MALVERN, Pa., May 27, 2014 (GLOBE NEWSWIRE) -- TetraLogic Pharmaceuticals Corporation (Nasdaq:TLOG) today 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.
"Although this study is continuing to accrue patients, we are proceeding with a randomized Phase 2 study to directly compare the efficacy and safety of birinapant and azacitidine to azacitidine alone in first line higher risk MDS patients," said Dr. Lesley Russell, TetraLogic's Chief Operating Officer and Chief Medical Officer. "We believe that the data showing inhibition of NFkB in leukemic cells demonstrates that birinapant, at a dose of 13mg/m2 twice weekly for three weeks out of four, is pharmacologically active and should have an acceptable tolerability profile when administered with IV azacitidine. The fact that we have also seen signs of early activity in terms of bone marrow blast count reductions provides additional rationale to test this combination in a randomized study."
The myelodysplastic syndromes (MDS) are hematological conditions with ineffective production (or dysplasia) of the myeloid class of blood cells. The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The outcome is poor, and without treatment, most patients will progress within a few months to refractory acute myeloid leukemia. The median survival rate varies from years to months, depending on type. Stem cell transplantation offers cure, with survival rates of 50% at 3 years, although older patients do poorly. Azacitidine (approved under the proprietary name Vidaza®) is a hypomethylating agent (HMA) approved worldwide for the treatment of patients with MDS, CMMoL and acute myelogenous leukemia (AML). Even though this therapy has significantly improved outcomes in patients with MDS, less than half achieve objective responses, and most responders lose response within 1 to 2 years. As a result there continues to be a great unmet need for effective therapies specifically targeted to treat higher risk (i.e., intermediate-2 or high-risk disease as classified by the International Prognostic Scoring System (IPSS)) MDS and CMMoL patients. The improved understanding of the biologic underpinnings of MDS has encouraged further development of investigational agents that could target disrupted molecular pathways critical to its pathogenesis. Combination treatment strategies using an azacitidine backbone may demonstrate promising response and survival outcomes.
Birinapant (TL32711) is a potent, bivalent SMAC-mimetic that binds with differential affinity to multiple members of the IAP family including cIAP1, cIAP2, XIAP, and ML-IAP. Birinapant is differentiated from other SMAC-mimetics in that it results in the selective degradation of cIAP1 bound to TRAF-2 in the TNF receptor complex, sparing non‑TRAF-2 bound cIAP1. This unique IAP antagonism profile of birinapant may result in the improved tolerability and therapeutic index observed with this agent.
TetraLogic is a clinical-stage biopharmaceutical company focused on discovering and developing novel small molecule therapeutics in oncology and infectious diseases. TetraLogic has two clinical-stage product candidates in development: birinapant and suberohydroxamic acid phenyl ester (SHAPE). Birinapant is currently being tested in Phase 1 and Phase 2 clinical trials for hematological malignancies and solid tumors. SHAPE is entering Phase 2 trials for early-stage CTCL.
Forward Looking Statements
Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or TetraLogic's pre-clinical and clinical development of birinapant, SHAPE and other clinical programs, future expectations, plans and prospects. Although TetraLogic believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. TetraLogic has attempted to identify forward-looking statements by terminology including ''believes,'' ''estimates,'' ''anticipates,'' ''expects,'' ''plans,'' ''projects,'' ''intends,'' ''potential,'' ''may,'' ''could,'' ''might,'' ''will,'' ''should,'' ''approximately'' or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including those discussed under the heading "Risk Factors" in our Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 19,2014 and our Quarterly Report of Form 10-Q filed with the Securities and Exchange Commission on May 8,2014. Any forward-looking statements contained in this release speak only as of its date. We undertake no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.
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