Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study

Francjan van Spronsen; Heidi Peters; Lali Margvelashvili; Dodo Agladze; Ida Vanessa D Schwartz; Maria Giżewska; Takashi Hamazaki; Laura Guilder; Anita MacDonald; Suresh Vijay; Anita Inwood; Maria Minami; Olivia Fjellbirkeland; Allan Lund; Melissa Lah; Janet A Thomas; Nicola Longo; Ertuğrul Kiykim; Mika Ishige; Alberto Burlina; Amaya Bélanger-Quintana; Frank Rutsch; Thomas Opladen; Halise Mungan; Fatih Ezgü; Drago Bratkovic; Anupam Chakrapani; Tetsuya Ito; Arlindo Guimas; Roberto Zori; Michel Tchan; Stephanie Sacharow; Anabela Oliveira; Patricia Janeiro; Ixiu-Cabrales Guerra; Jaume Campistol Plana; Yılmaz Yıldız; Ebru Canda; Aneal Khan; Jerry Vockley; Margo Sheck Breilyn; Filippo Manti; Alex Larkin; Catalina Hughes; Emelline Liu; Lan Gao; Kimberly Ingalls; Neil Smith; Ania C Muntau

doi:10.1016/j.gim.2026.101683

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study

Francjan van Spronsen^*, Heidi Peters, Lali Margvelashvili, Dodo Agladze, Ida Vanessa D Schwartz, Maria Giżewska, Takashi Hamazaki, Laura Guilder, Anita MacDonald, Suresh Vijay, Anita Inwood, Maria Minami, Olivia Fjellbirkeland, Allan Lund, Melissa Lah, Janet A Thomas, Nicola Longo, Ertuğrul Kiykim, Mika Ishige, Alberto BurlinaAmaya Bélanger-Quintana, Frank Rutsch, Thomas Opladen, Halise Mungan, Fatih Ezgü, Drago Bratkovic, Anupam Chakrapani, Tetsuya Ito, Arlindo Guimas, Roberto Zori, Michel Tchan, Stephanie Sacharow, Anabela Oliveira, Patricia Janeiro, Ixiu-Cabrales Guerra, Jaume Campistol Plana, Yılmaz Yıldız, Ebru Canda, Aneal Khan, Jerry Vockley, Margo Sheck Breilyn, Filippo Manti, Alex Larkin, Catalina Hughes, Emelline Liu, Lan Gao, Kimberly Ingalls, Neil Smith, Ania C Muntau

^*Corresponding author af dette arbejde

Abstract

PURPOSE: To report interim results from the ongoing, open-label, Phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria.

METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to Week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs).

RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at Week 26 (least-squares mean change [SE], 36.4 [2.8] mg/kg/day from baseline) (P<0.0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths.

CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria.

Originalsprog	Engelsk
Artikelnummer	101683
Tidsskrift	Genetics in medicine : official journal of the American College of Medical Genetics
Vol/bind	28
Udgave nummer	4
Sider (fra-til)	101683
ISSN	1098-3600
DOI	https://doi.org/10.1016/j.gim.2026.101683
Status	E-pub ahead of print - 12 jan. 2026

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10.1016/j.gim.2026.101683Licens: CC BY

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van Spronsen, F., Peters, H., Margvelashvili, L., Agladze, D., Schwartz, I. V. D., Giżewska, M., Hamazaki, T., Guilder, L., MacDonald, A., Vijay, S., Inwood, A., Minami, M., Fjellbirkeland, O., Lund, A., Lah, M., Thomas, J. A., Longo, N., Kiykim, E., Ishige, M., ... Muntau, A. C. (2026). Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study. Genetics in medicine : official journal of the American College of Medical Genetics, 28(4), 101683. Artikel 101683. Advance online publication. https://doi.org/10.1016/j.gim.2026.101683

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study. / van Spronsen, Francjan; Peters, Heidi; Margvelashvili, Lali et al.
I: Genetics in medicine : official journal of the American College of Medical Genetics, Bind 28, Nr. 4, 101683, 04.2026, s. 101683.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

van Spronsen, F, Peters, H, Margvelashvili, L, Agladze, D, Schwartz, IVD, Giżewska, M, Hamazaki, T, Guilder, L, MacDonald, A, Vijay, S, Inwood, A, Minami, M, Fjellbirkeland, O , Lund, A, Lah, M, Thomas, JA, Longo, N, Kiykim, E, Ishige, M, Burlina, A, Bélanger-Quintana, A, Rutsch, F, Opladen, T, Mungan, H, Ezgü, F, Bratkovic, D, Chakrapani, A, Ito, T, Guimas, A, Zori, R, Tchan, M, Sacharow, S, Oliveira, A, Janeiro, P, Guerra, I-C, Plana, JC, Yıldız, Y, Canda, E, Khan, A, Vockley, J, Breilyn, MS, Manti, F, Larkin, A, Hughes, C, Liu, E, Gao, L, Ingalls, K, Smith, N & Muntau, AC 2026, 'Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study', Genetics in medicine : official journal of the American College of Medical Genetics, bind 28, nr. 4, 101683, s. 101683. https://doi.org/10.1016/j.gim.2026.101683

van Spronsen F, Peters H, Margvelashvili L, Agladze D, Schwartz IVD, Giżewska M et al. Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study. Genetics in medicine : official journal of the American College of Medical Genetics. 2026 apr.;28(4):101683. 101683. Epub 2026 jan. 12. doi: 10.1016/j.gim.2026.101683

