Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at Ania C Muntau  1 , Alberto Burlina  2 , François Eyskens  3 , Peter Freisinger  4 , Vincenzo Leuzzi  5 , Hatice Serap Sivri  6 , Gwendolyn Gramer  7 , Renata Pazdírková  8 , Maureen Cleary  9 , Amelia S Lotz-Havla  10 , Paul Lane  11 , Ignacio Alvarez  11 , Frank Rutsch  12 Affiliations Expand Affiliations 1 University Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. muntau@uke.de. 2 University Hospital, Padua, Italy. 3 Universitair Ziekenhuis Antwerpen, Antwerp, Belgium. 4 Children's Hospital Kreiskliniken, Reutlingen, Germany. 5 Universita La Sapienza, Rome, Italy. 6 Hacettepe University School of Medicine, Ankara, Turkey. 7 Division for Neuropaediatrics and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 8 Department of Children and Adolescents, Third Faculty of Medicine, Charles University, Prague, Czech Republic. 9 Great Ormond Street Hospital, London, UK. 10 Dr. Von Hauner Children's Hospital, Munich, Germany. 11 BioMarin Europe Ltd., London, UK. 12 Muenster University Children's Hospital, Muenster, Germany. PMID: 34344399 PMCID: PMC8335897 DOI: 10.1186/s13023-021-01968-1 Free PMC article Item in Clipboard

Abstract

Background: During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0-4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin.

Results: All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only ('sapropterin extension' group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period ('sapropterin continuous' group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the 'sapropterin continuous' group (95% CI 28.9, 48.6; p < 0.0001). In the 'sapropterin extension' group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI - 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters.

Conclusions: Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://ichgcp.net/clinical-trials-registry/NCT01376908 .

Keywords: Hyperphenylalaninaemia; Infants; Phenylketonuria; Sapropterin dihydrochloride; Therapy recommendations.

Conflict of interest statement

PL is an employee and shareholder of BioMarin. IA was an employee of BioMarin at the time of this study and during the initial preparation of this manuscript. All other authors had no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

a Dietary Phe tolerance during the extension period. b Dietary Phe tolerance (mg/kg/day) change in baseline during the extension period. The Month 1 visit in the extension period was only for patients who entered the extension period and who had received only a Phe-restricted diet in the 26-week study period. *Baselines are not contemporaneous; for the ‘sapropterin continuous’ group, the baseline was 26 weeks prior to that for the ‘sapropterin extension’ group (indicated by the dotted blue line in a). †p < 0.05 versus Baseline. ‡p < 0.001 versus Baseline. Phe phenylalanine

Fig. 2

a Blood Phe levels during the extension period. b Blood Phe levels change in baseline during the extension period. The Month 1 visit in the extension period was only for patients who entered the extension period and who had received only a Phe-restricted diet in the 26-week study period. Range between dotted grey line indicates target range for blood Phe level. *Baselines are not contemporaneous; for the ‘sapropterin continuous’ group, the baseline was 26 weeks prior to that for the ‘sapropterin extension’ group (indicated by the dotted blue line in a). †p < 0.05 versus Baseline. Phe phenylalanine, SE standard error

Fig. 3

Study design. BL indicates the time point for baseline Phe levels for the ‘sapropterin continuous’ and ‘sapropterin extension’ groups in the SPARK Extension Study. BL was defined as the Day 1 of receiving sapropterin treatment in the 26-week SPARK study for the ‘sapropterin continuous’ group; for the ‘sapropterin extension’ group, baseline was defined as Day 1 of the SPARK Extension study, when patients started to receive sapropterin treatment on enrolment in the extension study. *A defined level of Phe tolerance consistent with a diagnosis of PKU, ≥ 2 previous blood Phe concentrations ≥ 400 μmol/L obtained on two separate occasions. †BH4 responsiveness defined as a decrease of > 30% in Phe concentrations following a 20 mg/kg BH4 challenge of at least 24 h. Alternatively, 75% of the last four assessed values of Phe concentrations (either from venous blood or dry blood spot) should have been maintained in the therapeutic range. BH4 tetrahydrobiopterin, BL baseline, HPA hyperphenylalaninaemia, Phe phenylalanine, PKU phenylketonuria, R randomisation