Burosumab for adults with tumor-induced osteomalacia in China

Abstract

Abstract

A better understanding of the benefit of burosumab for treating tumor-induced osteomalacia (TIO) in Chinese patients is needed. The objective of this open-label, multicenter, single-cohort, post-marketing phase 4 study was to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of burosumab after repeated administration in Chinese adults with TIO. Burosumab was administered subcutaneously every 4 weeks for up to 48 weeks at an initial 0.3 mg/kg dose. We investigated the change from baseline in mean serum phosphorus level over time and changes in serum and urinary phosphorus levels, bone turnover biomarkers, patient-reported outcomes, and other parameters after repeated burosumab administration. Nine patients were treated. Serum phosphorus levels increased and remained above baseline and lower limit of normal at the end of the dosing cycles (averaged over weeks 20–48) (mean (standard deviation) change, 1.5 (0.86) mg/dL). Tubular reabsorption of phosphate and the ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate increased and remained above baseline values. Alkaline phosphatase (ALP), bone-specific ALP, carboxy-terminal cross-linked telopeptide of type I collagen, and procollagen type 1 N-terminal propeptide levels increased, reaching maximums at weeks 16 or 24. The distance walked in 6 min nearly doubled from baseline by week 48. Patients reported improvements in pain and quality of life over time. There were no serious adverse events and only five treatment-related adverse events (all mild in severity) in three patients. In Chinese patients with TIO, continued treatment with burosumab can provide sustained clinical benefit and a favorable safety profile.

Clinical trial registration

ClinicalTrials.gov (NCT05357573).

Introduction

Osteomalacia is characterized by increased osteoid and decreased bone strength due to defective mineralization in bone and cartilage (1). In developing skeletons and before growth plate closure, osteomalacia is referred to as rickets (2). Defective mineralization can be caused by impaired vitamin D action, hypophosphatemia, chronic metabolic acidosis, metal-induced disorders, and tumors (1, 3).

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by phosphaturic mesenchymal tumors (4, 5, 6, 7). These tumors lead to excessive fibroblast growth factor 23 (FGF23) production, resulting in renal phosphate wasting, hypophosphatemia, and impaired 1,25-dihydroxyvitamin D synthesis. The elevated FGF23 levels in TIO represent a similar biochemical profile to that of X-linked hypophosphatemic rickets/osteomalacia (XLH). Still, FGF23 levels in TIO are often far higher (8, 9), with more severe symptoms affecting the individual’s daily life and health-related quality of life. TIO is a rare condition both globally and in China, where it is a major cause of adult-onset hypophosphatemia (4, 10).

Surgery, the first choice of treatment for tumors causing TIO, leads to a decline in FGF23 levels and remission of the clinical syndrome (7). If surgery is not an option because of the extent/location of the disease or because tumors cannot be localized (11, 12), conventional therapy for TIO is implemented, including phosphorus supplementation in combination with active vitamin D metabolites or analogs (e.g., calcitriol). However, this approach has limited efficacy owing to the magnitude of the FGF23 level increase and the severity of the resulting phosphate wasting. In addition to requiring frequent monitoring to mitigate risks of nephrocalcinosis, hypercalciuria, and hyperparathyroidism, this approach can also lead to tolerability issues and severe side effects, such as gastrointestinal side effects, that may affect adherence (13). These limitations highlight the need for alternative therapeutic options that can better address the above-mentioned concerns.

Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to FGF23 and inhibits its activity (14). Burosumab was approved for the treatment of XLH and TIO (14, 15, 16, 17) based on the results of several clinical trials (11, 15, 16, 17, 18, 19, 20, 21). TIO is a rare disease (4, 10), and previous clinical studies have shown no ethnic differences in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, or safety between Asian patients (Japanese and Korean) and Western (United States and European) populations. Thus, burosumab was also approved for TIO treatment in China on March 23, 2021 (16, 22). This phase 4 commitment study was designed to evaluate the efficacy, PK, PD, and safety of burosumab after multiple subcutaneous administrations in adult Chinese patients with TIO.

Materials and methods

Ethics

This study adhered to the Declaration of Helsinki and complied with Good Clinical Practice and associated local laws and regulations. The ethics committees at each of the three participating centers reviewed and approved the study protocol and associated documents. This study was registered in ClinicalTrials.gov under the identifier NCT05357573. All patients provided written informed consent.

