Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia

Abstract

Context

Burosumab was developed as a treatment option for patients with the rare, lifelong, chronically debilitating, genetic bone disease X-linked hypophosphatemia (XLH).

Objective

Collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab.

Methods

UX023-CL203 (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. The long-term UX023-CL203 study (January 5, 2015 through November 30, 2018) provided data up to 184 weeks. Participants in UX023-CL203 received burosumab based on the last dose in the prior KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12, burosumab could be titrated upward/downward to achieve fasting serum phosphate levels within the normal range. Primary objectives included long-term safety, the proportion of subjects achieving fasting serum phosphate in the normal range, changes in bone turnover markers, patient-reported outcomes for pain and stiffness, and measures of mobility.

Results

Fasting serum phosphate levels at the midpoint of the dosing interval (2 weeks postdose, the time of peak effect) were within the normal range in 85% to 100% of subjects. Measures of phosphate metabolism and bone biomarkers generally improved with burosumab therapy, approaching or reaching their respective normal ranges by study end. Improvements in patient-reported outcomes and mobility were sustained throughout the observation period. No new safety findings emerged with longer-term burosumab treatment.

Conclusion

These data support the conclusion that burosumab therapy may be a safe and effective long-term treatment option for adult patients with XLH.

X-linked hypophosphatemia (XLH) is a rare, lifelong, chronically debilitating, genetic bone disease characterized biochemically by reduced renal phosphate reabsorption, causing hypophosphatemia driven by overproduction of fibroblast growth factor 23 (FGF23) (1). In addition, elevated FGF23 leads to diminished circulating levels of 1,25 dihydroxyvitamin D (1,25(OH)₂D) stemming from both decreased synthesis and increased catabolism (1); these metabolic derangements result in deficient bone and growth plate mineralization presenting as lower-extremity bowing, rickets, and osteomalacia. Other features of the disorder include fractures and pseudo-fractures, dental abscesses, hearing loss, fatigue, and weakness among other manifestations (2).

Previously, XLH management sought to address FGF23-mediated deficiencies of 1,25(OH)₂D and phosphate through administration of activated vitamin D metabolites and oral phosphate salts (1). More recently, burosumab has been developed as a treatment option for patients with XLH (3). Burosumab is a recombinant human IgG1 monoclonal antibody to FGF23 (2, 3). At the time the present study was initiated, clinical experience with burosumab in adult subjects with XLH included a Phase 1/2 single-dose study (KRN23-US-02; NCT00830674), a Phase 1/2 repeat-dosing study (KRN23-INT-001; NCT02312687), and an associated long-term Phase 1/2 extension study (KRN23-INT-002; NCT01571596) (2, 4).

Data from these earlier clinical trials suggested that burosumab administered every 4 weeks as a subcutaneous injection of 0.3–1.0 mg/kg increased serum phosphate into the low–normal range (3, 4). Subjects reported improvement in pain and stiffness with treatment (5). After the initial repeated dose studies ended, subjects discontinued burosumab per protocol.

Here, we report the results of an open-label extension study which enrolled adults with XLH who previously participated in studies KRN23-INT-001 or KRN23-INT-002 to collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab, providing data up to 15.3 months.

Materials and Methods

The UX023-CL203 study (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. Subjects who discontinued from KRN23-INT-001 or KRN23-INT-002 due to a treatment-emergent adverse event (TEAE) classified as possibly or probably related to treatment were eligible for participation in this study based on the judgment of the investigator and with agreement from the sponsor. The present study began on January 5, 2015, and concluded on November 30, 2018.

The present study was designed, conducted, recorded, and reported in accordance with the principles established by the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Patients. Institutional review boards at each site approved the protocols. Investigators obtained written informed consent from each participant. Principal investigators and the sponsors, Ultragenyx Pharmaceutical Inc. and Kyowa Kirin Co., Ltd. designed the study. The sponsors and investigators collected, analyzed, and interpreted the data. Authors vouch for the completeness and accuracy of the data. The present article was written by the authors with medical writing support from the sponsors. All authors had access to the data and agreed to publish the manuscript.

