Leaflet SEPHIENCE 1000mg oral powder in sachet
Indicated for: phenylketonuria
Route of administration: oral
Substance: sepiapterin (enzyme inhibitor)
ATC: A16AX28 (Alimentary tract and metabolism | Other alimentary tract and metabolism products | Various alimentary tract and metabolism products)
Sepiapterin is a medicine used for certain forms of phenylketonuria, a genetic condition in which the body cannot process phenylalanine properly. Phenylalanine is an amino acid found in protein foods; high levels can affect the brain and development. Sepiapterin is a precursor of the BH4 cofactor and may help lower blood phenylalanine levels.
It is taken by mouth as an oral powder once daily with food, at a dose calculated according to age and body weight. It must be used together with a phenylalanine-restricted diet, not as a replacement for diet. Response is checked through repeated blood phenylalanine tests and regular review of protein and phenylalanine intake.
Common side effects include diarrhoea, headache, abdominal pain, throat pain and yellow or orange stool discoloration. Blood phenylalanine can become too low, which may require diet or dose adjustment. Sepiapterin may also increase bleeding risk; tell your doctor about unusual bruising, red or purple skin marks, bleeding that lasts longer than usual or much heavier periods.
Treatment should be supervised by clinicians experienced in phenylketonuria, especially for infants and children, because growth, nutrition and blood levels must be balanced carefully. Tell your doctor about levodopa, blood-pressure medicines and products that may affect blood vessels. Do not change the diet or dose on your own, as high and low phenylalanine levels can be harmful.
General data about SEPHIENCE 1000mg
- Substance: sepiapterin
- Date of latest medicines list: 01-09-2025
- Product code: W71276001
- Concentration: 1000mg
- Pharmaceutical form: oral powder in sachet
- Quantity: 30
- Product type: Original
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for sepiapterin
- 1000mg
- 250mg
Leaflet SEPHIENCE 1000mg
Contents of the package leaflet for the medicine SEPHIENCE 1000mg oral powder in sachet
1. NAME OF THE MEDICINAL PRODUCT
Sephience 250 mg oral powder in sachet
Sephience 1 000 mg oral powder in sachet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Sephience 250 mg oral powder in sachet
Each sachet contains 250 mg of sepiapterin.
Sephience 1 000 mg oral powder in sachet
Each sachet contains 1 000 mg of sepiapterin.
Excipient(s) with known effectSephience 250 mg oral powder in sachet
Each sachet contains 400 mg of isomalt.
Sephience 1 000 mg oral powder in sachet
Each sachet contains 1 600 mg of isomalt.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Oral powder.
Yellow to orange powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Sephience is indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatricpatients with phenylketonuria (PKU).
4.2 Posology and method of administration
Treatment with Sephience must be initiated and supervised by a physician experienced in thetreatment of PKU.
PosologyThe recommended dose (mg/kg/day) of Sephience to be administered orally once daily is based on ageand body weight (see Table 1). The maximum recommended dose is 60 mg/kg/day. The recommendeddose of Sephience in patients ≥ 2 years of age is 60 mg/kg/day. However, the dose may be adjusted toa lower dose if the treating physician considers it necessary or appropriate.
Table 1: Recommended dose based on patient’s age and body weight
Age Recommended dose (mg/kg) of Sephience per day0 to < 6 months 7.5 mg/kg/day6 to < 12 months 15 mg/kg/day12 months to < 2 years 30 mg/kg/day≥ 2 years 60 mg/kg/day
Tables 2 to 5 below provide dosing information by age group for patients weighing 16 kg or less atdifferent doses (7.5, 15, 30, and 60 mg/kg/day).
