BACKGROUND. Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme.
METHODS. In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up.
RESULTS. Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient.
CONCLUSION. BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP.
After administration of BPS804, mean ALP enzymatic activity (A) increased between days 2 and 29 after the third infusion compared with baseline. (B) Similarly, for BSAP, the enzymatic activity increased between days 2 and 29 after the third infusion compared with baseline. Individual BSAP values for patient 4 (screening, EoS) and patient 5 (days 1, 2, 8, 85, and 133 and EoS) were below the LOQ and are not represented in the graph. (C) PEA levels showed inter-individual variability; thus, changes during treatment are given as ratio versus individual baseline. (D) PLP values showed large intra- and inter-patient variability. A consistent decline upon treatment was seen in patients 4 and 5, who had the highest baseline values. Vertical lines indicate time of infusion (days 1, 15, and 29). Shaded area indicates the time period of days 2–29 after the third infusion. Horizontal lines indicate lower normal limit for ALP by sex in A, LOQ in B, and normalized baseline in C. The y axis in C and D is broken to include outliers and still clearly visualize lower individual PEA/PLP levels.