On December 07, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported the presentation of pre-clinical data describing the synergy of the Company’s next generation PI3K-delta inhibitor, TGR-1202, with proteasome inhibitors in various hematologic cell lines and patient donor cells (Press release, TG Therapeutics, DEC 7, 2015, View Source [SID:1234508473]). The oral presentation was delivered by Changchun Deng, MD, PhD, Assistant Professor, Center of Lymphoid Malignancies, Columbia University Medical Center at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

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Combination data was generated using TGR-1202, the PI3k-delta inhibitor idelalisib, and the proteasome inhibitors carfilzomib and bortezomib. Data revealed that the combination of TGR-1202 and carfilzomib was uniquely synergistic as compared to any other combination of a PI3K-delta inhibitor and proteasome inhibitor, including the combination of idelalisib and cafilzomib and idelalisib and bortezomib. These data were generated as part of a large pre-clinical research collaboration with the Center for Lymphoid Malignancies, whereby the activity and mechanism of action of TGR-1202 is being studied in a variety of in-vitro and in-vivo models.

Presently there are no agents approved that specifically target c-Myc, an oncogene often found constitutively active in a variety of cancers, including Diffuse Large B-Cell Lymphoma, and has recently been the target of a class of drugs knows as BET (bromodomain and extraterminal domain family) inhibitors. The combination of TGR-1202 and carfilzomib was found to potently inhibit cap dependent translation of c-Myc in all cell lines tested, including DLBCL, mantle cell lymphoma, multiple myeloma, T-cell lymphoma, and CLL cells. In these cell lines, inhibition of c-Myc expression resulted in increased caspase 3/7 activity and complete cleavage of PARP, both mechanisms of apoptosis. Importantly, the combination was not found to be cytotoxic when evaluated on healthy patient lymphocytes indicating the specificity towards malignant cells. As a result of these data, the combination of TGR-1202 and carfilzomib is intended to be studied in a Phase I/II clinical trial to be led by investigators at Columbia University Medical Center.

Commenting on the data, Owen A. O’Connor, MD, PhD, Professor of Medicine and Experimental Therapeutics, and Director of the Center for Lymphoid Malignancies at Columbia University Medical Center stated, "The development of agents that have the ability to inhibit the expression or activity of c-Myc, a key driver in a large variety of hematologic and solid-tumor malignancies, has long been an area of focused research which to date has yielded modest results. The potential for this unique combination is far reaching, and begins to explain the differentiated pharmacologic profile demonstrated by TGR-1202 in patients. We look forward to continuing to elucidate the mechanisms for TGR-1202’s unique tolerability and efficacy, as well as evaluating this combination in patients in our upcoming Phase I/II study."

Michael S. Weiss, the Company’s Executive Chairman and Interim CEO stated, "TGR-1202 has demonstrated strong activity with a differentiated safety and tolerability profile in patients across a variety of clinical trials, and we are eager to explore and understand the mechanisms that contribute to TGR-1202’s potential best-in-class attributes. We thank the investigators at Columbia University, especially Dr. Deng and Dr. O’Connor, for all their efforts on this important research program."

PRESENTATION DETAILS

A copy of the slides used for the oral presentation is available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.

On December 7, 2015 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapeutics for cancer patients, reported updated results from the ongoing phase 1 trial of tazemetostat (EPZ-6438), a first-in-class oral EZH2 inhibitor (Press release, Epizyme, DEC 7, 2015, View Source [SID:1234508454]). Data from this trial continue to show meaningful clinical activity with tazemetostat when used as an oral monotherapy in patients with either relapsed or refractory Non-Hodgkin Lymphoma (NHL). Nine of 16 response-evaluable patients with NHL have achieved an objective response, with the duration of responses lasting up to 19 months as of the data cutoff. The data were presented today by Vincent Ribrag, M.D., Institut Gustave Roussy, at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper).

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"In this ongoing phase 1 study, we continue to observe meaningful and durable clinical activity with tazemetostat in NHL patients," said Dr. Ribrag. "The phase 2 five-arm study, which is currently underway, will advance our understanding of the clinical utility of this agent in the different subsets of NHL. I believe tazemetostat has the potential to become an important new addition to the available treatment options for our patients."

