Methylgene and Pharmion Start Phase II Combination Clinical Trial With MGCD0103 and Vidaza(R) in Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma
MethylGene Inc. (TSX: MYG) and Pharmion Corporation (NASDAQ: PHRM) today announced the enrollment of the first patient in a Phase II clinical trial (Trial 012) evaluating MGCD0103, the Companies’ isotype-selective histone deacetylase inhibitor (HDACi) product candidate, in combination with Vidaza(R) (azacitidine for injection), Pharmion’s DNA demethylating agent, in patients with relapsed or refractory Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL).
Patients will receive 75 mg/m2 of Vidaza either intravenously or subcutaneously in combination with an oral dose of MGCD0103 in 28 day cycles. Key objectives for this study are to determine the overall response rate, progression free survival and duration of response. The trial will enroll up to 75 patients at cancer centers in North America and will include a pharmacokinetic equivalency study.
“We are aggressively exploring the utility of epigenetic drug combinations in the treatment of cancer,” said Andrew Allen, Pharmion’s Executive Vice President and Chief Medical Officer. “The biology of cancer suggests multiple epigenetic mechanisms cooperate to silence tumor suppressor genes, which raises the simple hypothesis that attacking these mechanisms with drug combinations may be superior to single-agent therapy. In this trial, we are combining Vidaza, our DNA methyltransferase inhibitor, with MGCD0103, our isotype-selective HDAC inhibitor, in a clinical study of this therapeutic approach. We are unique in our ability to conduct a trial like this, using drugs from our own portfolio.”
“We are delighted to be participating in this trial of Vidaza and MGCD0103,” commented Dr. Anas Younes, Professor of Medicine and Director, Clinical Investigation and Translational Research in the Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center and a principal investigator for this trial. “There have been no new approved therapies in relapsed/refractory Hodgkin lymphoma for decades. As epigenetics is thought to play a role in lymphoma, this clinical study will help build an understanding of the role of HDAC inhibitors and demethylating agents in the treatment of non-Hodgkin and Hodgkin lymphoma.”
Encouraging anti-tumor activity has been demonstrated in a Phase II clinical study of MGCD0103 as a single agent in the relapsed or refractory Hodgkin lymphoma patient population. Data from the ongoing study, presented at the American Society of Hematology (ASH) annual meeting last month, reported an objective complete and partial response (CR and PR) rate of 38 percent and a disease control rate of 43 percent in 21 evaluable patients in the 110mg cohort. Eighty-six percent of patients who had CT scans experienced a reduction in tumor size, with 57 percent experiencing a tumor reduction of greater than 30 percent. The two CR patients have a preliminary progression-free survival (PFS) of 14 and nine months at the time of analysis, and the range of PFS from the responder group is 56 to greater than 396 days. Adverse events associated with MGCD0103 administration of grade 3 or higher included pneumonia (15 percent), thrombocytopenia (12 percent) and fatigue (nine percent). Dose modification was effective in many of these patients.
About MGCD0103
MGCD0103 is an orally-administered, isotype-selective HDAC inhibitor. The compound is currently in one Phase I combination clinical trial with Taxotere(R) for solid tumors, two Phase I/II combination trials with Vidaza(R) for hematological malignancies and with Gemzar(R) for pancreatic cancer, and five Phase II clinical trials in hematological malignancies.
MGCD0103 has received orphan drug designation from the U.S. Food and Drug Administration (FDA) and has been designated an orphan medicinal product by the European Medicines Agency (EMEA) for the treatment of Hodgkin lymphoma.
About Vidaza
In May 2004, Vidaza became the first drug approved by the FDA for the treatment of patients with Myelodysplastic Syndromes (MDS). The FDA approved Vidaza, the first in a new class of drugs called demethylation agents, for treatment of all five MDS subtypes. These subtypes include: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) if accompanied by neutropenia or thrombocytopenia or requiring transfusions; refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
Vidaza is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of Vidaza required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of Vidaza cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non- proliferating cells are relatively insensitive to Vidaza. Vidaza was approved for IV administration in January 2007.
About Epigenetic Therapy
DNA methylation and histone deacetylation are the two most studied epigenetic regulators of gene expression. Vidaza reverses the effects of DNA hypermethylation with subsequent tumor suppressor gene re-expression. MGCD0103 exerts its epigenetic effects by acting as an oral isotype-selective HDAC inhibitor. Together, the two act synergistically to induce suppressor gene re-expression and favorably influence the clinical course of cancer. Pharmion strongly believes that by targeting two separate epigenetic pathways simultaneously, the combination of drugs targeting DNA methylation and histone deacetylation can either increase the susceptibility of cancer cells to standard chemotherapy or act as a potent therapeutic regimen in its own right.
About Hodgkin Lymphoma
Hodgkin lymphoma (HL) is a cancer of the lymphatic system that begins in the lymph nodes and progresses to other organs, including the lungs, liver, bone and bone marrow. It is characterized by the presence of Reed-Sternberg cells. Currently, there is no known cause of the disease, but epigenetic alterations including changes in histone acetylation, have been identified. In addition, the Epstein-Barr virus, HIV and familial history are known risk factors. The disease is slightly more prevalent in men than women, and the median age of diagnosis is 38.
About Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) are any of a large group of cancers of the immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever, and weight loss. There are many different types of NHL, which can be divided into aggressive (fast-growing) and indolent (slow-growing) types and can be classified as either B-cell or T-cell NHL. B-cell NHLs include Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T-cell NHLs include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas related to lymphoproliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHLs. Currently, there is no known cause of the disease, but epigenetic alterations including histone acetylation, have been identified. In addition, the Epstein-Barr virus, HIV, Hepatitis-C and familial history are known risk factors. The disease is slightly more prevalent in men then women, and is most common in those over the age of 60.
According to the American Cancer Society, there are approximately 59,000 new cases of non-Hodgkin lymphomas diagnosed each year in the U.S. DLBCL is the most common form of NHL lymphomas accounting for up to 30 percent of newly-diagnosed cases.
Important Vidaza Safety Information
Vidaza is contraindicated in patients with a known hypersensitivity to Vidaza or mannitol and in patients with advanced malignant hepatic tumors.
In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%) and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%) and malaise (10.9%). The most common adverse reactions by IV route also included petechiae (45.8%), rigors (35.4%), weakness (35.4%) and hypokalemia (31.3%).
Because treatment with Vidaza is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. Because Vidaza is potentially hepatotoxic in patients with severe pre- existing hepatic impairment, caution is needed in patients with liver disease. In addition, Vidaza and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Vidaza may cause fetal harm. While receiving treatment with Vidaza, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with Vidaza should not nurse.
About MethylGene
MethylGene Inc. (TSX: MYG) is a publicly-traded biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for cancer. The Company’s lead product, MGCD0103, is an oral isotype-selective HDAC inhibitor presently in multiple clinical trials for solid tumors and hematological malignancies, including Phase II monotherapy and Phase I and Phase II combination trials with Vidaza(R), Gemzar(R) and Taxotere(R). MGCD265 is an oral kinase inhibitor targeting the c-Met, Tie-2, Ron and VEGF receptor tyrosine kinases. In addition, MethylGene has several preclinical programs: MGCD290 an HDAC inhibitor in combination with azoles for fungal infections; an HDAC program for Huntington’s disease; and a sirtuins program for cancer. MethylGene’s development and commercialization partners include Pharmion Corporation, Taiho Pharmaceutical and EnVivo Pharmaceuticals. Please visit our website at http://www.methylgene.com.
About Pharmion
Pharmion is a leading global oncology company uniquely focused on acquiring, developing and commercializing innovative products for the treatment of hematology and oncology patients in the U.S., Europe and additional international markets. Pharmion has a number of products on the market including the world’s first approved epigenetic drug, Vidaza(R), a DNA demethylating agent. For additional information about Pharmion, please visit the company’s website at http://www.pharmion.com.
Certain statements contained in this news release, other than statements of fact that are independently verifiable at the date hereof, may constitute forward-looking statements. Such statements, based as they are on the current expectations of management of MethylGene, inherently involve numerous risks and uncertainties, known and unknown, many of which are beyond MethylGene’s control. These risks and uncertainties could cause future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Such results, performance or achievements include, but are not limited to, the timing and effects of regulatory action; the continuation of collaborations; the impact of unilateral decisions and/or strategies of our collaborators; the results of clinical trials; the ability to demonstrate pharmacokinetic / bioequivalency; the timing of enrollment or completion of clinical trials; the success, efficacy or safety of MGCD0103, MGCD265 or MGCD290; the ability to scale up, formulate and manufacture sufficient GMP, clinical or commercialization quantities of MGCD0103, MGCD265 or MGCD290, and the relative success or the lack of success in developing and gaining regulatory approval and/or market acceptance for any compound or new product including MGCD0103, MGCD265 or MGCD290. Such risks include, but are not limited to, the impact of general economic conditions, economic conditions in the pharmaceutical industry, changes in the regulatory environment in the jurisdictions in which MethylGene does business, stock market volatility, fluctuations in costs, expectations with respect to our intellectual property position and our ability to protect our intellectual property and operate our business without infringing upon the intellectual property rights of others, changes in the competitive landscape including changes in the standard of care for the various indications in which MethylGene is involved, and changes to the competitive environment due to consolidation, as well as other risks, which you are urged to read, as described in MethylGene’s Annual Information Form for the fiscal year ending December 31, 2006, under the heading ‘risk factors’, the final prospectus filed on February 23, 2007, and all other documents filed by the Company that can be found at www.sedar.com. Consequently, actual future results may differ materially from the anticipated results expressed in the forward-looking statements. The reader should not place undue reliance on the forward-looking statements included in this presentation. These statements speak only as an update on the date they are made and MethylGene is under no obligation to revise such statements as a result of any event, circumstance or otherwise except in accordance with law.
Contacts: Rx Communications Group, LLC Rhonda Chiger 917-322-2569 rchiger@rxir.com MethylGene Inc. Donald F. Corcoran President & CEO 514-337-3333 ext. 373 mctavishk@methylgene.com Pharmion Corporation Breanna Burkart Director, Investor Relations and Corporate Communications 720-564-9144 bburkart@pharmion.com Anna Sussman Director, Investor Relations and Corporate Communications 720-564-9143 asussman@pharmion.com
SOURCE: MethylGene Inc.