Eligibility Criteria

Adult subjects ≥18 years of age with a diagnosis of XLH (confirmed by demonstration of a PHEX variant of clinical significance identified either in the participant or in a direct family member consistent with X-linked transmission to the subject, or a serum intact FGF23 ≥30 pg/mL using the Kainos assay) who received at least 2 doses of burosumab in the KRN23-INT-001 or KRN23-INT-002 studies with an estimated glomerular filtration rate (GFR) ≥60 mL/minute at screening (or 45–<60 mL/min at screening with confirmation that renal insufficiency was not due to nephrocalcinosis) were eligible. Of note, inclusion criteria for the KRN23-INT-001 and KRN23-INT-002 studies were a corrected serum calcium level <10.8 mg/dL, a renal maximum reabsorption rate of phosphate (TmP)/GFR <2.0 mg/dL, an intact FGF23 level >30 pg/mL, and an estimated GFR of ≥60 mL/min at screening.

In order to provide long-term safety follow-up of burosumab treatment, this study aimed to include as many patients from the prior KRN23-INT-001 or KRN23-INT-002 studies as possible, including those for whom TEAEs were reported. However, patients were excluded from the present study if they experienced a safety-related event in either of the prior studies such that the investigator or sponsor believed it unsafe to resume treatment, or during screening for the present study had hypercalcemia, or severe nephrocalcinosis on ultrasound that the investigator felt precluded the resumption of treatment with burosumab.

Treatment Schedule

Prior to screening for this study, participants discontinued burosumab for at least 21 months and had undergone a 21-day washout from oral phosphate and active vitamin D therapy. Initial burosumab dosing for each individual was based on the participant's last dose in either KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12 of the present study, dose levels of participants who had not achieved serum phosphate levels above the lower limit of normal (2.5 mg/dL), based on fasting trough levels, could be titrated upward every 4 weeks to a maximum dose of 1.0 mg/kg, or downward if exceeding the upper limit of normal (4.5 mg/dL) (6). The planned treatment duration was up to 184 weeks (+5 days) to assess long-term safety, immunogenicity, pharmacodynamic response, and clinical efficacy of burosumab.

Study Outcomes

The primary safety objective of this study was to assess the long-term safety of subcutaneous administration of burosumab in adult subjects with XLH by the occurrence of TEAEs. Nephrocalcinosis was evaluated by renal ultrasound at screening and every 6 months thereafter. Echocardiogram was performed at baseline and every 6 months thereafter.

Primary efficacy objectives were to determine the proportion of subjects achieving fasting serum phosphate in the normal range (2.5-4.5 mg/dL) (6) with long-term administration of burosumab, and the long-term response to burosumab as measured by changes in fasting serum 1,25(OH)₂D, intact parathyroid hormone (iPTH), and calcium, the TmP/GFR ratio, 24-hour urine calcium excretion, and bone biomarkers including serum alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), and procollagen type 1 N-terminal propeptide (P1NP). Blood chemistry analyses were performed by ACM Global Central Laboratory (Rochester, NY) or Quest Diagnostics, Inc. (San Juan Capistrano, CA) (1,25(OH)₂D and BALP) 4 weeks after a dose, immediately before next dose, at the time of expected trough effect. In addition, the long-term immunogenicity of burosumab, as measured by presence of antiburosumab antibodies, as detected by electrochemiluminescent assay (BioAgilytix Labs; Durham, NC), was assessed.

Secondary clinical response objectives included evaluation of pain, physical function, physical and mental health, mobility, and fractures. To this end, patient-reported outcome instruments were used including the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), Bone Pain Inventory-Short Form (BPI-SF), and 36-Item Short Form Survey (SF36) v2.

Provided normative ranges represent the aggregate population including the smallest available lower limit and greatest available upper limit of normal. A more detailed breakdown by age and sex is provided elsewhere (Supplementary Table 1 (7)).

Statistical Methods

Statistical tests were 2-sided at an alpha = .05 significance level, with 2-sided 95% CI. All P values were nominal, and no adjustments for multiplicity were made. Continuous variables were summarized with means, SD, SE, medians, quartiles, minimums, and maximums. Categorical variables were summarized by counts and by percentages of subjects in corresponding categories.