Summary Results

As of the November 7, 2015 cutoff, the following clinical data were reported:

Twenty-one patients with relapsed or refractory NHL were enrolled into the phase 1 study; 16 of the 21 patients were response-evaluable as defined by the study protocol.
Nine of 16 (56 percent) response-evaluable NHL patients achieved an objective response.
On an intent-to-treat basis, seven of 12 (58 percent) response-evaluable NHL patients treated at or above the recommended phase 2 dose of 800 mg twice daily (BID) achieved an objective response.

Four patients remained on study at data cutoff with ongoing objective responses, including three patients who had been on drug for at least 18 months.

800 mg BID showed superior tolerability, equivalent anti-tumor activity and equivalent pharmacodynamic activity as compared to the 1600 mg BID dose.

The majority of adverse events were grade 1 or grade 2 within the 55 patients with NHL and solid tumors who were evaluable for safety. The most common adverse events, regardless of attribution, were asthenia, anorexia, thrombocytopenia, nausea, constipation, diarrhea, and vomiting. Four grade 3 or greater treatment-related adverse events have been observed including one each of: grade 3 hypertension, grade 3 liver function test elevation, grade 4 thrombocytopenia, and grade 4 neutropenia.

Study Design

This open-label, multi-center, phase 1 study is investigating tazemetostat as monotherapy in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma or advanced solid tumors. The study objectives include identification of the recommended phase 2 dose or maximum tolerated dose, safety, tolerability, pharmacokinetics and preliminary evaluation of anti-tumor activity. Five cohorts were studied in the dose escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase. All doses were given twice daily. In addition, the study included two clinical pharmacology sub-studies: one for food effect and the other for drug-drug interaction. In the food effect sub-study, patients received a single 200 mg dose of tazemetostat either fasted or immediately after a high-fat breakfast in a randomized crossover fashion with seven days between doses. Patients received 400 mg BID after completing the seven-day crossover component of the study. Five of the 21 NHL patients were in the food effect sub-study.

Expanded Tazemetostat Registration-Supporting Phase 2 Program in NHL

Epizyme is conducting an international, multi-center, phase 2 study comprised of five independent arms. This study, which began enrolling patients in the second half of 2015, will assess the safety and efficacy of 800 mg BID of tazemetostat in patients with relapsed or refractory NHL, stratified by cell of origin and EZH2 mutation status. Epizyme plans to present interim results from the phase 2 study at a medical conference in mid-2016.

About EZH2 in Cancer

EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include Non-Hodgkin Lymphoma, INI1-deficient cancers such as malignant rhabdoid tumors, epithelioid sarcomas and synovial sarcoma; and a range of other solid tumors.

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many 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 EPZ-6438.

Additional information about this program, including clinical trial information, may be found here: View Source

On December 07, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported the presentation of updated clinical results from its ongoing Phase I single agent study of TGR-1202, the Company’s next generation PI3K delta inhibitor, as well as its Phase II combination study of TG-1101 (ublituximab), the Company’s novel, glycoengineered monoclonal antibody plus ibrutinib, the oral BTK inhibitor (Press release, TG Therapeutics, DEC 7, 2015, View Source [SID:1234508474]). Data from these studies are being presented today, Monday December 7, 2015 at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We are extremely pleased that the activity and safety profile of TGR-1202 continues to exhibit best in class attributes. As a once daily PI3K delta inhibitor, we believe the added convenience along with a low occurrence of hepatic toxicity, will make TGR-1202 a very appealing treatment option for physicians. More importantly, with over 80 patients having been exposed to TGR-1202 for over 6 months and another 42 on drug for more than a year, we believe the data supports that colitis associated with other PI3K deltas is not likely to be a major concern for TGR-1202. We are also excited about the final data from our 1101 plus ibrutinib study in patients with advanced Mantle Cell Lymphoma. More and more, physicians are recognizing the need to deepen ibrutinib responses to avoid relapse and the data demonstrating a doubling of CRs in patients with MCL compared to historical data of single agent ibrutinib seems very encouraging, although in a small number of patients. The deepening of responses in MCL, primarily a nodal disease, is further confirmation of the ability of TG-1101 to penetrate the nodes and improve responses. This is consistent with the deepening of responses seen with the combination in CLL, where we reported 25% CR and/or MRD negativity in rel/ref CLL, which compares favorably to the ibrutinib label. We believe this is further confirmation of the benefit we expect to see in our GENUINE Phase 3 trial."

