On December 28, 2015 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapies for cancer patients, reported the U.S. Food and Drug Administration’s (FDA) Division of Hematology Products has accepted the company’s investigational new drug (IND) application for tazemetostat for the treatment of adults with diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin Lymphoma (NHL) (Press release, Epizyme, DEC 28, 2015, View Source [SID:1234508643]).

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An ongoing five-arm registration-supporting, international phase 2 clinical trial assessing the safety and activity of tazemetostat in patients with relapsed or refractory B-cell NHL was initiated in July 2015 (NCT02601950). The IND acceptance will allow the company to enroll DLBCL patients in the United States into this ongoing trial.

"Tazemetostat has demonstrated clinically meaningful anti-tumor activity and an acceptable safety profile in patients with NHL in our phase 1 study," said Robert Bazemore, President and Chief Executive Officer. "We are excited to enable U.S. investigators to gain experience with tazemetostat in DLBCL."

"Patients with relapsed or refractory NHL have a significant need for new treatment options," said Dr. Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "We believe tazemetostat has the potential to become an important therapy for B-cell NHL patients, both as a monotherapy and in combination, and look forward to extending the ongoing five-arm NHL study to allow access to DLBCL patients in the U.S."

About the Tazemetostat Clinical Trial Program

The phase 2 NHL trial is a five-arm, multi-center, international study that will use a two-stage design to assess the safety and activity of tazemetostat in multiple populations of patients with relapsed or refractory Non-Hodgkin Lymphoma. The study will enroll up to 30 patients in each arm. Patients will be prospectively stratified for EZH2 mutation status and cell-of-origin. The five study arms are enrolling relapsed/refractory patients with:

Germinal center DLBCL with mutant EZH2
Germinal center DLBCL with wild-type EZH2
Non-germinal center DLBCL
Follicular lymphoma with mutant EZH2
Follicular lymphoma with wild-type EZH2
Epizyme expects to present interim data from the phase 2 study in NHL at a medical conference in mid-2016.

In the first half of 2016, the Company also plans to initiate additional clinical evaluations of tazemetostat, including a combination study with R-CHOP in front-line, high-risk patients with DLBCL, and a combination study with a B-cell signaling agent or immuno-oncology agent in B-cell NHL.

In August 2015, the FDA’s Division of Oncology Products 2 accepted Epizyme’s IND application to study adult and pediatric patients with INI1-negative solid tumors or synovial sarcoma.

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of patients with Non-Hodgkin Lymphoma and for patients with INI1-negative solid tumors, certain SMARCA4-negative solid tumors or synovial sarcoma. 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 misregulation 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 this program, including clinical trial information for the adult five-arm NHL study, can be found here: View Source

Information about the company’s Phase 2 clinical trial of tazemetostat in adults with INI1-negative solid tumors, certain SMARCA4-negative solid tumors or synovial sarcoma can be found here: View Source

Information about the company’s Phase 1 clinical trial of tazemetostat in children with INI1-negative solid tumors, certain SMARCA4-negative solid tumors or synovial sarcoma can be found here: View Source

On December 23, 2015 Cellectis (Alternext: ALCLS – Nasdaq: CLLS) reported the submission of a clinical trial application (CTA) to the Medicines & Healthcare products Regulatory Agency (MHRA) requesting approval to initiate UCART19 First-in-Human clinical investigation in leukemia in the United Kingdom (Press release, Cellectis, DEC 23, 2015, View Source [SID:1234508638]).

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This study aims to include CD19-positive Acute Lymphoblastic Leukemia (ALL) patients. Other eligibility criteria to enter clinical trials will be assessed by the investigators.

"It has been a privilege preparing this application with our team, partners, investigators and subcontractors, in close interaction with MHRA, rewarding many years of intense work to overcome the challenges that are inherent to advanced therapy medicinal products. This achievement marks an important step toward making UCART19 available to patients," said Stephan Reynier, Chief Regulatory and Compliance Officer, Cellectis.

"The UCART19 CTA filing is a great recognition for the Company’s preclinical and manufacturing accomplishments in developing a therapeutic for Acute Lymphoblastic Leukemia. We are all pleased with Cellectis’ progress to date with UCART19, including the filing of this CTA, and we look forward to following the progress of this program through the course of its clinical development," said Dr. Mathieu Simon, EVP, Chief Operating Officer, Cellectis.

About UCART19

UCART19 is a potential best-in-class allogeneic TALEN gene edited T-cell product for treatment of CD19 expressing hematological malignancies, initially developed in Chronic lymphocytic leukemia (CLL) and Acute lymphoblastic leukemia (ALL). Engineered allogeneic CD19 CAR T-cells currently stand out as a real therapeutic innovation for treating various types of leukemia and lymphoma. Cellectis’ approach with UCART19 is based on the preliminary positive results from clinical trials using products based on the CAR technology and has the potential to overcome the limitation of the autologous current approach by providing an allogeneic frozen, "off the shelf" T-cell based medicinal product.

On November 18, 2015 Servier exercised its worldwide option to license UCART19 and entered into a global development and commercialization collaboration with Pfizer on UCART19. According to their recent agreement, Cellectis will hand over the clinical development of UCART19 to Servier and their US partner Pfizer. Due to the early exercise, Cellectis is no longer responsible for funding the UCART19 Phase I clinical program.