No imputations for estimation of missing data were made. Change from baseline over time and binary endpoints over time were analyzed using a generalized estimating equation model that included time as the categorical variable adjusted for baseline measurement. The covariance structure used for the generalized estimating equation model was compound symmetry, which specified constant variance for the assessments and constant covariance between the assessments over time; all measurements were included in the model.

Binary variables were summarized at each time point and 95% CI for the estimated proportions were obtained using the Wilson score method. P values for testing statistical significance of change from baseline were provided for primary PD endpoints, select safety endpoints (eg, estimated GFR, creatinine, amylase), and select exploratory efficacy endpoints. Prespecified subgroup analyses and post-hoc analyses were conducted for select exploratory efficacy endpoints.

This end of study analysis was conducted when all enrolled subjects had completed the end of treatment visit and the safety follow-up telephone call or had discontinued study.

Results

Baseline Demographics

A total of 20 subjects were enrolled in UX023-CL203; all 20 had participated in the KRN-INT-001 study, 17 of whom also participated in the KRN-INT-002 study. Six subjects (30%) were male and 14 (70%) were female (Table 1). Mean (SD) age was 49.8 (12.9) years and most (95%) were White. Mean (SD) time since XLH diagnosis was 40.7 (16.2) years. Mean (SD) time since first XLH signs or symptoms was 47.9 (13.5) years. Baseline laboratory parameters are reported after discontinuing burosumab for at least 21 months with a 21-day washout from oral phosphate and active vitamin D therapy prior to screening, representing an untreated state, and are shown in Table 1.

Table 1.

Baseline demographics and clinical characteristics

Parameter	n = 20
Age, mean (SD)	49.8 (12.9)
Sex, n (%)
Female	14 (70%)
Race, n (%)
White	19 (95%)
Black or African American	1 (5%)
Ethnicity, n (%)
Not Hispanic or Latino	19 (95%)
Hispanic or Latino	1 (5%)
Height (cm), mean (SD)	147.8 (10.6)
Weight (kg), mean (SD)	78.9 (22.7)
Laboratory parameters, mean (SE)
Serum phosphate (mg/dL)	1.9 (0.1)
Serum calcium (mg/dL)	9.1 (0.1)
Serum 1,25(OH)2D (pg/mL)	32 (3)
Serum iPTH (pg/mL)	111 (10)
TmP/GFR (mg/dL)	1.6 (0.1)

Abbreviations: iPTH, intact parathyroid hormone; TmP/GFR, tubular maximum reabsorption of phosphate to glomerular filtration rate ratio.

At baseline, patients reported XLH-related medical histories included short stature (95%), bowing of lower legs (95%), abnormal gait (85%), and dental abscess (85%), among others. Most subjects (85%) had previously been treated with phosphate supplements and/or an active vitamin D metabolite. Complete findings are included in Table 2. Within the prior year, all subjects reported joint stiffness/limited range of motion, and a minimum of 21 months had passed since the last dose of burosumab in studies KRN-INT-001/KRN-INT-002 and the first dose of burosumab in this study.

Table 2.

XLH-related medical histories

Parameter	n = 20
Time since XLH diagnosis (years), mean (SD)	40.7 (16.2)
Time since first XLH symptoms (years), mean (SD)	47.9 (13.5)
Diagnosed with, n (%)
Short stature	19 (95%)
Bowing of lower legs	19 (95%)
Abnormal gait	17 (85%)
Dental abscesses	17 (85%)
Calcium deposits on bone	17 (85%)
Osteoarthritis	15 (75%)
Excessive cavities	14 (70%)
Bowing of upper leg	14 (70%)
Enthesopathy	12 (60%)
Widened wrists	8 (40%)
Kidney stones	7 (35%)
In-toeing	7 (35%)
Hearing loss	7 (35%)
Knock-knees	5 (25%)
Bowing of forearms	5 (25%)
Nephrocalcinosis	4 (20%)
Impaired renal function	4 (20%)
Delayed walking (first walked ≥15 months)	4 (20%)
Ribcage abnormalities	2 (10%)
Cranial synostosis	2 (10%)
Chiari malformation	2 (10%)
Other	1 (5%)
XLH symptoms in the last year, n (%)
Joint stiffness/limited range of motion	20 (100%)
Muscle pain	16 (80%)
Muscle weakness	14 (70%)
Tingling in arms/legs	12 (60%)
Tinnitus (ringing in ears)	9 (45%)
Other	5 (25%)

