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.

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations

“…A recent publication reports the treatment of 8 adult patients with HPP with a monoclonal anti‐sclerostin antibody (BPS804) in a phase IIA escalating‐dose trial . Treatment for 29 weeks increased bone formation markers as well as a transient decrease in the bone resorption marker C‐telopeptide.…”

Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca2+ channel internalization in mesenchymal stem cells

“…Bone anabolic treatment, such as treatment with recombinant human parathyroid hormone analogs yielded debatable efficacy. 26 Asfotase alfa (Strensiq, Alexion), a bone-targeted enzyme replacement therapy, was approved for the long-term treatment of pediatric-onset HPP in the United States, Europe, Canada, and Japan. However, there are no guidelines for selecting adult patients for treatment, evaluating the results of treatment, or determining the optimal duration of treatment at this time.…”

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

“…Recent reports on the clinical trials of Scl-Ab aimed at treatment for bone fragility diseases such as osteoporosis demonstrate promising results (3,4) . Scl-Ab may also play a therapeutic role in many sclerostin-mediated diseases other than osteoporosis, such as rheumatoid arthritis (18) , hypophosphatasia (19) , osteogenesis imperfecta (20) and bone rebuilding in multiple myeloma (21) . However, the impacts of Scl-Ab therapy on the immune system have not yet been examined.…”