Table 2: Recommended dose of Sephience oral powder in sachet by body weight in paediatricpatients aged less than 6 months
Dose 7.5 mg/kg/day
Age 0 to < 6 months
Weight Total dose (mg) Number of sachets (250 mg) Volume to be administered(kg) (mL) (25 mg/mL)2 15 1 0.63 22.5 1 0.94 30 1 1.25 37.5 1 1.56 45 1 1.87 52.5 1 2.18 60 1 2.49 67.5 1 2.710 75 1 311 82.5 1 3.312 90 1 3.613 97.5 1 3.914 105 1 4.215 112.5 1 4.516 120 1 4.8
Table 3: Recommended dose of Sephience oral powder in sachet by body weight in paediatricpatients aged 6 months to less than 12 months
Dose 15 mg/kg/day
Age 6 months to < 12 months
Weight Total dose (mg) Number of sachets (250 mg) Volume to be administered(kg) (mL) (25 mg/mL)2 30 1 1.23 45 1 1.84 60 1 2.45 75 1 36 90 1 3.67 105 1 4.28 120 1 4.89 135 1 5.410 150 1 611 165 1 6.612 180 1 7.2
Dose 15 mg/kg/day
Age 6 months to < 12 months
Weight Total dose (mg) Number of sachets (250 mg) Volume to be administered(kg) (mL) (25 mg/mL)13 195 1 7.814 210 1 8.415 225 1 916 240 1 9.6
Table 4: Recommended dose of Sephience oral powder in sachet by body weight in paediatricpatients aged 12 months to less than 2 years
Dose 30 mg/kg/day
Age 12 months to < 2 years
Weight Total dose (mg) Number of sachets (250 mg) Volume to be administered(kg) (mL) (25 mg/mL)2 60 1 2.43 90 1 3.64 120 1 4.85 150 1 66 180 1 7.27 210 1 8.48 240 1 9.69 270 2 10.810 300 2 1211 330 2 13.212 360 2 14.413 390 2 15.614 420 2 16.815 450 2 1816 480 2 19.2
Table 5: Recommended dose of Sephience oral powder in sachet by body weight inpaediatric patients aged 2 years and older
Dose 60 mg/kg/day
Age ≥ 2 years
Weight Total dose (mg) Number of sachets Volume to be administered (mL)(kg) (250 mg) (25 mg/mL)5 300 2 126 360 2 14.47 420 2 16.88 480 2 19.29 540 3 21.610 600 3 2411 660 3 26.412 720 3 28.813 780 4* 31.214 840 4* 33.615 900 4* 3616 960 4* 38.4
* Instead of four 250 mg sachets, one full 1 000 mg sachet can be mixed with 36 mL of water or apple juice.
This mixture should be administered with a syringe, according to the volume to be administered detailed in
Table 5.
Recommended dose of Sephience oral powder in sachet by body weight for patients 2 years and olderand weighing more than 16 kg
The recommended dose is 60 mg/kg/day.
The calculated daily dose should be rounded to the nearest multiple of 250 mg or 1 000 mg, asappropriate. For instance, a calculated dose of 1 251 to 1 374 mg should be rounded down to 1 250 mgcorresponding to 1×250 mg sachet and 1×1 000 mg sachet. A calculated dose of 1 375 to 1 499 mgshould be rounded up to 1 500 mg corresponding to 2×250 mg sachets and 1×1000 mg.
Missed doseA missed dose should be taken as soon as possible. The normal dosing schedule should be resumed thefollowing day.
Discontinuation of treatmentIn the pivotal Phase 3 clinical study, a threshold of 15% or greater reduction in blood phenylalanine(Phe) levels was utilised for determination of response.
No controlled efficacy and safety data are available in patients who do not experience a reduction of15% or greater reduction in blood Phe levels after receiving sepiapterin for 14 days.
The determination of responsiveness for a patient with PKU and the discontinuation of the medicinalproduct is at the discretion of the treating physician.
Special populationsElderly
The safety and efficacy of Sephience in patients 65 years of age and older have not been established.
Caution should be exercised when prescribing in patients 65 years of age and older.
Renal impairmentThe safety and efficacy of Sephience in patients with renal impairment have not yet been established.
No data are available (see section 5.2).
Hepatic impairmentThe safety and efficacy of Sephience in patients with hepatic impairment have not yet beenestablished. No data are available (see section 5.2).
Paediatric populationIn the Phase 3 clinical studies of Sephience, some paediatric patients experiencedhypophenylalaninaemia including some patients with multiple low blood Phe levels (see section 4.8).
Method of administrationOral use.
Sephience should be administered once daily with a meal, using mg/kg dosing.
Sephience oral powder comes in individual sachets of 250 mg or 1 000 mg and should be mixed inwater, apple juice, or a small amount of soft food such as apple sauce and jams.
Sephience is intended for long-term use.
