ARRY 614 – p38/Tie2 Program for Myelodysplastic Syndromes
ARRY-614, a dual inhibitor of p38 mitogen-activated protein kinase (p38) and Tie2 receptor tyrosine kinase, offers a unique mechanism of action for the treatment of MDS. p38 and Tie2 are dysregulated in the bone marrow of patients with MDS. ARRY-614 is believed to restore bone marrow function by blocking myelosuppression, thereby enabling the repopulation of red blood cells, platelets and neutrophils. ARRY-614 inhibits inflammation and cytokine-dependent tumor growth in preclinical models.
MDS are diseases characterized by over-production of myelosuppressive cytokines leading to aberrant apoptosis in hematologic progenitor cells and refractory peripheral cytopenias. p38 is implicated in dysregulation of apoptosis and myelosuppressive cytokine signaling and production. Tie2 may affect this process by promoting cytokine production and altering stromal cell quiescence. It is hypothesized that disrupting cytokine-driven apoptosis in the normal progenitors and stromal cells may improve hematopoiesis in MDS patients.
As presented at the December 2011 and 2012 ASH Annual Meetings, ARRY-614 has demonstrated activity as measured by hematologic improvement (increased neutrophils, platelets and/or red blood cells) in patients with MDS and was generally well tolerated.
In a Phase 1 dose-escalation/expansion trial of 44 evaluable patients, ARRY-614 demonstrated activity as a single agent in patients with low or intermediate-1 risk MDS under the International Prognostic Scoring System, or IPSS, and for whom treatments with approved therapies have failed, including hypomethylating agents (e.g., Vidaza®, Dacogen®) and Revlimid®. A 38% response rate for hematologic improvement in patients receiving the highest dose of 1200 mg daily (n=16) was observed. At this dose, ARRY-614 demonstrated multilineage hematologic improvement, improving more than one cytopenia (neutropenia, thrombocytopenia and/or anemia), in 67% of the responders.
Hematologic improvement with ARRY-614 was durable (five month median response duration), with multiple patients remaining on therapy for over 12 months. Clinically significant hematologic toxicity was minimal. Observed changes in pharmacodynamic markers included decreases in circulating erythropoietin, as well as decreases in phospho-p38 and disease-related apoptosis in the bone marrow.
During fiscal 2013, Array continued to evaluate an optimized formulation of ARRY-614 in a clinical trial with a similar patient population. This Phase 1 dose-escalation trial, currently in an expansion phase after establishing the maximum tolerated dose, has the goal of identifying the recommended dose and schedule for future clinical trials. As presented at the 2012 ASH Annual Meeting, this new formulation has demonstrated improved bioavailability and target coverage, including higher peak plasma concentrations and overall exposures, as compared to the original formulation.
Also during fiscal 2013, the U.S. Food and Drug Administration, or FDA, provided guidance on future development for this program, including the use of endpoints other than overall survival as the basis for approval. The FDA also agreed that Low / Int-1 patients who have failed a hypomethylating agent can be considered a high unmet medical need population.
Development Plan: During the next fiscal year, we expect to complete the ongoing Phase 1 expansion trial and, pending additional data from the ongoing study, plan to make decisions on future study designs.