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ARRY 614 – p38 /Tie–2 for Myelodysplastic Syndrome Program
ARRY-614, an orally active compound that inhibits both p38 and Tie-2, has been found to block cytokine/chemokine signaling production and attenuate apoptosis. ARRY-614 demonstrates inhibition of inflammation and cytokine dependent tumor growth in preclinical models.
Myelodysplastic syndromes (MDS) are late onset diseases that are characterized by over-production of myelosuppressive cytokines which leads to aberrant apoptosis in hematological progenitor cells. p38 MAP kinase (p38) is implicated in dysregulation of apoptosis and myelosuppressive cytokine signaling and production. Tie-2 may affect this process by promoting cytokine production and altering stromal cell senescence. It is hypothesized that disrupting cytokine driven apoptosis in the normal progenitors and stromal cells may improve hematopoiesis in lower risk MDS patients.
In a Phase 1 clinical trial in healthy volunteers, ARRY-614 demonstrated dose-dependent suppression of IL-1ß, PGE2, IL-6 and TNFa, as measured in ex vivo LPS-stimulated whole blood samples. Based on these data, as well as work done on Tie-2 in other experiments, the plasma exposure observed in the volunteers was predicted to result in significant inhibition of p38 and Tie-2 activity in human tissue and plasma.
During fiscal 2011, we completed a Phase 1 trial in patients with MDS to determine safety, maximum tolerated dose and pharmacokinetics, and to obtain preliminary efficacy data, of ARRY-614 in this patient population. In future trials, we will use a new formulation of ARRY-614 with improved drug exposure and reduced variability, as demonstrated in a recently completed human bioequivalence study.
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