting PAH activity, or by a PAH-independent phenylalanine breakdown pathway.
Distinct from Kuvan and Palynziq, BioMarin’s new investigational therapy, BMN 307, is designed to target the genetic cause of the disease.
BMN 307 uses a harmless version of the adeno-associated virus (AAV) to deliver a functional PAH gene into cells, which is expected to induce the production of PAH, normalize phenylalanine levels, and prevent further damage.
According to the company’s third quarter 2019 financial results, preclinical studies have shown that BMN 307 induces a lifetime normalization of phenylalanine levels in a mouse model of PKU.
After MHRA’s expected approval, BioMarin plans to open a Phase 1/2 clinical trial to evaluate the safety, tolerability, and effectiveness of a single BMN 307 administration, directly into the bloodstream, in people with PKU.
The study will consist of a dose-escalation phase, where several doses of BMN 307 will be tested, followed by a dose expansion phase with selected doses. In terms of effectiveness goals, the trial will determine whether BMN 307 treatment can restore phenylalanine breakdown, normalize phenylalanine levels in the blood, and allow patients to follow a non-restrictive diet.
The company expects to start patient recruitment early next year and is preparing similar applications to regulatory agencies of other countries.
On Oct. 21 the U.S. Food and Drug Administration (FDA) granted orphan drug designation to BMN 307 for the treatment of PKU.
This designation is given to investigative treatments for disorders that affect fewer than 200,000 people in the U.S. It is meant to provide regulatory support and financial benefits, accelerate the clinical development and review of BMN 307, and ensure marketing exclusivity for seven years upon regulatory approval.
BMN 307 represents BioMarin’s second investigational gene therapy program, the first being valoctocogene roxaparvovec for severe hemophilia A, currently being evaluated in two Phase 3 studies (NCT03370913; NCT03392974).
“Leveraging our expertise in gene therapy, we are pleased to be adding a new gene therapy product, which is potentially a transformative solution, to build on our current achievements for the PKU community,” Fuchs said.
The company also is conducting an observational study (NCT03505125) in up to 88 adults with PKU to identify the most relevant and meaningful disease markers and clinical outcomes to use in future clinical trials.