Summary Basis of Decision for Crysvita
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.
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Crysvita is located below.
Recent Activity for Crysvita
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Crysvita
The following table describes post-authorization activity for Crysvita, a product which contains the medicinal ingredient burosumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02483629 – 10 mg/mL, burosumab, solution, subcutaneous administration
- DIN 02483637 – 20 mg/mL, burosumab, solution, subcutaneous administration
- DIN 02483645 – 30 mg/mL, burosumab, solution, subcutaneous administration
Post-Authorization Activity Table (PAAT)
|Activity/submission type, control number
|Decision and date
|Summary of activities
|NDS # 260747
Submission filed to transfer ownership of the drug product from Kyowa Kirin Limited to Kyowa Kirin, Inc. An NOC was issued.
|SNDS # 249112
Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the treatment of FGF23-related hypophosphatemia in tumour-induced osteomalacia (TIO) associated with tumours that cannot be curatively removed or localized in adult patients. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
|NC # 247429
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of the reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.
|NC # 240660
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
|SNDS # 229313
Submission filed as a Level I – Supplement for a new indication and to add week 64 results from study UX023-CL301 to the PM. The age limit for the indication was lowered from 1 year old to 6 months of age. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
|NC # 222969
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the shelf life specifications for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
|Drug product (DINs 02483629, 02483637, 02483645) market notification
|Date of first sale:2019-01-28
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
|NDS # 216239
NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Crysvita
Date SBD issued: 2019-05-06
The following information relates to the new drug submission for Crysvita.
Drug Identification Number (DIN):
- DIN 02483629 - 10 mg/mL, solution, subcutaneous administration
- DIN 02483637 - 20 mg/mL, solution, subcutaneous administration
- DIN 02483645 - 30 mg/mL, solution, subcutaneous administration
Kyowa Kirin Ltd.
New Drug Submission Control Number: 216239
On December 5, 2018, Health Canada issued a Notice of Compliance to Kyowa Kirin Limited for the drug product Crysvita.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Crysvita is favourable for the treatment of X-linked hypophosphatemia in adult and pediatric patients 1 year of age and older.
1 What was approved?
Crysvita is a fibroblast growth factor 23 inhibitor. It was authorized for the treatment of X-linked hypophosphatemia in adult and pediatric patients 1 year of age and older.
Safety and efficacy for Crysvita in pediatric patients with X-linked hypophosphatemia below the age of 1 have not been established.
Clinical studies with Crysvita did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
The use of Crysvita is contraindicated:
- in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container;
- with oral phosphate and active vitamin D analogues;
- if serum phosphorus is within or above the normal range for age; and
- in patients with severe renal impairment or end-stage renal disease because these conditions are associated with abnormal mineral metabolism.
Crysvita was approved for use under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Crysvita (10 mg/mL, 20 mg/mL, 30 mg/mL, burosumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains D-sorbitol, L-histidine, L-methionine, polysorbate 80, water for injection, and hydrochloric acid (for pH adjustment).
Additional information may be found in the Crysvita Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Crysvita approved?
Health Canada considers that the benefit-risk profile of Crysvita is favourable for the treatment of X-linked hypophosphatemia in adult and pediatric patients 1 year of age and older.
X-linked hypophosphatemia is a rare, genetic, chronically debilitating disorder of phosphate homeostasis that leads to defective bone mineralization and manifests as rickets in children and osteomalacia in adults. The disease incidence is approximately 1 per 20,000 live births. Patients with X-linked hypophosphatemia have elevated levels of fibroblast growth factor 23 (FGF23). Excess FGF23 suppresses proximal renal tubular reabsorption of phosphate, leading to phosphaturia, and inhibits the renal production of 1,25-dihydroxyvitamin D, resulting in decreased intestinal absorption of calcium and phosphate.
At present, treatment of X-linked hypophosphatemia in children involves supplementation of phosphate, usually via multiple daily doses of oral phosphate salts, and vitamin D supplementation with active vitamin D analogs. In adults, primary treatment is usually symptomatic and consists of pain management and orthopedic interventions.
