Sephience Approved for Phenylketonuria in Adults, Children

The Food and Drug Administration (FDA) has approved Sephience^™ (sepiapterin) for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU).

Sepiapterin is a phenylalanine hydroxylase (PAH) activator that reduces blood phenylalanine (Phe) levels by increasing the intracellular concentrations of tetrahydrobiopterin (BH₄) and protecting against PAH enzyme misfolding. The approval was based on the 2-part phase 3 APHENITY trial (ClinicalTrials.gov Identifier: NCT05099640), which evaluated the efficacy of sepiapterin in adult and pediatric patients aged 1 to 61 years with a diagnosis of PKU and hyperphenylalaninemia with at least 2 blood Phe measurements of at least 600μmol/L. 

In Part 1, study participants (n=157) received daily open-label treatment with sepiapterin 7.5mg/kg in patients 0 to less than 6 months of age; 15mg/kg in patients 6 to less than 12 months of age; 30mg/kg in patients 12 months to less than 2 years of age; or 60mg/kg in patients at least 2 years of age for 14 days. Findings showed 66% of participants had at least a 30% reduction in Phe level. 

In Part 2, after a 2-week washout period, study participants aged 2 years and older who demonstrated a 30% or greater reduction in blood Phe levels from Part 1 were randomly assigned to receive sepiapterin 20mg/kg daily for weeks 1 and 2, 40mg/kg daily for weeks 3 and 4, and 60mg/kg daily for weeks 5 and 6 (n=49) or placebo (n=49) for 6 weeks. The primary endpoint was the mean change in blood Phe level from baseline to weeks 5 and 6.

Results showed sepiapterin, compared with placebo, reduced the mean blood Phe levels from baseline to weeks 5 and 6 by 64.2% (95% CI, 74.1-54.4). The mean change in blood Phe from baseline to weeks 5 and 6 was -415.8μmol/L with sepiapterin vs -19.9μmol/L with placebo (treatment difference, -395.9μmol/L [95% CI, -463.1, -328.7]; P <.0001). 

Supportive data were also provided from an ongoing, open-label trial in adult and pediatric patients aged 2 months to 55 years. As of the cutoff date, 169 participants received treatment with sepiapterin. Initial findings showed that among the 9 participants less than 2 years of age, 6 patients had at least a 30% decrease in blood Phe from baseline at weeks 1 and 2. The mean absolute change in Phe from baseline to weeks 1 and 2 was -125μmol/L (standard deviation: 265.9μmol/L). 

The most common adverse reactions reported were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain.

“We are excited to have reached this important milestone for those affected by PKU,” said Matthew B. Klein, MD, Chief Executive Officer of PTC Therapeutics. “The broad labeling reflects the potential of Sephience to meet the significant unmet need of PKU patients.”

The recommended dose of Sephience is based on the patient’s age and should be administered once daily with food. Before starting treatment, a baseline Phe concentration should be obtained. The product should be used in conjunction with a Phe-restricted diet. 

Sephience is supplied as an oral powder containing either 250mg or 1000mg of sepiapterin. The unit-dose foil packets are available in a carton of 30 or as a single packet. 

This article originally appeared on MPR