Sapropterin
Regulatory sources consulted
Approved indications
- Treatment of hyperphenylalaninaemia in adult and paediatric patients with phenylketonuria who have demonstrated a response to treatment.
- Treatment of hyperphenylalaninaemia in adult and paediatric patients with tetrahydrobiopterin deficiency who have demonstrated a response to treatment.
Contraindications
Absolute
- Hypersensitivity to the active substance or any excipient.
Clinical warnings
- Major warning · Maintain a phenylalanine-restricted diet and regularly monitor phenylalanine, tyrosine, nutritional intake and psychomotor development; persistent or recurrent hypophenylalaninaemia may affect neurological development. — AEMPS CIMA, Sapropterina Stada, ficha técnica 89442, sección 4.4
- Major warning · After treatment discontinuation, plasma phenylalanine may rebound above pre-treatment values. — AEMPS CIMA, Sapropterina Stada, ficha técnica 89442, sección 4.4
Drug interactions
- ModerateLevodopa
Mechanism: In BH4 deficiency, seizures, seizure exacerbation, increased excitability and irritability have been observed with co-administration.
Recommendation: Use with caution and monitor seizures, excitability, irritability and neurological status.
https://cima.aemps.es/cima/dochtml/ft/89442/FT_89442.html
- ModerateDihydrofolate-reductase inhibitors, such as methotrexate or trimethoprim
Mechanism: They may interfere with tetrahydrobiopterin metabolism.
Recommendation: Use with caution and monitor biochemical phenylalanine control during clinical follow-up.
https://cima.aemps.es/cima/dochtml/ft/89442/FT_89442.html
- ModerateMedicines affecting the nitric-oxide pathway, including nitric-oxide donors, PDE-5 inhibitors and minoxidil
Mechanism: Tetrahydrobiopterin is a nitric-oxide synthase cofactor.
Recommendation: Use with caution when co-administering medicines that affect nitric-oxide metabolism or action.
https://cima.aemps.es/cima/dochtml/ft/89442/FT_89442.html
Adverse events
Common (≥1%)
Headache · Rhinorrhoea · Hypophenylalaninaemia · Vomiting
Rare but serious
Severe allergic reactions · Seizures or seizure exacerbation with levodopa
Pregnancy and lactation
During pregnancy, strictly control phenylalanine; consider sapropterin only if a strict diet does not control it satisfactorily. Do not use during breastfeeding.
Recent literature (PubMed)
This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 μmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Untreated, PKU may result in severe and irreversible intellectual impairment due to marked hyperphenylalaninemia (HPA). Guidelines recommend lifelong reduction in Phe levels, usually achieved via a strict low-protein diet and sometimes medications. We discuss the role of tetrahydrobiopterin (BH4), an essential PAH cofactor in Phe metabolism, describe the pharmacodynamics, pharmacokinetics, and metabolism of sepiapterin, as well as reporting on its efficacy and safety in children and adults with PKU. Sepiapterin, an oral synthetic form of a natural precursor of BH4, can reduce HPA in some patients with PKU. In relatively short-term studies, sepiapterin has been shown to be safe, well tolerated, and like the BH4 analog sapropterin dihydrochloride effective in reducing blood Phe levels in responsive individuals. The reductions in blood Phe observed with sepiapterin in the phase III APHENITY trial has the potential to allow more PKU patients to attain Phe treatment targets or alternatively easing of the onerous dietary Phe restrictions. Results of longer-term studies in patients with PKU, including neurocognitive and functional outcomes, nutritional status, and quality of life are awaited.
To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency. The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review. Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy. We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities. Sapropterin is a synthetic form of the naturally occurring enzyme cofactor tetrahydrobiopterin (BH4) and is used in the treatment of phenylketonuria. BH4 is found in normal human milk and is a cofactor in multiple reactions including serving as a catalyst to phenylalanine hydroxylase. In two postmarketing pregnancy registries of women taking sapropterin, a total of 16 women were identified as breastfeeding for a mean of 3.5 months. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin. United States and
Phenylketonuria (PKU) is an inherited metabolic disorder characterized by the accumulation of toxic phenylalanine levels in the brain that can lead to neurocognitive impairment if untreated. This review evaluates unmet needs in PKU, the importance of newborn screening (NBS), and considerations for chronic treatment options. An international group of experts reviewed the available literature across ethnicities and geographies to identify unmet needs of individuals with PKU. Treatment was assessed in a global context to address patient benefit. Reflecting challenges to the worldwide PKU community, some countries have been unable to implement NBS programs and/or do not apply a treatment-for-life approach. Ongoing challenges for individuals with PKU include maintaining adherence to treatment guidelines for patient- and practice-specific reasons, such as inadequate access to low-cost treatment, insufficient social support, limited clinical staffing, and disease burden. Dietary interventions may not adequately address all symptoms, and some of the current pharmacotherapies may be associated with limited efficacy or adverse events. Several new therapies are being evaluated for the treatment of PKU, offering the potential to address unmet needs. Global availability of NBS programs, access to treatments, and a tenacious commitment to treatment-for-life are expected to improve outcomes for individuals with PKU across geographic regions.