Long-term safety of sapropterin in paediatric and adult individuals with phenylalanine hydroxylase deficiency: Final results of the Kuvan® Adult Maternal Paediatric European Registry multinational observational study.

Phenylketonuria is a rare inherited disorder that disrupts the metabolism of phenylalanine (Phe) to tyrosine by phenylalanine hydroxylase (PAH). Sapropterin dihydrochloride (Kuvan®) is approved for use in Europe to reduce blood Phe levels and improve Phe tolerance in sapropterin-responsive individuals. KAMPER (NCT01016392) is an observational, multinational registry assessing long-term safety and efficacy of sapropterin. Five hundred and seventy-six participants with PAH deficiency were enrolled from nine European countries (69 sites; December 2009-May 2016). Participants were aged <4 years (n = 11), 4 to <12 years (n = 329), 12 to <18 years (n = 141), and ≥18 years (n = 95) at enrolment. Overall, 401 (69.6%) participants experienced a total of 1960 adverse events; 61 events in 42 participants were serious, and two were considered sapropterin-related by the investigator. Mean (standard deviation) actual dietary Phe intake increased from baseline across all age groups: 957 (799) mg/day to a maximum of 1959 (1121) mg/day over a total study period of 11 years. Most participants exhibited an increase in Phe tolerance while blood Phe levels remained in the target range for their age (120-360 μmol/L for <12 years; 120-600 μmol/L for ≥12 years). Most participants exhibited normal growth for height, weight, and body mass index. No additional safety concerns were identified. As an observational study, limitations include variability in routine care practices and inconsistent availability of data. Long-term sapropterin use demonstrates a favourable safety profile in real-world settings and increases Phe tolerance in participants with PAH deficiency while maintaining blood Phe levels in the target ranges.

Feillet F ，Arnoux JB ，Delgado MB ，Burlina A ，Chabrol B ，Kucuksayrac E ，Lagler FB ，Muntau AC ，Olsson D ，Paci S ，Rutsch F ，van Spronsen FJ ，KAMPER investigators ... -  《-》

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU-MOMs sub-registries.

Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 μmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk-benefit ratio when used during pregnancy. Data from the maternal sub-registries-KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU-MOMs sub-registry)-were collected to assess the long-term safety and efficacy of sapropterin in pregnant women in a real-life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as 'normal' at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well-tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real-world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.

Feillet F ，Ficicioglu C ，Lagler FB ，Longo N ，Muntau AC ，Burlina A ，Trefz FK ，van Spronsen FJ ，Arnoux JB ，Lindstrom K ，Lilienstein J ，Clague GE ，Rowell R ，Burton BK ，KAMPER and PKUDOS investigators ... -  《-》

Evaluating change in diet with pegvaliase treatment in adults with phenylketonuria: Analysis of phase 3 clinical trial data.

Rohr F ，Burton B ，Dee A ，Harding CO ，Lilienstein J ，Lindstrom K ，MacLeod E ，Rose S ，Singh R ，van Calcar S ，Whitehall K ... -  《-》

Safety and Effectiveness of a Biosimilar Recombinant Growth Hormone in Adults with Growth Hormone Deficiency: Analysis of Final Data from PATRO Adults, an International Post-Marketing Surveillance Study.

Long-term studies are needed to investigate the safety of recombinant human growth hormone (rhGH) for the treatment of growth hormone deficiency (GHD) in routine practice. The objective of this study was to evaluate the safety and effectiveness of biosimilar rhGH (somatropin; Omnitrope®) in adults with GHD. PAtients TReated with Omnitrope (PATRO) Adults was a post-marketing surveillance study conducted across Europe. The primary objective was the safety of biosimilar rhGH in adults, particularly the occurrence of glucose intolerance or diabetes mellitus and malignancies. All adverse events (AEs) were recorded throughout treatment. Treatment effectiveness was a secondary objective. By December 2021, 1527 patients (50.3% male) were enrolled from 84 centers in 10 European countries. Most patients had adult-onset GHD (n = 1243; 81.4%) and 771 (50.5%) were rhGH-naïve at study entry. Median (interquartile range) treatment duration was 4.4 (1.90-7.30) years. Overall, 1181 patients (77.3%) reported 6667 AEs. Treatment-related AEs were reported in 143 patients (9.4%; 216 AEs); arthralgia was most common (n = 24). There were 49 confirmed diabetes mellitus events; 44 in newly diagnosed patients. Overall, 84 malignancies were reported. There were 46 treatment-related serious AEs in 39 patients (2.6%). The most frequently reported treatment-related serious AE was "metabolism and nutrition disorders" (n = 12). In rhGH-naïve patients, an increase in mean insulin-like growth factor-1 (IGF-1) standard deviation score (SDS) was observed from -2.03 at baseline to +0.28 at 5 years. An increase in IGF-1 SDS was also observed in previously treated patients from -0.71 to +0.35. Body mass index remained stable while blood lipid levels improved from baseline to 5 years. Final data from PATRO Adults confirm that biosimilar rhGH (Omnitrope) is not associated with any unexpected safety signals, with no evidence of increased diabetogenic or carcinogenic risk, and is effective in real-world clinical practice.

Beck-Peccoz P ，Höybye C ，Simsek S ，Stalla G ，Murray RD ，Esmael A ，Urosevic D ，Boldea A ，Zabransky M ... -  《Drug Design Development and Therapy》

Tyrosine supplementation for phenylketonuria.

Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. This is an update of previously published versions of this review. To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references. Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 07 December 2020. All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. Two authors independently assessed the trial eligibility, methodological quality and extracted the data. Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. The trials were assessed as having a low to moderate risk of bias across several domains. From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence. However, given this is not an active area of research, we have no plans to update this review in the future.

Remmington T ，Smith S 《Cochrane Database of Systematic Reviews》