Drug Trials Snapshots: SEPHIENCE
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the SEPHIENCE Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
SEPHIENCE (sepiapterin)
(seh-FIGH-ence)
PTC Therapeutics, Inc.
Approval date: July 28, 2025
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
SEPHIENCE is a prescription medicine used to lower blood levels of phenylalanine (Phe) in adults and children 1 month of age and older with a certain type of phenylketonuria (PKU). SEPHIENCE is used along with a Phe-restricted diet.
How is this drug used?
SEPHIENCE is an oral powder that is mixed with liquid or soft food to be taken once daily with food. The dose is based on the patient’s weight and age.
Who participated in the clinical trials?
The FDA approved SEPHIENCE based on evidence from Trial 1 (NCT05099640) of patients with PKU and supportive clinical evidence from Trial 2. Trial 1 enrolled 157 pediatric and adult patients 1 to 61 years of age with PKU and was conducted at 34 centers among 13 countries, including the United States, Canada, Denmark, Germany, Australia, Georgia, the United Kingdom, Turkey, Italy, Portugal, Mexico, Brazil, and Spain. There were 20 patients from the United States while 137 were from outside the United States. Trial 2 included 104 patients from Trial 1 and an additional 65 patients. Trial 2 enrolled 65 adult and 104 pediatric patients with an age range of 2 months to 55 years old. There were 25 patients from the United States while 144 were from outside the United States.
How were the trials designed?
Trial 1 was a two-part trial. Part 1 evaluated sepiapterin responsiveness over 14 days. Part 2 was a six-week, randomized, double-blind, placebo-controlled portion for subjects aged 2 years and older with PKU who were sepiapterin responsive in Part 1. The primary endpoint was the average blood Phe level reduction from baseline to Weeks 5 and 6.
Trial 2 is an ongoing, multicenter, open-label trial in adult and pediatric patients with a clinical diagnosis of PKU with hyperphenylalaninemia.
How were the trials designed?
In Trial 1 Part 1, 157 patients received open-label treatment with SEPHIENCE: 7.5 mg/kg orally in patients 0 to <6 months of age, 15 mg/kg in patients 6 to <12 months of age, 30 mg/kg in patients 12 months to <2 years of age, or 60 mg/kg in patients ≥2 years of age per day for 14 days. In Part 1, 66% of PKU patients showed a biochemical response to SEPHIENCE, defined as a >30% or greater reduction in Phe level. In Part 2, 98 patients aged 2 years and older who demonstrated a ≥30% reduction in blood Phe levels to SEPHIENCE in Part 1 were randomized in a double-blind fashion to either SEPHIENCE 20 mg/kg daily for Weeks 1 and 2, 40 mg/kg daily for Weeks 3 and 4, 60 mg/kg daily for Weeks 5 and 6 (N=49), or placebo (N=49) for six weeks. The primary endpoint was change in blood Phe level from baseline to Weeks 5 and 6.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many females and males enrolled in Trial 1 Part 2 used to evaluate the efficacy and safety of SEPHIENCE.
Figure 1. Baseline Demographics by Sex, Primary Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race enrolled in Trial 1 Part 2 used to evaluate the efficacy and safety of SEPHIENCE.
Figure 2. Baseline Demographics by Race, Primary Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age enrolled in Trial 1 Part 2 used to evaluate the efficacy and safety of SEPHIENCE.
Figure 3. Baseline Demographics by Age, Primary Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity enrolled in Trial 1 Part 2 used to evaluate the efficacy and safety of SEPHIENCE.
Figure 4. Baseline Demographics by Ethnicity, Primary Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics, Primary Efficacy Population
| Demographic | SEPHIENCE N=49 |
Placebo N=49 |
|---|---|---|
| Sex, n (%) | ||
| Male | 26 (53.1) | 22 (44.9) |
| Female | 23 (46.9) | 27 (55.1) |
| Age, years | ||
| Mean (SD) | 16.3 (11.53) | 18.1 (10.63) |
| Median (min, max) | 13 (2, 47) | 15 (4, 54) |
| Age category, years, n (%) | ||
| ≥2 to <6 | 7 (14.3) | 3 (6.1) |
| ≥6 to <12 | 15 (30.6) | 11 (22.4) |
| ≥12 to <18 | 12 (24.5) | 17 (34.7) |
| ≥18 | 15 (30.6) | 18 (36.7) |
| Race, n (%) | ||
| American Indian or Alaska Native | 3 (6.1) | 2 (4.1) |
| White | 45 (91.8) | 45 (91.8) |
| Other | 1 (2) | 2 (4.1) |
| Ethnicity, n (%) | ||
| Hispanic or Latino | 8 (16.3) | 11 (22.4) |
| Not Hispanic or Latino | 40 (81.6) | 38 (77.6) |
Source: Adapted from FDA Review
Abbreviations: SD, standard deviation
What are the benefits of this drug?
