Written by: Priya Bhaware M.Pharm (Pharmacology) and Samiksha Benke M.Pharm (Pharmacology)
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has accepted a positive opinion recommending the approval of Sephience (sepiapterin) for the treatment of hyperphenylalaninaemia (HPA) in both adult and pediatric patients with phenylketonuria (PKU). Sephience most likely will be approved with orphan drug designation. Sephience will be made available as an oral powder in 250 mg and 1000 mg strengths. PTC Therapeutics International, the creator of the drug, is expected to receive marketing authorization based on this recommendation. Sephience is in position to represent a major advancement in the treatment of this rare metabolic condition.
Background and Need for New Treatments
Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by the body’s inability to break down phenylalanine, an amino acid present in many protein-rich foods. This condition arises from mutations in the gene responsible for producing phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine into tyrosine. When PAH is deficient or malfunctioning, phenylalanine accumulates in the blood, leading to a condition known as hyperphenylalaninemia (HPA). Without treatment, elevated phenylalanine levels can result in severe neurological impairments, developmental delays, and neuropsychiatric complications.
The current conventional treatment is mostly consisting of lifelong commitment to a phenylalanine-restricted diet, which is often begun in infancy. Even if effective in lowering phenylalanine levels, dietary reduction is difficult to maintain, particularly during adolescence and adulthood, and has a significant impact on quality of life. The pharmacological options are limited; however, sapropterin dihydrochloride, a synthetic version of the cofactor tetrahydrobiopterin (BH4), is approved for use in some BH4-responsive individuals. The therapeutic response to sapropterin differs, and many patients do not attain appropriate metabolic control.
There is still a considerable need for effective, well-tolerated, and easier-to-manage medicines for both pediatric and adult patients with PKU. Sephience is a promising therapeutic innovation that can improve metabolic regulation, reduce reliance on restrictive diets, and improve long-term clinical results and quality of life.
Sephience (sepiapterin): A Novel Approach
Sephience offers a novel therapeutic approach. It works through a dual mechanism of action to reduce elevated phenylalanine levels in patients with PKU.
BH4 Precursor: Sepiapterin is a naturally occurring precursor of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase (PAH). It is converted to BH4 through the salvage pathway, allowing it to bypass deficiencies in BH4 synthesis. This process helps boost residual PAH activity, thereby facilitating the breakdown of phenylalanine.
Molecular Chaperone: Sepiapterin also functions as a pharmacological chaperone, helping to stabilize misfolded phenylalanine hydroxylase (PAH) enzymes resulting from specific genetic mutations. By promoting proper folding, cellular trafficking, and functional activity of PAH within liver cells, sepiapterin enhances the enzyme’s overall effectiveness in metabolizing phenylalanine.
Clinical trial and approval
The CHMP’s positive opinion is supported by strong clinical evidence, primarily from the Phase 3 APHENITY trial (NCT05099640). This multinational, randomized, double-blind, placebo-controlled study enrolled 156 patients with hyperphenylalaninemia (HPA) across 13 countries. Participants, including children as young as one year old, had a baseline blood phenylalanine (Phe) level of ≥ 360 μmol/L, with individuals diagnosed with primary BH4 deficiency excluded.
The trial began with a 14-day open-label run-in phase to identify responders who achieved at least a 15% reduction in Phe levels. These responders then entered a 6-week double-blind phase, receiving either sepiapterin or a placebo. Sepiapterin demonstrated a significant therapeutic effect, reducing blood Phe levels by 63%, compared to just a 1% reduction in the placebo group. The study also assessed the drug’s safety and tolerability, both of which were favorable.
Following the Phase 3 APHENITY trial, the Open-Label Extension Study (NCT05166161) was conducted to evaluate the long-term safety and efficacy of sepiapterin in patients with PKU. Participants who responded to initial treatment continued on sepiapterin and maintained sustained metabolic control along with greater dietary flexibility. Over 97% of patients were able to increase their intake of natural protein by an average of 126% while keeping phenylalanine levels within the therapeutic range. Additionally, 66% of participants met or surpassed age-appropriate daily protein intake recommendations, reflecting a meaningful reduction in dietary restrictions.
