Summary Basis of Decision for Sephience

Clinical Pharmacology

Phenylketonuria (PKU) is caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene that lead to a deficiency of the hepatic enzyme, PAH, resulting in elevated blood and urine concentrations of phenylalanine and its metabolites, phenylacetate and phenyllactate.

Sepiapterin, the medicinal ingredient in Sephience, is a precursor of the enzymatic co-factor tetrahydrobipterin (BH₄) which activates the PAH enzyme. It is thought that sepiapterin lowers phenylalanine by helping increase the body's level of BH₄, which supports PAH in breaking down phenylalanine.

Pharmacodynamics

Phenylalanine is a pharmacodynamic biomarker of clinical outcomes in the development of treatments for PKU. Blood phenylalanine concentration was a surrogate primary clinical efficacy endpoint in the pivotal, randomized, controlled, Phase III study (Trial 003, described in the Clinical Efficacy section). Data showed that administration of Sephience was associated with a significant reduction in blood phenylalanine concentration.

QT Prolongation

A randomized, partially-blinded, placebo- and positive-controlled, crossover electrocardiogram assessment study was performed in 31 healthy adult subjects. They were administered a single oral dose of sepiapterin 60 mg/kg (therapeutic), sepiapterin 120 mg/kg (two times the maximum recommended dose, supratherapeutic), moxifloxacin 400 mg, and a placebo.

The results of the study demonstrated corrected QT interval (QTc) shortening at the therapeutic 60 mg/kg dose, with a maximum mean difference from placebo of -3.2 ms (90% Confidence Interval [CI]: -5.42, -0.94) at 6 hours post dose. At the supratherapeutic 120 mg/kg/day dose, QTc shortening was also observed with a maximum mean difference from placebo of -2.3 ms (90% CI: -4.50, ‑0.06) at 5 hours post dose. This shortening of the QT interval was not considered to be clinically relevant but is included in the Product Monograph for Sephience for information. There were no reported effects on heart rate, PR interval or QRS duration.

Pharmacokinetics

Following oral administration, sepiapterin is quickly absorbed, and the peak plasma concentrations occur in approximately 1 to 3 hours and decline to below limit of quantitation rapidly, generally by 12 hours. High variability was observed in the plasma concentrations of sepiapterin. No accumulation of sepiapterin was observed following repeated dosing.

Plasma sepiapterin is metabolized extensively to form the pharmacologically active metabolite BH₄ and peak BH₄ concentrations are achieved in approximately 4 hours after oral administration of sepiapterin. The apparent terminal half-life for BH₄ is approximately 5 hours. There is no accumulation of BH₄ following repeated daily doses of sepiapterin up to 60 mg/kg for 7 days. Plasma sepiapterin concentrations and exposures were generally less than 2% of BH₄ maximum concentration (C_max) and area under the concentration-time curve from 0 to 24 hours (AUC_0-24h). The pharmacokinetics (AUC_0-24h and C_max) of BH₄ are lower by 14.1% and 39.6% in PKU patients compared to healthy volunteers at the 60 mg/kg/day dose administered with a low-fat low-calorie diet.

Sepiapterin is converted to BH₄ through a two-step, unidirectional process involving sepiapterin reductase (SR)/carbonyl reductase and dihydrofolate reductase (DHFR). In addition, in humans extensive metabolism of sepiapterin has been observed including the formation of volatile metabolites. Sepiapterin accounted for a minor component in urine (6.7%) but was one of the major components detected in feces (26.1%).

Comparative Bioavailability

A comparative bioavailability study evaluated two sepiapterin formulations in healthy volunteers under low-fat, low-calorie fed conditions as well as the effect of high-fat, high-calorie fed conditions on the absorption of sepiapterin. After oral administration, sepiapterin is detectable in plasma, however, levels are not reliably measurable as sepiapterin is rapidly metabolized to BH₄. As the pharmacokinetics of sepiapterin have not been fully characterized, the bioequivalence assessment was based the active metabolite of sepiapterin, BH₄.

Consumption of a low-fat, low-calorie or a high-fat, high-calorie meal 30 minutes before Sephience administration increased BH₄ exposure by two- to three-fold compared with administration under fasted conditions. Sephience should be administered with food, which is consistent with the administration conditions during the pivotal Phase III clinical study (Trial 003).

