– Biomarker data demonstrate osteoclast activation at low doses of vantictumab without impacting osteoblast activity, strengthening therapeutic rationale for the treatment of autosomal dominant osteopetrosis type 2 (ADO2)
– Analysis of international genetic database is consistent with prior prevalence estimates and suggests a substantial population affected by CLCN7-related ADO2
BURLINGAME, Calif.--(BUSINESS WIRE)--āshibio, a privately held, clinical-stage biotechnology company developing novel therapeutics for bone and connective tissue disorders, presented new clinical biomarker and genetic prevalence data supporting the development of vantictumab for autosomal dominant osteopetrosis type 2 (ADO2). These data were presented at the 2026 Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in Boston, Mass.
Clinical biomarker findings support the therapeutic rationale for vantictumab
In a plenary poster presentation at ASBMR,1 Victoria Smith, PhD, Chief Scientific Officer of āshibio, reported results from an analysis of bone turnover markers from a legacy first-in-human (FIH) study of vantictumab in patients with cancer.2 Vantictumab is a monoclonal antibody that selectively binds to certain frizzled (FZD) receptors and inhibits WNT signaling pathways.3 Low doses of vantictumab (0.5-5mg/kg), administered once weekly (QW) or every two or three weeks (Q2W or Q3W), increased osteoclast activity without inhibiting osteoblast activity, consistent with findings from the ADO2 mouse model presented at the 2025 Annual Meeting of ASBMR4 and supporting the therapeutic hypothesis that vantictumab can restore bone homeostasis in patients with ADO2.
“We observed a clear exposure-response relationship for bone biomarkers in patients with cancer treated with vantictumab, suggesting we can modify the dose or regimen to activate osteoclasts and restore bone homeostasis without compromising safety in patients with ADO2,” noted Dr. Smith. “Based on analysis of nonclinical toxicity studies, we predict a large therapeutic index for vantictumab, with margins up to 200-fold, consistent with safety data from oncology clinical trials. Taken together, these data support the therapeutic rationale for vantictumab in ADO2.”
Originally intended for the treatment of cancer, vantictumab has been previously evaluated in oncology clinical trials demonstrating a favorable safety and pharmacokinetic profile. Analysis of biomarker data from the prior FIH trial supports the advancement of vantictumab into clinical development for ADO2 (also known as Albers-Schönberg disease), a genetic disorder caused by reduced function of osteoclasts. Impaired osteoclast function results in dense, brittle bone and leads to complications such as multiple poorly healing fractures, osteomyelitis, low blood counts (due to bone marrow sequestration), and painful nerve compression.
Of the 31 patients in the Phase 1 study, 29 (94%) experienced a >25% increase in C-terminal telopeptide (βCTX), a measure of the rate of bone resorption, and 23 patients (74%) experienced a ≥50% increase in this bone biomarker post-baseline. For a subset of lowest-dose QW regimens that overlap with the high end of the predicted dose range from the ADO2 mouse model (0.5 and 1.0 mg/kg QW), βCTX elevation was apparent for all participants at day 28 (35-377% of baseline). Additionally, with the short half-life of vantictumab (3.5 days), there was a rapid decrease in βCTX upon cessation of dosing. Furthermore, consistent with ADO2 mouse model findings, comparative analysis of bone biomarkers such as βCTX and P1NP indicated selectivity for osteoclast activation versus osteoblast inhibition, especially at lower vantictumab doses.
Genetic analysis estimates CLCN7-related ADO2 prevalence at 1–4 per 20,000
In a separate poster presentation at ASBMR, āshibio and academic collaborators presented an analysis of a worldwide genetic database that estimated the prevalence of CLCN7-related ADO2 at 1 to 4 per 20,000 individuals, a range that is consistent with prior publications.5
The most common form of ADO2 results from a mutation in the chloride channel 7 (CLCN7) gene. The published ADO prevalence of 1 in 20,000 births is based on hospital records (N=450,000) from Funen County, Denmark, in 1988.6 Data presented at ASBMR provide a contemporary estimate of CLCN7-related ADO2 prevalence using a worldwide genetic database.
“Our analysis, using different variant inclusion criteria and a penetrance of 66%, yields a CLCN7-related ADO2 prevalence that increases our confidence in assessing the size of the patient population,” said Deborah Wenkert, MD, Chief Medical Officer of āshibio. “Even when we exclude R657Q, the most common ADO CLCN7 variant in gnomAD, whose penetrance, if different would have skewed the estimate, we established that ADO2 is at least as prevalent as previously estimated, a key step in estimating the number of patients in need of intervention.”
Using the Genome Aggregation Database (gnomAD™ v.4.1.1), a genetic database from worldwide, large-scale sequencing projects, the investigators identified ADO2-related CLCN7 variants from the literature containing supportive radiographic data, supplemented with pathogenic and likely pathogenic (P/LP) variants with clinical information from ClinVar, a public archive of reports of human variations classified for diseases and drug responses. This study provides further support for the lower bound of the total addressable market (TAM) for vantictumab in ADO2, estimated at approximately 40,000 patients in US, Europe, and Japan.
About āshibio
āshibio is a privately held, clinical-stage biotechnology company developing a pipeline of novel therapeutics for bone and connective tissue disorders. The company is advancing andecaliximab for the treatment of heterotopic ossification (HO), including fibrodysplasia ossificans progressiva (FOP) and non-hereditary heterotopic ossification (NHHO). āshibio is also developing vantictumab for autosomal dominant osteopetrosis type 2 (ADO2), a genetic disorder characterized by impaired osteoclast function. āshibio intends to advance vantictumab into clinical trials in patients with ADO2 in the first half of 2028. For more information, visit www.ashibio.com.
References
1 Smith V, Lemire I, Mathias A, et al. Vantictumab, a semi-selective FZD inhibitor, activates osteoclasts at low doses in humans. Presented at American Society for Bone and Mineral Research (ASBMR) Annual Meeting, Boston, Mass., October 9, 2026, Presentation number Fri-467.
2 Smith DC, Rosen LS, Chugh R, et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18/R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J Clin Oncol 31, 2013 (suppl; abstr 2540).
3 Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci 2012;109(29):11717-22.
4 Alam I, Smith V, Gerard-O’Riley R, et al. Vantictumab, an anti-FZD antibody, Rescues the Osteopetrotic Bone Phenotype in Heterozygous ADO Mice. Presented at American Society for Bone and Mineral Research (ASBMR) Annual Meeting, Seattle, Wash., September 7, 2025, Presentation number Sun-582.
5 Wenkert D, Econs MJ, Savarirayan R, Imei EA. Prevalence of autosomal dominant osteopetrosis type 2 (ADO; Albers-Schönberg disease) calculated from the Allele Frequency of ADO-causing choloride channel 8 (CLCN7) variants in gnomADv4.1.1. Presented at American Society for Bone and Mineral Research (ASBMR) Annual Meeting, Boston, Mass., October 10, 2026, Presentation number Sat-496.
6 Bollerslev J, Anderson PE Jr. Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone. 1988;9(1):7-13.
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