Burosumab, the medicinal ingredient in Crysvita, is a recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that binds to the N-terminal domain of FGF23. This inhibits the biological activity of FGF23, thereby increasing renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxyvitamin D.
Crysvita has been shown to be efficacious in patients with X-linked hypophosphatemia. The market authorization of Crysvita was based on efficacy and safety data derived from two clinical trials conducted in 65 pediatric patients aged 1 to 12 years, and five clinical trials conducted in 176 adult patients. One trial in adult patients had a 24-week double-blind placebo-controlled period, while other trials and extension periods were of open-label design.
In the pediatric patient population, patients received a range of doses of Crysvita and all patients underwent dose titration towards a target range of serum phosphorus. After 40 weeks of treatment, pediatric patients showed significant improvements in radiographic endpoints (as measured by the Rickets Severity Scale and the Radiographic Global Impression of Change Scale scores) and biomarkers (e.g., alkaline phosphatase).
In adult patients given 1 mg/kg Crysvita every 4 weeks, there were significant improvements in the primary endpoint (achieving serum phosphorus above the lower limit of normal) and one of the key secondary endpoints (patient-reported stiffness) as compared to placebo at week 24. Clinically significant differences were observed between the Crysvita and placebo arms in the exploratory endpoints of healing of active fractures and pseudofractures. Interim results from an ongoing histomorphometric trial using assessments of bone biopsies from Crysvita-treated adults with X-linked hypophosphatemia have demonstrated marked improvements in the proportions and distribution of osteoid (i.e., unmineralized bone) tissue. The results reflect a shift towards more normal bone remodelling processes in the adult population.
The safety profile of Crysvita did not raise any serious concerns and was characterized by a very low number of serious or severe adverse events, no discontinuations, and no safety signals among adverse events of special interest (including hyperphosphatemia, ectopic mineralization, hypersensitivity, injection site reactions, and restless leg syndrome) that would necessitate enhanced risk management procedures. The most common adverse drug reactions in both children and adults were injection-site reactions. Appropriate warnings and precautions are included in the Crysvita Product Monograph to address the identified safety concerns.
The primary risk regarding the use of Crysvita in the pediatric population (i.e., patients younger than 18 years of age) is the lack of information about its use in the adolescent population, as no clinical trials in the Crysvita development program enrolled patients aged 13 to 17 years. However, simulations based on the population pharmacokinetic and pharmacokinetic/pharmacodynamic models support the use of the pediatric dose (0.8 mg/kg starting dose every two weeks) as the appropriate dose regimen for adolescents. The adolescent population, aged 13 to 17 years, will have characteristics of both pediatric and adult disease due to the closure of growth plates during that period. Based on the efficacy and safety data submitted for children from 1 to 12 years of age and adult patients as well as other similarities between the two studied populations and the adolescent population, it was deemed reasonable to include the adolescent age range in the target patient population for Crysvita (i.e., patients 1 year of age and older). Limited data in patients who entered the adolescent age bracket during the extension period of the pediatric trial in children aged 5 to 12 years have not indicated any differences in safety profile. In both adults and children, there were limited data on long-term use of Crysvita.
A Risk Management Plan (RMP) for Crysvita was submitted by Kyowa Kirin Limited to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Crysvita Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Crysvita was accepted.
Crysvita has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are included in the Crysvita Product Monograph.
This 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. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Crysvita?
The drug submission for Crysvita was reviewed under the Priority Review Policy. Crysvita demonstrated a significant increase in efficacy with an improved benefit-risk profile compared to existing therapies for X-linked hypophosphatemia, a condition that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Crysvita
|Request for priority status
|Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics:
|Screening Acceptance Letter issued:
|Review of Risk Management Plan complete:
|2018-10-22 - 2018-10-26
|Quality Evaluation complete:
|Labelling Review complete, including Look-alike Sound-alike brand name assessment:
|Clinical/Medical Evaluation complete:
|Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:
The Canadian regulatory decision on the non-clinical and clinical review of Crysvita was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Burosumab, the medicinal ingredient in Crysvita, binds to fibroblast growth factor 23 (FGF23) and inhibits the FGF23 biological activity, thereby increasing renal phosphate reabsorption and the serum concentration of 1,25 dihydroxyvitamin D.
