TetraLogic Pharmaceuticals Corporation announced that, based upon data from its Phase 1b study of birinapant in combination with azacitidine in patients with relapsed/refractory or naïve higher risk MDS, it selected a dose of 13mg/m2 twice weekly for three weeks out of four to be used in its Phase 2 clinical trial. The primary objective of the Phase 1b clinical study is to characterize the safety and tolerability and determine the recommended phase 2 dose of birinapant when administered in combination with azacitidine. Additional objectives of the study are to assess any preliminary indications of efficacy and pharmacodynamics of the combination.

Based on the currently available data, no dose limiting hematological toxicities of the combination have been reported. A number of patients who received subcutaneous azacitidine experienced local injection site skin reactions/cellulitis. Although a known effect of azacitidine, several of these were considered to be of increased severity with the combination, possibly reflecting a localized synergistic pharmacodynamic effect in the skin.

This toxicity should be mitigated by the use of IV azacitidine as no patient whose route of administration has been changed to IV azacitidine experienced further injection site cellulitis. Birinapant, at the selected phase 2 dose, achieved inhibition of NFkB in circulating blast cells. Although too early to detect durable responses, preliminary data from the first nine evaluable subjects enrolled into the Phase 1b study have shown the following: one subject who received one prior cycle of azacitidine as a single agent showed a bone marrow blast count reduction from 25% to 2% at the end of cycle 1; one subject naïve to azacitidine showed a bone marrow blast count reduction from 17% to 2% at the end of cycle 3 and is now scheduled to undergo a hematopoietic stem cell transplant; and one subject refractory to single agent azacitidine showed a bone marrow blast count reduction from 21% to 7% at the end of cycle 2.