On December 5, 2016 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported three oral data presentations on vadastuximab talirine (SGN-CD33A; 33A) in patients with acute myeloid leukemia (AML) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016 (Press release, Seattle Genetics, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227547 [SID1234516931]). The data included updated results from an ongoing phase 1 clinical trial evaluating 33A in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline older AML patients. Further oral presentations focused on results from phase 1 clinical trials evaluating 33A in three distinct settings, including 1) as monotherapy in newly diagnosed older AML patients, 2) in combination with high-dose cytarabine for younger AML patients in first remission and 3) as monotherapy maintenance for younger AML patients who have completed frontline therapy or after allogeneic stem cell transplant. 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33, a protein which is expressed on leukemic cells in nearly all AML patients.

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Seattle Genetics is broadly evaluating 33A across multiple lines of therapy in patients with myeloid malignancies. In addition to the clinical trials presented at ASH (Free ASH Whitepaper) this year, 33A is currently being evaluated in combination with HMAs in the ongoing global phase 3 CASCADE study. This trial is randomized, double-blind, and being conducted at multiple centers globally to evaluate if 33A in combination with azacitidine or decitabine can extend overall survival compared to azacitidine or decitabine alone in approximately 500 older patients with newly diagnosed AML. Additional phase 1 and 2 clinical trials for frontline younger AML and frontline myelodysplastic syndrome (MDS) are also underway. More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

"We are pleased with the growing body of data demonstrating that vadastuximab talirine, also known as 33A, has a promising overall tolerability and activity profile in clinical trials for patients with AML," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "We are committed to improving the therapeutic options for AML patients through innovative, targeted approaches. Our most advanced 33A clinical study, CASCADE, is a randomized phase 3 trial designed to test 33A in combination with hypomethylating agents, or HMAs, in approximately 500 older patients with newly diagnosed AML. Based on the encouraging data presented at ASH (Free ASH Whitepaper), we believe 33A has the potential for clinical development in multiple AML settings, with the goal of providing new treatment options for patients struggling with this aggressive and life-threatening disease."

"AML therapy has not meaningfully changed over the past 40 years, and there is a dire need for improved treatment options. Older AML patients have a particularly poor prognosis with the standard of care, hypomethylating agents or HMAs," said Amir Fathi, M.D., Massachusetts General Hospital Cancer Center. "I am pleased with the balance of activity and tolerability we have observed in phase 1 clinical trials evaluating 33A both as monotherapy and combination therapy in AML patients. For older patients with newly diagnosed AML, the 73 percent remission rate of 33A in combination with HMAs, with 50 percent of those patients negative for minimal residual disease, signals promise in improving long-term outcomes."

The following data from the ongoing phase 1 studies evaluating 33A combination therapy or monotherapy in AML patients were presented:

Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients With Acute Myeloid Leukemia (Abstract #591, oral presentation on Monday, December 5, 2016 at 7:30 a.m. PT)

Outcomes for AML patients who are older or ineligible to receive standard chemotherapy remain poor. HMAs are frequently used in this setting, but efficacy is limited. Updated results from an ongoing phase 1 study evaluating 33A in combination with HMAs (either azacitidine or decitabine) in newly diagnosed older AML patients were presented by Dr. Amir Fathi, Massachusetts General Hospital Cancer Center.

Data were reported from 53 frontline AML patients with a median age of 75 years and predominantly intermediate or adverse cytogenetic risk who had declined intensive therapy. Regarding additional poor-prognosis indicators, 42 percent of patients had evidence of underlying myelodysplasia, 11 percent had FLT3-mutated disease and 43 percent had secondary AML, which is AML that arises from prior chemotherapy, a pre-existing MDS or myeloproliferative disease. Key findings include:

Of 49 patients evaluable for response, complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) was observed in 36 patients (73 percent).
Remissions were observed in higher-risk patients, including 17 of 22 patients (77 percent) with secondary AML, five of five patients (100 percent) who were FLT3/ITD positive and 17 of 26 patients (65 percent) age 75 or older.
Eighteen of the 36 patients (50 percent) who achieved remission (CR or CRi) were negative for minimal residual disease (MRD), which means no cancer could be detected with a sensitive test.
With a median follow-up of 14.7 months, median overall survival for all patients was 11.3 months and 28 percent of patients remained alive and on study as of last follow-up. The 30- and 60-day mortality rates were two and eight percent, with no treatment-related deaths occurring during that time.
For patients who achieved MRD-negative remission, the median survival had not yet been reached.
The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were thrombocytopenia, febrile neutropenia, anemia and neutropenia.
The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were fatigue, nausea, constipation, peripheral edema and decreased appetite.
Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (Abstract #590, oral presentation on Monday, December 5, 2016 at 7:15 a.m. PT)

Interim results from 93 patients in the ongoing phase 1 study evaluating 33A monotherapy in AML patients were previously presented at the 2015 ASH (Free ASH Whitepaper) Annual Meeting. New results describing the safety and activity of the recommended 33A monotherapy dose of 40 micrograms per kilogram (mcg/kg) in an expansion cohort of treatment-naïve older AML patients were presented by Dr. Anjali Advani, Cleveland Clinic.