Patients

The full list of inclusion and exclusion criteria is available in the Supplementary Materials (see section on Supplementary materials given at the end of the article). The main inclusion criteria were as follows: Chinese adults (≥18 years) with a clinical diagnosis of TIO, based on evidence of excessive FGF23, that was not amenable to cure by surgical excision of the offending tumor (documented by the investigator); fasting serum phosphorus level <2.5 mg/dL (0.81 mmol/L) at screening; serum intact FGF23 level ≥100 pg/mL by Kainos assay at screening; ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) <2.5 mg/dL at screening; estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² (using the Chronic Kidney Disease Epidemiology Collaboration formula (23)) at screening; and corrected serum calcium level <10.8 mg/dL (2.69 mmol/L) at screening (corrected serum calcium = serum calcium in mg/dL + 0.8 × (4 − serum albumin in g/dL)).

Study design and intervention

This was an open-label, multicenter, single-cohort, post-marketing phase 4 study conducted at three tertiary-level care sites in China (Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; West China Hospital, Sichuan University; and Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine). This study was required by the China National Medical Products Administration to evaluate the efficacy and safety of burosumab in adult Chinese TIO patients following its approval. Because TIO is a rare disease in China (4, 10), the three centers were selected because of the presence of investigators with substantial experience in the diagnosis and treatment of TIO. Furthermore, the leading investigator is a recognized key opinion leader in the field and contributed to the development of the Chinese guidelines for TIO and XLH.

The study had a screening period from day −28 to week 0 (day 1) and a 44-week treatment period (end of treatment), with end-of-study visits taking place at week 48 (Supplementary Fig. 1). Patients were selected for screening only if they were considered to have inoperable disease, defined as a patient with a TIO diagnosis based on an excessive FGF23 level and who could not be cured by surgery. This included participants for whom the tumor could not be localized or whose tumor had recurred post-surgery and could not be removed completely. Both outpatient and inpatient individuals who met the study criteria could be selected for the study. Eligible patients were followed up in one of the three tertiary centers during the study.

After signing an informed consent form, patients underwent screening assessments (for details, see the Supplementary Materials). Patients on pharmacologic vitamin D, oral phosphate for TIO, aluminum hydroxide antacids, acetazolamide, or thiazide diuretics were eligible but had to stop these treatments at least 14 days before screening.

Patients received a maximum of 12 subcutaneous injections of burosumab, once every 4 weeks from the first dose on week 0 (day 1) through to week 44 (end of treatment). Each patient received an initial 0.3 mg/kg dose of burosumab, with potential dose adjustment steps of 0.6, 1.0, 1.4, and 2.0 mg/kg, rounded to the nearest 10 mg for convenience of administration.

The dose adjustment criteria are provided in Table 1. Dosing was adjusted one step at a time up to week 16 based on serum phosphorus levels. For levels >4.5 mg/dL, drug administration was interrupted and restarted at one step lower than the previous dose when levels returned to ≤2.5 mg/dL.

Table 1.

Dose adjustment criteria and dose steps.

Serum phosphorus level marked 2 weeks before dose adjustment	Dose adjustment
≤2.5 mg/dL (0.81 mmol/L)	The dose increases to the next step
From >2.5 mg/dL (0.81 mmol/L) to ≤4.0 mg/dL (1.29 mmol/L)	The same dose as in the preceding step
From >4.0 mg/dL (1.29 mmol/L) to ≤4.5 mg/dL (1.45 mmol/L)	The dose is reduced by one step
>4.5 mg/dL (1.45 mmol/L)	Administration is interrupted
Initial burosumab dose	0.3 mg/kg
Dose increase steps	0.6 mg/kg
	1.0 mg/kg
	1.4 mg/kg
	2.0 mg/kg

From week 20, the burosumab dose remained the same as at week 16 unless safety or efficacy concerns arose from the serum phosphorus level obtained 4 weeks earlier. Serum phosphorus levels were checked 2 weeks after dose increases, reduction, or interruption.

Study endpoints

The primary endpoint was the change from baseline (CFB) in mean serum phosphorus level at the end of the dosing cycles (4 weeks after dosing), as averaged over weeks 20–48. The calculation was based on the period of stable dosing regimen, which started at week 20. The secondary endpoints were CFB in mean serum phosphorus level at week 22, proportion of patients achieving serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL (0.81 mmol/L)) at week 22, and proportion of patients achieving mean serum phosphorus level > LLN at the end of the dosing cycles (averaged over weeks 20–48); CFB in mean serum 1,25-dihydroxyvitamin D, urinary phosphorus, serum creatinine, tubular reabsorption of phosphate (TRP), and TmP/GFR over time; and change in bone turnover biomarkers, including alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), procollagen type 1 N-terminal propeptide (P1NP), and osteocalcin over time. Changes in 6 min walking test (6MWT) results over time were also recorded. Patient-reported outcomes included CFB in brief pain inventory (BPI) and brief fatigue inventory (BFI) scores over time and scores on the 36-item Short-Form Health Survey (SF-36) to examine health-related quality of life.