SEPHIENCE decreased blood Phe levels in both adult and pediatric patients with sepiapterin-responsive PKU compared to placebo.
What are the benefits of this drug (results of trials used to assess efficacy)?
The primary efficacy endpoint was mean change in blood Phe levels from baseline to Weeks 5 and 6 in Trial 1 Part 2 (i.e., the average Phe level at Day 5, 10, and 14 in the two-week period of double-blind treatment). The Week 5 to 6 mean change from baseline in blood Phe levels was greater in the SEPHIENCE-treated patients than the placebo-treated patients.
Table 2 and Figure 5 summarize the clinical efficacy results of SEPHIENCE from Trial 1 Part 2.
Table 2. Change in Blood Phe Levels From Baseline at Weeks 5 and 6 For Patients Who Had a ≥30% Reduction in Blood Phe Levels During Part 1 of Trial 1
| Parameter | SEPHIENCE N=49 |
Placebo N=49 |
|---|---|---|
| Baseline blood Phe levela (μmol/L) | ||
| Mean (±SD) | 646.1 (253) | 654 (261.5) |
| Weeks 5 and 6b | ||
| Mean (±SD) | 236 (174.9) | 637.9 (259.9) |
| Mean change in blood Phe from baseline to Weeks 5 and 6 (μmol/L) | ||
| Adjusted mean (±SE)† | -415.8 (24.1) | -19.9 (24.2) |
| Treatment difference (95% CI) in adjusted mean† | -395.9 (-463.1, -328.7) | |
| Mean percent change in blood Phe from baseline to Weeks 5 and 6 (%) | ||
| Mean (±SD) | -62.8 (20.7) | 1.4 (29.2) |
| Treatment difference (95% CI) in adjusted mean | -64.2 (-74.1, -54.4) |
Source: SEPHIENCE Prescribing Information
a Baseline is the average of Day -1 and Day 1 blood Phe levels in Part 2.
b Blood Phe levels were based on average values during Weeks 5 and 6.
† Adjusted mean and standard error, p-value <0.0001 for treatment difference were from a mixed model for repeated measures (MMRM) with change in blood Phe from baseline to post-baseline assessments as the response variable, and fixed effects for treatment, baseline blood Phe, baseline Phe stratum, visit and treatment-by-visit interaction.
Abbreviations: CI, confidence interval; Phe, phenylalanine; SD, standard deviation; SE, standard error
Figure 5. Mean (±SD) Blood Phe Levels Over Time For Patients Who Had a ≥30% Reduction in Blood Phe Levels During Part 1 of Trial 1 (N=98)
Source: SEPHIENCE Prescribing Information
Abbreviations: Phe, phenylalanine; SD, standard deviation
Supportive efficacy data were provided from Trial 2. Of the nine patients under the age of 2 years, six patients (66%) had a ≥30% decrease in blood Phe level from baseline at Weeks 1 and 2. The baseline Phe level in patients 2 years and under was 311.4 µmol/L and the mean absolute change in Phe from baseline to Weeks 1 and 2 in this age group was -125 µmol/L (standard deviation 265.9 µmol/L).
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: SEPHIENCE worked similarly in males and females.
- Race: The number of patients of races other than White was small; therefore, differences in efficacy among races could not be determined.
- Age: SEPHIENCE worked similarly in adult and pediatric patients. There were no data to inform safety or efficacy in neonates.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3 summarizes the results of Trial 1 Part 2 by age, sex, race, and ethnicity.
Table 3. Efficacy Results by Subgroup, Primary Efficacy Population From Trial 1 Part 2
| Subgroup | SEPHIENCE n |
PLACEBO n |
LS Mean Difference (95% CI)a,b |
|---|---|---|---|
| Age, years | |||
| ≥2 to <6 | 7 | 3 | -512.41 (-725.19, -299.62) |
| ≥6 to <12 | 15 | 11 | -411.12 (-566.22, -256.01) |
| ≥12 to <18 | 12 | 17 | -321.22 (-414.85, -227.59) |
| ≥18 | 15 | 18 | -448.22 (-574.77, -321.67) |
| Sex | |||
| Female | 23 | 27 | -385.22 (-485.86, -284.57) |
| Male | 26 | 22 | -401.74 (-496.57, -306.90) |
| Ethnicity | |||
| Hispanic or Latino | 8 | 11 | -380.39 (-529.37, -231.42) |
| Not Hispanic or Latino | 40 | 38 | -396.9 (-475.5, -318.3) |
Source: Adapted from FDA Review
a Based on mixed model for repeated measures (MMRM) analysis.
b LS mean difference = SEPHIENCE minus Placebo. Negative values favor SEPHIENCE.