Abbreviation: XLH, X-linked hypophosphatemia.

At the start of this study, mean (SE) burosumab dose was 0.7 (0.1) mg/kg. Dose levels were individually titrated throughout the study based on serum phosphate, safety, and tolerability, with a mean (SE) peak dose of 0.8 (0.1) mg/kg at Week 76. Of note, 1 participant remained at a 0.3 mg/kg dose for the duration of the study with overall positive outcomes. The mean duration of burosumab exposure in the present extension study was 38.4 months, and 90% of subjects received between 37 and 45 monthly burosumab doses.

Serum Phosphate

The mean (SE) serum phosphate concentration at baseline of 1.9 (0.1) mg/dL (range 1.3-2.6 mg/dL) was below the normal range (2.5-4.5 mg/dL) (6), and it increased following the first dose of burosumab, remaining above baseline at all subsequent assessments (Fig. 1). Mean increases from the baseline serum phosphate were assessed (4 weeks after a dose; immediately before next dose, the time of trough effect) at Weeks 24, 48, 72, 96, 120, 144, and 168, and End of Treatment Visit and were statistically significant (P < .0001) at all time points examined. Across the various time points of the study, trough phosphate levels were within the normal range in 45% to 74% of subjects. Phosphate values measured at the midpoint of the dosing interval (2 weeks after a dose, the time of peak effect), were within the normal range in most subjects (85-100%).

Figure 1.

Mean (SE) serum phosphate increased from baseline to within the normal range following burosumab initiation and remained above baseline values for all subsequent assessments. Statistical analysis examined change from baseline using trough values from Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (***P < .0001). Closed markers represent expected peaks of burosumab activity 2 weeks after the previous dose. Open markers represent expected troughs of burosumab activity 4 weeks after the previous dose and immediately prior to dosing. Gray shading indicates normal range (2.5-4.5 mg/dL).

TmP/GFR

Mean fasting TmP/GFR measured at trough was greater than baseline throughout the course of burosumab treatment, indicative of increased renal phosphate reabsorption; however, levels remained below the lower limit of normal (normal range 2.5-4.2 mg/dL; (8, 9)) (Fig. 2) (10).

Figure 2.

Mean (SE) TmP/GFR measured at trough visits was increased from baseline throughout the study. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (***P < .0001). Normal range (2.5-4.2 mg/dL). GFR, glomerular filtration rate; TmP, tubular maximum reabsorption of phosphate.

Serum 1,25(OH)₂D

Mean (trough) serum 1,25(OH)₂D concentration increased from baseline as expected at Weeks 12 and 24 with burosumab treatment, reaching statistical significance at Week 24 before returning to near-baseline levels at Week 36. Levels remained near baseline, but within the normal range (18-72 pg/mL), throughout the rest of the study (Fig. 3).

Figure 3.

Mean (SE) serum 1,25(OH)₂D concentration increased from baseline and then returned to near-baseline levels. Levels remained within the normal range for the duration. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (*P < .05). Gray shading indicates normal range (18-72 pg/dL).

Serum iPTH

Mean (SE) serum iPTH concentration was 111 (10) pg/mL at baseline (normal range 14-72 pg/mL) (6) and decreased steadily throughout the study, with least squares mean change from baseline (−19 pg/mL) achieving significance at Week 72. At Week 168, mean (SE) serum iPTH concentration remained above the upper limit of normal at 74 (11) pg/mL (Fig. 4).

Figure 4.