Burosumab pharmacokinetic and pharmacodynamic data were derived from eight clinical trials in X-linked hypophosphatemia patients (six trials were conducted in adult patients and two in pediatric patients). The studies evaluated a dose range of 0.05 to 2.0 mg/kg burosumab administered subcutaneously every two weeks (Q2W) and/or every four weeks (Q4W). Data from seven of these studies were combined to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of burosumab.
Following subcutaneous administration of burosumab, higher burosumab concentrations were found to be associated with greater increases of serum phosphorus levels. The serum phosphorus levels returned to near baseline following systemic elimination of burosumab. Elevation in serum total FGF23 was observed after initiation of burosumab treatment. However, the clinical implication of elevated total FGF23 serum concentrations remains unknown.
Burosumab exhibited linear pharmacokinetics following subcutaneous injections within the dose range of 0.1 to 1.0 mg/kg. Population pharmacokinetic analysis indicated that burosumab clearance and volume of distribution increase when body weight increases. The apparent volume of distribution of burosumab was estimated to be 8 L for a patient of 70 kg of body weight and 3.4 L for a patient of 30 kg of body weight. The apparent clearance was estimated to be 0.29 L/day for a patient weighing 70 kg and 0.136 L/day for a patient weighing 30 kg. The estimated half-life of burosumab is approximately 19 days.
The pharmacokinetic and pharmacodynamic data support a starting dose of 0.8 mg/kg Q2W in pediatric patients and 1 mg/kg Q4W in adult patients. In the absence of clinical trial data in the adolescent population, simulations based on the population pharmacokinetic and pharmacokinetic/pharmacodynamic models support the use of the pediatric dose of burosumab (a starting dose of 0.8 mg/kg Q2W) as the appropriate dose regimen for adolescents.
As with all therapeutic proteins, the use of burosumab is associated with potential for immunogenicity. Due to the limitation of the anti-drug antibody assay, anti-burosumab antibodies could not be effectively evaluated and the effect of these antibodies on the pharmacokinetics, efficacy, and safety of burosumab remains unknown.
The clinical pharmacology data support the use of Crysvita for the recommended indication.
For further details, please refer to the Crysvita Product Monograph, approved by Health Canada and available through the Drug Product Database.
The efficacy of Crysvita was evaluated in pediatric and adult patients with X-linked hypophosphatemia.
Pediatric X-linked Hypophosphatemia
Clinical trials in pediatric patients included one pivotal (UX023-CL201) and one supportive trial (UX023-CL205).
The pivotal trial, UX023-CL201, was a randomized, single-arm, multicentre, open-label, dose-finding Phase II trial in children with X-linked hypophosphatemia aged 5 to 12 years. Fifty-two patients were treated with Crysvita, all of whom remained in the ongoing trial at the time of the study report. The trial began with a range of starting doses (0.1 to 0.6 mg/kg) administered subcutaneously every two weeks (Q2W) and every four weeks (Q4W). Every patient received individualized dose titration towards a target range of fasting serum phosphorus concentration of 3.5 to 5.0 mg/dL (the pediatric reference range for serum phosphorus was 3.2 to 6.1 mg/dL). At optimal dosing, mean dose was approximately 1 mg/kg Q2W (range of 0.4 to 2.0 mg/kg Q2W) and the group mean serum phosphorus level was within the normal pediatric range.
Tools used for radiographic evaluation of rickets were the Rickets Severity Scale (RSS), originally devised as a radiographic quantitative scoring method to assess the severity of nutritional rickets, and a novel Radiographic Global Impression of Change (RGI-C) Scale, a qualitative scoring system specific for X-linked hypophosphatemia and intended to compare rachitic change between two time points. Validation reports for the RSS and RGI-C were provided to Health Canada. The use of these tools was deemed adequate despite some shortcomings (e.g., data demonstrating clinically meaningful difference threshold or lack of fully independent validation).
