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Epizyme Unveils Corporate Strategy to Guide Efforts over Next Five Years

On March 9/2016 Epizyme, Inc., (NASDAQ:EPZM) a clinical stage biopharmaceutical company creating novel epigenetic therapies for patients with cancer, reported its corporate vision and strategy through 2020 (Press release, Epizyme, MAR 9, 2016, View Source [SID:1234509477]).

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During the next five years, Epizyme will focus on four transformative activities:

Transitioning to a commercial-stage organization through the global launch of tazemetostat in patients with non-Hodgkin lymphoma (NHL) and in patients with certain genetically defined solid tumors;
Expanding the clinical program for tazemetostat to support its utilization in earlier lines of therapy, in combination regimens, and in at least five new tumor types;
Growing the pipeline, with at least three new oncology product candidates in clinical development and a robust set of preclinical assets behind those; and,
Further establishing the company’s leadership in the field of epigenetics and chromatin remodeling in oncology and beyond to enable long-term, sustainable business growth.
"Our entire company is driven by our vision of rewriting cancer therapy through targeted medicines for patients with unsolved diseases," said Robert Bazemore, President & Chief Executive Officer. "Epizyme is committed to scientific excellence and pipeline innovation, which has allowed us to become the leading company in the discovery and development of epigenetic therapies in oncology. We have a clear set of priorities for 2016 designed to position us to deliver for patients and our stakeholders over the short, intermediate, and long term."

Accelerating Tazemetostat Registration

Epizyme is focused on a number of critical activities intended to accelerate the development of tazemetostat, aiming to bring it patients who may benefit as quickly as possible. Tazemetostat has demonstrated the potential to treat both hematologic malignancies and solid tumors, which laid the foundation for its aggressive development plan. Epizyme is currently evaluating tazemetostat in multiple global registration-supporting clinical trials, including a phase 2 five-arm study in patients with NHL, a phase 2 three-arm study in adult patients with certain genetically defined solid tumors, and a phase 1 dose-escalation and expansion study in pediatric patients with genetically defined solid tumors. Planned activities include:

Accelerating enrollment in the ongoing tazemetostat clinical trials through expansion into the U.S. and other countries, doubling the number of trial sites for the NHL study, and opening up to 45 trial sites for the genetically defined solid tumor studies.
Assessing expedited paths to market, including opportunities to proceed without randomized clinical trials prior to market entry.
Advancing clinical pharmacology studies to support registration and making manufacturing investments to prepare for approval.
Strengthening company functions needed to support an expedited development and launch plan.
"We have a number of important clinical and data milestones on the horizon in 2016, including reporting interim findings from our five-arm phase 2 study of tazemetostat in patients with NHL in the middle of this year," said Peter Ho, M.D., Ph.D., Chief Medical Officer. "The study is enrolling patients ahead of our expectations, and we look forward to assessing the data mid-year and with sufficient evidence of activity, we intend to move quickly into discussions with regulatory authorities to establish the path forward in each subtype of NHL."

Maximizing Tazemetostat Potential

In parallel to the accelerated development efforts for tazemetostat, Epizyme is working to expand the future utility of tazemetostat for a broad range of patients and physicians. Company activities to enable this include:

Exploring the potential of tazemetostat in front-line NHL by initiating a phase 1b/2 clinical trial of tazemetostat in combination with the current standard of care, R-CHOP. This study is expected to initiate in the second quarter of 2016.
Evaluating the additional potential of tazemetostat to enhance the clinical activity of immuno-oncology therapies by combining with an anti-PD1 or PDL-1 agent. Preclinical studies in the field show that EZH2 inhibitors, including tazemetostat, may potentially prime tumor cells and the microenvironment for synergy with immune checkpoint inhibitors. We plan to enter into a collaboration with a partner for this phase 1b combination study in the second quarter of 2016, and initiate the study mid-year.
Identifying new indications where tazemetostat may provide benefit and initiating clinical development in five new indications over the next five years. The first of these is BAP1 loss-of-function mesothelioma, which will enter clinical development in the third quarter of 2016.
Acting rapidly to initiate proof-of-concept studies where there is strong preclinical evidence of tumor sensitivity to EZH2 inhibition in a clearly defined patient population.
Continuing to invest in academic collaborations to evaluate the role of tazemetostat in new preclinical models.
Pipeline Growth and Scientific Leadership

Epizyme’s scientific expertise has led the company to expand its efforts to encompass histone methyltransferases (HMTs), as well as other chromatin modifying proteins (CMPs), which are implicated in multiple forms of hematological malignancies, solid tumors and other serious illnesses.

"Epizyme’s leadership in the areas of epigenetics and chromatin modification is the foundation of our long-term growth," said Robert Copeland, Ph.D., President of Research and Chief Scientific Officer. "We have demonstrated that our discovery platform can rapidly identify important therapeutic targets and effectively create small molecule drug candidates against those targets. We believe we have many opportunities to replicate the success we’ve seen with tazemetostat as we go forward."

