Summary Basis of Decision for Kuvan ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
KuvanTM
Sapropterin dihydrochloride, 100 mg, Tablet, Oral
BioMarin Pharmaceutical Inc.
Submission control no: 128151
Date issued: 2010-08-12
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02350580
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On April 30, 2010, Health Canada issued a Notice of Compliance to BioMarin Pharmaceutical Inc. for the drug product, Kuvan.
Kuvan contains the medicinal ingredient sapropterin dihydrochloride which is an enzyme activator.
Kuvan is indicated in conjunction with a phenylalanine (Phe)-restricted diet to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4)-responsive phenylketonuria (PKU).
Kuvan is a synthetic formulation of BH4, the co-factor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the oxidative metabolism of Phe, and decrease Phe levels in some patients.
The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical studies that were submitted demonstrated evidence of clinical efficacy and safety for the use of Kuvan in patients with PKU. Blood Phe levels were significantly reduced in the groups of PKU patients that were treated with Kuvan, and the safety data presented showed that the drug was generally well-tolerated.
Kuvan (100 mg, sapropterin dihydrochloride) is presented in tablet form. The recommended starting dose of Kuvan is 10 mg/kg/day. Response to therapy is determined by the change in blood Phe levels following treatment with Kuvan at 10 mg/kg/day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of Kuvan treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg/day, the dose may be increased weekly to a maximum of 20 mg/kg/day, with frequent monitoring of blood Phe levels over a one month period. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day are considered non-responders, and treatment with Kuvan should be discontinued in these patients. Once responsiveness to Kuvan has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. Doses of Kuvan above 20 mg/kg/day have not been evaluated in the clinical studies. Dosing guidelines are available in the Product Monograph.
Kuvan is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, or to any component of the container. Kuvan should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Kuvan are described in the Product Monograph.
Priority Review status was granted for the evaluation of Kuvan as it appeared to provide an effective treatment for a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Kuvan is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Sapropterin dihydrochloride, the medicinal ingredient of Kuvan, is an enzyme activator. In patients with PKU, the activity of the PAH enzyme is absent or deficient resulting in increased levels of Phe in the blood. Sapropterin dihydrochloride has been shown to increase the activity of endogenous PAH, leading to the partial restoration of oxidative metabolism of Phe, which results in decreased blood Phe levels in PKU patients.
Manufacturing Process and Process Controls
Sapropterin dihydrochloride is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of Sapropterin dihydrochloride has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from batch analysis, and therefore are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of Sapropterin dihydrochloride are considered acceptable.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated, long-term, and stress testing show that Sapropterin dihydrochloride is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Kuvan (sapropterin dihydrochloride) tablets are round, off-white to light yellow, mottled, and debossed with "177'. Each tablet contains 100 mg of sapropterin dihydrochloride and the following non-medicinal ingredients: ascorbic acid, crospovidone, dibasic calcium phosphate, D-mannitol, riboflavin, and sodium stearyl fumarate.
Kuvan is supplied in high-density polyethylene bottles, sealed with aluminized film, and closed with child-resistant caps. Each bottle contains 120 tablets, a silica gel desiccant cartridge, and a pharmaceutical-grade polyester coil.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of sapropterin dihydrochloride with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is adequately controlled within justified limits.
Control of Drug Product
Kuvan is tested to verify that its identity, appearance, content uniformity, assay, dissolution, disintegration, friability, loss on drying, ascorbic acid content, levels of degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
Validation results of the analytical method used for the determination of sapropterin dihydrochloride and the drug-related impurities are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life of 36 months is considered acceptable when the tablets are packaged in their approved commercial packaging and stored at a controlled room temperature (15-30°C).
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Kuvan are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Kuvan has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Sapropterin dihydrochloride is the hydrochloride salt of R-tetrahydrobiopterin (6R-BH4), which is a coenzyme of PAH, tyrosine hydroxylase, and tryptophan hydroxylase, and contributes to the biosynthesis of monoamine neurotransmitters [for example (e.g.) dopamine, norepinephrine, serotonin (5-HT)]. 6R-BH4 is the naturally occurring pteridine and is only biochemically active in the enantiomeric R form.