Drug-Drug Interactions

In vitro studies indicate that sepiapterin and BH₄ are unlikely to be perpetrators of cytochrome P450 (CYP)-mediated metabolism. Sepiapterin did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or induce CYP1A2, CY2B6, or CYP3A4. In vitro data indicated that sepiapterin is an inhibitor of the transporters organic anion transporting polypeptide 1B1 (OATP1B1) and organic cation transporter 1 and 2 (OCT1 and OCT2), and is a substrate of the transporters equilibrative nucleoside transporter 1 (ENT1), multidrug resistance 1 (MDR1), and multidrug and toxin extrusion protein 2 (MATE2-K), but clinical drug interactions were considered unlikely. Warnings and precautions were added to the Product Monograph for Sephience regarding co-administration with dihydrofolate reductase (DHFR) inhibitors (trimethoprim, methotrexate) due to possible effects on efficacy, as well as for levodopa, due to concerns of exacerbation of convulsions and other neurological effects. Sepiapterin reductase inhibitors (sulfasalazine, sulfamethoxazole), as well as drugs that cause vasodilation, such as nitric oxide donors (glyceryl trinitrate, isosorbide dinitrate) and phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, vardenafil, or tadalafil), were also included in the Drug Interactions section, as a theoretical concern exists based on reduced efficacy and increased risk of hypotension, respectively.

Dosage and Administration

Sephience was originally proposed for dosing by age and weight as follows: 0 to less than 6 months - 7.5 mg/kg/day; 6 months to less than 12 months - 15 mg/kg/day; 12 months to less than 2 years -30 mg/kg/day; and 2 years or older - 60 mg/kg/day. A Notice of Deficiency (NOD) was issued on December 20, 2024 citing major deficiencies that included uncertainty regarding appropriate dose selection and the absence of dosing flexibility, sepiapterin responsiveness as a requirement for use, and the absence of data to support use without dietary restrictions.

The sponsor filed a response to the NOD on March 19, 2025, in response to Health Canada’s concerns. Rationale and new data were submitted that supported the selection of 60 mg/kg/day as the safe and effective recommended dose for patients 2 years of age and older. Dosing was revised for patients less than 2 years of age to allow for an incremental up-titration to 60 mg/kg/day in cases of non-response at the recommended starting dose. This revision was made to ensure adequate drug exposure prior to determining non-response, based on observed and simulated pharmacokinetics data, which supported 60 mg/kg to provide similar exposure across all ages. These revisions were consistent with the United States Prescribing Information, which helped inform the direction with respect to dosing in patients less than 2 years of age. Furthermore, daily dose adjustments within the range of 7.5 to 60 mg/kg for the management of hypophenylalaninemia were added as well as the requirement for patients to be sepiapterin-responsive, given this requirement for the pivotal studies. Finally, the indication was revised to indicate that Sephience is to be used in conjunction with a phenylalanine-restricted diet. All of these changes were captured in the Product Monograph for Sephience.

Overall, the clinical pharmacology data support the use of Sephience for the recommended indication. Based on the clinical pharmacology review, the Product Monograph for Sephience includes information concerning use in special populations, including age (lower exposure in patients less than 2 years of age observed with the recommended starting doses), sex (no effects), race and ethnicity (no clinically relevant effects) with the absence of data in pregnancy, breastfeeding, renal and hepatic impairment specified.

For further details, please refer to the Product Monograph for Sephience, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Sephience was primarily evaluated based on the results of the pivotal studies, Trial 003 and Trial 004, in patients with PKU.

Trial 003 was a Phase III global, randomized, placebo-controlled, double-blind, study conducted in 157 pediatric and adult patients with PKU, most of whom were on a phenylalanine-restricted diet. The median age of enrolled patients was 14 years (range: 1 to 61 years). The study was conducted in two-parts. Part 1 assessed responsiveness to Sephience, with 14 days of open-label treatment with Sephience, followed by a minimum 14-day washout period. Patients who were 2 years of age or older who experienced a 15% or greater reduction in blood phenylalanine levels were classified as responsive and continued to Part 2 of the study. Part 2 assessed the primary efficacy of Sephience over 42 days in the 110 patients who responded in Part 1. In accordance with the study protocol, the two patients younger than 2 years of age who responded to Sephience in Part 1 were enrolled directly in Trial 004.

