Results That Matter to Patients
Comprehensive data to guide your treatment choices
APHENITY Study: From Identification to Confirmation
Two-part design: Identify responders, then confirm efficacy1,2
SEPHIENCE was evaluated in a two-part, global, double-blind, randomized, placebo-controlled study in patients with PKU. The primary efficacy was assessed by the mean change in blood Phe levels from baseline to Week 6 in the SEPHIENCE-treated group compared to the placebo group.
Consistent and Significant Phe Reduction1,2
APHENITY: Results observed across all ages, from pediatrics to adults2
At baseline, blood Phe levels were 646 µmol/L for SEPHIENCE and 654 µmol/L for placebo.
Additional Efficacy Analyses
The following analyses were not prespecified in the Phase 3 trial and are not included in the approved Prescribing Information for SEPHIENCE. Always refer to the full Prescribing Information for SEPHIENCE use. See additional study details below for more information.
Considerable Responsiveness Across Subgroups
APHENITY subgroup analysis was consistent with the results of the primary efficacy2
Mean % Change in Blood Phe from Baseline to Week 6 in Part 22,3
Classical PKU
BH4 Non-Responsive
SEPHIENCE (N=6)
-69%
SEPHIENCE (N=13)
-54%
Placebo (N=9)
+3%
Placebo (N=10)
-12%
(p<0.0001)
(p=0.001)
At baseline, blood Phe levels were 761 µmol/L for SEPHIENCE and 772 µmol/L for placebo in patients with classical PKU, and 650 µmol/L for SEPHIENCE and 662 µmol/L for placebo in those who were BH4 non-responsive.2
The mean absolute change in blood Phe from baseline to Week 6 was greater with SEPHIENCE than with placebo in both Classical PKU (-523 μmol/L vs -42 μmol/L) and BH4 non-responsive patients (-354 μmol/L vs -78 μmol/L).2
Additional study details2
Muntau et al. 2024 Study Summary
Efficacy and safety of oral sepiapterin in patients with phenylketonuria (APHENITY)
A phase 3, double-blind, randomized, placebo-controlled study in participants with PKU aged
2 years and older across 34 sites in 13 countries.
The primary efficacy endpoint was mean change in blood Phe concentration from baseline to Week 6. Sepiapterin significantly reduced blood Phe concentration compared to placebo (least squares mean difference: –395.9 μmol/L; p<0.0001). Secondary analyses showed that 93% of participants with a baseline blood Phe level of ≥600 µmol/L and 84% with a baseline level of ≥360 µmol/L achieved target Phe levels with sepiapterin, compared to 30% and 9% with placebo, respectively (both p<0.0001). Additionally, 22% of sepiapterin-treated participants achieved normal Phe levels (35‑120 μmol/L) compared to none with placebo.
Sepiapterin was generally well tolerated. The most common treatment-emergent adverse events were mild gastrointestinal symptoms, with no deaths, serious adverse reactions, or severe adverse events reported.
Study Limitations
Only participants who were sepiapterin-responsive (≥15% Phe reduction) were randomized, and the study duration was limited to 6 weeks.
Financial Disclosures of Study Sponsors
Funded by PTC Therapeutics.
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(10460):1333-1345.
Achieving Guideline-Target Blood Phe Levels
APHENITY: Percentage of patients who reached US guideline target levels (all ages)
US guidelines for all ages2
84%
of patients treated with SEPHIENCE reached ≤360 μmol/L (n=37/44)*
22%
of patients treated with SEPHIENCE had blood Phe levels within the normal range (n=11/49) vs 0% (n=0/49) of patients with placebo
Additional study details2
Muntau et al. 2024 Study Summary
Efficacy and safety of oral sepiapterin in patients with phenylketonuria (APHENITY)
A phase 3, double-blind, randomized, placebo-controlled study in participants with PKU aged 2 years and older across 34 sites in 13 countries.
The primary efficacy endpoint was mean change in blood Phe concentration from baseline to Week 6. Sepiapterin significantly reduced blood Phe concentration compared to placebo (least squares mean difference: –395.9 μmol/L; p<0.0001). Secondary analyses showed that 93% of participants with a baseline blood Phe level of ≥600 µmol/L and 84% with a baseline level of ≥360 µmol/L achieved target Phe levels with sepiapterin, compared to 30% and 9% with placebo, respectively (both p<0.0001). Additionally, 22% of sepiapterin-treated participants achieved normal Phe levels (35‑120 μmol/L) compared to none with placebo.
Sepiapterin was generally well tolerated. The most common treatment-emergent adverse events were mild gastrointestinal symptoms, with no deaths, serious adverse reactions, or severe adverse events reported.
Study Limitations
Only participants who were sepiapterin-responsive (≥15% Phe reduction) were randomized, and the study duration was limited to 6 weeks.
Financial Disclosures of Study Sponsors
Funded by PTC Therapeutics.
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(10460):1333-1345.
Increased Dietary Phe Consumption
APHENITY Extension: Mean dietary Phe consumption and blood Phe concentration over time
The APHENITY extension study is an ongoing, phase 3, open-label trial evaluating long-term safety and dietary Phe tolerance in children and adults with PKU treated with SEPHIENCE. Only participants with a mean blood Phe <360 μmol/L at month 1 were eligible to begin dietary Phe increases, monitored biweekly over 26 weeks. Those with Phe ≥360 μmol/L continued treatment without dietary adjustment.