On December 23, 2015 Agenus Inc. (NASDAQ: AGEN), an immunotherapy company developing innovative treatments for cancer, reported that it has acquired privately-held PhosImmune Inc., a company that has discovered an entirely new portfolio of cancer neoantigens (Press release, Agenus, DEC 23, 2015, View Source [SID:1234508637]). The acquisition provides Agenus the ability to accelerate the development of new cancer vaccines and other single agent immuno-oncology approaches, as well as combination therapies.

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"PhosImmune’s groundbreaking neoantigen assets significantly expand Agenus’ current efforts, and present exciting near-term opportunities for new products and partnerships," said Dr. Garo H. Armen, Chairman and Chief Executive Officer of Agenus. "This acquisition expands our immuno-oncology pipeline and strengthens our neoantigen capabilities to enable the development of best-in-class cancer vaccines and other novel therapies."

Novel Neoantigens

PhosImmune’s neoantigens have unique advantages in cancer immunotherapy. The company’s phosphopeptide tumor targets (PTTs) are fragments of proteins expressed in cancer cells. These fragments are phosphorylated due to signal dysregulation involved in the development of cancers and, as a result, appear as foreign to the immune system. The approach is synergistic with Agenus’ AutoSynVax vaccine program for targeting patient-specific tumor neoantigens. PTTs can expand AutoSynVax and other immunotherapeutic approaches to include patients with lower levels of mutations that may not have enough neoantigens to activate the immune system effectively. PTTs can also be shared by patients with specific cancers, providing the potential for "off-the-shelf" vaccines.

PhosImmune’s scientific founders, Donald Hunt, Ph.D. and Vic Engelhard, Ph.D., both of University of Virginia, and Mark Cobbold, M.D., Ph.D., of Massachusetts General Hospital, have identified a large number of proprietary, tumor-specific PTTs. These PTTs are found on a wide variety of cancer types.

"By acquiring PhosImmune, we are accessing a capability with transformational potential for both patient-specific and off-the-shelf cancer vaccine products," said Robert B. Stein, M.D., Ph.D., Chief Scientific Officer and Head of R&D for Agenus. "In addition, our entire portfolio will benefit from the world-class peptide analytics expertise of PhosImmune’s founders. We believe there are a number of near-term opportunities to advance potentially powerful cancer therapies into the clinic that build on and leverage the ongoing work at Agenus."

"Agenus has deep knowledge and expertise in the immunotherapy field, and we are excited to join forces with their research and development team," said Donald Hunt, President and Scientific Founder of PhosImmune. "We are confident that by working together we can more rapidly advance the development of immuno-oncology products and realize the potential of our extensive research into how the immune system recognizes cancers as non-self."

Terms

Under the terms of the agreement, Agenus paid PhosImmune’s equity holders an upfront payment of $2.5 million in cash and $7.4 million in shares of Agenus common stock at closing. Additional payments of up to $35 million in cash and/or stock at Agenus’ election are payable upon the achievement of certain milestones.

About Neoantigens

Both genetic mutations and abnormal phosphorylation processes found in cancer cells can result in the formation of aberrant proteins with altered function. When degraded inside cancer cells, these proteins are broken up into short peptide fragments that can be presented on the cell surface. These peptides, termed neoantigens, have the potential to alert the immune system that a cancer is developing.

About AutoSynVax

Agenus’ AutoSynVax (ASV) program targets cancer neoantigens with an autologous synthetic vaccine approach. By utilizing next generation sequencing and advanced bioinformatics, patient-specific tumor mutations are identified for rapid and accurate selection of neoantigens. The ASV platform generates synthetic peptide neoantigens complexed with heat shock proteins (HSPs) that shuttle these neoantigens to antigen presenting cells. The ASV program builds on Agenus’ extensive clinical experience with individualized and synthetic HSP vaccines.

On December 23, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported that it has completed the submission of its rolling New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy (Press release, Exelixis, DEC 23, 2015, View Source [SID:1234508634]). Exelixis has requested Priority Review as part of the NDA filing.

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In August 2015, the FDA granted Breakthrough Therapy designation to cabozantinib for this potential advanced RCC indication. Breakthrough Therapy designation can expedite the development and review of drugs that are intended to treat serious or life-threatening diseases, and for which preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Drugs that receive Breakthrough Therapy designation may benefit from the involvement of FDA senior leadership in the review process, rolling submission, and other benefits. Prior to receiving Breakthrough Therapy designation, cabozantinib received Fast Track designation for its potential advanced RCC indication in April 2015.

"Completing the submission of our rolling New Drug Application brings us closer to our goal of improving the treatment options for patients with advanced kidney cancer," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Following the release of positive top-line results from our phase 3 pivotal trial in July, the Exelixis team worked expeditiously to complete the U.S. regulatory filing by year end. We look forward to continuing to work with the FDA team during the review process."

The NDA submission is based on results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

In the European Union, Exelixis aims to complete its Marketing Authorization Application (MAA) in early 2016. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recently granted accelerated assessment to cabozantinib for advanced RCC. As a result, when filed, the company’s MAA may be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested from CHMP).

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA for advanced RCC.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and a checkpoint inhibitor have been approved for the treatment of patients who have received prior VEGF receptor TKIs. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.