The majority of patients (65.5%) who participated in Part 2 were less than 18 years of age and were predominantly White (91.8%). Over half of these patients (65.5%) had PKU diagnosed at birth and the majority (82.7%) had biochemically-defined non-classical PKU.

In Part 1, 103 (66%) patients showed a biochemical response to Sephience with a 30% or greater reduction in blood phenylalanine level.

After the washout period, Part 2 was initiated. Patients who responded to Sephience in Part 1 were randomized equally (1:1) to treatment with Sephience (20 mg/kg daily for Weeks 1 and 2, 40 mg/kg daily for Weeks 3 and 4, and 60 mg/kg daily for Weeks 5 and 6; 56 patients), or placebo (54 patients) for 6 weeks.

In Part 2, among patients who had previously demonstrated a 30% or greater reduction in blood phenylalanine levels during Part 1 (the primary efficacy analysis population), the primary endpoint showed a mean reduction in blood phenylalanine levels from baseline to Weeks 5 and 6 of 410.0 µmol/L in patients treated with Sephience (49 patients), compared to a mean reduction of 16.2 µmol/L for patients treated with placebo (49 patients), with a mean difference of -395.9 µmol/L, favouring Sephience, p <0.0001.

Secondary efficacy endpoints supported the primary findings showing statistically significant results in favour of Sephience over placebo, including for the proportion of patients with baseline phenylalanine levels greater than or equal to 360 μmol/L, who achieved levels less than 360 μmol/L (37 of 44 [84%] patients treated with Sephience versus 4 of 43 [9%] patients treated with placebo]; p <0.0001).

Of the 35 patients with classical PKU enrolled in Trial 003, 16 (45.7%) responded to Sephience (30% or greater reduction in baseline blood phenylalanine levels). An exploratory analysis in this subgroup of patients, showed a mean decrease of 69% in blood phenylalanine from baseline to Week 6 in patients taking Sephience (6 patients), compared to a mean increase of 3.5% in patients taking placebo (9 patients).

Trial 004 was a Phase III, multicentre, long-term, open-label, uncontrolled safety and efficacy study in patients who completed Trial 003 (feeder patients) and in patients who had not participated in Trial 003, but who were eligible to enrol based upon response to Sephience determination (non-feeder patients). This study was ongoing at the time of authorization.

Eligible feeder participants originally included patients aged less than 2 years who were Sephience-responsive in Part 1 of Trial 003 and patients 2 years of age or older who completed Part 2 of Trial 003. Eligible non-feeder-controlled patients included those who had not completed a feeder study and who had blood phenylalanine concentrations less than 360 μmol/L at study entry. Eligible non-feeder-uncontrolled patients included those who had not completed a feeder study and who had blood phenylalanine concentrations greater than or equal to 360 μmol/L at study entry.

With the exception of the inclusion of the Sephience-responsive patients less than 2 years from Part 1 of Trial 003, demographics and baseline characteristics were comparable with Trial 003.

A Notice of Deficiency (NOD) was issued on December 20, 2024 citing major deficiencies including insufficient data supporting use in patients less than 2 years of age. A response to the NOD was filed by the sponsor on March 19, 2025, providing new data in response to the concerns outlined in the NOD. Updated data was provided from Trial 004, including data from 15 patients who were less than 2 years of age. In addition, updated pharmacometric modeling results were provided to support exposure predictions in patients as young as 4 months, with published models of BH₄ applied to extrapolate the relative exposure to patients aged 1 month and older.

Interim data was assessed from 169 patients (mean age: 17.1 years; range: 0.2 to 55 years) exposed to Sephience for a mean of 387.5 days (SD = 242.2 days), including 95 (56%) patients exposed for 12 months. These results demonstrated that 65% of patients responded to Sephience (experienced a 30% or greater reduction in blood phenylalanine level from baseline) within the first 2 weeks of treatment, including patients under the age of 2 years (67% responded with a mean reduction from baseline of 127.9 µmol/L [SD = 277.8 µmol/L]; total number [n] = 12). Evidence of long-term efficacy was shown with the mean percentage of patients less than 2 years and greater than or equal to 2 years of age maintaining target blood phenylalanine levels (defined as less than 360 µmol/L) at any given 2-week interval being 84.2% (SD = 19.6) and 74.3% (SD = 24.8), respectively.