To enable Epizyme’s long-term growth, the company plans to:

Build on the significant anti-tumor potential of histone methyltransferase inhibition and chromatin modifying protein inhibition by investing in the continued expansion and utilization of its proprietary platform to develop a pipeline of HMT and other CMP inhibitors.
Identify the most attractive targets for program development by utilizing CRISPR-based screening methodology to pinpoint targets where there is a clear signal for activity in specific tumor types.
Develop small molecule inhibitors against five novel targets identified by Epizyme that the company has designated as priority programs. These efforts are underway along with preclinical drug discovery to evaluate their viability as future clinical programs.
Initiate clinical development of at least three new small molecule oncology programs by 2020.
Retain rights to its wholly owned programs in the U.S., as well in certain foreign areas as part of potential future partnerships.
Evaluate potential new platform and program partnering opportunities both within and outside of oncology that might benefit from having a strategic partner, and provide additional downstream value-creation.
Summary

Bazemore concluded: "We are confident that we will continue to achieve great things to bring value for patients and our stakeholders. We have significant assets in tazemetostat, our early-stage pipeline, and our scientific platform, and following our financing in January, we have the resources to maximize their value through key milestones. In short, we have a clear strategy and are in a strong position to accomplish our goal."

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of patients with non-Hodgkin lymphoma and for patients with certain genetically defined solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In some human cancers, aberrant EZH2 enzyme activity results in dysregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for compound EPZ-6438.

Additional information about tazemetostat, including clinical trial information, can be found here.

Advaxis Truly Personalized Cancer Immunotherapy Moves Forward With Signing of an Exclusive Supply Agreement With Synthetic Genomics for Synthetic DNA

On March 09, 2016 (Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, and SGI-DNA, a wholly owned subsidiary of Synthetic Genomics, Inc. (SGI), reported that the companies have entered into a five-year exclusive supply agreement (Press release, Advaxis, MAR 9, 2016, View Source [SID:1234509453]). Under the terms of the agreement, SGI-DNA will manufacture for Advaxis synthetic DNA which will be used in Advaxis’ personalized Listeria monocytogenes (Lm)-based immunotherapy, known as MINE (My Immunotherapy Neo-Epitopes).

The goal of MINE is to use Advaxis’ Lm Technology to develop neo-epitope immunotherapies based on the specific and unique neo-epitopes found in an individual patient’s tumor. These neo-epitopes are built into DNA plasmids made exclusively by SGI-DNA for Advaxis and then inserted by Advaxis into patient specific immunotherapy constructs (ADXS-NEO), targeting the unique neo-epitope sequences identified in the patient’s tumor cells.

SGI-DNA’s synthetic DNA business is built on scientific advancements and breakthroughs from leading scientists including J. Craig Venter, Hamilton Smith, Clyde Hutchison, Dan Gibson and their teams, and utilizes DNA technologies to produce complex synthetic DNA. SGI-DNA also offers the BioXpTM 3200 System, the world’s first DNA printer, as well as a comprehensive suite of genomic services, including whole genome sequencing, library design, bioinformatics services, and reagent kits to enable synthetic biology.

"SGI-DNA is unparalleled in its commitment to innovative science, genomic services, bioinformatics and their ability to support DNA synthesis of components of Advaxis Lm immunotherapies," said Daniel O’Connor, President and Chief Executive Officer of Advaxis. "Our work with SGI-DNA will assist us in the development of our Lm Technologies and our innovative work with neo-epitopes to move us toward our planned filing of an Investigational New Drug Application later this year."

"We are excited to work with the Advaxis team and support their research and development program," said Nathan Wood, President of SGI-DNA. "We believe that SGI’s technical expertise in gene synthesis will help Advaxis meet its goal of making practical and effective personalized neo-epitope based treatments available for patients with cancer."

SGI-DNA’s proficiency with genomic sequencing, synthesis, and bioinformatics will factor in Advaxis’ current MINE research with Memorial Sloan Kettering Cancer Center (MSK).

Genmab Announces European Regulatory Submission for Ofatumumab in Combination with Fludarabine and Cyclophosphamide for Relapsed CLL

On March 9, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that a variation to the Marketing Authorization has been submitted to the European Medicines Agency (EMA) for the use of ofatumumab (Arzerra) in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) (Press release, Genmab, MAR 9, 2016, View Source [SID:1234509441]).

The application was submitted by Novartis under the ofatumumab collaboration between Novartis and Genmab.

The application is based on the results from a Phase III study, COMPLEMENT 2, which evaluated ofatumumab in combination with FC versus FC alone in patients with relapsed CLL. Top-line results from this trial were reported in April 2015. The study met the primary endpoint with a median progression free survival in patients receiving ofatumumab in combination with FC of 28.9 months compared to 18.8 months in patients receiving FC alone (HR =0.67, p=0.0032).

