Summary Basis of Decision for Crysvita

Clinical Pharmacology

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.

Clinical Efficacy

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.

Clinical Safety

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.