Mean (SE) serum iPTH concentration decreased steadily from baseline with burosumab treatment, nearing the upper limit of normal at Week 168. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (*P < .05; ***P < .0001). Gray shading indicates normal range (14-72 pg/dL). iPTH, intact parathyroid hormone.

Serum Calcium

Mean (SE) serum calcium was 9.1 (0.1) mg/dL at baseline (normal range 8.6-10.2 mg/dL). Levels increased significantly from baseline at Week 24, with a mean (SE) change of 0.2 (0.1) mg/dL, before gradually declining over the remainder of the study; however, levels were within the normal range at all assessments (Fig. 5).

Figure 5.

Mean (SE) serum calcium increased from baseline with burosumab before gradually declining over the remainder of the study. Statistical analysis examined change from baseline using trough values at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (*P < .05; **P < .001). Closed markers represent expected peaks of burosumab activity 2 weeks after the previous dose. Open markers represent expected troughs of burosumab activity 4 weeks after the previous dose and immediately prior to dosing. Gray shading indicates normal range (8.6-10.2 mg/dL).

24-Hour Urinary Calcium

Mean (SE) 24-hour urinary calcium was 96.2 (18.4) mg/24 hour at baseline, measuring just below the lower limit of normal (normal range 100–250 mg/24 hour). Over the course of the study, levels measured at the end of each dosing cycle, increased to within the normal range where they fluctuated slightly, but always remained within or just below the normal range (Fig. 6). At Week 168, mean (SE) urinary calcium measured 97.1 (16.6) mg/24 hour.

Figure 6.

Mean (SE) 24-hour urinary calcium concentration was just below the lower limit of normal at baseline. With burosumab treatment, levels measured at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing at Weeks 12, 24, 36, 48, 72, 96, 120, 144, 168) reached the normal range where they fluctuated between normal and just below normal through Week 168. Gray shading indicates normal range (100-250 mg/24 hour).

Bone Biomarkers

Biomarkers of bone turnover demonstrated initial increases by 20 to 24 weeks of therapy and subsequent declines to baseline levels or lower (Fig. 7A-7D).

Figure 7.

Mean (SE) bone biomarker levels increased from baseline following treatment initiation before declining to baseline levels or lower. P1NP (A) reached peak levels at Week 24 before declining to within the normal range. CTx (B) levels increased significantly from baseline at Week 24 but were not significantly different at any other time point. Total ALP (C) and BALP (D) increased slightly from baseline at Weeks 20 to 24 before declining to within their respective normal ranges. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (*P < .05; **P < .001; ***P < .0001). Gray shading indicates normal ranges.

Mean baseline serum P1NP (a marker of bone formation) was normal at baseline (20–110 µg/L). Levels increased with treatment to a maximum value at Week 24. Although mean values subsequently declined, at Week 96 P1NP levels remained significantly above the baseline. Similarly, the mean serum CTx level (a marker of bone resorption) was significantly higher than baseline at Week 24 of burosumab treatment (Fig. 7A and 7B) but declined more rapidly toward baseline than P1NP. Mean CTx significantly differed from the baseline value only at Week 24. Total ALP and BALP levels increased initially, also peaking at Weeks 20 to 24, and then declined with significant decreases from baseline at Week 72 through Week 168 and at the end of treatment visit (Fig. 7C and 7D). For both ALP and BALP, mean values had normalized by Week 72 and remained within the normal range throughout the remainder of the study.

Patient-reported Outcomes

Patient-reported outcome assessments of pain, stiffness, and physical functioning demonstrated impairment at baseline, which generally improved with burosumab therapy (Fig 8A and 8C).

Figure 8.

Patient-reported outcome measures showed impairment at baseline with improvements following initiation of burosumab therapy. BPI-SF (A) decreased (improved) from baseline, reaching significance at Week 24. A BPI-SF score of 0 indicates no pain, with greater scores indicating increased pain. WOMAC scores (B) improved from baseline following burosumab initiation; improvements were generally maintained through Week 72. A WOMAC score of 0 equates to best possible health, with greater scores indicating worsening. SF-35 v2 scores (C) showed significant improvements in physical health by Week 24, while the mental health score remained stable for the duration of the study. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, and 144 from baseline (*P < .05; **P < .001; ***P < .0001). Gray shading indicates normal range (50 ± 10). BPI-SF, Bone Pain Inventory-Short Form; SF36, 36-Item Short Form Survey; WOMAC, Western Ontario and McMaster Universities osteoarthritis index.

Scores for Pain Severity, Worst Pain, and Pain Interference by BPI-SF decreased (improved) from baseline after initiation of burosumab treatment, reaching significance by Week 24 assessment, where they remained for the duration of the study (Fig. 8A).

Additional subgroup analysis compared those patients with severe pain at baseline (Worst Pain score >6 or ≤6). Nine subjects (45%) had a BPI-SF Worst Pain scores of >6 at baseline (ie, severe pain) and 11 subjects (55%) had Worst Pain scores of ≤6 at baseline (ie, mild to moderate pain). In both subgroups, scores decreased from baseline for all 3 components of the BPI-SF through Week 144 of burosumab treatment (data not shown).

Decreases from baseline in Worst Pain and Pain Severity scores were greater at each timepoint in the subgroup with severe pain at baseline compared with the subgroup with mild to moderate pain at baseline. The majority of subjects in both subgroups reported a decrease from baseline of ≥30% for Worst Pain at any time point, including 7 subjects (78%) with Worst Pain scores of >6 at baseline and 9 subjects (82%) with Worst Pain scores of ≤6 at baseline.

Mean WOMAC scores improved from baseline following burosumab initiation across Pain, Stiffness, and Physical Function domains. Improvements were generally maintained through Week 72 (Fig. 8B).

The SF-35 v2 health survey was used to assess the mental and physical impacts of burosumab therapy on patients with XLH (Fig. 8C). Mean Physical Component Score showed a significant increase (improvement) from baseline at Week 24, which persisted throughout the remainder of the study. The mean Mental Component Score was stable from baseline throughout the study.

Mobility

Gait disturbance and impaired mobility are common in adults with XLH. Exploratory efficacy endpoints for mobility were evaluated using the 6-minute walk test and the timed up and go (TUG) test. Subjects demonstrated substantial impairment at baseline, with a mean (SE) 322.4 (31.4) meters walked (normal range 400-700 m) (11). With treatment, subjects achieved significant, sustained increases from baseline in distance walked during the 6-minute walk test, reaching a mean (SE) 366.0 (26.1) meters at Week 72 (P = .0103). Similarly, subjects had impaired mean (SE) TUG test score at baseline of 12.8 (1.3) seconds (normal range 8.6-9.9 seconds) (12). Throughout treatment, TUG test scores steadily improved from baseline (Fig. 9), reaching the normal range (12) with a mean (SE) 9.9 (0.8) seconds by Week 72 (P < .0001).

Figure 9.

Mean (SE) TUG test improved steadily from baseline with burosumab therapy, reaching the upper limit of normal by Week 72. Statistical analysis examined change from baseline at expected troughs of burosumab activity (4 weeks after the previous dose and immediately prior to dosing) at Weeks 24, 48, 72, 96, 120, 144, and 168 from baseline (*P < .05; **P < 0.001; ***P < .0001). Gray shading indicates normal range (8.6-9.9 seconds). TUG, timed up and go.

Safety

The safety profile of burosumab was similar to that observed in the prior studies in adults with XLH, with no new safety findings emerging during longer-term observation (2, 4). Investigators considered 51 adverse events in 12 (60%) subjects to be related to burosumab treatment. Treatment-related TEAEs that were reported for more than 2 (10%) subjects are summarized in Table 3.

Table 3.

Summary of related TEAEs

TEAE, n (%)	n = 20
Total	12 (60)
Injection site reaction	4 (20)
Injection site erythema	3 (15)
Injection site pain	1 (5)
Increased amylase	2 (10)
Arthralgia	2 (10)
Nephrolithiasis	2 (10)
Restless leg syndrome	2 (10)

Abbreviation: TEAE, treatment-emergent adverse event.