Abbreviations: CI, confidence interval; LS, least-squares
What are the possible side effects?
SEPHIENCE may cause serious side effects including increased bleeding or low blood Phe levels. Patients on both SEPHIENCE and levodopa may have an increased risk of seizures, overstimulation, or irritability.
The most common side effects of SEPHIENCE include diarrhea, headache, stomach (abdominal) pain, yellow or orange stool (feces), and throat pain.
What are the possible side effects (results of trials used to assess safety)?
Table 4 summarizes the most common side effects of SEPHIENCE that occurred in Trial 1 Part 2.
Table 4. Adverse Reactions for SEPHIENCE in Adult and Pediatric Patients With PKU That Occurred in at Least 2% of SEPHIENCE-Treated Patients and More Frequently Than Placebo in Trial 1 Part 2
| Adverse Reaction | SEPHIENCE N=56 n (%) |
Placebo N=54 n (%) |
|---|---|---|
| Diarrhea | 4 (7) | 1 (2) |
| Headache | 4 (7) | 1 (2) |
| Abdominal paina | 3 (5) | 1 (2) |
| Hypophenylalaninemia | 2 (4) | 0 |
| Feces discoloration | 2 (4) | 0 |
| Oropharyngeal pain | 2 (4) | 1 (2) |
Source: SEPHIENCE Prescribing Information
a Includes Abdominal pain, Abdominal pain upper, and Abdominal discomfort
Abbreviations: PKU, phenylketonuria
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was higher in females compared to males. Because of limited data, the cause of this difference is not clear. The difference may be due to chance or due to differences in how males and females report side effects.
- Race: The number of patients of races other than White was small; therefore, differences in side effects among races could not be determined.
- Age: The occurrence of side effects was similar in pediatric patients and adult patients except for low blood Phe levels, which was seen in some pediatric patients and in no adult patients. Some pediatric patients had multiple low blood Phe levels.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5 summarizes the incidence of side effects by sex, race, age, and ethnicity in Trial 1 Part 2.
Table 5. Side Effects by Subgroup, Safety Population
| Subgroup | SEPHIENCE N=56 n/Ns (%) |
Placebo N=54 n/Ns (%) |
Risk Difference % (95% CI) |
|---|---|---|---|
| Sex | |||
| Female | 19/26 (73.1) | 10/27 (37.0) | 36.0 (9.1, 58.1) * |
| Male | 14/30 (46.7) | 8/27 (29.6) | 17.0 (‑8.5, 40.3) |
| Age group, years | |||
| ≥2 to <6 | 5/7 (71.4) | 0/3 (0) | 71.4 (0.1, 92.3) * |
| ≥6 to <12 | 9/17 (52.9) | 7/12 (58.3) | ‑5.4 (‑39.3, 30.5) |
| ≥12 to <17 | 5/13 (38.5) | 5/17 (29.4) | 9.0 (‑24.3, 42.0) |
| ≥17 | 14/19 (73.7) | 6/22 (27.3) | 46.4 (15.7, 68.9) * |
| Race | |||
| American Indian or Alaska Native | 2/3 (66.7) | 0/2 (0) | 66.7 (‑29.1, 94.8) |
| Other | 0/1 (0) | 1/3 (33.3) | -33.3 (‑82.7, 66.9) |
| White | 31/52 (59.6) | 17/49 (34.7) | 24.9 (5.4, 42.6) * |
| Ethnicity | |||
| Hispanic or Latino | 5/8 (62.5) | 3/12 (25.0) | 37.5 (‑7.2, 70.4) |
| Not Hispanic or Latino | 28/47 (59.6) | 15/42 (35.7) | 23.9 (3.0, 42.7) * |
| Unknown | 0/1 (0) | 0/0 (NA) | NA |
Source: Adapted from FDA Review
Risk difference (with 95% confidence interval) is shown between total treatment and comparator.
Asterisk (*) indicates that 95% confidence interval excludes zero.
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients with adverse event; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.
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