The primary efficacy endpoint was change from baseline in severity of rickets as measured by the RSS total score. In the primary efficacy analysis conducted at week 40, the RSS mean total score was significantly reduced (i.e., improved) by 50% (1.80 at baseline versus 0.89 at week 40). The RSS mean total score remained decreased from baseline by ≥50% at week 64. Individual components of the RSS total score (wrist and knee scores) were also reduced from baseline at weeks 40 and 64.
A key secondary endpoint was change from baseline at week 40 in the radiographic appearance of rickets and bowing as measured by RGI-C global, knee, wrist, and long leg scores.
The results of the primary and key secondary endpoints (as measured by the RSS and RGI-C scores) were complementary and indicated significant regression of disease, with a greater treatment effect in patients with a higher RSS total score at baseline and in patients on the Q2W dosing regimen. Serum markers of rickets (total and bone-specific alkaline phosphatase [ALP and BALP]), renal phosphate reabsorption (the ratio of tubular maximum reabsorption of phosphate [TmP] to glomerular filtration rate [GFR]), and biomarkers of bone turnover (procollagen type 1, N propeptide [P1NP] and carboxy-terminal cross-linked telopeptide of type I collagen [CTx]) also showed improvements to normal or near-normal ranges.
The supportive trial, UX023-CL205, is a 64-week, single-arm, open-label Phase II trial in 13 infants/toddlers aged 1 to 4 years. The trial report included data to week 40, with all patients continuing treatment at the time of the data cut-off. All patients received a starting dose of Crysvita 0.8 mg/kg Q2W and their dose could be increased to 1.2 mg/kg if improvement in serum phosphorus was insufficient on the lower dose. At week 40, mean serum phosphorus was within the normal age-specific range. There was a significant decrease (i.e., improvement) from baseline in the RSS total score as well as the component RSS wrist and knee scores. All subjects had RGI-C scores (global, knee, and wrist) of ≥ +2 at week 40, indicating substantial healing of rickets when compared to baseline.
Adult X-linked Hypophosphatemia
Clinical trials in adult patients with X-linked hypophosphatemia included one pivotal (UX023-CL303) and one supportive trial (UX023-CL304).
The pivotal trial, UX023-CL303, was a randomized, double-blind, placebo-controlled Phase III trial that assessed 1 mg/kg Crysvita administered every four weeks [Q4W] versus placebo in 134 adult patients with X-linked hypophosphatemia for 24 weeks. The placebo-controlled treatment period was followed by a 24-week open-label period in which all patients received Crysvita at a dose of 1 mg/kg Q4W. Patients whose serum phosphorus was above the adult normal range of 2.5 to 4.5 mg/dL received reduced dose of Crysvita.
The primary efficacy endpoint was the proportion of patients achieving a mean serum phosphorus concentration above the lower limit of normal (2.5 mg/dL) at the midpoint of the dose interval (time of peak pharmacodynamic effect) and averaged across the 24 weeks of double-blind treatment. Over 24 weeks of treatment, 94.1% of Crysvita-treated patients and 7.6% of patients in the placebo group achieved mean serum phosphorus above the lower limit of normal.
There were three key secondary endpoints: change from baseline to week 24 in Brief Pain Inventory (BPI) Question 3 (worst pain in past 24 hours) score; change from baseline to week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness score; and change from baseline to week 24 in the WOMAC Physical Function score. The multiple testing procedure used to control for the family-wise error rate at the 0.05 level found no difference for the BPI Question 3 (worst pain in past 24 hours) score. Numerical but not statistically significant differences between Crysvita and placebo were found for the change from baseline to week 24 in the WOMAC Physical Function score. However, Crysvita was found to be significantly better than placebo in the improvement of the WOMAC Stiffness score.
There were also clinically meaningful exploratory endpoints, which demonstrated improvements in adults treated with Crysvita. At week 24, the proportion of active fractures or pseudofractures that had healed was 43.1% among Crysvita patients compared to 7.7% in placebo patients.
