PTC Therapeutics will be advancing CNSA-001 (sepiapterin) — an investigational oral therapy for phenylketonuria (PKU) and other metabolic disorders — because the company is acquiring the original developer of the treatment, Censa Pharmaceuticals.
The acquisition is expected to be completed in June, depending on the fulfillment of certain conditions. PTC now is planning to start a Phase 3 trial of CNSA-001 in PKU patients.
“It is the right time to have an excellent fully integrated, patient-focused biotechnology organization like PTC Therapeutics take over the late-stage development of CNSA-001 so that this promising compound becomes available to patients in the near future,” Jonathan Reis, MD, president and CEO of Censa, said in a press release.
PKU is characterized by insufficient activity of phenylalanine hydroxylase (PAH), an enzyme responsible for the conversion of phenylalanine into tyrosine. (Both phenylalanine and tyrosine are amino acids, the building blocks of proteins.)
This causes the buildup of phenylalanine in organs such as the brain, namely a defective production of neurotransmitters, the signaling molecules that brain cells use to communicate with each other.
Currently approved therapies for PKU include BioMarin Pharmaceutical’s Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase-pqpz). While Kuvan is an oral treatment for a specific subset of PKU patients — those with BH4-responsive PKU — Palynziq is given by injection and includes an engineered form of phenylalanine ammonia lyase (PAL), an enzyme that breaks down phenylalanine.
As is Kuvan, which consists of lab-made tetrahydrobiopterin (BH4), a key protein for PAH function, CNSA-001 also is designed to boost activity of this enzyme. Its active ingredient is sepiapterin, a molecule involved in the production of BH4.
Sepiapterin is more stable and better transported across cells than BH4, suggesting its potential to boost PAH activity and lessen symptoms of PKU better than Kuvan.
CNSA-001 showed promising results in preclinical studies and, more recently, in a Phase 2 trial in Australia (ACTRN12618001031257). This study compared the safety and effectiveness of two oral doses of CNSA-001 to those of Kuvan in 24 adults with PKU.
Participants, age 60 or younger, were assigned randomly to one of six treatment regimens, each with a different sequence of 20 mg/kg per day of CNSA-001, 60 mg/kg/day of CNSA-001, and 20 mg/kg per day of Kuvan (its maximum recommended dose). Each group received the therapy daily for a week, followed by a one-week break before resuming treatment.
The main goal was to assess whether CNSA-001 reduced the levels of phenylalanine in the blood, compared to both baseline levels (at study start) and to Kuvan. The secondary goal was to assess the safety and tolerability of the two CNSA-001 doses.
Results showed that both goals were achieved. CNSA-001 led to a clinically meaningful reduction in phenylalanine blood levels compared with the start of the trial, and with the reduction seen with Kuvan. Also, CNSA-001 was well-tolerated, with no reports of serious adverse side effects or treatment discontinuations.
The decrease in phenylalanine levels with CNSA-001 was seen across different levels of this amino acid at the start of the trial, supporting the therapy’s effectiveness for people with mild-to-severe PKU.
“Results from a Phase 2 clinical trial of CNSA-001 demonstrated significant and clinically relevant reductions in phenylanaline levels compared to current first-line treatment,” said Stuart W. Peltz, PhD, CEO at PTC Therapeutics.
“We believe that CNSA-001 has the potential to address the majority of PKU patients whose condition is not adequately managed by current treatments,” he added.
PTC now is planning a Phase 3 trial after the promising results seen in the Phase 2 study.
“We look forward to initiating a Phase 3 study in PKU so that patients diagnosed with this devastating condition can have a new oral treatment option as soon as possible,” Peltz said.