Patients weighing 16 kg or less
Sephience should be mixed with water or apple juice (9 mL for each 250 mg sachet; 36 mL for each1 000 mg sachet), and a portion of this mixture corresponding to a required dose should beadministered orally via an oral dosing syringe. The preparation should be mixed well for at least30 seconds until uniform and free of lumps, before drawing into the dosing syringe. Once mixed, thedose should be administered immediately. If not administered immediately, the liquid mixture can beadministered within 6 hours or 24 hours, when stored at room temperature (below 25 °C) or in arefrigerator (2 °C - 8 °C), respectively. The preparation should be mixed once again for at least30 seconds, before administration. The syringe should be rinsed with additional water or juice (at least15 mL) to remove any residual and swallowed immediately.
Patients weighing more than 16 kg
Sephience should be mixed with water or apple juice (9 mL for each 250 mg sachet; 20 mL for each1 000 mg sachet) or soft foods (2 tablespoons total). The preparation should be mixed well for at least30 seconds with water or apple juice and for at least 60 seconds with soft foods until uniform and freeof lumps. Once mixed, administer the dose immediately. If not administered immediately, the liquidand soft food mixtures can be administered within 6 hours or 24 hours when stored at roomtemperature (below 25 °C) or in a refrigerator (2 °C - 8 °C), respectively. The liquid mixture and softfood mixtures should be mixed once again for at least 30 seconds and 60 seconds, respectively, beforeadministration. The container should be rinsed with additional water or juice (at least 15 mL) toremove any residual and swallowed immediately.
Administration via enteral feeding tube
Sephience oral powder may be administered via an enteral feeding tube 6 Fr or 8 Fr after mixing withwater. The manufacturer’s instructions for the feeding tube should be followed prior to administeringthe medicinal product. For instructions on preparation of Sephience before administration, seesection 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Dietary intake
Patients treated with Sephience should undergo regular clinical assessments to align with their healthcare provider on appropriate dietary Phe intake (such as monitoring of blood Phe and tyrosine levelsand nutritional intake).
Concomitant use with dihydrofolate reductase (DHFR) inhibitors
Co-administration of sepiapterin with DHFR inhibitors (e.g. trimethoprim, methotrexate, pemetrexed,pralatrexate, and trimetrexate) may require more frequent monitoring of blood Phe levels (see section4.5).
Long-term safety data
Long-term safety data in patients with PKU are limited (see section 4.8 for adverse reactions evaluatedto date for sepiapterin).
Excipients with known effectSodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially‘sodium-free’.
Isomalt content
Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Sepiapterin reductase (SR) inhibitors
Orally administered sepiapterin is quickly absorbed and rapidly and extensively converted by SR andcarbonyl reductase to 7,8-dihydrobiopterin (BH2), which is then unidirectionally converted to BH4 by
DHFR. Co-administration of a SR inhibitor is expected to have minimal effect on biotransformation ofsepiapterin due to the compensatory effect of carbonyl reductase. Normal blood Phe levels werereported in patients with SR deficiency. Nevertheless, caution and more frequent monitoring of blood
Phe are recommended when Sephience is co-administered with SR inhibitors, such as sulphasalazineor sulphamethoxazole.
DHFR inhibitors
DHFR mediates the conversion of BH2 to BH4, inhibition of DHFR could potentially result in lower
BH4 concentration. However, the impact on sepiapterin concentration is expected to be minimal dueto the existence of multiple pathways for the elimination. Caution and more frequent monitoring ofblood Phe are required in patients when sepiapterin is co-administered with a DHFR inhibitor, such astrimethoprim, methotrexate, pemetrexed, pralatrexate, and trimetrexate (see section 4.4).
Vasodilatory medicinal products
Caution is recommended during concomitant use of Sephience with medicinal products that causevasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g.glyceryl trinitrate [GTN], isosorbide dinitrate [ISDN], sodium nitroprusside [SNP], and molsidomin),phosphodiesterase type 5 (PDE-5) inhibitors (e.g. sildenafil, vardenafil, or tadalafil), and minoxidil. Inanimal studies, BH4 administered orally in combination with a PDE-5 inhibitor had no effect on bloodpressure.
Levodopa
Caution should be exercised when prescribing Sephience to patients receiving treatment with levodopato monitor neurological disorders such as exacerbation of convulsion, increased excitability andirritability, seizures, and exacerbation of seizures.