As there are no adequate animal models of PKU with residual PAH activity, the primary pharmacodynamic evaluations investigated the role of sapropterin on dopamine-related enzyme systems in normal animals and in various chemically-induced animal models of monoamine depletion. Results suggest that sapropterin may act by inducing the release of dopamine. The results of the in vitro studies indicated that the chemically synthesized sapropterin exhibited bioactivity equivalent to the endogenous cofactor 6R-BH4.
Animal safety pharmacology studies provided adequate evidence that sapropterin and its metabolites did not produce significant effects on the central and autonomic nervous systems, respiratory and cardiovascular systems, and gastrointestinal system. High doses of sapropterin produced emesis in dogs. This finding could be expected to occur in humans.
3.2.2 Pharmacokinetics
Sapropterin dihydrochloride is a synthetic formulation of 6R-BH4, and it cannot be distinguished from endogenous 6R-BH4 in vivo. When 6R-BH4 is used in vivo as a cofactor, it is converted to quinoid dihydrobiopterin (R-q-DHBP) and is metabolized to dihydrobiopterin (DHBP) and biopterin (BP). R-q-DHBP and DHBP are reduced by pteridine reductase and folate reductase to 6R-BH4, which is recycled. Therefore, to understand the pharmacokinetics (PKs) of sapropterin, it is important to not only observe the unchanged 6R-BH4, but also the fluctuation of these four biopterins.
Absorption
Sapropterin is absorbed mainly by the small intestine, including the duodenum. The time to maximum plasma concentration (Tmax) ranged from 1-3 hours after oral administration in mice, rats, and monkeys. The half-lives were 1.2, 1.1, and 1.4 hours in mice, rats, and monkeys, respectively. Bioavailability was 7-12% in rats and approximately 9% in monkeys.
Sapropterin did not accumulate in rats following repeat-dose administration of 100 mg/kg/day for 14 days. The absorption and elimination kinetics were relatively unchanged with repeated oral administration.
Distribution
Studies revealed that sapropterin was distributed mainly to the kidney and liver. Pregnant rats showed no significant increases in sapropterin concentration in the placenta and foetus compared to the endogenous levels found in this species. Although sapropterin concentrations were increased in the mammary glands of rat dams, no increases were observed in the milk at the dose of 10 mg/kg.
Plasma protein binding studies in rats (in vivo) and in humans (in vitro) revealed no significant binding of total biopterins to plasma proteins.
Metabolism
Studies in rat liver microsomes demonstrated that sapropterin does not activate the cytochrome P450 metabolic pathway. Instead, the enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of sapropterin.
Based on scientific literature, the rat and human catabolic pathways are similar. Tetrahydrobiopterin [6R-BH4 (presumed unchanged drug)], dihydrobiopterin, biopterin, pterin, and 6-hydroxylumazine were the urinary metabolites detected following intravenous administration of 10 mg/kg sapropterin to rats.
Excretion
Following oral administration of radiolabelled sapropterin in rats, approximately 7% of the administered radioactivity was excreted in urine and approximately 75% was excreted in the faeces, within 72 hours.
3.2.3 Toxicology
Single-Dose Toxicity
Acute single-dose toxicity studies were performed in mice, rats, and marmosets. There were no specific clinical signs or necropsy findings. Based on the median lethal dose (LD50) values, sapropterin administered orally demonstrated relatively low acute toxicity in the species tested. The data indicates a large safety margin over the proposed clinical dose of 20 mg/kg/day.
Repeat-Dose Toxicity
Although the repeat-dose general toxicity studies were conducted in accordance with Good Laboratory Practices and indicated negative findings, their major shortcoming was that the dose selection was arbitrary and the high dose did not achieve the maximum tolerated dose. The high dose, 400 mg/kg/day in rats, was also the no-observed-adverse-effect-level (NOAEL) in the subchronic studies.
In toxicity studies, it is generally expected that the selected doses produce some toxicity in the test animals in order to be useful as a predictive tool for the drug effects in humans. While the sponsor claimed that the high dose was about 20% of the acute LD50 dose, based on body surface area (an accepted way of expressing exposure) the high dose was approximately 3-times the human maximum recommended dose of 20 mg/kg.
