BioMarin files investigational NDA for PEG-PAL for the treatment of phenylketonuria

BioMarin Pharmaceutical Inc. has announced that it has filed an investigational new drug application (IND) with the U.S. Food and Drug Administration (FDA) for PEG-PAL (Poly Ethylene Glycol-Phenylalanine Ammonia Lyase), formerly known as Phenylase, for the treatment of phenylketonuria (PKU).

The company expects to initiate a clinical study of PEG-PAL in PKU patients in the first quarter of 2008.

"Filing this IND is a notable milestone in the advancement of our PEG-PAL program and our overall commitment to support the PKU community," said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. "With the Kuvan action date quickly approaching and the completion of the PEG-PAL IND filing, we are continuing our progress towards providing PKU patients with important new treatment options."

The Phase I study will assess the safety and pharmacokinetics of single injections of PEG-PAL in approximately 35 PKU patients in a series of escalating dose cohorts. The patients in the Phase 1 study will be offered continuation into a Phase 2 study that will evaluate the safety and efficacy of weekly injections for eight weeks followed by a dose titration period. Preclinical data has demonstrated that PEG-PAL administered subcutaneously once weekly to PKU mice resulted in a sustained decrease in blood phenylalanine (Phe) levels in a twelve week study and has also shown potent Phe level reductions in primates.

PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism of phenylalanine, 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 mental retardation and brain damage, mental illness, seizures, tremors, and limited cognitive ability. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all PKU patients under the age of 40 in developed countries have been diagnosed at birth. Currently, PKU can only be managed by a Phe-restricted diet, which is supplemented by nutritional replacement products, like formulas and specially-manufactured foods; however, the strict diet is difficult for most patients to adhere to the extent needed for achieving adequate control of blood Phe levels. To learn more about PKU, please visit

Kuvan(TM) is an investigational oral small molecule therapeutic for the treatment of PKU. The active ingredient in Kuvan, sapropterin dihydrochloride, is the synthetic form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that works in conjunction with phenylalanine hydroxylase (PAH) to metabolize Phe. Clinical data suggest that treatment with Kuvan results in significant reductions in blood Phe levels in BH4-responsive patients. BioMarin and Merck Serono estimate that Kuvan could be a potential treatment option for approximately 30 percent to 50 percent of the estimated 50,000 identified PKU patients in the developed world.

Kuvan has received orphan drug designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). If approved, it will receive seven years of market exclusivity in the United States and 10 years in the European Union for this indication. Additionally, the FDA has granted Kuvan Fast Track designation, which is designed to facilitate the development of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase) is an investigational enzyme substitution therapy for the treatment of PKU. Pharmacology studies evaluated in the PKU mouse model demonstrated that weekly subcutaneous administrations of PEG-PAL resulted in a significant and stable decrease of plasma phenylalanine. BioMarin estimates that PEG-PAL could be a potential treatment option for a significant portion of the PKU population. BioMarin has filed an IND application to the U.S. FDA and expects to initiate clinical testing in PKU patients in 2008.


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