Data were reported from 27 treatment-naïve older AML patients with a median age of 74 years and intermediate or adverse cytogenetic risk of 70 percent and 26 percent, respectively. Regarding additional poor-prognosis indicators, 48 percent of patients had evidence of underlying myelodysplasia and 22 percent had FLT3 mutated disease. Key findings include:

Of the 26 patients evaluable for response, remission (CR or CRi) was observed in 15 patients (58 percent), with a median time to remission of 1.4 months.
Forty-three percent of patients who achieved remission were MRD negative.
Responses were observed in higher-risk patients, with remissions achieved in seven of 12 patients (58 percent) with underlying myelodysplasia and three of four patients (75 percent) who were positive for FLT3/ITD.
The 30- and 60-day mortality rates were zero and 15 percent, respectively. The median overall survival for all patients was seven months.
The most common Grade 3 or higher treatment-emergent adverse events occurring in 20 percent or more of patients were thrombocytopenia, febrile neutropenia and anemia.
The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were peripheral edema, decreased appetite, fatigue, diarrhea and dizziness.
A Phase 1b Study of Vadastuximab Talirine as Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (Abstract #340, oral presentation on Sunday, December 4, 2016 at 10:15 a.m. PT)

Interim results from an ongoing phase 1b study evaluating 33A in the AML post-remission setting, as a single agent for maintenance therapy or in combination with consolidation therapy (high-dose cytarabine; HiDAC), were presented by Dr. Jay Yang, Karmanos Cancer Institute.

About Acute Myeloid Leukemia

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive cancer of the bone marrow and blood that progresses rapidly without treatment. Cancerous cells called leukemic blasts multiply and crowd out normal cells in the bone marrow and interfere with normal blood cell production leading to anemia, infection, and bleeding. According to the SEER database and Kantar Health Sciences, in 2016 approximately 33,000 new cases of AML (mostly in adults) will be diagnosed in the U.S. and Europe. In the U.S. alone, nearly 10,500 deaths will occur from AML this year. Treatment options for AML have remained virtually unchanged for nearly 40 years and frontline treatment consists primarily of chemotherapy. A subset of patients (typically those over 60 years of age) cannot tolerate such therapy and are typically given lower intensity therapies agents, supportive care, or are recommended for clinical trials.

About Vadastuximab Talirine (SGN-CD33A)

Vadastuximab talirine (SGN-CD33A; 33A) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.

33A was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

On December 5, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation of two preclinical data sets, one oral presentation and one poster presentation, for TGR-1202, the Company’s once-daily PI3K delta inhibitor, at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in San Diego, California (Press release, TG Therapeutics, DEC 5, 2016, View Source [SID1234516932]).

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Michael S. Weiss, the Company’s Executive Chairman and Interim Chief Executive Officer, stated, "We want to thank the teams at Columbia and Moffitt for their extensive laboratory work on TGR-1202 to better understand the mechanism of action and impact on the immune system. The preclinical data they have generated helps to better explain and perhaps offer a rationale for the differentiated safety profile seen with TGR-1202 as compared to earlier generation PI3K delta inhibitors. We believe these preclinical findings along with the robust safety and efficacy data we have observed in the clinic, support our belief that TGR-1202 is a differentiated best in class PI3K delta inhibitor. We look forward to continuing our research collaborations with Columbia and Moffitt and to presenting updated safety and efficacy data for TGR-1202 to further confirm its unique profile."

"Dr. Deng’s presentation today has really begun to shed some long-needed light on the important differences among the PI3K delta inhibitors. His work has identified that a novel kinase important in the PI3K pathway, CK-1epsilon, is uniquely inhibited by TGR-1202, which may explain the drug’s effects on c-Myc. These chemical differences may also help to explain the important immunologic differences in the safety profiles of these agents," stated Dr. Owen A. O’Connor, Professor of Medicine and Experimental Therapeutics, Director Lymphoid Malignancies at Columbia Presbyterian Medical Center.