The only toxicity finding was in the 52-week repeated-dose oral toxicity study in rats. There were some histopathologic changes, consisting of an increase in the incidence of basophilic changes in the collecting tubules of the kidneys in some male and female rats in the 400 mg/kg/day dose group. The kidney alterations were mild, and no associated changes were observed in the urinalysis and blood biochemistry parameters; therefore, the toxicological significance was believed to be low. The NOAEL was considered to be 40 mg/kg/day in this study.
A similar shortcoming, in the selection of treatment doses, was noted in the toxicity studies conducted with marmosets. In this species, the high dose did not produce any significant toxicity. The high dose (320 mg/kg/day) is estimated to be 4-times the human recommended does of 20 mg/kg, based on body surface area.
Genotoxicity/Mutagenicity
The in vitro genotoxicity assays, bacterial gene mutation and chromosomal aberration in mammalian cells, provided evidence that sapropterin has mutagenic activity. The mutagenic activity in the Ames test was considered to be weak, as only the high dose (5 mg/plate) was positive.
The chromosomal aberration assay in Chinese hamster lung cells, as well as in the Chinese hamster ovary cells, was considered to be positive, as significant increases in the incidence of chromosome aberrations on 24-hour exposure or 48-hour exposure at various concentrations of sapropterin were observed. However, in a third chromosomal aberration assay conducted with human peripheral lymphocytes, sapropterin did not show any positive responses.
Based on the results of the above in vitro assays, it is concluded that sapropterin has in vitro mutagenic activity.
However, the two in vivo assays (a single and a repeated dose) conducted in mice to evaluate the ability of sapropterin to induce micronuclei formation in the bone marrow resulted in negative findings. Induction of micronuclei in bone marrow erythrocytes is considered to be an in vivo chromosomal aberration assay. Results of the in vivo assays are considered to be more important than the in vitro results as they are more relevant for evaluating the genotoxic risk for humans.
Therefore, based on the weak positive findings in the in vitro assays and the negative findings in the in vivo assays, sapropterin is considered to have low potential for genotoxic activity in patients treated with sapropterin at the recommended doses.
Carcinogenicity
Although there was no evidence of carcinogenic activity in mice treated daily with oral doses of sapropterin up to 250 mg/kg/day for 78 weeks, the study duration (78 weeks) was considered inadequate to determine the carcinogenic potential in a carcinogenicity study; 104 weeks of treatment is considered an adequate duration.
In a 2-year rat carcinogenicity study, the male rats in the 250 mg/kg/day dose group had a higher incidence of benign pheochromocytomas of the adrenal medulla compared to the vehicle control group. This is a common finding in the strain of rat used in this study (Fisher 344 rats).
In summary, because there was only a slight increase in the incidence of benign tumours in male rats (pheochromocytomas of the adrenal medulla) and no evidence of increased incidence of tumours in female rats, it is concluded that sapropterin has a low or negligible carcinogenic potential in humans.
Reproductive and Developmental Toxicity
In reproductive toxicology studies, including embryo-foetal development through the organogenesis period, and pre-and peri-natal effects on the maternal and first filial (F1) generations, sapropterin had no effect on fertility or implantation in rats, and no significant effects on gross external, soft, and skeletal tissues in rat and rabbit foetuses. However, rabbits treated at the highest dose level (600 mg/kg/day) exhibited non-significant increases in some external malformations, skeletal abnormalities, and skeletal variations, when compared to vehicle-treated control rabbits.
Based on the reproductive studies, it is concluded that sapropterin does not impair fertility of male or female rats, and it has no teratogenic potential in rats and rabbits.
3.2.4 Conclusion
The pharmacological activity of sapropterin as an enzyme activator has been demonstrated in the non-clinical studies. The results suggest that sapropterin has equivalent bioactivity to the endogenous cofactor, 6R-BH4.
The non-clinical toxicology studies conducted in mice, rats, rabbits, and marmosets indicate that sapropterin has little potential to cause adverse effects in humans. Thus, these studies support the long-term administration of sapropterin in the proposed clinical population.
