Abstract 2602: The nonclinical toxicology profile of pacritinib, a JAK2FLT3 inhibitor with no dose-limiting clinical myelosuppression

Pacritinib is an orally active kinase inhibitor being developed for the treatment of myelofibrosis (MF). Pacritinib is a particularly potent inhibitor of wild-type and mutant isoforms of JAK2 and FLT3 (IC50 values < 15 nM), and it does not suppress JAK1 at clinically relevant concentrations. Additional kinases targeted by pacritinib include IRAK1 (IC50 13.6 nM) and c-fms (or CSF1R; IC50 39.5 nM). Pacritinib is pharmacologically active in nonclinical tumor models driven by JAK2 or FLT3 overexpression, and clinical trials have demonstrated that pacritinib can ameliorate symptoms in MF patients. A key differentiating feature of pacritinib over currently available JAK2 inhibitors is its lack of dose-limiting clinical myelosuppression, allowing for treatment of patients with cytopenias. The comparatively reduced myelosuppressive activity of pacritinib is thought to be due to its lack of pharmacological activity on JAK1, andor its inhibition of IRAK1 and c-fms, which may contribute to anti-inflammatory activity. Nonclinical pacritinib data from rodent and canine studies were evaluated in comparison to publicly available information for other JAK2 inhibitors to determine if differences in nonclinical endpoints might correlate with the observed clinical differences in myelosuppressive effects. The qualitative nonclinical findings seen in rodents were similar for all JAK2 inhibitors, and included decreases in leukocytes, red cell mass, and reticulocytes; lymphoid depletion in the spleen, thymus, andor lymph nodes; and hypocellularity of the bone marrow. Interestingly, platelet decreases were not observed in rodent or canine nonclinical models, even with JAK2 inhibitors associated with clinical thrombocytopenia. However, in the dog, pacritinib is unique for its minimal myelosuppressive effects in the pivotal 30-day and 39-week studies, despite being performed at higher exposure levels relative to other similar JAK2 inhibitor studies. With pacritinib, non-adverse lymphoid reduction was seen in the spleen, lymph nodes, Peyer's patches, andor thymus; but there were no clinical pathology findings indicative of marked myelosuppression, nor were there any treatment-related findings in detailed bone marrow evaluations. Overall, these comparisons suggest that nonclinical bone marrow data and clinical pathology in the dog may be informative endpoints for estimating the myelosuppressive potential of JAK2 inhibitors in the clinic.