4.6 Fertility, pregnancy and lactation
There is a limited amount of data from the use of sepiapterin in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3). There are no adequate and well-controlled studies with sepiapterin in pregnantwomen .
As a precautionary measure, it is preferable to avoid the use of Sephience during pregnancy.
Breast-feedingIt is unknown whether sepiapterin/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Sephience therapy taking into account the benefit of breast-feeding forthe child and the benefit of therapy for the woman.
FertilityNo clinical studies on the effect on human fertility have been conducted for sepiapterin. Animalstudies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Sephience has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
As presented in the table below, the most frequent adverse reactions were: upper respiratory tractinfection (19.8%); headache (15.3%); diarrhoea (14.9%); followed by abdominal pain (12.2%); faecesdiscoloured (4.5%) and hypophenylalaninaemia (2.7%).
Tabulated list of adverse reactionsThe selection of adverse reactions to sepiapterin was based on evidence from clinical trials. Thefrequency of adverse reactions, as presented below in the tabulated list, was calculated based onpooled data from the 2 pivotal clinical studies in patients with PKU (study PTC923-MD-003-PKU andstudy PTC923-MD-004-PKU). These data included 222 patients who were exposed to sepiapterin upto 60 mg/kg/day of which: 15 (6.8%) were < 2 years old, 25 (11.3%) were 2 to < 6 years old,46 (20.7%) were 6 to < 12 years old, 55 (24.8%) were 12 to < 18 years old, and 81 (36.5%) were ≥ 18years old, and the median duration of treatment (in weeks) was 34.286.
Adverse reactions are listed below (Table 6) by MedDRA System Organ Class (SOC). Within each
SOC adverse reactions are presented in order of decreasing frequency. Frequencies are defined asfollows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare(≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (cannot be estimated from availabledata).
Table 6: Adverse reactions
MedDRA Frequency Adverse reactionssystem organ class
Infections and infestations Very common Upper respiratory tract infection
Nervous system disorders Very common Headache
Gastrointestinal disorders Very common Diarrhoea
Abdominal pain*
Common Faeces discoloured
Metabolism and nutrition Common Hypophenylalaninaemiadisorders
* Grouping of 3 MedDRA Preferred Terms: Abdominal pain, Abdominal pain upper, Abdominaldiscomfort.
Paediatric populationOverall, in PKU clinical studies, sepiapterin was well tolerated in paediatric patients. Frequency, type,and severity of adverse reactions in all age groups of paediatric patients were consistent with those inadults. Long-term safety data are limited.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
No specific antidote is available for overdose with Sephience. Treatment of overdose with Sephienceshould consist of supportive medical care including monitoring of vital signs and observation of theclinical status of the patient.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tractand metabolism products, ATC code: A16AX28
Mechanism of actionSepiapterin is a natural precursor of the enzymatic co-factor BH4, a critical co-factor for phenylalaninehydroxylase (PAH). Sepiapterin acts as a dual pharmacological chaperone (sepiapterin and BH4 eachwith its own binding affinity to variant PAH), including PAH variants commonly found in PKU andknown to be insensitive to BH4, to improve the activity of the defective PAH enzyme, achieving ahigh concentration of BH4 intracellularly. By enhancing the conformational stability of misfolded
PAH enzyme and increasing the intracellular concentrations of BH4, sepiapterin is able to effectivelyreduce blood Phe levels.
Clinical efficacy and safetyThe efficacy of sepiapterin was evaluated in four clinical studies in patients with PKU.
Study 1 (PTC923-MD-003-PKU) was a 2-part, global, double-blind, randomised, placebo-controlledclinical study of 157 patients of all ages with PKU.
Part 1 of the study tested for responsiveness to sepiapterin, with 14 days of open-label treatment withsepiapterin followed by a minimum of 14 days of sepiapterin washout. Further, 73.1% (114/156) ofstudy participants demonstrated a ≥ 15% reduction in blood Phe levels in response to sepiapterin. Thedose of sepiapterin in patients ≥ 2 years of age was 60 mg/kg/day.
Subjects were instructed to continue their usual diet without modification.
