Interim Results From the APHENITY Extension Study: Sepiapterin Reduces Blood Phe With Improved Dietary Phe Tolerance in Participants With Phenylketonuria
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Phenylketonuria (PKU) is an autosomal-recessive inborn error of metabolism caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). This results in elevated phenylalanine (Phe) levels, associated with neurological, cognitive, psychiatric and behavioral impairments. The current standard of care is a Phe-restricted diet. Sepiapterin is an endogenous precursor of tetrahydrobiopterin (BH4) an essential cofactor for PAH; it increases intracellular BH4 bioavailability and acts as a distinct pharmacologic chaperone, leading to increased PAH enzymatic activity in both BH4-responsive and non-responsive PAH variants. Sepiapterin is being developed as a novel oral treatment for PKU. The Phase 3 APHENITY trial (NCT05099640) was a global, two-part, registration-directed study evaluating sepiapterin in a broad PKU population. Upon completion, participants could enroll directly into the APHENITY open-label extension study (NCT05166161). Here, we describe updated results from the extension study (30 June 2024 data cut), including those from participants on the extension study who were not involved in the APHENITY trial.
Methods:
The extension study includes both participants with PKU who have completed the APHENITY Phase 3 trial (referred to as feeder participants), and participants who have not been included before in a PTC-sponsored Phase 3 trial (referred to as non-feeder participants). All participants received oral sepiapterin once daily for ≥12 months. At the Month 2 Day 1 visit, mean blood Phe from Month 1 was reviewed. Participants with mean blood Phe <360 μmol/L underwent a concurrent Dietary Phe Tolerance Assessment. For a 26-week period, mean blood Phe was assessed along with dietary Phe consumption from 3-day diet records every 2 weeks, with changes in prescribed Phe allowed. Those with mean blood Phe ≥360 μmol/L continued receiving daily treatment but without active Phe Tolerance Assessment.
Results:
As of the June 30, 2024 data cut, 169 participants (median age, 14.0 years [min, max: 0.2, 55.0]) were treated with sepiapterin. Dietary Phe Tolerance Assessments were performed in 100 participants; 27 of whom were non-feeder participants. The median (min, max) treatment exposure was 465.0 (26, 868) days for the participants who undertook Dietary Phe Tolerance Assessments: 497.0 (26, 868) days for feeder participants and 147.5 (26, 273) for non-feeder participants. For all participants undertaking the Dietary Phe Tolerance Assessment, the least-square mean change (95% confidence interval) for change in dietary Phe consumption from baseline to Week 26 was 38.0 mg/kg/day (32.1, 43.9) (protein: 0.76 g/kg/day [0.64, 0.88]). An approximately 2.3-fold increase from baseline (27.6 mg/kg/day [protein: 0.55 g/kg/day]) in mean daily Phe consumption was achieved at Week 26 (63.6 mg/kg/day [protein: 1.27 g/kg/day]) in the overall Dietary Phe Tolerance Assessments. Mean blood Phe remained within the recommended target of <360 μmol/L during the Dietary Phe Tolerance Assessment commensurate with increase in Phe consumption.
Overall, sepiapterin showed a favorable safety profile and was well tolerated in the study. In the overall group (n=169), treatment-related TEAEs reported in ≥2% of participants were diarrhea (13 participants, 7.7%), headache (11 participants, 6.5%), discolored feces (7 participants, 4.1%), vomiting (4 participants, 2.4 %), and fatigue (4 participants, 2.4%). There was a low rate of discontinuation due to TEAES of 1.8% (3 TEAEs in 2 patients); 1 patient discontinued due to increased bleeding tendency, and one patient discontinued due to nausea and constipation. All 3 TEAEs were resolved. There were no treatment-related serious TEAEs and no deaths during the study.
Conclusion:
Updated results from the APHENITY extension study further confirms clinical benefit and a consistent safety profile with sepiapterin in patients with PKU, potentially allowing for liberalization of the highly restrictive diet these patients otherwise must maintain. Sepiapterin was well tolerated, and no safety concerns related to long-term use were observed.
