CYT387
CYT387 is an orally-administered, potent, selective inhibitor of the JAK1 and JAK2 kinases, enzymes which have been implicated in a number of disorders including myeloproliferative neoplasms (MPNs), inflammatory diseases and certain cancers. The molecule possesses an excellent selectivity and safety profile with minimal
off-target activity, a favorable pharmacokinetic and toxicological profile, and the prospect of limited drug/drug interactions. Data from MPN patient samples demonstrate suppression of JAK enzyme over-activity.[1]
CYT387: Mechanism of Action
JAK1/2 in Myeloproliferative Neoplasms
MPNs are debilitating and potentially fatal diseases of blood cell production. MPNs such as myelofibrosis, polycythemia vera and essential thrombocythemia are disorders for which there are limited and poorly efficacious therapeutic options. Myelofibrosis is the most serious of these disorders, and is the first clinical indication being studied with CYT387.
A gain-of-function genetic mutation in the JAK2 enzyme, which results in constitutive activity of the enzyme, has been shown present in over 95% of patients with polycythemia vera and in approximately 50% of patients with essential thrombocythemia and myelofibrosis. Clinical manifestations of myelofibrosis include progressive anemia and splenomegaly, along with constitutional symptoms including fatigue, night sweats and bone pain. Reduction of splenomegaly and improvement of constitutional symptoms have been observed in clinical trials of JAK 1/2 inhibitors.
More information about myeloproliferative neoplasms can be found at www.mpdfoundation.org.
JAK1/2 in Cancer
JAK2 and JAK2, and their related biochemical pathways, are now known to play a key role in the proliferation of certain types of epithelial cancer cells, such as prostate, breast, head & neck, lung, ovarian, renal cell, glioma, pancreatic and liver cancers, as well as hematological cancers such as multiple myeloma, lymphomas and and leukemias. Preclinical research is underway to evaluate the clinical potential of CYT387 for the treatment of various solid tumors and hematological malignancies.
JAK1/2 in Inflammatory Disease
JAK1 and JAK2 activity are implicated in various inflammatory diseases, including rheumatoid arthritis and psoriasis. Preclinical research is underway to evaluate the potential of CYT387 for the treatment of inflammatory diseases, including rheumatoid arthritis.
Clinical Progress and Development
CYT387 has completed enrollment in a 166 patient international Phase I/II clinical trial for the treatment of myelofibrosis and is being studied in an ongoing 60 patient Phase II BID clinical trial in myelofibrosis. Myelofibrosis, a frequently fatal myeloproliferative neoplasm, is a chronic debilitating unmet medical need, in which a patient’s bone marrow is replaced by fibrotic scar tissue, and for which treatment options are limited or unsatisfactory. The Phase I dose escalation portion of the study is complete and recruitment into the dose confirmatory Phase II portion of the study is ongoing. Initial findings from this study demonstrate that CYT387 has a favorable safety profile in patients with myelofibrosis, and has shown significant activity in reducing spleen size, improving anemia and controlling constitutional symptoms in these patients. Detailed interim safety and activity data from the Phase I/II study were presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011.
| [1] | Pardanani A, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 2009; 23: 1441-1445 |