The following summarizes the oral presentation and poster presentation which occurred yesterday:

Oral Presentation: Silencing c-Myc Translation as a Therapeutic Strategy through Targeting PI3K Delta and CK1 Epsilon in Hematological Malignancies (Abstract Number 291)

This oral presentation includes data from the manuscript titled, "Silencing c-Myc Translation as a Therapeutic Strategy through Targeting PI3K Delta and CK1 Epsilon in Hematological Malignancies," which was recently published in Blood, the Journal of the American Society of Hematology (ASH) (Free ASH Whitepaper). The presentation was delivered by Changchung Deng, MD, PhD of Columbia Presbyterian Medical Center and included the following highlights:

TGR-1202 and carfilzomib, but not combinations of other drugs in the same classes, synergistically inhibit c-Myc translation and c-Myc dependent gene transcription, by potently inhibiting phosphorylation of 4E-BP1;
TGR-1202 and carfilzomib synergistically induce apoptosis in lymphoma cells through targeting c-Myc, whereas the other combinations did not;
TGR-1202, but not idelalisib or duvelisib, was found to uniquely inhibit casein kinase-1 (CK1) epsilon; and
Based on this extensive preclinical work, the Company recently announced the launch of a Phase 1/2 study to evaluate the safety and efficacy of TGR-1202 in combination with carfilzomib, in patients with relapsed or refractory lymphoma.
Poster Presentation: Modulation of T Cell Compartment in a Preclinical CLL Murine Model By a Selective PI3K Delta Inhibitor, TGR-1202 (Abstract Number 3236)

This poster presentation included preclinical data describing the differential regulation of human T-cells by TGR-1202 in a preclinical CLL murine model. Highlights from this poster include:

Both TGR-1202 and duvelisib oral administration demonstrated comparable efficacy by reducing CLL burden over time in leukemic mice;
TGR-1202 and duvelisib both targeted the T cell population in vivo, however:
TGR-1202 relatively maintained the number of Tregs and Th17 cells and expression of functional markers on Tregs compared to duvelisib treatment in vivo and ex vivo; and
Duvelisib resulted in greater disruption of Treg/Th17 ratio compared to TGR-1202 in vivo, which may have implications for occurrence of autoimmune-like organ toxicity.
PRESENTATION DETAILS:
Copies of the above referenced presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications page.

TG THERAPEUTICS INVESTOR & ANALYST EVENT DETAILS:
TG Therapeutics will also host an investor and analyst reception on Monday, December 5th, 2016 beginning at 8:00pm PT. The event will take place at the Marriott Gaslamp, in San Diego, California, in the Presidio AB Ballroom.
NOTE: This event will be webcast live and will be available on the Events page, located within the Investors & Media section of the Company’s website at www.tgtherapeutics.com, as well as archived for future review. This event will also be broadcast via conference call. In order to access the conference line, please call 1-877-407-8029 (U.S.), 1-201-689-8029 (outside the U.S.), and reference Conference Title: TG Therapeutics 2016 Investor & Analyst Event.

On December 5, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq: BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported the presentation of preclinical results on the Company’s GoCAR-T and GoTCR technologies at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California (Press release, Bellicum Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227609 [SID1234516934]).

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"We are pleased to report further supportive preclinical data on the utility of our proprietary iMC activation switch, which is incorporated into our BPX-601 GoCAR-T product candidate now entering a Phase 1 clinical study," commented Tom Farrell, President and CEO of Bellicum Pharmaceuticals. "We believe our novel technology provides a powerful and unique solution for overcoming the efficacy and safety challenges of T-cell therapies, especially when targeting solid tumors."

The Company’s GoCAR-T platform incorporates an inducible MyD88/CD40 (iMC) costimulatory switch, which requires presence of both a target antigen and rimiducid to trigger the full effect of CAR T cell activity. The presence of rimiducid and antigen results in upregulation of cytokines such as IL2, leading to T-cell proliferation, persistence and improved anti-tumor efficacy. Unlike traditional CAR T constructs, GoCAR-T is designed to support persistence of CAR T cells in the body in the absence of cancer antigen to provide continued anti-tumor surveillance.

In a poster presentation titled, "Inducible MyD88/CD40 (iMC) Costimulation Provides Ligand-Dependent Tumor Eradication By CD123-Specific Chimeric Antigen Receptor T Cells," Bellicum scientists targeted CD123, which is highly expressed in acute myeloid leukemia (AML) and leukemic stem cells. Results demonstrated that GoCAR-T removed CD123-positive leukemic cells in animal models through rimiducid-activated costimulation. Conversely, infrequent costimulation with rimiducid led to reduced activity of CAR T cells, supporting the technology’s potential to provide control over the activation, expansion and persistence of cells to achieve a desired level of safety and anti-tumor potency.