- As of the September 2, 2024 data cutoff, interim results showed that participants could meaningfully increase dietary Phe intake while maintaining blood Phe within the target range (n=169)
Slide chart to view more
†RDA is 0.8 g protein/kg, equivalent to ~40 mg/kg/day Phe (1 g protein = 50 mg Phe).
Interim results: Challenging dietary barriers in PKU management
Nearly all patients were able to increase their dietary Phe intake at any time point—with a significant gain by Week 26 (p<0.0001).
Two-thirds of patients reached their RDA for protein while on SEPHIENCE.
‡Based on an estimated conversion of 50 mg Phe per gram of dietary protein.
Additional study details
APHENITY Extension Study Summary
Long-term efficacy and safety of oral sepiapterin in patients with phenylketonuria (PKU)
An ongoing, phase 3, open-label, multinational extension study evaluating long-term treatment with sepiapterin in participants with PKU who completed the APHENITY phase 3 trial (feeder participants) as well as newly enrolled participants with baseline blood Phe <360 μmol/L (nonfeeder-controlled) or ≥360 µmol/L at study entry (nonfeeder-uncontrolled).
All participants received oral sepiapterin once daily for at least 1 year. Participants with mean blood Phe <360 μmol/L at Month 1 underwent a 26-week dietary Phe tolerance assessment, with dietary Phe intake and blood Phe measured biweekly. Participants with mean Phe ≥360 μmol/L continued sepiapterin without active dietary adjustment. The primary endpoints were long-term safety and change in dietary Phe/protein consumption from baseline to Week 26.
Interim results (data cutoff: September 2, 2024) in 169 participants (median age: 14.0 years [range: 0.2–55.0]) showed that 97% were able to increase dietary Phe intake at any time point. From baseline to Week 25–26, mean dietary Phe significantly increased (p<0.0001), with 66% reaching their age-adjusted protein RDA, 73% doubling, and 34% tripling their baseline Phe intake. Among those previously treated with BH4, 52% doubled their intake compared to levels seen when they’re BH4-treated.
Sepiapterin was generally well tolerated. The most common treatment-emergent adverse reactions were mild gastrointestinal symptoms, with no deaths, serious adverse reactions, or severe adverse events reported.
Study Limitations
These are interim results from an ongoing study with data through Week 26. Not all participants had completed full follow-up. Dietary tolerance assessments were only conducted in those with Phe <360 μmol/L at Month 1.
Financial Disclosures of Study Sponsors
Funded by PTC Therapeutics.
ACMG 2025 Poster Presentation. Longo N et al. Interim results from the APHENITY extension study: sepiapterin reduces blood Phe with improved dietary Phe tolerance in participants with phenylketonuria. P047. Presented at ACMG 2025, Los Angeles, CA.
Consistent Safety Profile Across Age Groups
APHENITY Safety: Most adverse reactions were mild or moderate1,2
Warnings and Precautions:
- Increased Bleeding: SEPHIENCE may increase the risk of bleeding. Consider treatment interruption in patients with active bleeding.
- Hypophenylalaninemia: Some pediatric PKU patients experienced hypophenylalaninemia; monitor patients’ blood Phe levels during treatment
- Interaction with Levodopa: Seizures, over-stimulation, or irritability may occur; monitor patients for a change in neurologic status
Adverse Reactions That Occurred in ≥2% of SEPHIENCE-Treated Patients and Greater Than in Placebo (APHENITY, Part 2)1
Slide table to view more
Adverse Reaction
(Preferred Term)
Diarrhea
Headache
Abdominal pain*
Hypophenylalaninemia
Feces discolored
Oropharyngeal pain
SEPHIENCE (%)
N=56
4 (7)
4 (7)
3 (5)
2 (4)
2 (4)
2 (4)
Placebo (%)
N=54
1 (2)
1 (2)
1 (2)
0
0
1 (2)
*Includes abdominal pain, abdominal pain upper, and abdominal discomfort.
Proven safety profile with no serious adverse reactions reported1,2
No treatment-related serious adverse events were reported in SEPHIENCE-treated PKU patients in clinical trials.1,2
Adverse reactions were similar across both adult and pediatric populations, except for hypophenylalaninemia, which was observed in 5% (n=2/37) of pediatric patients but not in any adult patients APHENITY Part 2.1
APHENITY Extension: SEPHIENCE was well tolerated for up to 2.6 years in 169 participants, with a favorable safety profile.
- The most common treatment-emergent adverse events (≥2%), were headache (8.3%), diarrhea (7.7%), discolored feces (4.1%), vomiting (3.0%), and fatigue (2.4%).
- The safety profile remained consistent over time, with no safety concerns emerging with long-term use.
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BH4: Tetrahydrobiopterin; CI: Confidence interval; OR: Odds ratio; Phe: Phenylalanine; PKU: Phenylketonuria; RDA: Recommended daily allowance.
References: 1. SEPHIENCE. Package Insert. PTC Therapeutics, Inc; 2025. 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(10460):1333–1345. doi:10.1016/S0140‐6736(24)01556‐3 3. Data on file. PTC Therapeutics, Inc; 2025.
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