Overall, the non-clinical review supports the clinical use of sapropterin for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The data from the clinical development program for Kuvan (sapropterin dihydrochloride) demonstrated that the use of Kuvan in the dose range from 5 to 20 mg/kg/day significantly lowered blood Phe levels in patients with PKU.
Two substudies evaluated the ability of single, daily doses of Kuvan to reduce Phe levels over a 24-hour period. The results confirmed that a daily morning dose of 10 mg/kg/day resulted in a stable reduction of blood Phe levels over a 24-hour period.
3.3.2 Pharmacokinetics
Absorption
Following oral doses of 5, 10, and 20 mg/kg/day, sapropterin dihydrochloride was rapidly absorbed after a short lag time. After reaching peak plasma concentrations, measurable levels of sapropterin declined in a bi-exponential fashion. The PKs of sapropterin dihydrochloride can be described by a two-compartment, first-order input model with first-order elimination.
Half-life values using the final PK model produced alpha half-life values that ranged from approximately 0.578 to 2.94 hours. In the terminal elimination phase, the mean half-life was approximately 6.69 hours (range: 3.91 to 16.6 hours). Given that it takes approximately four half-lives to achieve clearance, coverage would be estimated to last 26.8 hours, on average, following dosing, which supports once-daily dosing.
Sapropterin absorption and bioavailability were substantially greater when taken after a meal. Two bioavailability studies have indicated that administration of sapropterin after a meal provides an increase in bioavailability of 30-80% in healthy subjects.
Distribution
After repeated, oral doses of 5, 10, and 20 mg/kg/day, results showed that there was little accumulation with daily doses, even at the highest dose regimen.
Protein binding in human plasma was relatively low. The data indicates a low potential for sapropterin to alter plasma protein function or displace other agents from plasma proteins.
Metabolism and Excretion
The biotransformation and excretion of sapropterin were characterized in the non-clinical studies. Scientific literature has shown that the rat and human catabolic pathways are similar.
3.3.3 Clinical Efficacy
The clinical efficacy and safety of Kuvan were primarily evaluated in four clinical studies; two pivotal controlled studies (PKU-003 and PKU-006), and two open-label studies (PKU-001 and PKU-004). Patients who responded to Kuvan in study PKU-001 participated in study PKU-003. Patients who completed study PKU-003 were offered participation in study PKU-004.
In PKU-001, 489 patients (8-48 years of age) with PKU whose blood Phe levels were ≥ 450 µmol/L at screening and who were not following a strict Phe-restricted diet were exposed to a 10 mg/kg/day oral dose of Kuvan for 8 days. Response to Kuvan treatment was defined as a ≥ 30% decrease in blood Phe levels from baseline. At Day 8, 96 (20%) of the patients with Day 1 and Day 8 results responded to Kuvan with a reduction in blood Phe levels of ≥ 30%. Patients in the stratum with a baseline blood Phe < 600 µmol/L had a higher response rate (54%) than those with baseline Phe levels ≥ 600 µmol/L (15%). However, it is notable that a number of patients with high baseline blood Phe levels also met the criteria as a Kuvan responder.
In the pivotal efficacy study PKU-003, 88 patients who met the criteria for responsiveness in PKU-001 received placebo [number (n)=47] or Kuvan 10 mg/kg/day (n=41) for 6 weeks. Kuvan treatment resulted in a mean (± standard error [SE]) decrease in blood Phe of - 245 ± 52.5 µmol/L compared to placebo treatment; this difference was highly statistically significant (p<0.001). The blood Phe decrease was evident at the earliest time point assessed (Week 1) and persisted throughout the treatment period. However, in this study where patients were not following a Phe-restricted diet, the mean blood Phe level in the Kuvan group by the end of the study (Week 6) was 607 ± 377 m mol/L, a level which was slightly above the upper recommended levels (600 µmol/L) for this patient population's age group (8-49 years of age). Patients who completed PKU-003 had the option of participating in study PKU-004.