A total of 12 serious TEAEs were reported for 9 (45%) subjects. Of the 12 serious TEAEs, 11 were considered by the investigators to be not related or probably not related to burosumab. One serious TEAE of life-threatening angioedema was considered by the investigator to be possibly related to burosumab treatment. No subject had hyperphosphatemia (defined as serum phosphate ≥6.5 mg/dL); 1 participant had a single serum phosphate measurement (4.9 mg/dL) that was above the upper limit of the normal range. In this participant, burosumab dose was decreased and serum phosphate returned to normal levels.

No meaningful changes in cardiac ectopic mineralization, assessed by echocardiogram, were observed, and no subject had a documented increase in nephrocalcinosis on renal ultrasound from baseline to the end of treatment visit.

Five subjects experienced ectopic mineralization TEAEs. Two subjects had nephrolithiasis TEAES that were mild (Grade 1) but were considered by the investigator as possibly related to burosumab. One of these subjects had a prior medical history of nephrolithiasis. For both of these subjects, nephrocalcinosis was not present at any assessment, and burosumab dose was not changed. The other 3 cases of ectopic mineralization (nephrolithiasis, nephrocalcinosis, pancreatic calcification) were determined to be not related to treatment.

No deaths occurred during the study and no TEAE led to withdrawal of study drug or study discontinuation. Four subjects, 2 of whom were positive for antidrug antibodies at baseline, were positive for antidrug antibodies during at least 1 visit postbaseline. All positive samples had low titers (≤1:4), and none were positive for neutralizing antibodies. The presence of antidrug antibodies had no discernable impact on the pharmacokinetics, efficacy, or safety of burosumab.

Discussion

The present study reports the long-term results of burosumab treatment in adult subjects with XLH who had previously received burosumab during the KRN23-INT-001 and KRN23-INT-002 studies, suspended treatment for at least 21 months, and were restarted and subsequently treated with burosumab for up to an additional 3.5 years.

Treatment with burosumab improved renal phosphate reabsorption as evidenced by an increase in TmP/GFR, which resulted in an increase in serum phosphate levels into the normal range in the majority of subjects. Burosumab therapy also led to increases in serum 1,25(OH)₂D levels and improvements in serum markers of bone turnover. The course of changes in markers of bone turnover reflected early increases with subsequent declines. P1NP, a marker of bone formation, showed a prolonged increase from baseline, while CTx, a marker of bone resorption decreased after Week 24, suggesting a possible positive remodeling balance. Subjects reported reductions in pain and stiffness from baseline through 72 weeks of burosumab treatment accompanied by clinically meaningful improvements in measures of mobility. While these patient-related outcome measures of pain and stiffness improved with burosumab therapy, they did not all fully normalize. A likely explanation for the lack of complete normalization is the presence of established XLH disease manifestations, such as osteoarthritis of the hip and knee and enthesopathy, that would be unlikely to resolve with burosumab (13, 14). Osteoarthritis and enthesopathy affect approximately 63% and 100% of adults with XLH, respectively, contributing to increased stiffness, pain, and decreased mobility (13–15). At present, the impact of burosumab therapy on the development and progression of osteoarthritis and enthesopathy in patients with XLH has not been established.

Between the conclusion of the prior KRN23-INT-002 study and the start of the present UX023-CL203 study, patients had a treatment gap of at least 21 months. During this period, many clinical outcome measures including serum phosphate, CTx, 1,25(OH)₂D, ALP, and TmP/GFR returned to near-pretreatment levels observed in the initial KRN23-INT-001 study (4). After resumption of burosumab therapy in the present study, these endpoints responded similarly to the initial treatment periods in the prior studies with rapid initial improvement which were sustained (serum phosphorus) or tapered with continued treatment (CTx, 1,25(OH)₂D, ALP, and TmP/GFR) indicating a consistent response to burosumab treatment (4).