The Phase 3 comparative trial (ISRCTN79102999) investigated the efficacy and safety of sepiapterin versus sapropterin in patients aged 2 years and older with phenylketonuria (PKU) over a treatment period of up to 173 days. This randomized open-label study monitored blood phenylalanine (Phe) levels to evaluate the extent and speed of Phe reduction, along with overall tolerability of the treatments. Preliminary results from this study indicated that sepiapterin may offer superior efficacy compared to sapropterin, suggesting its potential as a more effective therapeutic option for managing PKU.
Safety Profile
Sepiapterin has shown a favourable safety profile across clinical trials, including the Phase 3 APHENITY study and its Open-Label Extension trial. Most adverse events reported were mild to moderate, with the most common being temporary gastrointestinal symptoms such as nausea, abdominal discomfort, and diarrhea. No serious adverse events were attributed to sepiapterin, and there were no significant changes in laboratory values or vital signs. Long-term treatment further confirmed its tolerability and consistent metabolic control, with no safety issues. These results support the safe use of sepiapterin in both adults and children with phenylketonuria.
Conclusion
The EMA’s approval of Sephience represents a major progress in the treatment of hyperphenylalaninemia in both adults and children with phenylketonuria (PKU). Sepiapterin works by increasing tetrahydrobiopterin (BH4) levels, which helps restore phenylalanine hydroxylase (PAH) activity and reduces the accumulation of toxic phenylalanine (Phe). In the Phase 3 APHENITY trial, sepiapterin led to a 63% reduction in blood Phe levels compared to placebo. These benefits are maintained in the open-label extension study. Many patients were also able to increase their intake of natural protein while keeping Phe levels under control. Sepiapterin provides a valuable new treatment option, particularly for individuals who do not respond to sapropterin. Its dual mechanism of action may offer benefits across a broader spectrum of PKU patients. Ongoing research will focus on long-term cognitive outcomes, dosing strategies, and potential combination therapies to get maximum benefits.
References
Sephience™ (sepiapterin) Granted by EMA for treatment of hyperphenylalaninaemia (HPA) in both adult and pediatric patients with phenylketonuria (PKU), April 25, 2025, available from https://www.ema.europa.eu/en/medicines/human/EPAR/sephience#:~:text=information%20on%20Sephience-,Overview,children%20with%20phenylketonuria%20(PKU).
Van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet journal of rare diseases. 2017 Dec; 12:1-56.
Genetic and Rare Diseases Information Center (GARD), National Institutes of Health. Phenylketonuria (PKU). 2023. Available from: https://rarediseases.info.nih.gov/diseases/7383/phenylketonuria
Muntau AC, Longo N, Ezgu F, Schwartz IV, Lah M, Bratkovic D, Margvelashvili L, Kiykim E, Zori R, Plana JC, Bélanger-Quintana A. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. The Lancet. 2024 Oct 5; 404(10460):1333-45.
PTC Therapeutics Presents New Sepiapterin Data from Ongoing Studies, PTC Therapeutics, 20 March 2025, available from https://ir.ptcbio.com/node/17646/pdf
Nicola Longo, Francjan van Spronsen, Ania Muntau, et al, P047: Interim results from the APHENITY extension study: Sepiapterin reduces blood Phe with improved dietary Phe tolerance in participants with phenylketonuria, Genetics in Medicine Open, Volume 3, Supplement 2, 2025, 102891, https://doi.org/10.1016/j.gimo.2025.102891
A Phase III study of sepiapterin versus sapropterin in participants with phenylketonuria ≥2 years of age, ISRCTN79102999 https://doi.org/10.1186/ISRCTN79102999
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