So what is the reason for the apparent differential activity?
FWIW, CYT387 also hits CDK1 and something termed TBK1 (I have no idea what the latter is).
Just a reminder of their 2010 ASH abstract:
Efficacy: Thirty two of 36 subjects who completed at least 1 cycle were eligible for response assessment:
Anemia: Twenty two subjects were evaluable for anemia response (baseline Hgb <10 g/dL or red cell transfusion-dependent). Of these, 9 subjects (41%) achieved the threshold of response for “Clinical Improvement (CI)” per the International Working Group for MPN Research and Treatment (IWG-MRT) criteria, including 2 of 4 subjects who were previously treated with INCB018424. An additional 5 subjects experienced a >50% reduction in transfusion requirement, thus increasing the total anemia response rate to 63%.
Splenomegaly: Thirty of 32 evaluable subjects had splenomegaly at baseline: median 20 cm; range 10-32 cm. Twenty nine subjects (97%) had some degree of spleen size reduction (median 9 cm; range 2-18 cm): 11 (37%) patients have achieved a minimum 50% decrease in palpable spleen size, thus qualifying them for a CI, including 3 of 8 subjects (38%) who were previously treated with INCB018424..
Constitutional symptoms: The proportion of patients with the following symptoms at baseline, are: fatigue (97%), pruritus (22%), night sweats (38%), cough (13%), bone pain (28%), and fever (16%). At last follow up, improvement (complete resolution) in these symptoms was reported by 68% (16%), 86% (57%), 83% (75%), 75% (50%), 78% (44%), and 100% (100%), respectively.
Conclusions: CYT387 is first-in-class of the JAK inhibitors with a significant response rate in anemia in myelofibrosis patients. The drug also shows substantial activity in reducing spleen size and controlling constitutional symptoms. CYT387 is well tolerated, and treatment responses have been seen both at (300 mg/day) and below (150 mg/day) the MTD. |
