Phase I clinical trial data of GDC-0449 published in the New England Journal Of Medicine

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>

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.