In study PKU-004 Part 1, 80 patients who had participated in PKU-003 and who were not following a Phe-restricted diet received 3 consecutive 2-week courses of Kuvan at 5 mg/kg/day, followed by 20 mg/kg/day, followed by 10 mg/kg/day. Blood Phe levels were monitored after 2 weeks of treatment at each dose level. The mean [± Standard Deviation (SD)] blood Phe levels at the end of Part 1 were 744 (± 384) µmol/L, 640 (± 382) µmol/L, and 581 (± 399) µmol/L for the patients who received 5, 20, and 10 mg/kg/day, respectively. A direct relationship was observed with the dose of Kuvan, in terms of mean blood Phe level, change in blood Phe level, and the percentage of patients with a ≥ 30% reduction in blood Phe levels from Week 0.
In Part 2 of PKU-004, the patients were assigned a fixed dose of Kuvan for 12 weeks based on their response to the three doses given in Part 1. Of the 80 patients in Part 2, 6 (8%) received 5 mg/kg/day, 37 (46%) received 10 mg/kg/day, and 37 (46%) received 20 mg/kg/day. The mean (± SD) blood Phe levels at Week 22 for the 5, 10, and 20 mg/kg/day doses were 438 (± 106) µmol/L, 450 (±32) µmol/L, and 896 (± 68) µmol/L, respectively. The mean changes (± SD) in blood Phe levels from baseline to Week 22 for the 5, 10, and 20 mg/kg/day doses were -172 (± 391) µmol/L, -176 (± 259) µmol/L and -209 (± 437) µmol/L, respectively. During Part 2, the majority of patients attained similar mean blood Phe levels as they had achieved on the same dose in Part 1 and maintained these levels through to Week 22. Similar to study PKU-003, the mean blood Phe level in the Kuvan group by the end of the study (652.2 ± 382.5 µmol/L at Week 22) was still higher than the upper recommended levels for this age group (600 µmol/L). This highlights the fact that Kuvan should be used as an adjunct therapy to a Phe-restricted diet in order to control blood Phe levels within the recommended levels in patients with BH4-responsive PKU.
The second pivotal efficacy study was PKU-0 06. This was a dietary Phe tolerance study that enrolled 90 children (ages 4 to 12 years old) with PKU that were on Phe-restricted diets and that had blood Phe levels ≤ 480 µmol/L at screening. In Part 1 of this study, all patients were treated with open-label Kuvan 20 mg/kg/day for 8 days. Response to Kuvan was defined as a ≥ 30% decrease in blood Phe levels from baseline at Day 8, and a blood Phe level ≤ 300 µmol/L. At Day 8, 50 patients (56%) were considered responders to Kuvan. In Part 2 of this study, 45 of these responders were then randomized 3:1 to receive treatment with Kuvan 20 mg/kg/day (n=33) or placebo (n=12) for ten weeks. Measuring the change in blood Phe levels from Week 0 to Week 3 demonstrated that after 3 weeks of treatment, blood Phe levels were significantly reduced in the Kuvan group with a mean ± SD decrease from baseline in blood Phe level of 148 ± 134.2 µmol/L (p<0.001).
The results of the primary efficacy endpoint for Part 2 of study PKU-006 (Week 10 Dietary Phe Supplement Tolerance in the Kuvan versus the Placebo Group) demonstrated that the mean Phe supplement tolerated by patients treated with Kuvan at Week 10 was 20.9 ± 15.4 mg/kg/day, which was significantly larger (p<0.001) than the pretreatment value of zero when no Phe supplementation was prescribed. When the Kuvan group was compared with the Placebo group, the difference in the adjusted means in Phe supplement tolerated between the two treatment groups (17.7 ± 4.5 mg/kg/day) was statistically significant (p<0.001). Although this study demonstrated that daily dosing with 20 mg/kg of Kuvan led to statistically significant improvements in Phe tolerance while maintaining blood Phe control, the duration of Part 2 of this study is considered too short to draw any clinically significant conclusions regarding the increased tolerance for Phe in children (aged 4-12 years) on a Phe-restricted diet. Nonetheless, the importance of testing these children for response to Kuvan and the continued decreased levels of their blood Phe (within the recommended levels for their age group) in Parts 1 and 2 of study PKU-006, as well as in the ongoing safety study PKU-008, makes the use of Kuvan acceptable for these children to control their blood Phe levels in conjunction with a Phe-restricted diet.