"Today’s regulatory submission in Europe brings us another step closer to making ofatumumab available to a wider group of patients with relapsed CLL and we look forward to the EMA’s response," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About CLL
CLL is the most common form of leukemia in the western world, accounting for 30% of adult leukemias.1 Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment.2

About COMPLEMENT 2
COMPLEMENT 2 (NCT00824265) is an open-label, two-arm, randomized, Phase III study, which included 365 patients in 18 countries with relapsed CLL. Patients in the study were randomized 1:1 to treatment with up to six cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to six cycles with fludarabine and cyclophosphamide alone.

The primary endpoint of the study was PFS, which was assessed by an Independent Review Committee (IRC) according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines.3 Secondary endpoints included overall response rate, overall survival, patient reported outcomes, time to response, duration of response, time to progression, time to next therapy, safety assessments and quality of life.

About Ofatumumab (Arzerra)
Ofatumumab is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. Arzerra is also approved as extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL in the U.S. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.

Arzerra is not approved anywhere in the world in combination with fludarabine and cyclophosphamide as treatment for relapsed CLL.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Arzerra is marketed under a collaboration agreement between Genmab and Novartis. Novartis has rights to develop ofatumumab in autoimmune indications, including multiple sclerosis.

Genmab Achieves Second Milestone in Daratumumab NHL Study Under Collaboration with Janssen

On March 9, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported it has reached a USD 5 million milestone in its daratumumab collaboration with Janssen Biotech, Inc. (Janssen) (Press release, Genmab, MAR 9, 2016, View Source [SID:1234509440]).

This is the second milestone payment triggered by progress in the ongoing Phase II study ("Carina" LYM2001) of daratumumab in NHL. The study evaluates daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). This milestone is related to progress in the arm of the study treating patients with FL.

"The daratumumab study in NHL is now underway, and we are very pleased to have achieved milestones for progress in two of the disease areas included in the study, FL and DLBCL," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We remain optimistic about the therapeutic potential of daratumumab in indications outside of multiple myeloma."

Daratumumab has received Orphan Drug designation from the US FDA for DLBCL, MCL and FL.

About the LYM2001 study
This Phase II study (NCT02413489) is a three arm (DLBCL, FL, MCL), open-label multicenter study which will enroll up to 210 patients with relapsed or refractory non-Hodgkin’s lymphoma. Patients in the study will be treated with daratumumab monotherapy. The primary endpoint of the study is overall response rate. The safety profile of daratumumab in these diseases will also be assessed.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (Tregs) both of which express CD38. These reductions in MDSCs and Tregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

Onconova Announces Publication of Rigosertib Phase 3 ONTIME Data in Lancet Oncology

On March 09, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the publication of results from the ONTIME trial of intravenous (IV) rigosertib in higher-risk myelodysplastic syndromes (HR-MDS) in the top-tier, peer-reviewed journal, Lancet Oncology (Press release, Onconova, MAR 9, 2016, View Source [SID:1234509436]). The article, titled, "Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial," currently appears in the online edition, and will appear in an upcoming print issue of the journal.

The ONTIME trial was a randomized clinical study in HR-MDS patients following the failure of hypomethylating agents (HMAs). Overall survival was the primary endpoint in this international study of 299 patients. Although there was a trend to improvement in overall survival with IV rigosertib, no statistically significant difference was observed in the intention-to-treat (ITT) analysis between treatment and control (best supportive care, BSC) arms. Analyses in multiple clinically-important subgroups suggested that rigosertib may provide a meaningful survival benefit over BSC in some HR-MDS patients, including those with primary HMA failure (i.e., never benefited from first-line treatment with HMAs). Additionally, those HR-MDS patients who were classified as Very High Risk by the International Prognostic Scoring System (Revised), and patients with monosomy 7 or trisomy 8 chromosomal aberrations, showed encouraging overall survival results with rigosertib. Collectively, these results helped define a more homogenous patient population for a new Phase 3 study of IV rigosertib, referred to as INSPIRE, which was initiated by Onconova in the fourth quarter of 2015.

"This publication presents peer-reviewed results of the ONTIME trial with insights into the complexity of MDS, particularly in patients whose disease has failed the available HMA therapies," said Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the paper. "Rigosertib was well tolerated in patients with a high unmet medical need who have no approved therapeutic options. We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new Phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients."

Steven Fruchtman, MD, Chief Medical Officer of Onconova added, "The INSPIRE trial is now open at multiple sites in the U.S., and we intend to initiate sites in Canada, Europe, Israel, and Australia. In addition, we are pleased that our commercial partner for Japan and Korea, SymBio Pharmaceuticals, Ltd., will also shortly begin enrolling patients for this study in Japan. We believe that publication of the ONTIME results in Lancet Oncology serves to highlight an important unmet medical need and the ongoing Phase 3 INSPIRE trial, and broadens the awareness of this pivotal study among physicians and patients."

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.1 The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.