FDA Accepts Pegvaliase BLA, Grants Priority Review Designation

BioMarin announced the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) for pegvaliase, a PEGylated recombinant phenylalanine ammonia lyase enzyme product, to reduce blood phenylalanine (Phe) levels in adult patients with phenylketonuria (PKU) who have uncontrolled blood Phe levels on existing management.

The FDA has granted priority review designation to pegvaliase, which is granted to drugs that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of a serious condition. The PDUFA action date is February 28, 2018.  However, the FDA has requested additional Chemistry, Manufacturing, and Controls (CMC) information, which we expect, when submitted, will be classified as a major amendment and result in a three month extension of the PDUFA date. The Agency has not informed the company whether an advisory committee meeting to discuss the application will be needed.

"The acceptance of this filing marks a significant milestone as we seek approval for pegvaliase as a treatment option for adults whose blood Phe levels are not adequately controlled on existing management or who are not able to control and maintain their Phe levels," said Hank Fuchs, M.D., President Worldwide Research and Development at BioMarin. "In granting Priority Review, FDA recognizes the seriousness of PKU in adults and the associated morbidity that has substantial impact on day-to-day functioning, as well as the potential for pegvaliase to affect serious manifestations and symptoms of the disease in patients that are not adequately addressed with existing management. We look forward to working closely with FDA as they review the application to bring this important treatment to patients and offer patients an option to help with the lifelong management of PKU."

Pegvaliase is an investigational study drug that substitutes the deficient PAH enzyme in PKU with the PEGylated version of the enzyme phenylalanine ammonia lyase, to break down Phe. It is being developed as a potential treatment for adults with inadequately controlled blood Phe levels in the study.  In clinical studies, treatment with subcutaneous pegvaliase substantially reduced blood Phe compared to placebo using a randomized withdrawal study design, and led to long-term maintenance of Phe reduction in the majority of adult patients with PKU.  Pegvaliase was administered using a dosing regimen that achieved a manageable safety profile, consisting primarily of immune-mediated responses, including anaphylaxis, for which robust risk management measures effective in clinical trials will be proposed.

Phenylketonuria (PKU), or phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world and is caused by a deficiency of the enzyme PAH.  This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems and psychiatric symptoms. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU under the age of 40 in developed countries are diagnosed at birth and treatment is implemented soon after. PKU can be managed with a Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, the strict diet is difficult for most patients to adhere to the extent needed for achieving adequate control of blood Phe levels.