SAN DIEGO, Jan. 6, 2015 /PRNewswire/ -- Mirati Therapeutics, Inc. (NASDAQ: MRTX) today announced that Memorial Sloan Kettering Cancer Center in New York has dosed the first patient in an investigator-sponsored Phase 2 clinical trial of mocetinostat in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The trial will enroll patients whose tumors have mutations or deletions of the CREBBP and/or EP300 genes.
"Genetic sequencing is becoming more widely used to select patients for specific targeted therapy for cancer. We are excited to begin testing mocetinostat, an oral HDAC inhibitor, in patients with DLBCL and FL that harbor CREBBP and EP300 genetic alterations," said Anas Younes, M.D., medical oncologist, chief of Memorial Sloan Kettering's Lymphoma Service, and principal investigator in the study. "This study will help determine if these mutations are predictive of response to mocetinostat that could lead to a new treatment option for patients with DLBCL and FL."
Mocetinostat is a potent and 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 DLBCL, FL, as well as bladder cancer and other solid tumor types. In preclinical models, mocetinostat reverses aberrant acetylation resulting from HAT mutations and is predicted to decrease tumors resulting in clinical responses in patients. The CREBBP and EP300 mutations are prevalent in up to 25% of patients with DLBCL and FL.
"Clinical studies of mocetinostat showed responses in a subset of patients with DLBCL," said Charles M. Baum, M.D., Ph.D., president and CEO of Mirati. "Working closely with our investigators and reviewing emerging cancer genomics research, we've identified CREBBP and EP300 as potential drivers of disease progression that may be particularly susceptible to treatment with mocetinostat. We believe that selecting patients with these mutations will increase the benefit to these patients and may provide an accelerated path to regulatory approval."
The open-label Phase 2 study of mocetinostat is expected to enroll 54 patients with relapsed/refractory non-Hodgkin's lymphoma (NHL): 27 patients with diffuse large B-cell lymphoma and 27 with follicular lymphoma. The purpose of this trial is to determine the therapeutic efficacy of mocetinostat in selected DLBCL and FL patients with CREBBP and/or EP300 genetic alterations. Eligible patients will be treated with mocetinostat and monitored for overall response, event free survival, and duration of response. Patients are expected to receive mocetinostat at a dose of 90 mg orally three times per week on a 28 day schedule.
Additional information about this clinical trial of mocetinostat is available at www.clinicaltrials.gov using identifier: NCT02282358.
About DLBCL
According to the Lymphoma Research Foundation, diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma, accounting for up to 30 percent of newly diagnosed cases in the United States. DLBCL is an aggressive, fast-growing lymphoma. It can arise in lymph nodes or outside of the lymphatic system, such as the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Often, the first sign of DLBCL is a painless swelling of lymph nodes in the neck, armpit, or groin area. For some patients, the swelling may be painful due to rapid enlargement of the lymph nodes. Other symptoms include night sweats, unexplained fevers, and weight loss.
Epigenetics and Cancer
There is a growing body of evidence that epigenetic changes play a pivotal role in a wide variety of cancers, including DLBCL. 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 acetyltransferase (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 that has been studied in 13 clinical trials in more than 400 patients with a variety of hematologic malignancies and solid tumors. Mocetinostat is currently in an investigator-sponsored Phase 2 study for the treatment of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) that carry mutations of the histone acetyltransferase genes CREBBP and EP300. In addition, Mocetinostat is enrolling patients in a Phase 2 trial for the treatment of patients with bladder cancer that carry mutations of the histone acetyltransferase genes CREBBP and EP300. 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 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 the response rates to mocetinostat for patients with bladder cancer or DLBCL, the success around selecting patients whose cancers may be sensitive to mocetinostat, and the potential for accelerated approval paths.
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.
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