AML is a heterogeneous disease of the hematopoietic stem cells, and closely associated with age. Elderly AML patients ( > 60 yrs ) show low response and high relapse rate after first-line treatment, such as cytrabine and anthracycline. One of reason for the drug-resistance is known for aberrantly activating FLT3 mutations, which FLT3-ITD (internal tandem duplication) and FLT3-TKD (tyrosine kinase domain) mutations have been characterized in approximately 35% of AML pathology. Therefore, the most significant unmet need in AML is for more effective and tolerable therapies in elderly patients.
AML patients harboring FLT3 activating mutations (FLT3-ITD and FLT3-TKD)
Approval of US FDA IND (2016). Phase I clinical study is ongoing in us 5 sites.
SKI-G-801 (HCI salt of G-749) is highly potent against clinically known FLT3 mutants harboring FLT3-F691L and FLT3-D835Y that confer resistance to PKC412 and AC220. Notably, G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Intravenous administration of SKI-G-801 suppressed significant FLT3 pathway in tumor tissue, and yielded complete tumor regression and no tumor relapse in xenograft model without relapse in mouse xenograft model. Thus, SKI-G-801 appears to be a promising next generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance, Pharmacological results have been reported in Blood journal in 2014. Orphan drug designation obtained from us FDA in November 2018.