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CUDC-907 (HDAC, Pi3K inhibitor)

CUDC-907 is a small molecule targeted drug candidate designed and discovered by us to inhibit PI3K and HDAC enzymes.  Curis is developing CUDC-907 based on published and internally generated data demonstrating that HDAC and PI3K inhibitors have synergistic interaction in certain preclinical cancer models, and based on published observations of clinical activity of such agents in hematological cancers.  CUDC-907, with its synergistic mechanism of cancer signaling network disruption, has demonstrated potent preclinical antitumor activity in a variety of hematological tumor models including non-Hodgkin’s lymphoma and multiple myeloma.  Curis believes that CUDC-907 has the potential to possess clinical advantages over single targeted agents.  In November 2011, Curis entered into an agreement with The Leukemia & Lymphoma Society, or LLS, under which LLS will provide up to $4 million in funding to support the early clinical development of CUDC-907 in patients with relapsed or refractory lymphoma and multiple myeloma.

About the CUDC-907 Phase I Dose Escalation Trial

This study is designed as a standard dose escalationstudy in which CUDC-907 is orally administered to patients with relapsed orrefractory lymphoma or multiple myeloma. The primary objectives of the trial are to determine the maximumtolerated dose, or MTD, and recommended Phase II dose for CUDC-907administration.  The secondary objectivesof this study are to assess safety and tolerability, to assesspharmacokinetics, to evaluate biomarker activity and to assess preliminaryanti-cancer activity of CUDC-907 in this patient population.  In the absence of dose limiting toxicity,each patient will receive CUDC-907 orally once daily (QD) for a minimum of 21days (1 cycle), and may continue to receive additional cycles of treatmentuntil disease progression or if other treatment discontinuation criteria aremet. In July 2013, an amendment was made to the protocol of the ongoing Phase Istudy to include two additional dosing regimens, wherein oral CUDC-907 isadministered either two times per week (twice weekly, or BIW regimen) or threetimes per week (thrice weekly, or TIW regimen). 

InDecember 2013, interim data from the ongoing Phase I trial was presented at theAnnual Meeting of the American Society of Hematology, or ASH, in New Orleans. OurASH presentation included interim data on 13 patients in the QD or BIW regimensat doses of 30 mg QD (n=7), 60 mg QD (n=3) or 60 mg BIW (n=3). Dose limitingtoxicities (DLTs) of Grade 3 diarrhea and Grade 4 hyperglycemia were reportedin 1 patient at the 60 mg QD dose. Treatment-related serious adverseevents (AEs) of Grade 3 epistaxis (30 mg QD, n=1), and Grade 3 diarrhea andGrade 4 hyperglycemia (60 mg QD, n=1) were also reported with the dailyschedule. The most frequent Grade 3 or 4 AEs reported in 2 or more patientsinclude thrombocytopenia, diarrhea and neutropenia. Toxicities havelimited the ability to further dose escalate using the QD schedule. Bycontrast, no DLTs or dose interruptions have been reported for patientsenrolled onto the BIW regimen at the 60mg dose level and dose escalation is ongoingin the BIW and TIW regimens.

Out of the 13 patients included in the ASH presentation,11 were evaluable for response assessment per protocol. One patient with mixedfollicular lymphoma/ diffuse large B cell lymphoma achieved a partial response(PR), with a 70% reduction in a single target lesion observed at the 30 mg QDdose level. Seven other patients have met criteria for stable disease (SD)including 4 with SD lasting at least 4 cycles of treatment. Preliminarypharmacokinetic analysis shows low CUDC-907 plasma levels as compared to itsmetabolite species, M1 (minimal PI3K inhibitory activity and no HDAC inhibitoryactivity) and M2 (significant PI3K inhibitory activity and no HDAC activity).This is consistent with animal studies that demonstrated higher levels ofCUDC-907 in tissues as compared to plasma. Additional pharmacokinetic andpharmacodynamic analyses are ongoing. We expect to complete the dose-escalationphase approximately in mid-2014 and initiate enrollment in the expansioncohort(s) in patients with select malignancies in the second half of 2014. Inaddition to our ongoing Phase I clinical study in advanced lymphomas andmultiple myeloma patients, we are conducting preclinical studies with CUDC-907in solid tumor models and expect that we will initiate additional studies usingCUDC-907 in combination with other anti-cancer agents in patients with solidtumors around the end of 2014.

About CUDC-907

CUDC-907 is a small molecule targeted drug candidate designed and discovered by Curis to inhibit PI3K and HDAC enzymes.  Concurrent inhibition of PI3K and HDAC has synergistic effects in certain preclinical cancer models, and based on published observations of clinical activity of such agents in hematological and other cancers.  CUDC-907 has demonstrated potent antitumor activity in a variety of hematological tumor models including non-Hodgkin’s lymphoma and multiple myeloma.

About the LLS Agreement

Under the agreement, LLS will fund approximately 50% of the direct costs of the development of CUDC-907, up to $4 million.  Curis initiated a Phase I dose escalation clinical trial in patients with relapsed or refractory lymphomas or multiple myeloma in early 2013.  If this study is successful, LLS has also agreed to support Curis' subsequent Phase Ib or Phase IIa study in one or more specific indications as well as Curis' ongoing investigation of biomarkers for CUDC-907 in these diseases.

About The Leukemia & Lymphoma Society

The Leukemia & Lymphoma Society® (LLS) is the world's largest voluntary health agency dedicated to blood cancer.  The LLS mission:  Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families.  LLS funds lifesaving blood cancer research around the world and provides free information and support services.  Founded in 1949 and headquartered in White Plains, NY, LLS has chapters throughout the United States and Canada. To learn more, visit www.LLS.org or contact the Information Resource Center at (800) 955-4572, Monday through Friday, 9 a.m. to 6 p.m. ET. www.LLS.org.

 

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