Dr. Owen A. O’Connor, Professor of Medicine and the Director of the Center for Lymphoid Malignancies, at the Columbia University Medical Center and lead author for the TGR-1202 single agent poster presentation stated, "With many patients on daily TGR-1202 now for well over a year, and upwards of 2.5 years, we are very impressed with the continued tolerability and long term safety profile of TGR-1202, which we believe is truly differentiated from other PI3K delta inhibitors. Discontinuations due to adverse events have been particularly rare, translating into prolonged progression-free survival in relapsed and refractory CLL and indolent NHL patients of two years or more. We are excited at the potential to bring forward this important and needed treatment option for patients with advanced hematologic malignancies."

The following summarizes the posters presented today:

TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma (Abstract Number 4154)

This poster presentation includes data from patients with relapsed and refractory Chronic Lymphocytic Leukemia (CLL) and B-Cell lymphoma (NHL and Hodgkin’s) treated with TGR-1202 as a single agent. Eighty-one patients were evaluable for safety, and 63 patients evaluable for efficacy, which includes patients treated with 800 mg of the initial formulation or higher, and any micronized dose level. Patients in this study were heavily pretreated with 57% of patients having seen ≥ 3 prior therapies, and 49% of patients being refractory to their prior therapy.

Highlights from this poster include:

94% (16 of 17) of CLL patients achieved a nodal PR, with the remaining patient still on study pending further evaluation

59% (10 of 17) of these CLL patients achieved a response per the iwCLL (Hallek 2008) criteria

Median progression free survival (PFS) in the CLL cohort was approximately 24 months

75% (12 of 16) of follicular lymphoma patients demonstrated tumor reductions, with a preliminary ORR of 38% (6 of 16), with 2 additional patients achieving 49% reductions in tumor burden, each continuing on study pending further efficacy assessments
Median PFS for the indolent NHL cohort was 27.3 months

TGR-1202 continues to demonstrate a favorable safety profile, differentiated from the other PI3K deltas inhibitors, with only 7% of patients discontinuing due to an adverse event

Limited grade 3/4 adverse events were reported with anemia and neutropenia (each 9%) being the only grade 3/4 adverse events reported in greater than 5% of patients

Long-term safety has been well characterized with 47% (38 of 81) of patients on study more than 6 months, 27% (22 of 81) of patients on study more than 12 months, and the longest exposed to drug for more than 2.5 years

No events of colitis have been reported, and grade 3/4 AST/ALT elevations have been seen in 2% of patients (4% all grades)
Safety and efficacy profile supports combination therapy with other novel targeted agents

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination With Ibrutinib is Highly Active in Patients with Relapsed and/or Refractory Mantle Cell Lymphoma; Results of a Phase II Trial (Abstract Number 3980)

This poster presentation includes data from 15 patients with previously treated mantle cell lymphoma (MCL) treated with 900mg of TG-1101, in combination with ibrutinib at an oral daily dose of 560mg. There was no limit on prior type or number of therapies and patients previously treated with prior with a BTK inhibitor and/or a PI3K delta inhibitor were permitted. The combination appeared well tolerated in all patients treated, with neutropenia being the only reported grade 3/4 adverse event occurring in greater than 7% of patients and no infusion related reactions being reported for TG-1101.

Highlights from this poster include:

87% (13 of 15) investigator assessed ORR, including a 33% Complete Response rate which compares favorably to historical single agent ibrutinib data (66% investigator assessed ORR and 17% CR)
93% (14 of 15) of patients achieved some reduction in tumor burden on study, with the remaining patient having been refractory to prior anti-CD20 therapy and refractory to prior ibrutinib therapy progressing in Cycle 3
Greater depth of response was achieved over time, with a 62% median reduction in tumor burden at week 8 which increased to a 76% median reduction by week 20
No dose reductions were needed for TG-1101, however 20% (3 of 15) of patients had their ibrutinib dose reduced.

POSTER PRESENTATION DETAILS

A copy of the poster presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.

