Ambit Biosciences Begins Dosing Patients in Phase I Clinical Trial of Lead Kinase Inhibitor AC220
Ambit Biosciences today announced that the first patients have been dosed in its Phase I clinical trial to evaluate AC220 in the treatment of acute myeloid leukemiaterm (AML).
The Phase I trial is a multi-center, open-label, sequential dose-escalation study that will enroll 20-40 patients with relapsed or refractory AML. AC220 will be administered daily via oral solution, beginning at 12 mg for 14 days and then increasing until the maximum tolerated dose is established. In addition to evaluating the safety, tolerability and pharmacokinetics of AC220, the study will measure pharmacodynamics of the investigational drug by monitoring FLT3 receptor phosphorylation and peripheral blood blastterm counts.
â€œAC220 is a wonderful example of the power of Ambitâ€™s proprietary KinomeScan kinase profiling technology. By harnessing that power, our discovery team was able to advance from lead discovery to the clinic in just 20 months, all the while maintaining the best-in-class potency and selectivity we were aiming for,â€ said Scott Salka, Chief Executive Officer of Ambit. â€œAlone and in collaboration with partners, we continue to exploit the discovery advantages KinomeScan provides, and we anticipate advancing several more programs into the clinic over the next few years.â€
AC220 potently inhibits FLT3, a kinase that is mutated in approximately one-third of AML cases, and patients with FLT3 mutations are less responsive to traditional therapies. The FLT3 kinase is inhibited by several kinase inhibitors currently in development as well as by approved drugs such as SUTENTtermtermÂ®. All of these first-generation, multi-kinase inhibitors are limited in their use by undesirable side effectsterm resulting from off-target activity. Using KinomeScan, Ambit engineered AC220 to potently target FLT3, KIT, CSF1R/FMS, RET and PDGFRa/b kinases, all of which are validated drug targets.
In mouse xenograft tumor models using a human leukemia cell line, AC220 produced marked inhibition of tumor growth when administered orally once a day at 1Â mg/kg. In addition, administration of AC220 at 10Â mg/kg for 28 days prompted rapid tumor regressions with no evidence of tumor re-growth through day 90. In preclinical studies, AC220 demonstrated dose-dependent activity and favorable drug-like profiles in bioavailability, pharmacokinetics, cytochrome P450 (CYP) liability, and absorption, distribution, metabolism, excretion (ADME).