Mirati Therapeutics Doses First Patient in Phase 2 Study of Mocetinostat in Bladder Cancer Patients with Genetic Alterations of CREBBP and EP300

SAN DIEGO, Jan. 7, 2015 /PRNewswire/ -- Mirati Therapeutics, Inc. (NASDAQ: MRTX) today announced that the first patient has been dosed in a Phase 2 clinical trial designed to evaluate the efficacy, safety and pharmacokinetics of mocetinostat as a treatment for a select group of patients with bladder cancer. The trial will enroll patients whose tumors have mutations or deletions of the CREBBP and/or EP300 genes.

"Published research suggests that genetic alterations of CREBBP and EP300 appear in up to 25% of bladder cancer cases," said Charles M. Baum, M.D., Ph.D., president and CEO of Mirati. "This represents a promising patient enrichment strategy for clinical development and, if successful, may lead to an accelerated development path for a highly underserved population of patients with advanced bladder cancer."

"Histone acetyl transferase (HAT) gene loss of function has emerged as a potential predictive marker of response to mocetinostat in cancer. Mutations in these HAT genes, EP300 and CREBBP, are common in bladder cancer," said Jonathan E. Rosenberg, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center and principal investigator in the study. "Clinical responses have been seen in bladder cancer with HDAC inhibitors suggesting the potential benefit of targeting dysregulation in histone and DNA acetylation in bladder cancer. To evaluate this promising approach, we will focus on selecting bladder cancer patients with these particular genetic mutations who may be most likely to respond to mocetinostat treatment."

Mocetinostat is a potent spectrum selective inhibitor of HDAC 1, 2, 3 and 11, which are master regulators of cancer gene expression. Mocetinostat is being developed as a single agent treatment targeting mutations and deletions of the histone acetyltransferase (HAT) genes CREBBP and EP300. These genetic alterations are implicated in the pathogenesis and progression of bladder cancer and other solid tumor types, as well as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In preclinical models, mocetinostat reverses aberrant acetylation resulting from HAT mutations and is predicted to decrease tumors resulting in clinical responses in patients.

The primary objective of the Phase 2 study is to determine the efficacy of mocetinostat in patients with previously treated, locally advanced, unresectable or metastatic urothelial carcinoma harboring inactivating mutations or deletions of the HAT genes CREBBP and/or EP300. Secondary objectives include evaluation of safety, secondary efficacy endpoints and pharmacokinetics. Mocetinostat capsules will be administered orally three times per week on a 28-day cycle. 

Additional information about this clinical trial of mocetinostat is available at www.clinicaltrials.gov using identifier: NCT02236195.

About Bladder Cancer

The most common type of bladder cancer is known as urothelial carcinoma (UC) and accounts for approximately 90% of all bladder cancers. Approximately 60% of UC patients have non-muscle invasive disease (Stage 0 or Stage 1), 30% have muscle-invasive disease (Stages II – III) and 10% have metastatic UC at the time of initial diagnosis. Approximately 50% of patients with high-risk muscle-invasive disease may eventually develop metastasis. Metastatic UC of the bladder may be treated using chemotherapy, however, approximately 50% of patients will relapse and no standard second line therapies for metastatic disease have been shown to be of clinical benefit. The median survival rate for metastatic UC of the bladder is approximately 13 months, and this value has changed very little over the last 30 years suggesting there is a need to develop new therapies.

Epigenetics and Cancer

There is a growing body of evidence that epigenetic changes play a pivotal role in a wide variety of cancers, including bladder cancer. Epigenetic changes are those changes to DNA structure, such as methylation and acetylation, other than changes in the DNA sequence. Aberrant acetylation patterns in DNA can lead to dysregulated gene expression of oncogenes and tumor suppressor genes that can result in tumor formation and disease progression. A proper balance of acetylation and deacetylation is regulated by histone acetyltransferases (HAT) and histone deacetylases (HDACs), respectively.