The exploratory endpoints were the CFB in bone mineral density (BMD) over time assessed by dual-energy X-ray absorptiometry (Lunar iDXA; GE Healthcare, USA), with each participant’s assessments conducted on the same device throughout the study period, and radiologic healing or resolution of pre-existing fractures and/or pseudofractures as defined by skeletal survey at baseline, subsequent targeted radiography every 12 weeks (baseline, week 12, week 24, week 36, and week 48), and ^99mTc-labeled bone scans every 24 weeks (baseline, week 24, and week 48). Standard radiographs and ^99mTc-labeled bone scans were conducted at each study center, and the images were transferred to a central imaging center for assessment. The interpreting radiologist was provided solely with the relevant image data and blinded to other study information. In addition, tumor imaging by computed tomography or magnetic resonance imaging to determine changes in lesions was conducted at screening, week 24, and week 48 (or the end of treatment), using the same image management (submitted to a central imaging center for assessment) as previously described. The comprehensive schedule of assessments, detailing all biological, clinical, radiological, and safety assessments and their timing for each scheduled visit, is included as Supplementary Table 1.

The PK endpoints assessed in this study were peak burosumab concentrations and trough burosumab concentrations.

The safety endpoints were incidence of treatment-emergent adverse events (TEAEs), changes in vital signs, physical examinations, clinical laboratory tests, echocardiogram, and electrocardiogram. Renal ultrasound assessments were conducted, and nephrocalcinosis findings were classified into five grades. Anti-burosumab antibodies were also measured.

Statistical analysis

The study was planned to enroll at least six patients with TIO, which had a ≥90% power to detect a mean CFB of 0.9 mg/dL in mean serum phosphorus at the end of the dose cycle (the primary endpoint), assuming a standard deviation (SD) of 0.5 mg/dL and a two-sided type 1 error of 5%, as derived from Imanishi et al. (16). The analysis sets comprised the all-screened set, all-enrolled set, full analysis set (FAS), safety analysis set, and PK analysis set. Detailed definitions of the analysis sets are included in the Supplementary Materials. Continuous variables were summarized as the number of patients (n), mean, SD, minimum, median, and maximum. The number and percentage of patients with non-missing data are presented.

All statistical analyses were descriptive and were conducted using the SAS statistical software package (SAS Environment, version 9.4, SAS Institute Inc, USA). The primary endpoint (mean serum phosphorus level at the end of the dosing cycle) was analyzed using a paired t-test as an exploratory analysis. If the lower bound of the 95% confidence interval (CI) was greater than zero, the increase in serum phosphorus was considered equivalent to a two-sided P < 0.05. As this was an exploratory analysis, P-values were not reported explicitly.

Results

Patient disposition and baseline characteristics

Eleven patients were screened, and nine (81.8%) were enrolled (Fig. 1), all of whom were included in the analysis. The all-screened set included 11 patients; the all-enrolled set, FAS, safety analysis set, and PK analysis set each included nine patients. Two patients discontinued (one patient was found after enrollment to have not met the eligibility criteria; the other was unable to undergo the study examinations for personal reasons after tumor metastasis), and seven patients (77.8%) completed the study.

Figure 1.

Patient disposition. iFGF23, intact fibroblast growth factor 23.

The nine patients enrolled included eight (88.9%) men and one (11.1%) woman, with a median (range) age of 50.0 (31–60) years and a mean (SD) body mass index of 28.3 (2.49) kg/m². At baseline, the individual serum intact FGF23 values were highly variable, with a median value of 486.4 pg/mL and a range of 199.16–5,432.40 pg/mL; all patients had a baseline serum phosphorus level < LLN (2.5 mg/dL (0.81 mmol/L)), with a mean (SD) serum phosphorus level of 1.2 (0.25) mg/dL (Table 2). The mean (SD) serum iPTH level at baseline for patients who received phosphate (n = 6) was 234.5 (219.76) pg/mL, while for those who did not receive phosphate (n = 3), the mean (SD) level was 103.0 (18.39) pg/mL. At baseline, a total of 13 recent fractures and 3 recent pseudofractures were identified by standard radiograph, while 62 recent fractures and 6 recent pseudofractures were identified by ^99mTc-labeled bone scans.

Table 2.

Patient baseline characteristics.