The supportive trial, UX023-CL304, is an ongoing open-label, single-arm Phase III clinical trial that evaluates the effect of Crysvita on osteomalacia in adults with X-linked hypophosphatemia by bone histomorphometry. A bone biopsy of the iliac crest is performed at baseline and week 48 visits to assess histology and histomorphometric parameters used to establish the diagnosis and define the level of osteomalacia. Specifically, the trial evaluates change from baseline to week 48 in osteoid (unmineralized bone) volume/bone volume (as a primary efficacy endpoint), osteoid thickness, osteoid surface/bone surface, and mineralization lag time. Osteoid volume/bone volume (percent of a given volume of bone tissue that consists of osteoid), osteoid thickness, and osteoid surface/bone surface (percent of bone surface covered in osteoid) are used as markers of the amount of unmineralized bone, whereas mineralization lag time is the average time interval between formation of osteoid tissue and the subsequent mineralization.
At the time of the interim report, data at baseline and week 48 were available for 11 patients (out of the 13 patients who were continuing the study). While values obtained at week 48 did not fall within the range of a reference population, improvements were seen in each of the proxy measures. Mean changes from baseline were -57.1% for osteoid volume/bone volume, -32.6% for osteoid thickness, -25.8% for osteoid surface/bone surface, and -73.8% for mineralization lag time.
For more information, refer to the Crysvita Product Monograph, approved by Health Canada and available through the Drug Product Database.
The safety of Crysvita was evaluated in pediatric and adult patients with X-linked hypophosphatemia.
Sixty-five patients aged 1 to 12 years have been exposed to Crysvita for a mean duration of 108 weeks (minimum 40.9, maximum 150.0). The pivotal and supportive clinical trials (UX023-CL201 and UX023-CL205) are described in the Clinical Efficacy section. The safety profile evaluated in the pivotal trial (UX023-CL201) did not raise any serious concerns and was characterized by a very low number of serious or severe adverse events and absence of safety signals among adverse events of special interest (including hyperphosphatemia, ectopic mineralization, hypersensitivity). There were no deaths or discontinuations due to adverse events. The most common drug-related adverse events were injection-site reactions. The most common adverse events were headache (65.4%), cough (53.8%), nasopharyngitis (48.1%), pain in extremity (46.2%), vomiting (42.3%), injection-site reactions (40.4%), upper respiratory tract infection (40.4%), arthralgia (38.5%), injection-site erythema (38.5%), pyrexia (36.5%), and oropharyngeal pain (32.7%). The supportive trial (UX023-CL205) did not report any deaths, discontinuations, or dose reductions. Due to the small number of patients and relatively limited duration of exposure (<1 year), there was considerable variability in data, but no clear safety signals were identified.
There have been 175 adult patients with X-linked hypophosphatemia exposed to Crysvita for a mean duration of 61 weeks (minimum 12, maximum 184). During the 24-week double-blind period of the pivotal trial (UX023-CL303, described in the Clinical Efficacy section), 68 adult patients were treated with Crysvita and 66 received placebo. There were similar proportions of Crysvita and placebo patients that experienced adverse events, serious adverse events, severe adverse events, and adverse events related to treatment. Five Crysvita-treated patients underwent a dose reduction due to serum phosphorus levels above the upper limit of normal. No treatment discontinuations occurred, and all patients were continuing treatment in the open-label trial at the time of the data cut-off. The most common adverse events in the Crysvita arm were back pain (14.7%), nasopharyngitis (13.2%), tooth abscess (13.2%), headache (11.8%), restless leg syndrome (11.8%), nausea (10.3%), and dizziness (10.3%). There were four cases of new or worsening nephrocalcinosis with or without nephrolithiasis at about week 24, but two occurred in patients that had received placebo until that point.
Appropriate warnings and precautions are in place in the approved Crysvita Product Monograph to address the identified safety concerns.
