Burden of disease of X-linked hypophosphatemia in Japanese and Korean patients: a cross-sectional survey.

The burden of disease of X-linked hypophosphatemia (XLH) in East Asia is poorly understood. This was a cross-sectional study using an online questionnaire to evaluate health-related quality of life (HRQOL) and disease complications in Japanese and Korean patients with XLH. Adults with XLH and the caregivers of children <18 years of age with XLH in Japan and Korea were surveyed. Respondents disclosed demographic data, family history, diagnostic history, medical history, surgical history, disease-specific clinical symptoms, treatment, medications, and use of ancillary equipment. Patient-reported outcomes (PROs; the Western Ontario and McMaster Universities Osteoarthritis Index, the brief pain inventory, and the 36-item short form health survey version 2) were used to assess pain, disability, and HRQOL in adults. Of those surveyed, all 14 children (100%) and 30/32 adults (93.8%) were receiving treatment for XLH. However, despite oral phosphate and active vitamin D use, short stature, gait abnormalities, dental conditions, and decreased physical function were reported. Stapling of the growth plates was reported in 14.3% of children but no adults. Adult patients reported high rates of bone pain (59.4%) and joint pain (65.6%). Caregivers of children with XLH also reported the occurrence of bone pain (35.7%) and joint pain (35.7%). Many adult patients had a history of impaired renal function (9.5%), nephrocalcinosis (15.6%), hyperparathyroidism (15.6%), and parathyroidectomy (6.3%), all of which are associated with conventional XLH treatments. These data show that patients (both pediatric and adult) continue to have symptoms such as pain, disability, and various complications despite receiving conventional therapies.

Qualitative Research to Explore the Patient Experience of X-Linked Hypophosphatemia and Evaluate the Suitability of the BPI-SF and WOMAC® as Clinical Trial End Points.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by renal phosphate wasting and defective bone mineralization. Symptoms include bone pain, joint pain, stiffness, and fatigue. Published evidence regarding the patient experience of XLH is sparse and no XLH-specific outcome measures have been validated. OBJECTIVES: To understand the symptoms, impacts, and patient experience of XLH and to evaluate the face and content validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and the Brief Pain Inventory Short Form (BPI-SF) for use as end points in XLH clinical trials. METHODS: Face-to-face, qualitative, semistructured interviews were conducted with 18 adults with XLH in the United States using concept elicitation and cognitive debriefing techniques. Open-ended questioning elicited spontaneous concepts focusing on XLH-associated symptoms and functional limitations. Cognitive debriefing of the WOMAC® and BPI-SF assessed the relevance and patient understanding of item wording, recall period, and response options. RESULTS: Various distinct symptom concepts were elicited including pain symptoms, dental symptoms, sensory symptoms, tiredness/fatigue symptoms, and musculoskeletal symptoms. Participants reported experiencing significant bone and joint pain, stiffness, mobility limitations, and an impact on their ability to work. Cognitive interviewing found both instruments to be relevant and well understood by most patients. CONCLUSIONS: The interviews generated rich, qualitative insights into the patient experience of XLH. Cognitive debriefing of the BPI-SF and WOMAC® supported their value as XLH clinical trial end points. Future research will assess the psychometric properties of these instruments for use in the XLH population.

Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia.

CONTEXT: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown. OBJECTIVE: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH. METHODS: This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64. RESULTS: The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, -0.86; older, -1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, -31.15% of upper normal limit [ULN]; older, -52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children. CONCLUSION: Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D.

Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial.

BACKGROUND: Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia. METHODS: In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 µmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing. FINDINGS: Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64. INTERPRETATION: Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.