Characteristic	Burosumab
	n = 9
Age (years)
Median (min, max)	50.0 (31, 60)
Sex, n (%)
Male	8 (88.9)
Female	1 (11.1)
Body mass index (kg/m2), mean (SD)	28.3 (2.49)
Serum markers, mean (SD)
Intact fibroblast growth factor 23 (reference range: <71) (pg/mL)	1,034.9 (1,662.83)
Median (minimum, maximum)	486.4 (199.2, 5,432.4)
Albumin (reference range: 3.3–4.9) (g/dL)	4.8 (0.36)
Phosphorus (reference range: 2.5–4.5) (mg/dL)	1.2 (0.25)
Calcium (reference range: 8.3–10.6) (mg/dL)	9.2 (0.57)
Creatinine (reference range: 0.45–1.24 (male 18–50 years)/0.45–1.35 (male 50–70 years)/0.35–1.14 (female 18–70 years)) (mg/dL)	0.9 (0.30)
Intact parathyroid hormone (reference range: 18.4–80.1) (pg/mL)	190.7 (185.98)
25-Hydroxyvitamin D (reference range: ≥29) (ng/mL)	26.7 (14.18)
TmP/GFR (2 h urine, reference range: N/A) (mg/dL)	0.8 (0.28)
Renal ultrasound grade at baseline, n (%)
0 = normal	7 (77.8)
1 = faint hyperechogenic rim around the medullary pyramids	0
2 = more intense echogenic rim with echoes faintly filling the entire pyramid	0
3 = uniformly intense echoes throughout the pyramid	0
4 = stone formation: solitary focus of echoes at the tip of the pyramid	2 (22.2)
Skeletal involvement
Standard radiograph
Recent fractures	13
Recent pseudofractures	3
99mTc-labeled bone scan
Recent fractures	62
Recent pseudofractures	6

TmP/GFR, renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate.

In four out of nine (44.4%) patients, at least one tumor (tumor type: phosphaturic mesenchymal tumor) was detected, and all had undergone ≥1 previous tumor excision surgeries. For the five participants in whom no tumor was detected, the diagnosis of TIO was confirmed by the investigator based on clinical manifestations (e.g., ostealgia), hypophosphatemia, elevated serum FGF23 levels, and TmP/GFR <2.5 mg/dL.

Of the four patients with detected tumors, three had postoperative recurrences that could not be accessed, and the other patient’s tumor could not be localized. All patients underwent at least one form of TIO treatment prior to the study. Study inclusion was limited to patients with TIO considered not amenable to surgical cure owing to tumor recurrence or non-localization. All nine patients had received active vitamin D (such as calcitriol), six patients had received phosphate, and two had received other treatments (such as burosumab injection and radiotherapy). The patient who received burosumab injection prior to the study had a washout period greater than 90 days.

Dosing

All nine (100%) patients received the first 0.3 mg/kg burosumab dose on day 1 (week 0; Supplementary Fig. 2A). The mean (SD) prescribed doses were 1.5 (0.46) mg/kg at week 20 and 1.3 (0.60) mg/kg at week 44 (Supplementary Fig. 2A).

Study endpoints

Primary endpoint

Figure 2A shows the arithmetic mean (SD) serum phosphorus levels over time in the FAS. The mean (SD) serum phosphorus level increased from 1.2 (0.25) mg/dL at baseline to 2.7 (0.89) mg/dL at the end of the dosing cycles (averaged over weeks 20–48) (change, 1.5 (0.86) mg/dL). The resulting 95% CI was 0.793–2.227 mg/dL.

Figure 2.

Arithmetic mean (SD) serum phosphorus (A), 2 h urine TmP/GFR (B), serum ALP (C), serum BALP (D), serum CTx (E), serum P1NP (F), serum OC (G), iPTH (H), and corrected calcium (I) levels over time (full analysis set). The number of patients in the analysis set (n) at each time point is shown below each graph. In (A), the lower limit of the normal range (2.5 mg/dL) is indicated by the orange dashed line. ALP, alkaline phosphatase; BALP, bone-specific alkaline phosphatase; CTx, carboxy-terminal cross-linked telopeptide of type I collagen; OC, osteocalcin; P1NP, procollagen type 1 N-terminal propeptide; iPTH, intact parathyroid hormone; and TmP/GFR, tubular maximum reabsorption rate of phosphate to glomerular filtration rate.

Secondary endpoints

At both week 22 and the end of the dosing cycles (averaged over weeks 20–48), six out of seven patients who completed the study had serum phosphorus levels > LLN (2.5 mg/dL). The mean (SD) serum phosphorus level was 1.2 (0.25) mg/dL at baseline (n = 9), 2.7 (0.83) mg/dL at week 24 (n = 8; %CFB, 127.3% (84.71%)), and 3.0 (0.86) mg/dL at week 48 (n = 7; %CFB, 148.6% (96.77%)).