Additional data were presented on the Company’s GoTCR technology, which also uses an iMC costimulatory switch. The presence of GoTCR and rimiducid triggers the release of cytokines that upregulate MHC (major histocompatibility complex) on tumor cells, exposing them to potent immune response by both engineered and endogenous T cells. In the study outlined in a poster presentation titled, "Inducible MyD88/CD40 (iMC) Enhances Proliferation and Survival of Tumor-Specific TCR-Modified T Cells and Improves Anti-Tumor Efficacy in Myeloma," T cells were engineered to express tumor antigen-specific T-cell receptors (TCRs) targeting preferentially-expressed antigen in melanoma (PRAME) or Bob1. PRAME is overexpressed in a wide variety of cancers including melanoma, sarcoma and several types of leukemias. Bob1 is also found to be highly expressed in certain leukemias, along with lymphomas and myelomas. Results demonstrated that the rimiducid-driven iMC costimulatory switch provided potent T-cell activation, proliferation and persistence, synergizing with signals from PRAME- or Bob1-targeted TCRs for improved anti-tumor efficacy in vitro and in vivo.

On December 4, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that 82 percent of patients (9 out of 11) achieved complete remission or complete remission with incomplete or partial hematological recovery in a preliminary analysis of the Phase 1 ZUMA-3 and ZUMA-4 trials of KTE-C19 in adult and pediatric relapsed/refractory acute lymphoblastic leukemia (r/r ALL) (Press release, Kite Pharma, DEC 4, 2016, View Source [SID1234516909]). In these patients, 100 percent of responders tested negative for minimal residual disease (MRD), which has been shown to correlate with risk of disease relapse in ALL. The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

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In the Phase 1 trials, 13 patients were treated with KTE-C19. Eleven patients were evaluable for response and two patients have not reached the evaluation time point at the data cutoff. Patients received a low-dose conditioning chemotherapy regimen based on extensive clinical experience at the National Cancer Institute (NCI).

"We are encouraged by the KTE-C19 safety and efficacy profile in ALL that is suggested by these data," said David Chang M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer of Kite. "In the Phase 1 portion of these studies, we are enrolling patients with high disease burden to rigorously evaluate safety and efficacy of KTE-C19. We look forward to initiating the Phase 2 portions of these studies in 2017."

Five of 13 (38 percent) patients had ≥ grade 3 cytokine release syndrome (CRS) and five of 13 (38 percent) had ≥ grade 3 neurological events. One patient in ZUMA-3 died from KTE-C19 related CRS and one patient in ZUMA-4 died from a disseminated fungal infection unrelated to KTE-C19. No cerebral edema has been observed.

KTE-C19 was successfully manufactured in these 13 patients across a range of absolute lymphocyte and blast counts in a centralized and streamlined process of six to eight days. The KTE-C19 manufacturing process used in the multicenter ZUMA-3 and ZUMA-4 studies will be discussed in an oral presentation on Monday, December 5, 2016, at 6:45 p.m. PST.

Production of Anti-CD19 CAR T Cells for ZUMA-3 and -4: Phase 1/2 Multicenter Studies Evaluating KTE-C19 in Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL)

Abstract #1227 View Source
Presenter: Marianna Sabatino, M.D., Kite Pharma, Director of Product Sciences

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On December 4, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that it has initiated the rolling submission with the U.S. Food and Drug Administration (FDA) of the Biologics License Application (BLA) for KTE-C19 as a treatment for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT) (Press release, Kite Pharma, DEC 4, 2016, View Source [SID1234516910]). The pivotal ZUMA-1 study supporting this submission enrolled patients with chemorefractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), three subtypes of aggressive NHL. The company expects to complete its BLA submission by the end of the first quarter of 2017.

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"I am both proud and appreciative of the Kite team and our clinical investigators, who have helped to make this key milestone possible," said Arie Belldegrun, M.D., FACS, Chairman, President, and Chief Executive Officer of Kite. "This is an important first step toward Kite’s biggest goal – bringing to market a potentially life-saving treatment for patients suffering from aggressive NHL."

Kite also announced that the United States Adopted Name, or USAN, for KTE-C19 will be axicabtagene ciloleucel.

Axicabtagene ciloleucel (KTE-C19) received Breakthrough Therapy Designation (BTD) by the FDA in December 2015. If approved, Kite plans to commercially launch KTE-C19 in 2017. Kite is also planning a regulatory submission to the European Medicines Agency (EMA) for axicabtagene ciloleucel in 2017. Kite was granted access to Priority Medicines (PRIME) regulatory support in 2016 by the EMA for axicabtagene ciloleucel (KTE-C19) for the treatment of refractory DLBCL.

About axicabtagene ciloleucel

Kite Pharma’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.