PTC Therapeutics Reports Positive Results from Trial of Sepiapterin in Phenylketonuria Patients

PTC Therapeutics Reports Positive Results from Trial of Sepiapterin in Phenylketonuria Patients

Rare Daily Staff

PTC Therapeutics reported that the primary endpoint was achieved in the APHENITY, phase 3 registration-directed clinical trial of sepiapterin in adult and pediatric patients with phenylketonuria, a rare, inherited metabolic disease that affects the brain.

“The positive results from the APHENITY trial bring us one step closer to providing a therapy that could deliver meaningful benefit to PKU patients,” said Matthew Klein, CEO of PTC Therapeutics. “The Phe reductions observed in the placebo-controlled portion of the study are consistent with, and, in some cases, exceed the magnitude of Phe reductions recorded in the open label portion of the study. We look forward to meeting with regulatory authorities to discuss the path to approval.”

Phenylketonuria (PKU) is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. If left untreated or poorly managed, phenylalanine – an essential amino acid found in all proteins and most foods – can build up to harmful levels in the body. This causes severe and irreversible disabilities, such as permanent intellectual disability, seizures, delayed development, memory loss, and behavioral and emotional problems. Newborns with phenylketonuria initially don’t have any symptoms, but symptoms are usually progressive, and damage caused by toxic levels of phenylalanine in the first few years of life is irreversible. Diagnosis of phenylketonuria usually takes place during newborn screening programs. There are an estimated 58,000 people with phenylketonuria globally.

Sepiapterin (formerly PTC923) is an oral formulation of synthetic sepiapterin, a precursor to intracellular tetrahydrobiopterin, which is a critical enzymatic cofactor involved in the metabolism and synthesis of numerous metabolic products. Sepiapterin is a more bioavailable precursor than exogenously administered synthetic BH4 and has the potential to treat the broad range of PKU patients.

The placebo-controlled portion of the study included 98 patients in the primary analysis population. The mean percent Phe reduction in sepiapterin treated patients was 63 percent. In the subset of classical PKU patients, the mean percent Phe reduction was 69 percent. Minimal reductions in Phe levels were observed in the placebo treated patients resulting in a highly statistically significant sepiapterin treatment benefit. Sepiapterin was generally well tolerated with no serious adverse events.

APHENITY was a global double-blind, placebo-controlled, registration-directed study which enrolled 156 children and adults with PKU. Participants were randomized to receive sepiapterin or placebo for six weeks with the primary endpoint being reduction in blood phenylalanine levels. The trial consisted of two parts. Part 1 was a run-in phase, during which all screened subjects received sepiapterin for two weeks. Only those subjects who demonstrated a reduction in phenylalanine levels of 15 percent or more from baseline in Part 1 were randomized to receive either sepiapterin or placebo in Part 2 of the clinical trial. The primary analysis population consists of those who had greater than 30 percent reduction in phenylalanine levels from baseline during Part 1 of the trial.

The primary outcome measure is the reduction of blood phenylalanine levels from baseline compared to Weeks 5 and 6 in patients from Part 2 of the clinical trial. All patients are eligible to enroll in an open label long term clinical trial designed to further evaluate the long-term safety and durable effect of sepiapterin.

Photo: Matthew Klein, CEO of PTC Therapeutics