Serum 1,25-dihydroxyvitamin D findings were not analyzed, as most serum 1,25-dihydroxyvitamin D2 levels were below the lower limit of quantification. The mean 1,25-dihydroxyvitamin D3 level increased from 0.035 ng/mL at baseline to 0.089 ng/mL at week 24 and 0.102 ng/mL at week 48.

TmP/GFR increased from 0.8 (0.28) mg/dL at baseline (n = 9) to 2.8 (0.85) mg/dL at week 48 (n = 7), and TRP increased from 0.6 (0.15) at baseline (n = 9) to 0.9 (0.03) at week 48 (n = 7). The arithmetic mean (SD) TmP/GFR over time for the FAS is shown in Fig. 2B. The 2 h mean (SD) urinary phosphorus decreased from 81.6 (70.98) mg/dL at baseline (n = 9) to 48.2 (33.45) mg/dL at week 48 (n = 7) (Supplementary Fig. 3). The 24 h mean (SD) total urinary phosphorus decreased from 709.9 (275.87) mg/24 h at baseline (n = 9) to 640.8 (354.10) mg/24 h at week 24 (n = 7) and then increased to 767.6 (116.01) mg/24 h at week 48 (n = 5). The mean (SD) changes from baseline increased from −149.0 (297.93) mg/24 h at week 8 to 109.9 (223.03) mg/24 h at week 48.

The mean value of bone turnover biomarkers ALP, BALP, CTx, and P1NP (Fig. 2C, D, E, F) initially increased after the start of burosumab administration, reached their maximum values at weeks 16 or 24 and then gradually decreased. No similar trend was found for osteocalcin (Fig. 2G).

The 6MWT distance increased from baseline across all assessment points (week 12, week 24, and week 48). The mean distance was 199.2 (123.30) meters at baseline (n = 9) and increased to 361.5 (162.26) meters at week 48 (n = 7), representing the greatest improvement observed (Table 3).

Table 3.

6MWT results.

	6MWT distance, m, mean (SD)	Change from baseline, m, mean (SD)	Change from baseline, %, mean (SD)
Baseline (n = 8)	199.2 (123.31)	-	-
Week 12 (n = 7)	274.2 (128.72)	75.4 (55.04)	52.1 (47.96)
Week 24 (n = 8)	303.7 (161.53)	104.5 (159.96)	83.1 (158.44)
Week 48 (n = 7)	361.5 (162.26)	162.6 (152.71)	116.1 (109.56)

6MWT, 6 min walking test; SD, standard deviation.

Figure 3A, B, C summarizes the patient-reported outcomes over time. At week 48, the mean (SD) changes from baseline in BPI worst pain, severity, and interference scores were −2.6 (2.82), −2.0 (2.73), and −3.2 (3.38), respectively. The mean (SD) changes from baseline in BFI worst fatigue, severity, and interference scores were −1.6 (2.70), −1.4 (2.63), and −2.2 (2.83), respectively, at week 48. By week 48, the mean (SD) changes from baseline in physical and mental component scores of SF-36, version 2, were 12.6 (7.86) and −0.5 (9.93), respectively.

Figure 3.

Patient-reported outcomes. (A) BPI, (B) BFI, and (C) SF-36 scores. In (A), lower pain scores indicate less pain; in (B), lower fatigue scores indicate less fatigue; and in (C), higher SF-36 scores indicate higher functioning. BFI, brief fatigue inventory; BPI, brief pain inventory; and SF-36, 36-item Short-Form Health Survey.

Exploratory endpoints

The mean BMD and the corresponding T and Z scores generally increased over time for the body sites examined. The mean (SD) lumbar spine BMD increased from 0.97 (0.33) g/cm² at baseline to 1.1 (0.34) g/cm² at week 24 (CFB, 0.11 (0.08) g/cm²) and 1.2 (0.31) g/cm² at week 48 (CFB, 0.19 (0.13) g/cm²). The mean (SD) hip (total) BMD increased from 0.7 (0.26) g/cm² at baseline to 0.8 (0.30) g/cm² at week 24 (CFB, 0.04 (0.10) g/cm²) and 0.9 (0.24) g/cm² at week 48 (CFB, 0.17 (0.15) g/cm²).