The durability of Kuvan's effect in reducing blood Phe levels to within the recommended range in patients with PKU was seen for up to 18 months in a safety study (PKU-008) in which blood Phe was not measured as an efficacy endpoint but rather as a part of the safety evaluation of extended Kuvan treatment. A total of 111 patients (71 from study PKU-004 and 40 from study PKU-006 Part 2, with dietary Phe intake not specified or recorded) had their mean ± SD blood Phe concentration decrease from 614.2 ± 333.3 µmol/L at baseline to 504.6 ± 316.3 µmol/L at Month 3. These values remained at levels between 485.3 ± 308.8 µmol/L and 529.5 ± 32.1 µmol/L at subsequent visits through Month 18.
Collectively, the efficacy data presented in this submission support the use of Kuvan in conjunction with a Phe-restricted diet to reduce blood Phe levels in patients with HPA due to BH4-responsive PKU. Despite these findings, there is insufficient clinical evidence from the presented efficacy data to support the use of Kuvan to increase Phe tolerance in patients with HPA due to PKU, or to reduce blood Phe levels in patients with HPA due to BH4 deficiency.
3.3.4 Clinical Safety
The key safety data for this drug submission were provided from studies PKU-001, PKU-003, PKU-004, and PKU-006. Long-term safety data were also provided from the ongoing safety study PKU-008 which enrolled 111 patients who had participated in studies PKU-004 or Part 2 of PKU-006.
In these clinical studies (both controlled and uncontrolled), a total of 579 PKU patients were administered Kuvan in doses ranging from 5 to 20 mg/kg/day for a duration of 1 to 30 weeks. Patients were 4 to 49 years of age. The patient population was nearly evenly distributed in gender, and approximately 95% of patients were Caucasian.
Kuvan was generally well-tolerated in patients with HPA due to PKU. A total of 310 (54%) of the Kuvan-treated patients reported at least one adverse event (AE). The most commonly reported AEs (in ≥ 4% of the Kuvan-treated patients) were: headache (13%), diarrhoea (6%), abdominal pain (6%), upper respiratory tract infection (5%), pharyngolaryngeal pain (5%), vomiting (4%), and nausea (4%).
A total of 5 patients (1%) reported the following serious adverse events (SAEs): appendicitis, urinary tract infection, gastroesophageal reflux disease, spinal cord injury, tibia fracture, streptococcal infection, and testicular carcinoma. Mild to moderate neutropenia was noted during Kuvan administration in 24 of 579 patients (4%). Four patients reported SAEs in study PKU-008 (3 unrelated and 1 possibly related case of gastroesophageal reflux disease). Two patients withdrew from the study due to an AE (difficulty concentrating, and intermittent diarrhoea).
In the two double-blind, placebo-controlled trials (PKU-003 and PKU-006), 74 patients were treated with Kuvan at doses of 10 to 20 mg/kg/day for 6 to 10 weeks while 59 patients were treated with placebo. The overall incidence of AEs in patients receiving Kuvan (64%) was similar to that reported for patients receiving placebo (71%).
The most frequently reported treatment-emergent AEs that occurred in more than one patient (≥ 2%) treated with Kuvan versus (vs.) placebo in the double-blind, placebo-controlled clinical studies were headache (14.9% vs. 13.6%, respectively), respiratory tract infection (12.2% vs. 23.7%, respectively), rhinorrhoea (10.8% vs. 0.0%, respectively), pharyngolaryngeal pain (9.5% vs. 1.7%, respectively), diarrhoea (8.1% vs. 5.1%, respectively), vomiting (8.1% vs. 6.8%, respectively), pyrexia (6.8 % vs. 6.8% respectively), cough (6.8% vs. 5.1%, respectively), abdominal pain (5.4% vs. 8.5% respectively), contusion (5.4% vs. 1.7%, respectively), rash (5.4% vs. 6.8%, respectively), nasal congestion (4.1% vs. 0%, respectively), fatigue, streptococcal infection, and back pain (2.7% vs. 5.1%, respectively), tooth ache and urinary tract infection (2.7% vs. 0%, respectively).