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title = "Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study",

abstract = "PURPOSE: To report interim results from the ongoing, open-label, Phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria.METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to Week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs).RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at Week 26 (least-squares mean change [SE], 36.4 [2.8] mg/kg/day from baseline) (P<0.0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0\%; 3 participants (1.8\%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths.CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria.",

keywords = "Diet liberalization, Long-term safety, Phenylketonuria, Quality of life, Sepiapterin",

author = "\{van Spronsen\}, Francjan and Heidi Peters and Lali Margvelashvili and Dodo Agladze and Schwartz, \{Ida Vanessa D\} and Maria Gi{\.z}ewska and Takashi Hamazaki and Laura Guilder and Anita MacDonald and Suresh Vijay and Anita Inwood and Maria Minami and Olivia Fjellbirkeland and Allan Lund and Melissa Lah and Thomas, \{Janet A\} and Nicola Longo and Ertuğrul Kiykim and Mika Ishige and Alberto Burlina and Amaya B{\'e}langer-Quintana and Frank Rutsch and Thomas Opladen and Halise Mungan and Fatih Ezg{\"u} and Drago Bratkovic and Anupam Chakrapani and Tetsuya Ito and Arlindo Guimas and Roberto Zori and Michel Tchan and Stephanie Sacharow and Anabela Oliveira and Patricia Janeiro and Ixiu-Cabrales Guerra and Plana, \{Jaume Campistol\} and Yılmaz Yıldız and Ebru Canda and Aneal Khan and Jerry Vockley and Breilyn, \{Margo Sheck\} and Filippo Manti and Alex Larkin and Catalina Hughes and Emelline Liu and Lan Gao and Kimberly Ingalls and Neil Smith and Muntau, \{Ania C\}",

note = "Copyright {\textcopyright} 2026. Published by Elsevier Inc.",

year = "2026",

month = jan,

day = "12",

doi = "10.1016/j.gim.2026.101683",

language = "English",

volume = "28",

pages = "101683",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier BV",

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TY - JOUR

T1 - Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria

T2 - interim results from the Phase 3 APHENITY Extension Study

AU - van Spronsen, Francjan

AU - Peters, Heidi

AU - Margvelashvili, Lali

AU - Agladze, Dodo

AU - Schwartz, Ida Vanessa D

AU - Giżewska, Maria

AU - Hamazaki, Takashi

AU - Guilder, Laura

AU - MacDonald, Anita

AU - Vijay, Suresh

AU - Inwood, Anita

AU - Minami, Maria

AU - Fjellbirkeland, Olivia

AU - Lund, Allan

AU - Lah, Melissa

AU - Thomas, Janet A

AU - Longo, Nicola

AU - Kiykim, Ertuğrul

AU - Ishige, Mika

AU - Burlina, Alberto

AU - Bélanger-Quintana, Amaya

AU - Rutsch, Frank

AU - Opladen, Thomas

AU - Mungan, Halise

AU - Ezgü, Fatih

AU - Bratkovic, Drago

AU - Chakrapani, Anupam

AU - Ito, Tetsuya

AU - Guimas, Arlindo

AU - Zori, Roberto

AU - Tchan, Michel

AU - Sacharow, Stephanie

AU - Oliveira, Anabela

AU - Janeiro, Patricia

AU - Guerra, Ixiu-Cabrales

AU - Plana, Jaume Campistol

AU - Yıldız, Yılmaz

AU - Canda, Ebru

AU - Khan, Aneal

AU - Vockley, Jerry

AU - Breilyn, Margo Sheck

AU - Manti, Filippo

AU - Larkin, Alex

AU - Hughes, Catalina

AU - Liu, Emelline

AU - Gao, Lan

AU - Ingalls, Kimberly

AU - Smith, Neil

AU - Muntau, Ania C

PY - 2026/1/12

Y1 - 2026/1/12

N2 - PURPOSE: To report interim results from the ongoing, open-label, Phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria.METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to Week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs).RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at Week 26 (least-squares mean change [SE], 36.4 [2.8] mg/kg/day from baseline) (P<0.0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths.CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria.

AB - PURPOSE: To report interim results from the ongoing, open-label, Phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria.METHODS: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to Week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs).RESULTS: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at Week 26 (least-squares mean change [SE], 36.4 [2.8] mg/kg/day from baseline) (P<0.0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths.CONCLUSION: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria.

KW - Diet liberalization

KW - Long-term safety

KW - Phenylketonuria

KW - Quality of life

KW - Sepiapterin

UR - https://www.scopus.com/pages/publications/105030249942

U2 - 10.1016/j.gim.2026.101683

DO - 10.1016/j.gim.2026.101683

M3 - Journal article

C2 - 41537382

SN - 1098-3600

VL - 28

SP - 101683

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 4

M1 - 101683

ER -

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study

Abstract

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