In the standard radiograph, five patients had recent fractures or pseudofractures at the beginning of the study. For participants who had evaluable data at baseline and the specified post-baseline time point, these recent fractures or pseudofractures were no longer present in zero out of four patients at week 12, one out of four (25.0%) patients at week 24, one out of three (33.3%) patients at week 36, and one out of three (33.3%) patients at week 48. At baseline, 13 recent fractures and 3 recent pseudofractures were identified by standard radiograph; in addition, 8 fractures were assessed as ‘not detected at baseline’ at an unscheduled visit (week 6). At week 12, 9 fractures were ‘partially healed’, 11 fractures were ‘unchanged’, and 5 fractures and 1 pseudofracture were ‘not detected at baseline’. At week 24, 17 fractures and 1 pseudofracture were ‘partially healed’, 4 fractures were ‘unchanged’, 1 fracture was reported as ‘not detected at baseline’, and 1 fracture was reported as a ‘new finding’. At week 36, 9 fractures were assessed as ‘partially healed’. At week 48 (end of the study), 12 fractures were assessed as ‘partially healed’ and 3 were assessed as ‘unchanged’. No fractures or pseudofractures were ‘worsened’ at any assessment.

In the bone scan study, eight patients initially had recent fractures or pseudofractures. For participants who had evaluable data at both baseline and the specified post-baseline time point, these recent fractures or pseudofractures were no longer present in one out of six (16.7%) patients at week 24 and one out of six (16.7%) patients at week 48 (Supplementary Fig. 4). At baseline, 62 recent fractures and 6 recent pseudofractures were identified by ^99mTc-labeled bone scan. At week 24, 11 fractures were ‘partially healed’, 27 fractures and 2 pseudofractures were ‘unchanged’, 1 fracture was ‘worsened’, 2 fractures were ‘not detected at baseline’, and 1 fracture and 1 pseudofracture were ‘new findings’. At week 48, 1 fracture was assessed as ‘healed’, 22 fractures and 1 pseudofracture were assessed as ‘partially healed’, and 11 fractures were assessed as ‘unchanged’.

When assessing the completely healed status of fractures/pseudofractures (confirmed by both standard radiograph and ^99mTc-labeled bone scan) at week 24, 8 fractures and 1 pseudofracture were assessed as completely healed; 42 fractures and 5 pseudofractures were assessed as not completely healed. At week 48, 18 fractures and 3 pseudofractures were assessed as completely healed; 39 fractures and 1 pseudofracture were assessed as not completely healed.

PK endpoints

A summary of peak and trough burosumab concentrations is provided in Supplementary Table 2. The arithmetic mean (SD) peak serum burosumab concentration increased from 1,540 ng/mL (827) over weeks 0–4 to 8,850 ng/mL (4,740) over weeks 20–24. A similar increase was observed in the arithmetic mean (SD) trough serum burosumab concentration, which increased from 725 ng/mL (439) over weeks 0–4 to 5,390 ng/mL (3,100) over weeks 20–24. The arithmetic mean serum burosumab concentration–time profile is shown in Supplementary Fig. 5.

Safety

A summary of adverse events is provided in Table 4. Overall, nine (100.0%) patients experienced 66 TEAEs. Most TEAEs were mild (54 TEAEs in nine (100.0%) patients) or moderate (10 TEAEs in seven (77.8%) patients) in severity; one (11.1%) patient reported one TEAE that was considered severe; and the investigator did not assess the severity of one TEAE. The severe TEAE was tumor metastasis, which was considered unrelated to burosumab. Three (33.3%) patients experienced five TEAEs that were considered related to the study treatment, all of which were mild in severity. The specific events were hypercalcemia (3 events/participants), hyperphosphatemia (1 event/participant), which led to treatment interruption, and right bundle branch block (1 event/participant). There were no serious TEAEs and no serious treatment-related TEAEs.

Table 4.

Summary of TEAEs.

	Burosumab
	n = 9
	n (%), events
Any TEAE	9 (100.0), 66
Treatment-related TEAEs	3 (33.3), 5
TEAEs leading to the interruption of study treatment	1 (11.1), 1
TEAEs leading to the discontinuation of study treatment	0
TEAEs leading to death	0
Serious TEAEs	0
Other significant TEAEs	0
Mild TEAEs	9 (100.0), 54
Moderate TEAEs	7 (77.8), 10
Severe TEAEs	1 (11.1), 1
TEAEs occurring in ≥2 patients
COVID-19	5 (55.6), 5
Hypercholesterolemia	3 (33.3), 5
Hyperuricemia	3 (33.3), 5
Blood alkaline phosphatase increased	3 (33.3), 4
Hypertriglyceridemia	3 (33.3), 4
Hypercalcemia	3 (33.3), 3
Weight increased	2 (22.2), 2
Cough	2 (22.2), 2

TEAE, treatment-emergent adverse event.

