Curis Announces GDC-0449 Phase I Clinical Data Published in New England Journal of Medicine

Phase I Data in 33 Patients Demonstrates Molecule's Potential as Treatment for Locally Advanced and Metastatic Basal Cell Carcinoma

 

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Sep 3, 2009 - Curis, Inc. (NASDAQ: CRIS), a drug development company focused on developing proprietary targeted medicines for cancer treatment, today announced that two publications describing clinical data generated with GDC-0449 were published in the current edition of The New England Journal of Medicine (NEJM). The first publication, entitled “Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma,” provides an overview of the Phase I data for the 33 basal cell carcinoma (BCC) patients treated in this study. The second paper is a case study entitled “Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449,” which provides an overview of the treatment of a single adult medulloblastoma patient with GDC-0449.

 

"The data published by this distinguished journal build upon the existing body of evidence and provide further support for the belief that aberrant Hedgehog signaling is strongly implicated in solid tumors such as basal cell carcinoma and medulloblastoma,” said Curis President and CEO Dan Passeri. “The ongoing pivotal Phase II clinical trial of GDC-0449 in advanced BCC being conducted by our collaborator Genentech is progressing, and if the trial is successful, may serve as the basis for a future new drug application submission by Genentech. We are also hopeful that Genentech's ongoing Phase II clinical trials of GDC-0449 in metastatic colorectal cancer and advanced ovarian cancer patients will yield promising data supporting the use of GDC-0449 for ligand-driven cancers.”

 

Phase I BCC Publication

The publication entitled “Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma” provides efficacy, safety, pharmacokinetic and pharmacodynamic data summaries of the 33 BCC patients treated in the Phase I clinical trial.

 

Efficacy

In 18 patients with metastatic BCC, 8 patients had confirmed partial responses (7 by RECIST and 1 by clinical assessment), 1 patient had an unconfirmed partial response by RECIST, 7 patients had stable disease as a best response and 2 patients had progressive disease. RECIST provides standard parameters to be used when documenting patient response for solid tumors. The overall response rate was 50% (9 partial responses out of the 18 metastatic BCC patients in the study).

 

In 15 patients with clinically evaluable locally advanced BCC, 2 patients had complete clinical responses, 7 patients had partial responses, 4 patients had stable disease as the best response and 2 patients had progressive disease. The overall response rate was 60% (2 complete responses plus 7 partial responses out of the 15 locally advanced BCC patients in the study).

 

At the time of the data cut-off for the paper, the median time on study and the median duration of response for these patients was 9.8 and 8.8 months, respectively, with 19 patients still on study.

 

Safety Summary

In the Phase I study of GDC-0449, no Grade 5 adverse events were observed and there was a single Grade 4 adverse event that was not determined to be related to the study drug. The following Grade 3 adverse events were seen: fatigue (n=4), hyponatremia (n=2), weight loss (n=2), dyspnea (n=2), and one patient each with muscle spasms, atrial fibrillation, aspiration, back pain, corneal abrasion, dehydration, keratitis, lymphopenia, pneumonia, urinary tract infection, a prolonged QT interval, increased serum alkaline phosphatase, and increased serum potassium. Other adverse events were mild to moderate with 11 Grade 2 adverse events that were considered to be related to GDC-0449 treatment and that included muscle spasms (n=3), dysgeusia (n=2), anorexia (n=2), weight decrease (n=2), hypocalcemia (n=1), and dyspnea (n=1).

 

Pharmacokinetics (PK) and Pharmacodynamics (PD)

GDC-0449 demonstrated a favorable PK and PD profile with a median steady-state plasma concentration of 16.1 micromolar. The median time to reach this steady-state level was 14 days. Dose escalation from 150 mg to 270 mg did not result in higher total plasma concentrations of GDC-0449 and as a result, Genentech has selected a daily dose of 150 mg for the ongoing Phase II clinical trials.

 

Medulloblastoma Patient Articles in NEJM and Science

A brief report of an adult medulloblastoma patient treated with GDC-0449 was published in the same edition of the New England Journal of Medicine and a related paper was also published today in the online edition of Science. The NEJM brief report discusses a 26-year old medulloblastoma patient who was refractory to multiple prior therapies including surgical resection followed by radiation therapy and chemotherapy. This patient was subsequently treated with GDC-0449, resulting in symptomatic improvement and rapid but transient tumor regression. The authors of this report note that it marks the first demonstration of medulloblastoma tumor regression in a patient with a Hedgehog pathway inhibitor who had significant tumor burden and extensive metastatic disease. The Science article explores the potential mechanism of resistance in this same medulloblastoma patient. The authors found that a specific mutation in Smoothened (SMO) present in the tumor after relapse had no effect on Hedgehog signaling but did disrupt the ability of GDC-0449 to bind to SMO. Since SMO is the direct molecular target of GDC-0449, its inability to effectively bind to SMO in this patient likely led to the emergence of drug resistance. This work provides the first evidence that a family of receptors, of which SMO is included, may be subject to the development of drug resistance by mutation of a region of this receptor.