Phenylketonuria (PKU) is an autosomal-recessive inborn error of metabolism caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). This results in elevated phenylalanine (Phe) levels, associated with neurological, cognitive, psychiatric and behavioral impairments. The current standard of care is a Phe-restricted diet. Sepiapterin is an endogenous precursor of tetrahydrobiopterin (BH4) an essential cofactor for PAH; it increases intracellular BH4 bioavailability and acts as a distinct pharmacologic chaperone, leading to increased PAH enzymatic activity in both BH4-responsive and non-responsive PAH variants. Sepiapterin is being developed as a novel oral treatment for PKU. The Phase 3 APHENITY trial (NCT05099640) was a global, two-part, registration-directed study evaluating sepiapterin in a broad PKU population. Upon completion, participants could enroll directly into the APHENITY open-label extension study (NCT05166161). Here, we describe updated results from the extension study (30 June 2024 data cut), including those from participants on the extension study who were not involved in the APHENITY trial.
Methods:
The extension study includes both participants with PKU who have completed the APHENITY Phase 3 trial (referred to as feeder participants), and participants who have not been included before in a PTC-sponsored Phase 3 trial (referred to as non-feeder participants). All participants received oral sepiapterin once daily for ≥12 months. At the Month 2 Day 1 visit, mean blood Phe from Month 1 was reviewed. Participants with mean blood Phe <360 μmol/L underwent a concurrent Dietary Phe Tolerance Assessment. For a 26-week period, mean blood Phe was assessed along with dietary Phe consumption from 3-day diet records every 2 weeks, with changes in prescribed Phe allowed. Those with mean blood Phe ≥360 μmol/L continued receiving daily treatment but without active Phe Tolerance Assessment.
Results:
As of the June 30, 2024 data cut, 169 participants (median age, 14.0 years [min, max: 0.2, 55.0]) were treated with sepiapterin. Dietary Phe Tolerance Assessments were performed in 100 participants; 27 of whom were non-feeder participants. The median (min, max) treatment exposure was 465.0 (26, 868) days for the participants who undertook Dietary Phe Tolerance Assessments: 497.0 (26, 868) days for feeder participants and 147.5 (26, 273) for non-feeder participants. For all participants undertaking the Dietary Phe Tolerance Assessment, the least-square mean change (95% confidence interval) for change in dietary Phe consumption from baseline to Week 26 was 38.0 mg/kg/day (32.1, 43.9) (protein: 0.76 g/kg/day [0.64, 0.88]). An approximately 2.3-fold increase from baseline (27.6 mg/kg/day [protein: 0.55 g/kg/day]) in mean daily Phe consumption was achieved at Week 26 (63.6 mg/kg/day [protein: 1.27 g/kg/day]) in the overall Dietary Phe Tolerance Assessments. Mean blood Phe remained within the recommended target of <360 μmol/L during the Dietary Phe Tolerance Assessment commensurate with increase in Phe consumption.
Overall, sepiapterin showed a favorable safety profile and was well tolerated in the study. In the overall group (n=169), treatment-related TEAEs reported in ≥2% of participants were diarrhea (13 participants, 7.7%), headache (11 participants, 6.5%), discolored feces (7 participants, 4.1%), vomiting (4 participants, 2.4 %), and fatigue (4 participants, 2.4%). There was a low rate of discontinuation due to TEAES of 1.8% (3 TEAEs in 2 patients); 1 patient discontinued due to increased bleeding tendency, and one patient discontinued due to nausea and constipation. All 3 TEAEs were resolved. There were no treatment-related serious TEAEs and no deaths during the study.
Conclusion:
Updated results from the APHENITY extension study further confirms clinical benefit and a consistent safety profile with sepiapterin in patients with PKU, potentially allowing for liberalization of the highly restrictive diet these patients otherwise must maintain. Sepiapterin was well tolerated, and no safety concerns related to long-term use were observed.
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