Background: In XLH, high circulating FGF23 causes hypophosphatemia, rickets, and short stature.
Objective and hypotheses: To evaluate KRN23 effects on serum phosphate (Pi) level and rickets severity in XLH children in a Phase 2 study.
Method: 52 XLH children (ages 512 years, ≤Tanner 2) received KRN23 subcutaneously biweekly (Q2W) or monthly (Q4W). Serum Pi was measured at 2-week intervals. KRN23 dose was titrated (maximum 2 mg/kg) targeting age-appropriate serum Pi concentrations. Rickets severity was assessed by the Thacher Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C; −3=worsening; +3=complete healing).
Results: The first 36 subjects had a mean 6.6 years of standard-of-care treatment before washout. KRN23 increased serum Pi from baseline in all subjects to near normal levels (mean increase 0.30 mmol/l at 38 weeks; P<0.001) and was more stable with Q2W dosing; hyperphosphatemia did not occur. KRN23 significantly improved RSS with greater improvements seen with Q2W dosing (44% reduction; P=0.0126) and particularly in higher-severity subjects (baseline RSS ≥1.5) (59% reduction; P<0.0001). Q2W dosing improved RGI-C by +1.6 (P<0.0001) with higher-severity subjects showing substantial healing (+2.0; P<0.0001). Most treatment-related adverse events (AE) were mild; transient injection site reactions occurred most frequently (39%). One child experienced a serious AE (fever/muscle pain) that improved and the child continues in the trial. No clinically meaningful changes occurred in serum/urine calcium, serum iPTH, or renal ultrasound.
|All Patients||Patients with Baseline RSS ≥1.5|
|Baseline||Wk 40||Baseline||Wk 40|
|Mean Total RSS||All (N=36)||1.4||1.0*||All (N=18)||2.3||1.2*|
|Q2W (N=18)||1.5||0.9*||Q2W (N=9)||2.4||1.0*|
|Q4W (N=18)||1.3||1.1||Q4W (N=9)||2.2||1.4*|
|Mean RGI-C||All (N=36)||+1.4*||All (N=18)||+1.9*|
|Q2W (N=18)||+1.6*||Q2W (N=9)||+2.0*|
|Q4W (N=18)||+1.2*||Q4W (N=9)||+1.7*|
|*P<0.05, comparing Wk 40 to baseline.|
Conclusion: KRN23 improved phosphorus homeostasis and rickets in children with XLH.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology