ASP5878 / Astellas - LARVOL DELTA

Discovery of ASP5878: Synthesis and structure-activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity. (PubMed, Bioorg Med Chem) - "Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats."

Journal • Bladder Cancer • Brain Cancer • Cardiovascular • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR3

[VIRTUAL] A literature review of the potency and selectivity of FGFR-selective tyrosine kinase inhibitors, such as infigratinib, in the potential treatment of achondroplasia (ESPE 2021) - "In relation to other FGFR TKIs, one study showed that AZD4547 decreased survival in mice treated at doses of 1x10 6 to 2x10 6 nM, and another showed limb malformation in chicken embryos treated with PD173074 at doses of 1x10 6 to 50x10 6 nM...In vivo studies reporting treatment in mouse models of ACH with low doses of infigratinib or ASP5878 did not result in any of these abnormal findings. Recent studies indicate preclinical efficacy of infigratinib, including a survival advantage in Fgfr3 Y367C/+ mice. Given the totality of evidence, low-dose infigratinib appears to be a potentially safe option for further development in children with ACH."

Review • Genetic Disorders • Orthopedics • FGFR • FGFR3

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia. (PubMed, Sci Rep) - "We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests."

Journal • Endocrine Disorders • Genetic Disorders • Growth Hormone Deficiency (Adult) • Oncology • FGFR3

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer. (PubMed, Sci Rep) - "Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control...Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors. (PubMed, BMC Ophthalmol) - "EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops."

Adverse events • Journal • Brain Cancer • Glioblastoma • Keratitis • Ocular Infections • Oncology • Ophthalmology • Retinal Disorders • Solid Tumor

Discovery of ASP5878, a potent and selective fibroblast growth factor receptor (FGFR) inhibitor for the treatment of urothelial cancer (ACS-Sp 2020) - "Here, we report details of the optimization of pyrimidine derivatives as novel FGFR inhibitors. Structural optimization via a structure-based drug design approach based on X-ray co-crystal structure of FGFRs with the inhibitors led to the discovery of ASP5878, which showed potent FGFR inhibitory activity, high kinase selectivity, and a potent antitumor effect in a xenograft mouse model of human urothelial cancer."

FGFR3

A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1-4, as a single dose and multiple doses in patients with solid malignancies. (PubMed, Invest New Drugs) - "One death occurred that was not related to ASP5878. ASP5878 was well tolerated with manageable toxicities including hyperphosphatemia."

Clinical • Journal • P1 data