Patients ≥ 2 years of age who experienced a ≥ 15% reduction in blood Phe levels were classified asresponsive and continued into Part 2 (n=110). After the washout period from Part 1, patients wererandomised equally to either sepiapterin 20 mg/kg/day for Weeks 1 and 2, 40 mg/kg/day for Weeks 3and 4, 60 mg/kg/day for Weeks 5 and 6 (n=56), or placebo (n=54) for 6 weeks. The primary efficacywas assessed by the mean change in blood Phe levels from baseline to Weeks 5 and 6 in thesepiapterin-treated group as compared to the mean change in the placebo group in patients whodemonstrated a ≥ 30% reduction in blood Phe levels during Part 1. In Part 2, demographics were wellbalanced between the 2 treatment arms (Table 7). The median age at the time of informed consent was14 years (range: 2-54), and participants, in terms of race, were predominantly white (91.8%). Morethan half (65.5%) of the 110 participants had PKU diagnosed at birth, and the majority (82.7%) had‘biochemically defined’ non-classical PKU.
Table 7: Demographics and baseline characteristics
Participants in Randomised and treated participants in Overall
Part 1 only Part 2 treated(n=47) Sepiapterin Placebo Overall participants(n=56) (n=54) (n=110) (n=157)
Age (years)n 47 56 54 110 157
Mean (SD) 18.4 (15.07) 16.5 (11.12) 18.4 (10.65) 17.4 17.7 (12.24)(10.88)
Median (min, max) 15.0 (1, 61) 13.0 (2, 47) 15.0 (4, 54) 14.0 (2, 54) 14.0 (1, 61)
Age category, n (%)≥ 1 - < 2 years 3 (6.4) 0 0 0 3 (1.9)≥ 2 - < 6 years 5 (10.6) 7 (12.5) 3 (5.6) 10 (9.1) 15 (9.6)≥ 6 - < 12 years 11 (23.4) 17 (30.4) 12 (22.2) 29 (26.4) 40 (25.5)≥ 12 - < 18 years 10 (21.3) 14 (25.0) 19 (35.2) 33 (30.0) 43 (27.4)≥ 18 years 18 (38.3) 18 (32.1) 20 (37.0) 38 (34.5) 56 (35.7)
SD, standard deviation
The difference between the 2 treatment groups was statistically significant (p < 0.0001) (Table 8).
Table 8: Mean change in blood Phe levels from baseline to Week 5 and Week 6 in Part 2(primary analysis set with Phe reduction from baseline ≥ 30% during Part 1)
Sepiapterin Placebo Difference p value(n=49) (n=49) sepiapterin vsplacebo
Baseline*
Mean (SD) 646.11 654.04 (261.542)(253.007)
Weeks 5 and 6**
Mean (SD) 236.04 637.85 (259.886)(174.942)
Mean change from -410.07 -16.19 (198.642)baseline (μmol/L) (204.442)
Mean percent change -62.8% 1.4%from baseline (%)
LS mean estimate for the mean change from baseline
LS mean (SE) -415.75 -19.88 (24.223) -395.87 (33.848) < 0.0001(24.066)95% CI (-463.52, - (-67.97, 28.21) (-463.07, -328.66)367.97)
CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; Phe, phenylalanine;
SD, standard deviation; SE, standard error
* Baseline is the average of Day -1 and Day 1 blood Phe levels in Part 2.
** Blood Phe concentrations were based on average values during Weeks 5 and 6.
LS means, standard errors, confidence intervals, and p values were from an MMRM with change in blood Phefrom baseline to post-baseline assessments as the response variable, and fixed effects for treatment, baselineblood Phe, baseline Phe stratum, visit, and treatment-by-visit interaction.
Similar responses were observed in the population of patients with classical PKU (cPKU), with a 69%reduction in blood Phe at Week 6 in subjects receiving sepiapterin (n=6) versus an increase of 3%after placebo (n=9).
Study 2 (PKU-002) was a Phase 2, randomised, double-crossover, open-label, active-controlled,proof-of-concept clinical study of sepiapterin in patients with PKU.