No major changes from baseline were observed for most of the clinical laboratory parameters after burosumab administration. Mean (SD) iPTH levels decreased from 190.7 (185.98) pg/mL at baseline to 106.7 (42.51) pg/mL at week 24 and 98.1 (23.81) pg/mL at week 48 (end of study) (Fig. 2H). This indicates that mean serum iPTH levels were above the upper limit of the reference range (18.4–80.0 pg/mL) throughout the study but decreased over time after burosumab administration. Mean corrected calcium levels were within the reference range (8.3–10.6 mg/dL) and remained relatively unchanged from baseline after burosumab administration (Fig. 2I). Vital signs results, physical examination findings, electrocardiogram data, and echocardiogram data did not show any clinically meaningful changes from baseline.

The renal ultrasound findings for nephrocalcinosis remained unchanged for all patients except one. In this case, the patient’s condition progressed from grade 0 (normal) at baseline to grade 4 (stone formation) at weeks 24 and 48. This individual experienced a TEAE of lithiasis, which was characterized as mild in intensity and not deemed to be related to burosumab by the investigator.

All nine patients had computed tomography or magnetic resonance imaging at screening and/or subsequent visits. Among the patients with baseline and post-baseline data for lesion volume and lesion diameters, no specific trend was observed following burosumab administration.

There were no positive anti-burosumab binding antibody results at baseline, week 44 (end of treatment), or week 48 (end of study).

Discussion

This phase 4 study assessed the safety, PK, PD, and efficacy of burosumab for TIO in Chinese patients. This study is important as no previous clinical studies have evaluated these outcomes after multiple subcutaneous administrations in adult Chinese patients with TIO. Burosumab was approved for TIO treatment in China on March 23, 2021, with a condition for marketing based on overseas study results showing no ethnic differences in PK/PD, efficacy, or safety between Asian (Japanese and Korean) and other populations (16, 22).

The primary objective of this study was the correction of hypophosphatemia. Following repeated burosumab administration with dose adjustment, the mean serum phosphorus level increased gradually and remained stable above the LLN throughout the study after week 14. Out of seven patients who completed the study, six patients achieved serum phosphorus levels above the LLN at week 22 and at the end of the dosing cycles (averaged over weeks 20–48). This is consistent with the findings of Imanishi et al. in Japan (16), in which 8 out of 13 patients achieved serum phosphorus levels above the LLN at week 48.

Regarding the PD and clinical outcomes, serum TRP and TmP/GFR levels increased and remained consistently above the baseline values. Bone turnover biomarkers (ALP, BALP, CTx, and P1NP) increased and reached maximums at week 16 or week 24 and then decreased, while osteocalcin remained relatively stable after burosumab administration. The secondary endpoints focused on the CFB at week 22, the first assessment after the dose stabilized, and the time course up to week 48 to enable direct comparison with overseas studies. Parallel to the biochemical outcomes, the distance walked in 6 min increased nearly twofold from baseline values at week 48. This correlated with a reduction in BPI-pain and BFI-fatigue scores and may thus reflect the beneficial effects of burosumab on reducing pain and fatigue and, consequently, ambulatory function, which is in line with the findings of a previous study (19).

Exploratory assessment further supported the clinical benefits of burosumab. The mean BMD generally increased over time after burosumab administration. Recent fractures and pseudofractures either partially healed or remained unchanged.

Regarding patient-reported outcomes, the BPI and BFI scores decreased over time and remained below baseline after burosumab administration. The SF-36 assessment showed an improved physical component score and a relatively stable mental component score.

PD data confirmed that the peak and trough serum burosumab concentrations increased from the first dosing cycle (weeks 0–4) to the sixth dosing cycle (weeks 20–24). Trough serum burosumab concentrations were relatively stable at the end of each treatment cycle at weeks 16, 20, and 24 and increased slightly at week 48 (end of study).

In terms of safety, burosumab was well tolerated by adult Chinese patients, with most TEAEs being of mild or moderate intensity. One patient reported a TEAE of hyperphosphatemia, which was managed with dose interruption. Another patient experienced a TEAE of lithiasis, which was considered unrelated to burosumab treatment and highlights the importance of continued monitoring and individualized patient care.

Overall, burosumab showed positive effects for Chinese patients with TIO in the present study. The effects were consistent with and possibly exceeded those reported in previous studies in terms of serum phosphorus levels, TmP/GFR, TRP, 6MWT distance, bone turnover biomarkers, and patient-reported outcomes (BPI, BFI, and SF-36) (16, 17). Imanishi et al. (16) found that after burosumab treatment, bone biomarkers initially increased, reaching peak values at weeks 16 or 24, before gradually decreasing. Patients showed improved mobility, reported reduced pain, and displayed a tendency toward healing of baseline fractures and pseudofractures. Burosumab was generally well tolerated with no severe treatment-related adverse events (16).

