Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Abstract

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.

Trial registration: Clinicaltrials.gov NCT01406977.

Funding: Novartis Institutes for BioMedical Research, Basel, Switzerland.

Conflict of interest statement

Conflict of interest: L. Seefried reports grants and personal fees from Novartis and Alexion and personal fees from Lilly, Amgen, Servier, and Merck, Sharp & Dohme (MSD) during the course of the study. C. Hofmann reports grants, personal fees, as well as nonfinancial support from Alexion outside the scope of the present work. S. Hemsley, B. Kiese, Y. Huang, S. Chivers, M.A. Valentin, B. Borah, R. Roubenoff, and U. Junker report personal fees from Novartis during the course of the study and personal fees from Novartis outside the scope of the present work. F. Jakob reports grants and personal fees from Novartis, Servier, and MSD; personal fees from Lilly, Amgen, Enobia, and Nycomed; and grants, personal fees, and other support from Alexion during the course of the study.

Figures

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) diagram.

A total of 9 patients were screened for the study. Only 8 patients were enrolled in the study, as 1 patient did not meet the study entry criteria. Of the 8 patients, 7 completed the study as per the protocol. One patient discontinued the study due to SAEs of angina pectoris and dyspnea. All patients who received the study drug were included in the safety analysis set; patients with evaluable pharmacokinetic (PK) parameter data were included in the PK analysis set; and patients with evaluable pharmacokinetic (PD) parameter data were included in the PD analysis set.

Figure 2. Study design.

After an initial screening period of 21 days, an i.v. dose of 5 mg/kg BPS804 was administered on day 1, followed by a 2-week safety review. Patients completing this period without any significant safety concern received 10 mg/kg i.v. BPS804 on day 15, followed by a safety review period for the next 2 weeks. Similarly, patients completing the second safety review period without any concern received 20 mg/kg i.v. BPS804 on day 29 and were followed for 16 weeks.

Figure 3. Plots of individual patient PD data over time.

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.

Figure 4. Bone turnover markers.

Geometric mean plots of bone biomarkers. After infusion of BPS804, transient increases in bone formation markers (A) PINP (maximum 101% on day 43) and (B) OC (maximum 92% on day 43) were detected. (C) There was a concomitant transient decrease in the bone resorption marker CTX-1 (maximum –35% on day 36). (D) The bone formation biomarker PTH also showed an increase (maximum 60% on day 57) in the study.

Figure 5. BPS804 serum concentration– and total sclerostin concentration–time profiles.

(A) BPS804 mean serum concentration–time profile (linear plot). Peak serum concentrations were 158, 314, and 679 μg/ml after i.v. administration of 5, 10, and 20 mg/kg BPS804, respectively, with a time to maximum concentration of 2 hours. (B) Total sclerostin serum concentration–time profile (linear plot). Since the assay captures both free and antibody complex–bound sclerostin, values increased following each dose of 5, 10, and 20 mg/kg BPS804. Arithmetic mean (SD) and serum concentrations by each patient at different time intervals are presented.