While the overall data in patients less than 2 years of age was limited, multiple factors were taken into account to support the approved indication for patients 1 month of age and older. These factors took into account the rare and serious nature of the condition, clinical practice guidelines emphasizing the importance of early treatment to prevent irreversible adverse clinical outcomes, the similarity of underlying disease pathophysiology across age groups, the absence of safety concerns specific to patients under 2 years of age, as well as the characteristics of Sephience, including its mechanism of action and pharmacokinetics shown to be independent of age.

Based on the new data provided, the indication was revised to include patients as young as 1 month of age. Upon review of the submitted data package, Health Canada issued a Notice of Compliance for Sephience. The authorized indication clarified use for sepiapterin-responsive patients with instructions provided for evaluating response during a trial period.

Although selected patients with ‘well-controlled’ blood phenylalanine levels (defined as blood phenylalanine levels less than 360 µmol/L) were able to increase their mean dietary phenylalanine intake from baseline (24.4 mg/kg/day; n = 73) to Week 26 (79.3 mg/kg/day; n = 25) under careful monitoring, the results were not sufficient to support an indication without dietary phenylalanine restriction. This was due to limitations in the data, including the open-label, uncontrolled study design, and poor external validity.

Indication

The New Drug Submission for Sephience was filed by the sponsor with the following proposed indication:

Sephience (sepiapterin) is indicated for the treatment of hyperphenylalaninemia in pediatric and adult patients with phenylketonuria.

To support safe and effective use of the product, Health Canada approved the following indication:

Sephience (sepiapterin for oral suspension) is indicated for the treatment of hyperphenylalaninemia in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria. Sephience is indicated in conjunction with a phenylalanine-restricted diet.

For more information, refer to the Product Monograph for Sephience, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Overall, data from 222 patients with PKU comprised the integrated summary of safety (ISS). The data was provided from the two pivotal studies, Trial 003 and Trial 004 (described in the Clinical Efficacy section). The ISS included 95 patients with at least 1 year of exposure to Sephience. Among Sephience-exposed patients, there were no deaths, three (1.4%) patients had four serious adverse events (SAEs), 164 (73.9%) patients experienced at least one treatment-emergent adverse effect (TEAE), 74 (33%) patients experienced at least one treatment-related TEAE, and four patients (1.9%) discontinued the drug due to an TEAE. The most common TEAEs (occurring in 2% or more of patients and observed more frequently in those treated with Sephience) were: diarrhea, abdominal pain, discoloured feces, headache, upper respiratory tract infection, influenza, oropharyngeal pain, and hypophenylalaninemia. The most frequently reported (occurring in 2% or more of patients) treatment-related TEAEs were: diarrhea, headache, discoloured feces, vomiting, nausea, upper abdominal pain, and fatigue.

The four SAEs reported were acute pancreatitis, peptic ulcer hemorrhage, umbilical hernia, and asthmatic crisis. None were found to be related to the study drug. Treatment-emergent adverse effects that led to drug discontinuation included: vomiting, constipation, hemorrhagic diathesis, poor concentration, flatulence, and headache, with a case of hemorrhagic diathesis being severe. There was one pregnancy in Trial 003, however, the 20-year old female patient discontinued Sephience as soon as the pregnancy was detected, providing limited exposure (2 weeks) data with no reported adverse effects.

There were seven cases of hypophenylalaninemia, including six in children (age range: 0.29 to 10 years). Two cases involved multiple occurrences. Directions to monitor and manage low blood phenylalanine levels were added to the Product Monograph for Sephience to allow for a reduction in dose. In addition, two cases of hemorrhagic diathesis were observed with positive temporal sequence and a positive dechallenge/rechallenge in one case. There were 11 TEAEs that involved increased bleeding, including two cases of hemorrhagic diathesis, three cases of heavy menstrual bleeding, one case of peptic ulcer hemorrhage, two cases of epistaxis, and three cases of hematochezia.

