APHENITY Extension Study Results: Long-Term Data | SEPHIENCE™ (sepiapterin) for HCPs

APHENITY Extension Study

APHENITY Extension Study: Evaluating Long-Term Dietary Phe Tolerance and Safety

The dietary Phe consumption analysis was not prespecified in the APHENITY trial nor included in the SEPHIENCE Prescribing Information. Results are from a prespecified, interim analysis and should be interpreted accordingly.¹

Study Design & Objective¹

Phase 3, ongoing, open-label extension study

Evaluates the long-term safety of SEPHIENCE and its impact on dietary Phe tolerance in children and adults with PKU

All patients received SEPHIENCE daily for ≥1 year

Participants¹

N=169 enrolled as of September 2, 2024

Age range: ~2 months to 55 years (median: 14 years)

All participants had previously completed the APHENITY trial or were newly enrolled

Study Methods¹

Participants were stratified based on blood Phe levels at the end of the first 2 weeks:

Group 1: Mean blood Phe <360 µmol/L (n=102)

Entered a 26-week dietary Phe tolerance assessment group

Dietary Phe intake was gradually increased under close monitoring

Group 2: Mean blood Phe ≥360 µmol/L (n=49)

Continued SEPHIENCE without the dietary Phe tolerance assessment

Study Limitations¹

APHENITY Extension Study is an ongoing, open-label extension study with self‍-‍reported dietary protein intake. Missing diary records, wide age range, and a heterogeneous population may bias dietary Phe intake results. While the APHENITY Extension Study cannot determine whether evidence supports dietary Phe liberalization, it demonstrates the durability of SEPHIENCE’s effect in maintaining blood Phe <360‍ µmol/L, its long-term safety, and the potential for diet liberalization in some adults and children with PKU. Data are for informational purposes only and should be interpreted with caution. Individual results may vary.

Data Cutoff¹

September 2, 2024

Interim Results: Increased Dietary Phe Intake¹

In the dietary Phe tolerance assessment group:

of patients increased
their Phe intake¹

Nearly all patients (n=99/102) were able to increase their dietary Phe intake at any time during the 26-week assessment. During the trial, 73% (n=74/102) of patients doubled and 34% (n=35/102) tripled their baseline Phe intake.¹

met their
age-adjusted RDA¹

Two-thirds of patients (n=57/81) reached their RDA for natural protein while on SEPHIENCE.¹

protein/day by Week 26¹

A 110-lb (50 kg) patient could consume approximately 60 grams of dietary protein per day after 26 weeks of treatment.¹*

Results are from a prespecified, interim analysis and should be interpreted accordingly.

*Based on an estimated conversion (‍1 g protein = 50 mg Phe‍)‍.‍¹

Additional study details¹

van Spronsen et al. 2026 Study Summary

Long-term safety and dietary phenylalanine tolerance with oral sepiapterin in patients with phenylketonuria (APHENITY Extension Study)
A phase 3, ongoing, open-label extension study is evaluating the long-term safety of sepiapterin and its impact on dietary Phe tolerance in children and adults with PKU. As of the September 2, 2024 data cutoff, 169 participants (aged ~2 months to 55 years; median age 14 years) enrolled and received sepiapterin daily for ≥1 year. Participants were stratified based on blood Phe levels at the end of the first 2 weeks. Group 1 (n=102) had a mean blood Phe <360 μmol/L and entered a 26-week diet assessment phase where dietary Phe intake was gradually increased under close monitoring. Group 2 (n=49) had a mean blood Phe ≥360 μmol/L and continued sepiapterin without the dietary Phe tolerance assessment.

The primary endpoint is the mean change in dietary Phe intake from baseline to Week 26 in participants with blood Phe <360 μmol/L after the first 2 weeks (n=102). Primary safety endpoints include treatment-emergent adverse events, clinical laboratory tests, vital signs, and physical examinations. Sepiapterin increased dietary Phe tolerance, with mean dietary Phe intake increasing from 27.6 to 62.5 mg/kg/day at Week 26 (least squares mean difference: 36.4 mg/kg/day from baseline; p<0.0001). Nearly all participants (97%) increased dietary Phe intake during the 26-week assessment period, with 73% doubling and 34% tripling intake from baseline.

The long-term safety profile of sepiapterin was consistent with that observed in the APHENITY trial. Treatment-related TEAEs occurred in 29% of participants. The most commonly reported events were headache (8.3%), diarrhea (7.7%), discolored feces (4.1%), vomiting (3.0%), and fatigue (2.4%). Three participants (1.8%) discontinued due to adverse events, and no treatment-related serious adverse events or deaths occurred.

Financial Disclosures of Study Sponsors

Funded by PTC Therapeutics, Inc.

van Spronsen F, Peters H, Margvelashvili L, 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. Genet Med. 2026;28(4):101683.

The Safety Profile Of SEPHIENCE up to 2.6 Years in 169 Participants Was Consistent With That Observed in the APHENITY Trial

APHENITY OLE Safety: Most adverse reactions were mild or moderate²

The most common treatment-related TEAEs (≥2%) were headache (8.3%), diarrhea (7.7%), discolored feces (4.1%), vomiting (3.0%), and fatigue (2.4%)¹
The safety profile remained consistent over time, with no safety concerns emerging  with long-term use¹

Stay informed

OLE: Open-label extension; Phe: Phenylalanine; PKU: Phenylketonuria; RDA: Recommended daily allowance; TEAEs: Treatment-emergent adverse events. 

References: 1. van Spronsen F, Peters H, Margvelashvili L, 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. Genet Med. 2026;28(4):101683. doi:10.1016/j.gim.2026.101683 2. Muntau AC, Longo N, Ezgu F, et al. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2024;404:1333–1345. doi:10.1016/S0140-6736(24)01556-3