The study consisted of 6 sequence groups of 4 patients per group for a total of 24 patients. Eachsequence group was randomised to receive 7-day treatments of sepiapterin 60 mg/kg/day, sepiapterin20 mg/kg/day, and sapropterin dihydrochloride 20 mg/kg/day, in random order followed by a 7-daywashout after each treatment. Preliminary efficacy was assessed by the reduction in blood Pheconcentrations. Results of the primary efficacy weekly mean analysis demonstrated that treatment withsepiapterin resulted in a decrease in blood Phe concentrations relative to baseline that was statisticallysignificant for all treatments (n=24). A greater proportion of patients receiving sepiapterin treatment,regardless of dose, experienced plasma Phe reductions of at least 10%, 20%, and 30% compared withpatients receiving sapropterin 20 mg/kg/day. More patients receiving sepiapterin 60 mg/kg/dayachieved normalised plasma Phe concentrations (< 120 μmol/L) and blood Phe within the target range(≤ 360 μmol/L) compared with sapropterin 20 mg/kg/day. In subjects with cPKU, treatment withsepiapterin (60 mg/kg/day) resulted in a significant decrease in blood Phe concentration relative tobaseline.
Study 3 (PTC923-MD-004-PKU) is an ongoing, Phase 3, multicentre, open-label clinical study toassess the safety and dietary Phe tolerance during long-term treatment with sepiapterin in patients with
PKU. One hundred sixty-nine (169) patients received treatment with sepiapterin 7.5 mg/kg/day inparticipants 0 to < 6 months of age, 15 mg/kg/day in participants 6 to < 12 months of age,30 mg/kg/day in participants 12 months to < 2 years of age, or 60 mg/kg/day in participants ≥ 2 yearsof age. Interim data indicate that daily sepiapterin administration is associated with an approximately2.3-fold increase in mean daily Phe consumption (27.6 mg/kg/day at baseline versus 62.5 mg/kg/dayat Week 26) while maintaining Phe levels < 360 μmol/L. The majority of subjects reached at least a15% (76.7% of participants) or 30% (67.4% of participants) reduction in blood Phe (Figure 1).
Figure 1: Mean (SD) dietary Phe consumption over time during dietary Phe toleranceassessment (dietary Phe tolerance analysis set)
Dietary Phe Consumption cou nt 102 96 97 98 91 92 91 91 94 92 90 87 86 81
Parameters: Dietary Phe consumption (mg/kg/day) RDA
Phe, phenylalanine; PKU, phenylketonuria; RDA, recommended daily allowance; SD, standard deviation;
W, week
Note: Baseline is defined as the average of daily dietary Phe consumption (mg/kg/day) at Month 1. The RDA is0.8 g protein/kg, which is equivalent to approximately 40 mg/kg/day of Phe. Blood Phe levels baseline is themean of the pre-assessment period Week 1-2. 1 g of protein is equivalent to approximately 50 mg of Phe.
Mean (SD)dietary Phe consumption (mg/kg/day)
These data indicate that sepiapterin treatment may allow liberalisation of the highly restrictive diet thatpatients with PKU must adhere to.
Study 4 (PTC923-PKU-301) was a Phase 3, 2-part, open-label, randomised, active-controlledcrossover study of sepiapterin versus sapropterin in participants with PKU aged ≥2 years.
In Part 1 of the study, participants underwent a 14-day open-label treatment with sepiapterin 60mg/kg/day to assess their responsiveness, defined by a ≥20% reduction in blood Phe levels frombaseline. Of 82 participants, 67 (81.7%) were responsive, achieving a mean Phe reduction of415.5 μmol/L (59.1% decrease from baseline). Of these, 62 participants qualified for Part 2, wherethey were randomised into two sequences: sapropterin-sepiapterin (n=30) or sepiapterin-sapropterin(n=32), each treatment separated by a 14-day washout. The primary efficacy endpoint for Part 2 wasthe mean change in blood Phe levels from baseline to Weeks 3 and 4. The primary analysis showed astatistically significant treatment difference favouring 60 mg/kg/day sepiapterin over 20 mg/kg/daysapropterin (p<0.0001) in participants who demonstrated a ≥30% Phe reduction in Part 1. Sepiapterintreatment led to a rapid and sustained decrease in Phe levels. By Day 28 of treatment, the LS meanchange in blood Phe levels from baseline to Weeks 3 and 4 was -437.0 μmol/L with sepiapterin and -256.6 μmol/L with sapropterin, for an LS mean treatment difference of -180.4 μmol/L (p<0.0001). In
BH4-responsive participants, the mean absolute Phe concentration decreased from 775.9 to 323.7µmol/L with sepiapterin, versus 854.1 to 552 µmol/L with sapropterin dihydrochloride (LS meandifference: -214 µmol/L [95% CI: -274.1, -153.9]; p<0.0001). In patients who were receiving BH4 atstudy entry, the mean absolute Phe concentration decreased from 842.6 to 370.9 µmol/L withsepiapterin, versus a decrease from 910.8 to 629.0 µmol/L with sapropterin dihydrochloride (LS meandifference: -248.5 µmol/L [95% CI: -320.5, -176.5]; p<0.0001). Sepiapterin demonstrated astatistically significantly greater reduction in the primary endpoint versus sapropterin in the overallpopulation; enabling a greater proportion of patients to achieve target blood Phe levels.