The biochemical abnormalities seen in patients with XLH can occur regardless of age, allowing disease manifestations such as osteomalacia to persist throughout life, as indicated in bone histomorphometric studies of adults with this disease (16, 17). Although it remains to be determined whether life-long therapy with burosumab will prevent the long-term complications of XLH in adults, the favorable safety and efficacy profiles of burosumab demonstrated in the current study suggest that such treatment can be well-tolerated while providing beneficial biochemical and clinical outcomes. While conventional therapy of calcitriol and phosphorus shows efficacy in adults (17, 18) it has been associated with adverse effects including hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, and chronic kidney disease when administered long term (1). In the present study, the safety profile of long-term burosumab therapy was similar to that observed in previous studies (2, 14, 16, 19, 20). Only 1 SAE occurred that was possibly attributed to burosumab therapy, and no TEAEs led to patient withdrawal of the study drug or discontinuation. Further, no deaths occurred during the study. Overall, the results support the existing favorable safety profile of burosumab while avoiding many of the risks associated with prolonged conventional therapy in patients with XLH.

The present study has several limitations including its open label design and lack of a control group. There were variable treatment gaps between completion of prior studies and beginning the current study. Long-term effects of burosumab on bone mineralization was not examined histologically. Although data from a separate 1-year study showed histomorphometric improvement in osteomalacia, those parameters did not fully normalize, and it remains to be determined if longer term treatment leads to further healing of the osteomalacia. Patients in the original studies with TEAEs considered unsafe for continuation by the investigator or study sponsor were excluded from the present study. While this may contribute to a slight skew of the safety indications of the present analysis, the safety of study participants is of the utmost importance, and their exclusion was necessary. Finally, since only symptomatic individuals were enrolled, these data do not provide insight into whether asymptomatic or minimally symptomatic patients would benefit to the same extent.

The results of this study are consistent with earlier reports of short-term treatment, and of longer-term follow up of burosumab treatment in children with XLH (21). The efficacy of burosumab was sustained for an average of more than 3 years in adult patients with XLH, with no evidence of a diminished or impaired clinical response after reintroduction of the drug following a hiatus in therapy. This study further supports the existing favorable safety profile for burosumab and provides evidence that burosumab therapy can serve as a safe and effective long-term treatment option for symptomatic adult patients with XLH.

Abbreviations

1,25(OH)₂D

1,25 dihydroxyvitamin D

ALP

alkaline phosphatase

BALP

bone-specific alkaline phosphatase

BPI-SF

Brief Pain Inventory-Short Form

CTx

C-terminal telopeptide

FGF23

fibroblast growth factor 23

iPTH

intact parathyroid hormone

P1NP

procollagen type 1 N-terminal propeptide

SF36

36-Item Short Form Survey

TEAE

treatment-emergent adverse event

TmP/GFR

ratio of maximum reabsorption rate of phosphate to glomerular filtration rate

TUG

Timed Up and Go

XLH

X-linked hypophosphatemia

WOMAC

Western Ontario and McMaster Universities Osteoarthritis Index

Funding

Funding for the UX023-CL203 study was provided by Ultragenyx Pharmaceutical Inc.

Disclosures

T.W.: Research Investigator: Ultragenyx Pharmaceutical Inc.; Advisory Board: Ultragenyx Pharmaceutical Inc.; Other: travel support from Ultragenyx Pharmaceutical Inc. EI: Research Funding and Consulting: Ultragenyx Pharmaceutical Inc. T.C.: Research Support: Ultragenyx Pharmaceutical Inc.; Advisory Board: Ultragenyx Pharmaceutical Inc., Inozyme; Consulting fees: Alexion, Ultragenyx Pharmaceutical Inc., Inozyme, Ipsen, Kyowa Kirin International plc. M.P.: Research Investigator: Ultragenyx Pharmaceutical Inc. AP: Research support and honorarium: Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International plc. J.H.: Employee: Ultragenyx Pharmaceutical Inc. L.M.: Employee: Ultragenyx Pharmaceutical Inc. K.I.: Research Investigator: Ultragenyx Pharmaceutical Inc.; Other: travel support from Ultragenyx Pharmaceutical Inc.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Clinical Trial

UX023-CL203 (NCT02312687, registered December 9, 2014): https://clinicaltrials.gov/ct2/show/NCT02312687.