study to assess the safety, tolerability, pharmacokinetics and efficacy of burosumab in patients less than 1 year of age

Conditions: X-linked Hypophosphatemia (XLH)

Summary: a phase 1/2, open-label, multicenter, non-randomized study to assess the safety, tolerability, pharmacokinetics and efficacy of burosumab in paediatric patients from birth to less than 1 year of age with x-linked hypophosphatemia (xlh)

bur-cl207 is a multicenter, open-label, non-randomized phase 1/2 study in pediatric patients with xlh initiating treatment with burosumab at \<12 months of age. the study includes a total treatment period of up to 48 weeks across 3 cohorts. subjects will be enrolled in 2 age subgroups: (1) ≥6 months to \<12 months of age, and (2) \<6 months of age at initiation of burosumab treatment. cohorts will aim to include 3 subjects per cohort depending on the starting dose of burosumab and relative response of patients to treatment as assessed by serum phosphate levels and by the treating physician (investigator). cohorts will commence in a staggered manner starting with cohort 1, followed by cohorts 2 and 3, which may start in parallel after an adequate observation period (4 weeks) in cohort 1 and with approval from the sponsor's medical monitor and the dsmb. the cohorts are defined as follows: * cohort 1: pediatric subjects with xlh and hypophosphatemia (serum phosphate below the age-adjusted lower limit of normal \[lln\]), and age from ≥6 months to \<12 months of age at initiating treatment with burosumab with starting dose of 0.4 mg/kg. * cohort 2: pediatric subjects with xlh and hypophosphatemia (serum phosphate below the age-adjusted lln), and age from ≥6 months to \<12 months of age at initiating treatment with burosumab with a starting dose of 0.8 mg/kg (upon data safety monitoring board \[dsmb\] confirmation). * cohort 3: pediatric subjects with xlh and hypophosphatemia (serum phosphate below the age-adjusted lln), and \<6 months of age at initiating treatment with burosumab with a starting dose of 0.4 mg/kg (upon dsmb confirmation). following enrollment of the first 3 or 4 subjects in cohort 3, an interim population pk/pd evaluation may be performed to determine whether the starting dose for the cohort can be increased to 0.8 mg/kg.

Eligibility criteria:
inclusion criteria: 1. male or female pediatric subjects, aged \<12 months at burosumab treatment initiation. 2. pediatric subjects with phex mutation or variant of uncertain significance in either the subject or a directly related family member with appropriate x-linked inheritance. 3. presenting serum phosphate levels below the age-specific lln at screening. 4. a legally authorized representative has provided written informed consent prior to any research-related procedures. 5. a legally authorized representative must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments required by the study protocol, including providing access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history. exclusion criteria: 1. the pediatric subject's legally authorized representative is unwilling or unable to stop the subject's treatment with oral phosphate and/or pharmacologic vitamin d metabolite or analogue (e.g. calcitriol, alfacalcidol) for at least 1 week before planned treatment start and for the duration of the study. 2. preterm pediatric patients (defined as born before 37 weeks of pregnancy) with a chronological age of \<6 months. enrolment of preterm pediatric patients with a chronological age ≥6 months must be confirmed by the study medical monitor before study entry. 3. impairment of renal function measured as serum creatinine above the age-adjusted normal range and estimated gfr (calculated using the bedside schwartz equation) below the age-adjusted normal range. 4. presence of nephrocalcinosis on renal ultrasound. 5. hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits. 6. presence of a concurrent disease or condition that would interfere with study participation or affect subject safety. 7. predisposition to infection or known immunodeficiency. 8. severe dermatological conditions over the available injection sites. 9. use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. 10. metabolic bone disease, nutritional rickets and/or osteopenia of other origin than xlh at screening and/or baseline. 11. serum levels of 25-hydroxyvitamin d (25(oh)d) below the lln that are clinically significant in the opinion of the investigator. 12. evidence of any hyperparathyroidism not associated with xlh as determined by the investigator.