In the open-label, uncontrolled clinical trials (PKU-001, PKU-004) in which all patients received Kuvan in doses of 5 to 20 mg/kg/day, AEs were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials.
Clinically significant chemistry results and clinically significant changes from screening were infrequent in all of the completed studies in patients with PKU. Kuvan treatment was associated with transient clinically significant elevations in alanine aminotransferase (ALT). Clinically significant results or clinically significant changes from screening for other liver function tests [aspartate amonotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin] were also transient and were less frequent. No clinically relevant or abnormal mean changes in chemistry results were reported during the studies (over 18 months in study PKU-008).
In Japan , another formulation containing the same active ingredient (sapropterin) was evaluated in a 10-year post-approval safety surveillance program with 30 patients, 27 of whom had disorders other than PKU and had an underlying neurologic condition. The most common AEs were convulsions and exacerbation of convulsions in 3 of the non-PKU patients, and increased GGT in 2 of the non-PKU patients.
The following spontaneously reported AEs were identified during the post-approval use of Kuvan and are possibly related to Kuvan treatment: eyelid oedema, retching, oedema peripheral, hypersensitivity, cough, dyspnoea, oesophageal disorder, oropharyneal pain, throat tightness, urticaria, and pallor.
Overall, safety data from the submitted clinical studies in PKU patients demonstrated that Kuvan was well-tolerated in patients aged 4 to 49 years.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Kuvan was granted p riority review status as it appeared to provide an effective treatment for a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada. There is no approved medical therapy for the treatment of patients with PKU. The only available option is a highly restrictive, low-Phe diet starting in infancy. Kuvan, used as an adjunct therapy to a Phe-restricted diet, may provide a significant clinical benefit in the treatment of PKU by reducing severe dietary restrictions while maintaining acceptable blood Phe control.
Not all patients with PKU respond to treatment with Kuvan. In the clinical studies, approximately 20 to 56% of PKU patients responded to treatment with Kuvan. Response to treatment cannot be pre-determined by laboratory testing (e.g. genetic testing), and should only be determined by a therapeutic trial of Kuvan. P atients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet. The initiation of Kuvan therapy does not eliminate the need for appropriate monitoring by trained professionals to assure that blood Phe control is maintained in the context of ongoing dietary management.
Safety data from the submitted clinical studies in PKU patients demonstrated that Kuvan administered in the dose range from 5 to 20 mg/kg/day was well-tolerated in patients aged 4 to 49 years. No major safety signals were detected. No deaths were reported for any patient and SAEs were infrequent. In the placebo-controlled trials, the overall incidence of AEs reported was similar in the Kuvan and placebo-treated groups. Long-term exposure to Kuvan in PKU patients (18 months) revealed the same safety profile and AEs were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical studies.
Overall, the benefit-to-risk ratio supports the use of Kuvan (sapropterin dihydrochloride) 100 mg oral tablets in doses ranging from 5 to 20 mg/kg/day (the recommended starting dose of Kuvan is 10 mg/kg/day daily) in conjunction with a Phe-restricted diet to reduce blood Phe levels in patients with HPA due to BH4-responsive PKU. Restrictions to manage risks associated with safety concerns have been incorporated into the Kuvan Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Kuvan in conjunction with a Phe-restricted diet is favourable to reduce blood Phe levels in patients with HPA due to BH4-responsive PKU. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: KuvanTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-08-04 |
| Request for priority status | |
| Filed: | 2009-05-06 |
| Approval issued by Director, Bureau of Metabolism, Oncology and Reproductive Sciences: | 2009-06-30 |
| Submission filed: | 2009-07-30 |
| Screening | |
| Screening Deficiency Notice issued: | 2009-08-28 |
| Response filed: | 2009-10-08 |
| Screening Acceptance Letter issued: | 2009-11-02 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| KUVAN | 02350580 | BIOMARIN INTERNATIONAL LIMITED | SAPROPTERIN DIHYDROCHLORIDE 100 MG |