Subjects with history of allergies or adverse reactions to synthetic BH4 were excluded from theclinical studies.
The European Medicines Agency has deferred the obligation to submit the results of studies with
Sephience in one or more subsets of the paediatric population in HPA (see section 4.2 for informationon paediatric use).
5.2 Pharmacokinetic properties
Following oral administration, sepiapterin is quickly absorbed, and the peak plasma concentrationsoccur in approximately 1 to 3 hours and decline to below the limit of quantitation (0.75 ng/mL) rapidly(generally by 12 hours). Maximum plasma sepiapterin concentration (Cmax) was approximately2.80 ng/mL following the 60 mg/kg/day dose for 7 days with a high-fat high-calorie diet. Noaccumulation of sepiapterin was observed following repeated dosing.
Plasma sepiapterin is metabolised extensively to form the pharmacologically active metabolite BH4.
The apparent terminal half-life for BH4 is approximately 5 hours. Both BH4 Cmax and area under theconcentration-time curve from time zero to 24 hours postdose (AUC0-24h) increased with the dose,while the increase was less than dose proportional when the sepiapterin dose was above 20 mg/kg.
There is no accumulation of BH4 following repeated doses of sepiapterin up to 60 mg/kg for 7 days.
Effect of foodWhen sepiapterin was administered with a low-fat, low-calorie meal in the dose range of 20 to60 mg/kg, BH4 exposures were 1.69- to 1.72-fold higher for Cmax and 1.62- to 1.73-fold higher for
AUC0-24h compared to administration under fasted conditions. When sepiapterin was administered witha high-fat, high-calorie meal, BH4 exposures were 2.21- to 2.26-fold higher for Cmax and 2.51- to2.84-fold higher for AUC0-24h compared to administration under fasted conditions.
Sepiapterin can be taken with any meal at any time of the day at the same time every day.
DistributionBinding of sepiapterin or BH4 to plasma protein is low, and the majority of sepiapterin and BH4 inplasma are free to exert pharmacological effects. In vitro studies show that sepiapterin is bound (mean15.4%) to plasma protein in the presence of 0.1% dithiothreitol in the concentration range of 0.1 to10 μM. BH4 was 41.3% (at 2 μM), 33.0% (at 5 μM), and 24.1% (at 15 μM) bound to protein in humanplasma in the presence of 0.5% β-mercaptoethanol.
In healthy subjects, elevated BH4 concentration was observed in the cerebrospinal fluid followingrepeated sepiapterin oral administration.
BiotransformationSepiapterin is metabolised by SR/carbonyl reductase and DHFR in a 2-step unidirectional process toform BH4. The metabolism of BH4 is presumed to follow the same pathway as endogenous BH4,oxidised while acting as coenzymes for aromatic amino acid hydroxylases, such as PAH, tyrosinehydroxylase, tryptophan hydroxylase, and alkylglycerol monooxygenase, and nitric oxide synthase,and some metabolites, like 4α-hydroxy-tetrahydrobiopterin and quinonoid dihydrobiopterin, could berecycled to regenerate BH4 mediated by pterin-4α-carbinolamine dehydratase and dihydropteridinereductase.
Extensive metabolism of sepiapterin was observed in human following a single oral dose of14C-sepiapterin. The major metabolic pathway involved oxidation/dehydrogenation,reduction/oxidation, oxidative deamination, dehydration, side chain cleavage, and methylation, etc,alone or in combination.
EliminationFollowing oral administration in healthy human participants, sepiapterin was extensively metabolisedwith the metabolites excreted primarily in faeces. Plasma sepiapterin declined rapidly following Cmaxto below the limit of quantitation, generally by 12 hours post-dose. Plasma BH4 declinedmono-exponentially following Cmax. The terminal half-life was approximately 5 hours.
