CNSA-001 Safely and Effectively Reduces Phenylalanine Levels in PKU Patients, Phase 2 Trial Shows

CNSA-001 Safely and Effectively Reduces Phenylalanine Levels in PKU Patients, Phase 2 Trial Shows
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Censa Pharmaceuticals’ investigational oral therapy CNSA-001 (sepiapterin) is safe and more effective than Kuvan (sapropterin dihydrochloride) in reducing the levels of phenylalanine in people with phenylketonuria (PKU), data from a Phase 2 study suggest.

“The Phase 2 study data demonstrate that CNSA-001 could become a first line pharmacological therapy for responsive patients with PKU,” Drago Bratkovic, MD, the trial’s principal investigator and head of the metabolic clinic at Women’s and Children’s Hospital, in Adelaide, Australia, said in a press release.

The study’s detailed data will be presented at the American College of Medical Genetics and Genomics Meeting, to be held March 17–21, 2020, in San Antonio, Texas.

PKU is a genetic disorder characterized by an absent or deficient activity of phenylalanine hydroxylase (PAH), an enzyme responsible for the conversion of phenylalanine — an amino acid (the building blocks of proteins) obtained through the diet — into another amino acid, tyrosine.

This deficiency leads to the toxic build-up of phenylalanine in the blood and organs. Excessive amounts of this amino acid in the brain lead not only to toxicity-associated damage, but also to an impaired production of neurotransmitters, the signaling molecules that brain cells use to communicate with each other. Depending on PAH enzymatic activity, patients can develop mild to severe PKU.

Currently approved PKU treatments — BioMarin Pharmaceutical’s orally-administered Kuvan and injectable Palynziq (pegvaliase-pqpz) — help to control phenylalanine levels by boosting PAH activity or PAH-independent phenylalanine breakdown.

Similar to Kuvan — which consists of synthetic tetrahydrobiopterin (BH4), a protein essential for PAH function — CNSA-001 is an oral therapy designed to boost PAH activity. However, CNSA-001’s active ingredient is sepiapterin, a molecule involved in tetrahydrobiopterin synthesis.

Since sepiapterin is a more stable molecule and is transported more efficiently across cells, it has the potential to be more effective than Kuvan in boosting PAH activity, reducing phenylalanine levels, and lessening symptoms in PKU patients.

Previous preclinical studies and clinical trials in healthy volunteers showed that CNSA-001 was safe and was rapidly and efficiently converted into tetrahydrobiopterin, increasing its levels in the blood and target tissues more efficiently than equivalent doses of Kuvan.

CNSA-001 administration also corrected abnormally low levels of intermediate molecules involved in the production of neurotransmitters in one healthy volunteer, suggesting that it could promote similar corrections in PKU patients.

The randomized, multicenter Phase 2 trial (ACTRN12618001031257) evaluated the safety and effectiveness of two oral doses of CNSA-001, as well as its therapeutic effects compared with those of Kuvan, in 24 adults with PKU.

This proof-of-concept study was expected to help establish the best dose of CNSA-001 and to support the design of future Phase 2/3 studies investigating CNSA-001 in PKU patients.

Participants (up to 60 years old) were recruited at five Australian centers. They were randomly assigned to one of six treatment regimens, each including a different sequence of three treatments: 20 mg/kg/day of CNSA-001, 60 mg/kg/day of CNSA-001, and 20 mg/kg/day of Kuvan (its maximum recommended dose). Each treatment was given daily for a week and followed by a treatment-free week, before the next treatment period.

The study’s primary goal was to evaluate whether CNSA-001 treatment could reduce phenylalanine blood levels, compared with those prior to treatment (baseline levels), and compared to Kuvan. Secondary goal was to assess the safety and tolerability of the two CNSA-001 doses.

Results showed that the trial met its primary and secondary goals. CNSA-001 treatment led to a statistically significant and clinically meaningful reduction in phenylalanine blood levels compared with baseline, and also to the levels achieved during Kuvan treatment. CNSA-001 was well-tolerated, with no reports of serious adverse events or treatment discontinuations.

The CNSA-001-induced reduction in phenylalanine levels was consistent for all baseline levels, suggesting that the therapy may be effective for people with mild to severe PKU.

“There is a significant unmet need for an oral therapy that is effective in both mild and severe PKU patients,” said Jonathan Reis, MD, Censa’s CEO.

“Our preliminary results suggest that CNSA-001 better controls blood [phenylalanine] levels and has the potential to improve neurocognitive symptoms more effectively than current standard of care therapies,” he added.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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