For more information, refer to the Crysvita Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Burosumab, the medicinal ingredient in Crysvita, was shown to bind to human plasma fibroblast growth factor 23 (FGF23) and inhibit the FGF23 activity in vitro.
Pivotal toxicology studies were conducted in normal cynomolgus monkeys. In 40-week repeat-dose toxicity studies in adult and juvenile animals, burosumab administration resulted in dose-dependent increases in serum inorganic phosphorus and 1,25-dihydroxyvitamin D concentrations. The main adverse effects consisted of ectopic mineralization in various soft tissues at exposures lower than the predicted human adult and pediatric exposures. Ectopic mineralization, considered to be the result of elevated serum phosphorus concentrations, was predominantly observed in the kidneys, lungs, eye, sciatic nerve, and heart in adult animals, and in the kidneys in juvenile animals. In adult animals, clinical signs of toxicity as well as secondary adverse effects were observed in long bones, kidneys, and heart.
In an enhanced prenatal and postnatal developmental toxicity study, ectopic mineralization was observed in maternal tissues, including the placenta. No ectopic tissue mineralization in fetuses and infants and no teratogenicity or adverse developmental effects in infants occurred. However, maternal burosumab administration was associated with increased incidences of embryo/fetal losses and preterm births. A no-observed-adverse-effect level (NOAEL) for female reproductive toxicity could not be established as the increased incidence of preterm birth was observed at all doses (at maternal exposures equivalent to or greater than the predicted human exposure). The NOAEL for developmental toxicity corresponded to a maternal exposure sevenfold greater than the predicted human exposure based on the increased incidence of embryo/fetal losses observed at the highest dose. Burosumab was detected in fetal and infant serum indicating transport across the placenta.
Carcinogenicity and genotoxicity studies were not conducted for burosumab.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Crysvita Product Monograph. In view of the intended use of Crysvita, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Crysvita Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
The medicinal ingredient in Crysvita, burosumab, is a recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody against human fibroblast growth factor 23 (FGF23). Burosumab binds to FGF23 and blocks an interaction between soluble FGF23 and FGF23 receptor complex on the cell surface, thereby inhibiting the excessive biological activity of FGF23.
Detailed characterization studies were performed to provide assurance that burosumab consistently exhibits the desired characteristic structure and biological activity.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. Following harvesting, the cell culture supernatant is subjected to a series of purification and virus inactivation and removal steps. The drug substance is filled into plastic bags and stored at -40ºC ± 10ºC.
The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing burosumab of acceptable quality.
The drug product manufacturing process consists of drug substance thaw, formulated buffer preparation, preparation of the drug product formulated bulk, sterile filtration, filling, stoppering, capping, labelling, and packaging. All in-process control results, process parameters, and release testing results were consistent between the validation lots, demonstrating that the drug product manufacturing facility is capable of consistently manufacturing Crysvita of acceptable quality.
Through characterization and release testing, as well as comparative stability studies, the sponsor has demonstrated the comparability of the drug product manufactured for the clinical program to the drug product proposed for marketing.
Crysvita is provided as a sterile, preservative-free solution in a single-use vial. Each vial of Crysvita contains 10 mg, 20 mg, or 30 mg of burosumab in 1 mL solution. The drug product formulation also contains D-sorbitol (45.91 mg), L-histidine (1.55 mg), L-methionine (1.49 mg), polysorbate 80 (0.5 mg), water for injection, and hydrochloric acid (for pH adjustment).
The manufacturing process is considered to be adequately controlled within justified limits.
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 burosumab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation guidelines.
Through Health Canada's lot release testing and evaluation program, three consecutively manufactured lots of Crysvita were tested using a subset of release methods. The results obtained during consistency lot testing and in-house data analyses were acceptable and within the manufacturer's specifications.
As a Schedule D (biologic) drug, Crysvita is subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 36 months for Crysvita, when stored at 2ºC to 8ºC, is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
An on-site evaluation of the facilities involved in the manufacture and testing of the drug substance and drug product was completed by Health Canada with a satisfactory rating.
The site involved in production is compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The burosumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
Raw materials used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.