 

The National Cancer Institute's (NCI) Division of Cancer Treatment and Diagnosis (DCTD) is currently sponsoring a Phase I clinical trial to evaluate dose and safety of GDC-0449 in medulloblastoma patients up to 21 years of age, as well as a Phase II trial in adult patients with medulloblastoma. Details for both trials are available at ClinicalTrials.gov.

 

Medulloblastoma is a malignant tumor of the cerebellum and is the most common brain malignancy in children, with a median age of diagnosis of 5 years and with incidence extending into young adulthood. As in advanced BCC, aberrant activation of the Hedgehog signaling pathway is strongly implicated in the development of some medulloblastomas.

 

About the Curis-Genentech Collaboration

 

Under Curis' ongoing collaboration agreement with Genentech, a wholly-owned member of the Roche Group, Curis granted Genentech broad intellectual property rights relating to the Hedgehog pathway, including several classes of proprietary small molecule inhibitors. Through this collaboration, GDC-0449 was discovered by Genentech and was jointly validated by the parties through a series of preclinical studies. Genentech and Roche are responsible for the clinical development and commercialization of GDC-0449. Curis is eligible to receive cash payments upon successful achievement of certain clinical development and regulatory approval milestones and royalties upon commercialization of GDC-0449. GDC-0449 is currently being developed in three Phase II clinical trials by Genentech, including a pivotal trial in advanced basal cell carcinoma and Phase II trials in metastatic colorectal cancer and advanced ovarian cancer. Through a collaborative research and development agreement (CRADA) with NCI, the molecule is also being tested in medulloblastoma, small cell lung cancer and pancreatic cancer and is expected to be tested in additional NCI-sponsored trials in other indications in the future.

 

About Curis, Inc.

 

Curis is a drug development company that is committed to leveraging its innovative signaling pathway drug technologies to seek to create new medicines for cancer indications. In expanding its drug development efforts in the field of cancer through its targeted cancer drug development platform, Curis is building upon its previous experiences in targeting signaling pathways for the development of next generation targeted cancer therapies. For more information, visit Curis' website at www.curis.com.

 

Cautionary Statement: This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including without limitation: statements regarding the expected beneficial role of hedgehog signaling in certain cancers; plans for further testing of GDC-0449; and expectations relating to the outcomes of additional studies of GDC-0449. Forward-looking statements used in this press release may contain the words "believes", "expects", "anticipates", "plans", "seeks", "estimates", "will", "may" or similar expressions. These forward-looking statements are not guarantees of future performance and involve risks, uncertainties, assumptions and other factors that may cause the actual results to be materially different from those indicated by such forward-looking statements including, among other things:

 

 

 


  • Curis may experience adverse results, delays and/or failures in its internal drug development programs.

  • Curis's collaborators may experience adverse results, delays and/or failures in their strategic alliances with Curis. For example, Genentech may not be able to replicate in later trials any favorable outcomes from earlier trials of GDC-0449.

  • Curis and its collaborators may experience difficulties or delays in obtaining or maintaining required regulatory approvals for products under development.

  • Curis may not be able to obtain or maintain the intellectual property protection necessary for the development and commercialization of drug candidates based on its technologies.

  • Curis may not be able to obtain the substantial additional funding required to conduct research and development of its drug candidates.

  • Curis may experience unplanned cash requirements which could shorten the estimated period in which Curis will have cash to fund its operations and which could also adversely affect Curis' estimated operating expenses for 2009 and beyond.

  • Curis faces risks relating to its ability to enter into and maintain planned collaborations for development candidates under its targeted cancer programs, its ability to maintain its current collaborations with Genentech and Debiopharm, and the risk that any such collaborators will not perform adequately.

  • Curis also faces other risk factors identified in its Annual Report on Form 10-K for the year ended December 31, 2008, its Quarterly Report for the Quarter ended June 30, 2009 and other filings that it periodically makes with the Securities and Exchange Commission.

 

In addition, any forward-looking statements represent the views only as of today and should not be relied upon as representing Curis' views as of any subsequent date. Curis disclaims any intention or obligation to update any of the forward-looking statements after the date of this press release whether as a result of new information, future events or otherwise.

 

 

 

 

 

Contact: Curis, Inc.

Michael P. Gray, 617-503-6632

Chief Financial Officer

mgray@curis.com

 

 

Posted: September 2009

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