Hyperphosphatemic familial tumoral calcinosis (hfTC) is a disease in which patients cannot produce the bioactive form of the hormone Fibroblast growth factor-23 (FGF23), which is secreted by osteocytes to rid the body of phosphate by acting on the kidney. hfTC is characterized by markedly elevated serum phosphate (Pi) which causes large intramuscular calcifications to develop. The calcification burden in hfTC can be substantial, with some mineralizations growing to weigh 2-4 pounds, becoming very painful and recur after resection. Pediatricpatients can become debilitated, as the lesions can break the skin to increase infection rates, and some patients have had amputations due to loss of vascular blood flow. Currently there are no FDA-approved agents or clinical trials for hfTC. The only available treatments are off-label palliative care, which is minimally effective with poor adherence. Patients with hfTC have inactivating mutations in the FGF23 gene itself or in genes associated with the intracellular processing/secretion of bioactive FGF23. Dr. White carried out the original positional cloning ofFGF23 to identify the molecular basis of autosomal dominant hypophosphatemic rickets (ADHR; Nat Gen, 2000),and his lab characterized FGF23 inactivating mutations from hfTC families. The circulating half-life of humanFGF23 is 20-40 minutes, making endogenous FGF23 replacement therapy impractical. To fill this unmet therapeutic need, Dr. White and his partners with outstanding commercialization experience formed FGF Therapeutics to pursue novel therapies for diseases of aberrant phosphate handling. To extend the half-life ofFGF23 into a therapeutic range, Dr. White developed a humanized FGF23-Fc region fusion protein harboringFGF23-stabilizing mutations ("FGF23-Fc1'). Recombinant FGF23-Fc1 is secreted by mammalian cells in scale up cultures, and in the presence of the FGF23 co-receptor Klotho, retains bioactivity like native FGF23. Further,FGF23-Fc1 can be detected by human ELISAs in the nanogram range 24 h after injection in normal mice, whereas endogenous recombinant FGF23 was undetectable. The objective of this Phase I proposal is to develop a lead FGF23-Fc1 molecule for clinical investigation through the specific aims: 1) Verify and optimize the candidate pre-clinical FGF23-Fc1 protein in vitro; and 2) Test the in vivo bioactivity of FGF23-Fc1 for extended half-life and rescue of the Fgf23-KO hfTC mouse model. In sum, the primary outcome of this proposal is refinement and further development of a lead FGF23-Fc1 candidate for hfTC replacement therapy. Following successful accomplishment of these aims, the fully humanized FGF23-Fc1 will be used to perform IND-enabling studies in Phase II to establish PK and TK. Our worldwide connections with physicians and the team's >20 year experience in the FGF23 field will support these future studies.
Public Health Relevance Statement: Narrative Hyperphosphatemic familial tumoral calcinosis (hfTC) is a rare disease with no FDA approved treatments. The current anecdotal treatments are wholly ineffective. This STTR proposal focuses on the development and future commercialization of a humanized long-acting form of the hormone FGF23 as a novel treatment for hfTC.
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