Debio 0932Licensed to Debiopharm SA
Debio 0932 is an oral small molecule inhibitor of Heat Shock Protein 90 (HSP90) that is being developed by Curis’ licensee Debiopharm and is currently the subject of an ongoing Phase I/II clinical study in patients with advanced lung cancer. A Phase Ib expansion trial with Debio 0932 in advanced solid tumors was recently completed. In addition, Debiopharm also initiated a Phase I study in the fourth quarter of 2013 to investigate Debio 0932 in combination with mammalian target of rapamycin (mTOR) inhibitor (everolimus) in patients with renal cell carcinoma.
About the Debio 0932 Phase I/II Clinical Trial (HALO Trial)
In August 2012, Debiopharm initiated the HSP90 inhibition and lung cancer outcomes, or HALO, study. This study is a Phase I/II clinical trial of the safety and efficacy of Debio 0932 in combination with standard of care first- and second-line chemotherapy agents in patients with advanced stage IIIb or IV NSCLC that is characterized as wild-type EGFR. The Phase I portion of this trial is designed to determine the recommended Phase II dose of Debio 0932 when given in combination with cisplatin/pemetrexed or cisplatin/gemcitabine in treatment-naive patients, and with docetaxel in previously treated patients. Assuming the Phase I trial is completed successfully and the recommended Phase II dose of Debio 0932 in combination with each of the three chemotherapy regimens has been identified, Debiopharm expects to conduct a randomized, double-blind, placebo-controlled Phase II portion of this study where approximately 140 eligible patients will be randomized to receive chemotherapy in combination with either placebo or Debio 0932. We currently anticipate that the Phase II portion of the HALO could initiate in 2014.
About the Debio 0932 Phase I Renal Cell Carcinoma Trial
In October 2013, Debiopharm initiated a Phase I open label, dose-escalation clinical trial of Debio 0932 in combination with mTOR inhibitor everolimus in patients with advanced or metastatic RCC who have been previously treated with at least one VEGF-directed tyrosine kinase inhibitor. The primary objective of the study is to determine the maximum tolerated dose (MTD) of Debio 0932 in combination with everolimus and the secondary objectives include the determination of recommended dose, safety and tolerability of Debio 0932 in combination with everolimus along with the pharmacokinetic profiles and the potential for drug-drug interaction between the two agents.
The study is also designed to include an expansion cohort of 25 patients at the recommended dose to evaluate the safety and tolerability as well as preliminary clinical activity of the combination of Debio 0932 and everolimus in patients with metastatic clear cell RCC.
About the Debio 0932 Phase I Clinical Trial
In 2011, Curis licensee Debiopharm successfully advanced Debio 0932 through the dose escalation portion of a Phase I study. The first part of this study (Phase Ia) was an open-label, multi-center, dose escalation trial evaluating the safety and tolerability of escalating multiple dose levels of Debio 0932 as a single agent given orally in patients suffering from advanced solid tumors or lymphoma.
Debiopharm presented data from this Phase Ia study at the annual meeting of the American Society of Clinical Oncology in June 2012. Debio 0932 was tested in 50 patients in this portion of the study, including 22 patients that received Debio 0932 every other day and 28 patients that received daily dosing of Debio 0932. Debio 0932 was generally well tolerated in this study, with mostly adverse events classified as Grade 1 or 2, or mild to moderate, with no apparent dose or schedule relationship. In addition, no ocular or cardiac toxicities were observed and no consistent changes in hematology or biochemistry parameters were observed. The most common adverse events included asthenia, constipation, decreased appetite, diarrhea, nausea, and vomiting. Anti-tumor activity was assessed in 45 of the 50 patients enrolled in this study, with 2 patients achieving partial responses, including one patient with breast cancer and one patient with Kras-mutant lung cancer. Stable disease was observed in 12 patients and disease progression was observed in the remaining 31 patients.
The recommended dose for further study was determined by Debiopharm to be 1000 mg daily and Debiopharm advanced Debio 0932 into the Phase Ib expansion portion of the study in the beginning of 2012 at this 1000 mg daily dosing level. The primary objectives of the Phase Ib portion of the study were to further assess the safety profile, pharmacokinetics and pharmacodynamics of Debio 0932 and to make a preliminary assessment of anti-tumor activity. Debiopharm completed the Phase Ib expansion portion of the study, enrolling approximately 30 patients with advanced solid tumors, including patients with advanced NSCLC.
About Debio 0932
Debio 0932 demonstrated high potency in vitro and in vivo across a wide range of cancers. Most notably, Curis scientists observed complete tumor regression following oral administration of Debio 0932 in a mouse xenograft model of acute myelogenous leukemia (AML). Tumor regression has also been observed after treatment of Debio 0932 in mouse xenograft models of breast, non-small cell lung, gastric and glioblastoma brain cancers. In this preclinical testing, the compound also demonstrated an ability to effectively cross the blood brain barrier and demonstrated an ability to extend survival in an intracranial glioblastoma model. GLP toxicity studies suggest that Debio 0932 appears to be well tolerated at potentially efficacious doses.
About the Debiopharm License Agreement
On August 6, 2009, Curis entered into a license agreement with Debiopharm S.A., a Swiss corporation. Pursuant to the license agreement, Curis granted to Debiopharm a worldwide, exclusive royalty-bearing license with the right to grant sublicenses to develop, manufacture, market and sell any product containing the Company’s HSP90 inhibitor technology, including Curis’ lead HSP90 compound under development, CUDC-305 (since renamed Debio 0932). Debiopharm will assume all future development responsibility and incur all future costs related to the development, registration and commercialization of products under the agreement. Curis is eligible to receive up to an aggregate of $90 million in payments, as well as royalties on sales by Debiopharm or its sublicensees.
HSP90 is a member of a class of proteins called molecular chaperones that play a fundamental role in the folding, stabilization and degradation of their client proteins under normal or stressful conditions. HSP90, in particular, has become an attractive therapeutic target for the treatment of cancer because a majority of its client proteins are involved in cellular signaling transduction and have been identified as potential contributors to various aspects of cancer cell growth and survival. Inhibitors of HSP90 activity may be of therapeutic value if they can prevent HSP90 chaperones from protecting proteins involved in cancer and allow them to be degraded.