Following a single oral dose of 14C-sepiapterin to adult healthy subjects, a mean of 6.71% dosedradioactivity was recovered in urine and 26.18% in faeces with the combined total recovery of 32.9%by 240 hours. The majority of those radioactivity was recovered within the first 48 hours post-dose(28.2%). The total renal clearance of radioactivity derived from 14C-sepiapterin was 1.54 L/h(25.6 mL/min). Formation of volatile metabolites from sepiapterin in the gastrointestinal tract wasconfirmed in an in vitro study using human intestinal microbiota.
Special populationsAge
PKU patients of all ages had been included in the Phase 3 clinical studies. Except for allometric effecton clearance and volume of distribution, no further age effect was identified in the population PKstudy.
Ethnicity and race
Higher exposures to BH4 were observed for Asian subjects. In the Japanese ethno-bridging study,10% to 24% higher AUC0-last and 14% to 29% higher Cmax of BH4 were observed in Japanesecompared to non-Japanese subjects at sepiapterin dose range of 20 to 60 mg/kg.
Renal impairmentThe PK and safety of sepiapterin have not been studied in patients with renal impairment.
Hepatic impairmentThe PK and safety of sepiapterin have not been studied in patients with hepatic impairment.
Drug interactionsIn vitro studies
In vitro studies indicate that sepiapterin and BH4 are unlikely to be perpetrators of CYP450-mediatedmetabolism.
In vitro, sepiapterin did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or
CYP3A4, or induce CYP1A2, CYP2B6, or CYP3A4.
In vivo studiesIn healthy subjects, co-administration of sepiapterin (20 mg/kg) with a single dose of the breast cancerresistance protein (BCRP) inhibitor curcumin (2 g) increased the exposures of BH4 slightly. Theoverall estimated geometric mean ratios (GMRs) (90% CI) for BH4 Cmax and area under theconcentration-time curve from time zero to time of the last quantifiable measurement (AUC0-last) whensepiapterin was co-administered with curcumin compared to sepiapterin alone were 1.24 (1.15-1.33)and 1.20 (1.13 1.28), respectively. This modest increase is deemed not clinically relevant.
Co-administration of a single dose of sepiapterin at the maximum therapeutic dose of 60 mg/kg withthe BCRP substrate rosuvastatin (10 mg) had no effect on the of rosuvastatin. The overall estimated
GMRs (90% CI) for rosuvastatin Cmax and AUC0-last when rosuvastatin was co-administered withsepiapterin compared to rosuvastatin alone were 1.13 (1.00-1.28) and 1.02 (0.93-1.13), respectively.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
In rats, following repeated oral administration, sepiapterin-related renal tubuledegeneration/regeneration, interstitial inflammation, and fibrosis were noted as a result of crystaldeposition in the papillary collecting tubules. These findings were partially reversible after a 4-weekrecovery period and no kidney toxicity occurred at BH4 exposure levels 2 times the clinical BH4exposure levels at the maximum recommended human dose (MRHD).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose (E460)
Isomalt (E953)
Mannitol (E421)
Croscarmellose sodium (E468)
Xanthan gum (E415)
Silica colloidal anhydrous or colloidal silicon dioxide (E551)
Sucralose (E955)
Magnesium stearate (E470)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
After reconstitutionEach dose should be administered immediately after reconstitution. The reconstituted solution shouldbe discarded if not used within 24 hours when stored in a refrigerator (2 °C - 8 °C) or within 6 hoursbelow 25 °C.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Heat-sealed laminated aluminium foil sachet:
Polyethylene terephthalate, white extruded polyethylene (polyester/foil bond), aluminium foil(moisture barrier), and heat-sealed ionomeric resin (adhesive).
Each carton contains 30 unit-dose sachets.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed in accordance with localrequirements.
Instructions for administration via enteral feeding tube1) Ensure that the enteral feeding tube (size 6 Fr or 8 Fr) is free from obstruction beforeadministration.2) Flush the enteral feeding tube with 10 mL of water.3) Administer the required dose of Sephience oral powder within 30 minutes of mixing (see section4.2).4) Flush the enteral feeding tube with at least 5 mL (6 Fr tube) or 15 mL (8 Fr tube) of water andadminister the flush.
This medicinal product is compatible for use with silicone and polyurethane enteral feeding tube.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.