Jan de Beur et al. (17) conducted a study in the United States and Europe and found that serum phosphorus levels increased from 0.52 mmol/L (1.61 mg/dL) at baseline and remained stable from week 22 (0.91 mmol/L (2.82 mg/dL)) to week 144 (0.82 mmol/L (2.54 mg/dL)). In the present study, the mean (SD) baseline serum phosphorus levels of 1.2 (0.25) mg/dL were lower than in the previous study (17) and improved to 2.8 (0.73) mg/dL at week 22 and 3.0 (0.86) mg/dL at week 48. In addition, in the present study, TmP/GFR levels increased from a mean of 0.8 mg/dL at baseline to 2.6 mg/dL at week 24, compared with the increase from a mean of 0.36 mmol/L (1.11 mg/dL) at baseline to 0.60 mmol/L (1.85 mg/dL) at week 24 seen previously (17). In the present study, improvements in 6MWT distance were seen, from 199.2 meters at baseline to 361.5 meters at week 48, compared with improvements of 295.8–353.7 meters found by Imanishi et al. in Japan (16) over the same time period.

Jan de Beur et al. (17) also found that osteomalacia indicators improved at week 48; out of 249 fractures/pseudofractures at baseline, 33% were fully healed and 13% were partially healed by week 144; and patients reported reduced pain and fatigue and improved physical health. In addition, the present study and previous studies showed that the mean BMD of the lumbar spine and hip assessed by dual-energy X-ray absorptiometry noticeably increased with burosumab treatment (16, 17). Furthermore, most TEAEs were mild in the present study, which aligns with similar international studies conducted in Japan (Imanishi et al.) and the United States/Europe (Jan de Beur et al.) (16, 17). One reason for this may be that patients in the present study had worse clinical conditions at baseline than those in the other studies (16, 17).

This study had some limitations. The sample size was small, with only nine patients enrolled, fewer than in previous studies (16, 17); the number of sites was also small, with only three sites. In addition, this was an open study that lacked a control group. All these factors limit our ability to draw definitive conclusions about trends and affect the generalizability of the findings in China. The study duration was only 48 weeks, with 12 burosumab injections at most; thus, long-term effects could not be observed. The cohort was limited to patients who had received prior TIO treatment and whose tumors were deemed inoperable because of postoperative recurrence or inability to be localized, representing a severe or complex subset of TIO, which may affect external validity. One patient presented with a severe AE of tumor metastasis, which supports the idea that burosumab does not impede the progression of tumors causing TIO. Nevertheless, this treatment showed positive effects on important TIO disease indicators, confirming the efficacy of burosumab in adult Chinese patients. Although serum 1,25-dihydroxyvitamin D3 levels increased, serum 1,25-dihydroxyvitamin D2 levels were below the lower limit of quantification; thus, 1,25-dihydroxyvitamin D levels could not be analyzed.

In conclusion, the present data demonstrate that in Chinese patients with TIO that was not amenable to cure by surgical excision, continued treatment with burosumab led to sustained and progressive correction of serum phosphorus levels, as well as sustained improvement in urinary phosphorus reabsorption and patient-reported outcomes (pain, fatigue, and physical function). Burosumab was well tolerated and exhibited a favorable safety profile in Chinese patients with TIO, and its effectiveness and safety were similar to those seen in other studies.

Declaration of interest

The following authors served as clinical investigators for one or more studies, including this study, sponsored by Kyowa Kirin, Co., Ltd: Weibo Xia, Ruizhi Jiajue, Zhenlin Zhang, Jiemei Gu, and Chunyan Lu. Maiko Sugimoto, Chinwei Yung, and Masaaki Kuriki are employees of Kyowa Kirin, Co., Ltd.

Funding

This research and medical writing support were sponsored by Kyowa Kirin Co., Ltd.

Author contribution statement

Principal investigators WX and ZZ, and Kyowa Kirin Co., Ltd, designed the study. The sponsor and investigators collected, analyzed, and interpreted the data, and all authors participated in data interpretation, reviewing the manuscript, and approval of the final version.

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 upon reasonable request.

Ethics

This study adhered to the Declaration of Helsinki and complied with Good Clinical Practice and associated local laws and regulations. The ethics committees at each of the three participating centers reviewed and approved the study protocol and associated documents. This study was registered at ClinicalTrials.gov under the identifier NCT05357573. All patients provided written informed consent.