Appropriate warnings and precautions are in place in the approved Product Monograph for Sephience to address the identified safety concerns. In particular, hypophenylaninemia and increased bleeding risk were included in the Warnings and Precautions and Adverse Reactions sections. Other uncertainties were managed by including instructions in the Product Monograph to closely monitor blood phenylalanine levels and dietary phenylalanine intake as well as the inclusion of a statement that long-term safety is limited, especially in pediatric patients. There were no adequate and well-controlled studies with Sephience in pregnancy. Caution should be exercised when prescribing in pregnancy. It is unknown if sepiapterin is excreted in human milk. Caution should be exercised because many drugs can be excreted in human milk. The safety and efficacy of Sephience in patients with hepatic and/or renal impairment have not been established.

For more information, refer to the Product Monograph for Sephience, approved by Health Canada and available through the Drug Product Database.

The non-clinical package included data from pharmacology studies (primary/secondary pharmacology and safety), toxicology studies with toxicokinetic data (genotoxicity, repeated dose/subchronic oral exposure, reproductive and development toxicity, juvenile toxicity, impurities toxicity, and phototoxicity), and pharmacokinetic studies (in vitro assays and single oral administration in animals).

Based on the submitted pharmacology and pharmacokinetic data for sepiapterin, it was not possible to rule out that the pharmacodynamic effect associated with increased PAH enzyme activity was mainly driven by BH₄. Thus, the contributory role of sepiapterin as a pharmacological chaperone relative to BH₄ remains unknown.

The increase in human ether-a-go-go-related gene (hERG) current induced by BH₄ in the in vitro study combined with the corrected QT (QTc) interval shortening reported in the clinical studies suggest that it is likely the metabolite BH₄ that caused the QTc shortening in clinical studies.

Results of repeat-dose toxicity studies in rats showed reversible and non-reversible kidney toxicities that were dose-dependent and possibly relevant to humans. These findings occurred at doses of 100 mg/kg/day or more, corresponding to three-fold the BH₄ human exposure levels (area under the concentration-time curve from 0 to 24 h [AUC_0-24h]) at the maximum recommended human dose (MRHD). In contrast, renal toxicity was not observed in the 13- and 39-week repeat-dose toxicity studies in marmoset monkeys. These adverse effects in the kidneys were not indicative of carcinogenic potential of sepiapterin.

Based on a battery of genotoxicity studies, sepiapterin is not genotoxic at maximum tested limits as per recommendations found in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S2 and Organisation for Economic Co-operation and Development (OECD) Test Guidelines. In a 26-week carcinogenicity study in transgenic mice, sepiapterin did not increase the incidence of tumours at dose levels up to 300 mg/kg/day in males, and up to 1,000 mg/kg/day in females, corresponding respectively to nine- and twelve-fold the BH₄ human exposure (AUC_0-24h) levels at the MRHD. Following review of the integrative Weight of Evidence assessment, it was determined that sepiapterin is unlikely to be carcinogenic in humans. A two-year rat carcinogenicity study was not considered to provide additional value for carcinogenicity risk assessment.

A Notice of Deficiency (NOD) was issued on December 20, 2024 citing major deficiencies including the absence of a carcinogenicity study. The sponsor filed a response to the NOD on March 19, 2025, providing new data in response to Health Canada’s concerns outlined in the NOD. A new carcinogenicity study in transgenic mice provided data that showed no evidence of carcinogenic effects. Upon review of the submitted data package, Health Canada issued a Notice of Compliance for Sephience on October 7, 2025.

Studies in rats and rabbits did not identify a safety signal for reproductive or developmental toxicity associated with sepiapterin. There were no maternal or embryo-fetal developmental toxicities at doses up to 1,000 mg/kg/day in pregnant rats and rabbits, corresponding respectively to seven- and four-fold the BH₄ human exposure levels (AUC_0-24h) at the MRHD.

In a 10-week juvenile toxicity study, no sepiapterin-related adverse effects were observed at the no-observed-adverse-effect level (NOAEL), where animals received 30 mg/kg/day from postnatal day (PND) 4 to PND 28 and 300 mg/kg/day from PND 29 to PND 70, corresponding to approximately three-fold the BH₄ human exposure levels (AUC_0-24h) at the MRHD.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Sephience. In view of the intended use of Sephience, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Sephience, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Sephience has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the formulation of Sephience are of human or animal origin nor are they prohibited for use in drug products by the Food and Drug Regulations.