CREBBP and EP300 are histone acetyltranferase (HAT) genes that function as epigenetic "writers" by adding acetyl groups to key histone and non-histone proteins, while HDACs have an opposing function as epigenetic "erasers" by removing acetyl groups. HAT genes and HDACs act together to regulate the expression of important genes involved in cell growth, survival and differentiation. The loss of function of the CREBBP and EP300 genes results in impaired regulation of protein acetylation and dysregulation of gene expression leading to tumor progression. By reducing the degree of deacetylation, an HDAC inhibitor such as mocetinostat may be able to compensate for loss of function of CREBBP and EP300 genes, and thereby restore normal gene expression patterns.

About Mocetinostat

Mocetinostat is an orally-bioavailable, spectrum-selective HDAC inhibitor. Mocetinostat has completed 13 clinical trials in more than 400 patients with a variety of hematologic malignancies and solid tumors. Mocetinostat is currently in a Phase 2 trial for the treatment of patients with bladder cancer that carry mutations of the histone acetyltransferase genes CREBBP and EP300. An investigator-sponsored study evaluating mocetinostat as a treatment for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) is also underway. Mirati believes that focusing on patient populations enriched for these driver mutations presents opportunities for breakthrough therapies and accelerated approval paths.

The U.S. FDA has granted Orphan Drug Designation to mocetinostat as a treatment for DLBCL and MDS. Mirati retains worldwide rights to mocetinostat with the exception of certain Asian territories where the program is partnered with Taiho Pharmaceutical Co., Ltd.

About Mirati Therapeutics

Mirati Therapeutics is a targeted oncology company developing a pipeline of oncology therapeutics for precisely defined patient populations. Mirati's approach combines the three most important factors in oncology drug development – drug candidates targeting genetic and epigenetic drivers of cancer, creative and agile clinical development that selects for patients whose tumors are dependent on those driver alterations, and a highly accomplished precision medicine leadership team. The Mirati team is using a blueprint proven by their prior work for developing potential breakthrough therapies with accelerated development paths. Mirati is currently advancing three drug candidates through clinical development for multiple oncology indications. More information is available at www.mirati.com.

Forward Looking Statements

Certain statements contained in this news release, other than statements of fact that are independently verifiable at the date hereof, may constitute forward-looking information and forward-looking statements (collectively "forward-looking statements" within the meaning of applicable securities laws). Such statements, based as they are on the current expectations of management of Mirati and upon what management believes to be reasonable assumptions based on information currently available to it, inherently involve numerous risks and uncertainties, known and unknown, many of which are beyond Mirati's control. Such statements can usually be identified by the use of words such as "may", "would", "believe", "intend", "plan", "anticipate", "estimate" and other similar terminology, or state that certain actions, events or results "may" or "would" be taken, occur or be achieved. Forward-looking statements in this release include, but are not limited to, statements regarding ability to halt tumor progression and reduce tumor burden in patients, the size of the patient population, and the potential for accelerated approval path.

Whether actual results and developments will conform with our expectations and predictions is subject to a number of risks, assumptions and uncertainties, many of which are beyond our control, and the effects of which can be difficult to predict. These risks include those inherent in drug development, whether Mirati will be able to obtain financing when needed or on favorable terms, and other risks described in Mirati's filings with the Securities and Exchange Commission. In evaluating any forward-looking statements in this release, Mirati cautions readers not to place undue reliance on any forward-looking statements. Unless otherwise required by applicable securities laws, Mirati does not intend, nor does it undertake any obligation, to update or revise any forward-looking statements contained in this news release to reflect subsequent information, events, results or circumstances or otherwise.

Company Contact:
Mirati Therapeutics Inc.
Mark J. Gergen
Executive Vice President & COO
858-332-3410

Investor Relations and Media Relations:
Jason Spark
Canale Communications
619-849-6005
[email protected]

SOURCE Mirati Therapeutics, Inc.

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