On December 7, 2015 Nemucore Medical Innovations, Inc., a privately held, clinical-stage biopharmaceutical company dedicated to the development of therapies targeting multi-drug resistant cancers with a special emphasis on highly lethal women’s cancers, reported the completion of an option agreement with Cancer Research Technology Ltd (CRT), the commercial arm of Cancer Research UK, for the exclusive license of worldwide commercial rights to GSK1070916 (now designated NMI-900 by Nemucore), a potent Aurora B/C kinase inhibitor targeting a broad range of cancers (Press release, Nemucore Medical Innovations, DEC 7, 2015, View Source [SID1234563930]).

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"We are thrilled to be able to build on the excellent foundational clinical research conducted by Cancer Research UK, and continue the development of this innovative and very promising anticancer therapeutic," said Timothy P. Coleman, Ph.D., Chairman, Chief Executive Officer and President of Nemucore. "Based on its unique properties and pharmaceutical profile, we believe NMI-900 has best-in-class potential as a breakout therapy for treating women’s and other cancers associated with high mortality rates that have already been demonstrated to be intractable to conventional therapeutics."

NMI-900 is a potent ATP-competitive inhibitor of Aurora B kinase that has demonstrated high affinity for Aurora B, a significantly slower dissociation rate compared to its peers, potent anti-proliferative activity in multiple cancer cell lines, and minimal effects on non-proliferating normal human cells. In 2014, Cancer Research UK’s Centre for Drug Development successfully completed a Phase 1/2a trial of NMI-900. In this trial, NMI-900 elicited response in 61% of patients with no remaining standard therapies available to them across a wide variety of advanced and/or metastatic solid tumors. NMI-900 was well tolerated, with the most prevalent adverse event presenting as predictable and treatable neutropenia. NMI-900 was developed by Cancer Research UK’s Centre for Drug Development in partnership with GSK, under the Clinical Development Partnerships (CDP) initiative. This initiative, a joint effort launched by Cancer Research UK and Cancer Research Technology Ltd, provides a simple route for companies to progress oncology agents that would not otherwise be developed, and increase the number of clinical trials being undertaken for the treatment of cancer.

Dr. Keith Blundy, CEO of Cancer Research Technology commented, "We’re very pleased that Nemucore plans to take this promising new drug candidate and develop it through more clinical trials so that it has a greater chance of reaching patients who are in urgent need of new treatment options, sooner. The drug forms part of our Clinical Development Partnerships initiative, and is one of twelve drugs on the scheme that are moving out of the lab into clinical trials – something that wouldn’t have been possible otherwise."

Nemucore expects to initiate a Phase 2b clinical trial of NMI-900 in patients with advanced, platinum-resistant ovarian cancer in mid-2016 based on the supportive preclinical and early clinical trial results. As part of their clinical development and commercial strategy, the Company is concurrently developing a companion diagnostic with the Medical Prognosis Institute to identify patients most likely to respond to NMI-900. Nemucore expects to investigate the efficacy of NMI-900 in the treatment of EGF receptor-positive non-small cell lung cancer (NSCLC), myelodysplastic syndrome (MDS) and other difficult-to-treat cancers in the future.

On December 7, 2015 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported the establishment of an agreement with a major cancer research group, Alliance Foundation Trials, LLC (AFT), for the phase 3 registrational trial of its cancer immunotherapy ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, DEC 7, 2015, View Source [SID:1234508455]). AFT in conjunction with the Alliance for Clinical Trials in Oncology comprises nearly 10,000 cancer specialists at hospitals, medical centers, and community clinics across the United States. AFT will support the phase 3 trial by providing access to its large network of clinical sites and patients, with the goal of accelerating patient enrollment in the trial. Multiple phase 3 clinical trial sites have been opened for patient enrollment in the US, with additional sites anticipated to open in Canada and Europe in the coming weeks and months.

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Andrew Gengos, ImmunoCellular Chief Executive Officer, commented: "Working in collaboration with AFT has the potential to significantly accelerate enrollment in the ICT-107 phase 3 trial, and to engage the participation of important clinical sites throughout in the US. AFT is one of the most highly respected cancer organizations in America, and we are appreciative of their endorsement and support for our registrational trial."

ImmunoCellular has reached agreement with the FDA on a Special Protocol Assessment (SPA) with respect to the primary and secondary endpoints as well as the statistical plan for the phase 3 trial. ImmunoCellular has also been awarded a $19.9 million grant from the governing Board of the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, to implement the phase 3 registration trial.