On December 11, 2017 argenx (Euronext & Nasdaq: ARGX) a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported that it will provide interim data from its Phase 1/2 clinical trial of ARGX-110 in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) and an update on the Phase 2 part of its clinical trial with ARGX-110 in cutaneous T-cell lymphoma (CTCL) during a workshop being held in conjunction with the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place December 9-12, 2017 in Atlanta, Georgia (Press release, argenx, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2321978 [SID1234522502]).

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The workshop is being held on Monday, December 11, 2017 at 12:00pm EST. A live webcast of the presentation will be available on the Company’s website at www.argenx.com. A replay of the webcast will be available for 90 days following the presentation.

argenx is evaluating the safety, tolerability and efficacy of ARGX-110 in an open-label, Phase 1/2 clinical trial in combination with azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy. During the ASH (Free ASH Whitepaper) workshop today, argenx will announce interim results from the dose-escalation part of the Phase 1/2 clinical trial highlighting promising preliminary data from the first set of six AML patients. All six patients showed encouraging signs of clinical activity, including complete remission (3/6), complete remission with incomplete blood count recovery (1/6) and partial response (2/6). One of the patients that achieved a complete remission bridged to allogeneic stem cell transplant after five cycles. The preliminary data from the first set of patients suggest ARGX-110 is active both at the circulating and bone marrow blast levels and at the leukemic stem cell (LSC) level.

In addition, further data will be presented from the currently ongoing Phase 1/2 clinical trial of ARGX-110 in relapsed/refractory cutaneous T-cell lymphoma (CTCL) patients with confirmed overexpression of CD70 who have failed at least one line of prior therapy. The interim data analyses are from 22 patients, including 13 patients from the Phase 1 part of the trial, which has completed recruitment, and nine patients from the Phase 2 part of the trial. Of the 22 patients under analysis, there was one complete response, two partial responses and 10 with stable disease. ARGX-110 continues to show a favorable tolerability profile in CTCL patients.

Poster presentation at ASH (Free ASH Whitepaper)
argenx collaborators from the University of Bern/Inselspital presented a poster at ASH (Free ASH Whitepaper) highlighting the role of hypomethylating agents (HMA) in inducing upregulation of CD70 on LSCs, but not progenitor cells. There were additional data showing the synergistic effect of HMAs in combination with a variant of ARGX-110. More details can be found here. These data further validate the rationale to evaluate ARGX-110 in combination with azacitidine in the ongoing Phase 1/2 clinical trial.

About ARGX-110
ARGX-110 is a SIMPLE Antibody(TM) targeting CD70, an immune checkpoint target involved in hematological malignancies, several solid tumors and severe autoimmune diseases. ARGX-110 is designed to: i) block CD70, ii) kill cancer cells expressing CD70 through complement dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis and enhanced antibody-dependent cell-mediated cytotoxicity and iii) restore immune surveillance against solid tumors (Silence K. et al. mAbs 2014; 6 (2):523-532). ARGX-110 is currently being evaluated in patients with hematological and solid tumors, including a Phase 1/2 trial in combination with azacitidine in patients with newly diagnosed AML and high-risk MDS and the Phase 2 part of a Phase 1/2 trial in patients with relapsed/refractory CTCL. Preclinical work on ARGX-110 in AML was performed in collaboration with the Tumor Immunology Lab of Prof. A. F. Ochsenbein at the University of Bern, who won, together with Prof. Manz from the University Hospital of Zürich, the prestigious 2016 Otto Naegeli Prize for his breakthrough research on CD70/CD27 signaling with therapeutic potential for cancer patients.

On December 10, 2017 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company developing new gene and cell-based immunotherapies for cancer, reported data supporting its non-viral approach to rapid manufacture of chimeric antigen receptor (CAR)-modified T cells to treat patients with cancers were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta (Press release, Ziopharm, DEC 10, 2017, View Source [SID1234522501]).

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ZIOPHARM is advancing its non-viral Sleeping Beauty (SB) platform towards point-of-care (P-O-C) for very rapid manufacturing of genetically modified CAR+ T cells. Data presented from first- and second-generation SB clinical trials demonstrate safety, tolerability, disease response, long-term survival, and persistence of infused CD19-specific CAR+ T cells. Preclinical studies showed that P-O-C CAR+ T cells co-expressing membrane-bound interleukin-15 (mbIL15) and a control switch manufactured within two days do not require activation or propagation in tissue culture to achieve anti-tumor effects and prolonged T-cell survival. Building on these data, the Company plans to initiate its first P-O-C clinical trial in 2018.

"Together, these results underpin the paradigm-shifting potential of our P-O-C platform by demonstrating the persistence of our Sleeping Beauty-modified T cells, optimization of the CAR, and pro-survival effect resulting from mbIL15 expression. This reinforces our plans to deliver genetically modified products in less than two days," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM Oncology. "The need for a non-viral approach for commercialization of cell therapy is becoming increasingly evident as the challenges of lengthier, more complex, and more expensive viral-based approaches are scaled up. We look forward to advancing Sleeping Beauty and our P-O-C approach with the goal of producing genetically modified T cells to fight cancers at a fraction of current costs and manufacturing time."

These ASH (Free ASH Whitepaper) presentations are based on clinical trials and research being conducted in collaboration with The University of Texas MD Anderson Cancer Center and Intrexon Corporation (NYSE:XON). The three posters and slides for one oral presentation are available in the Presentations and Publications section of the Company’s website, www.ziopharm.com.

Poster Presentation: "Long Term Follow up after Adoptive Transfer of CD19-Specific CAR+ T Cells Genetically Modified Via Non-Viral Sleeping Beauty System Following Hematopoietic Stem-Cell Transplantation (HSCT)"

Partow Kebriaei, M.D., Professor, Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, presented updated results, building upon findings previously published in the Journal of Clinical Investigation. Two trials demonstrated that first-generation SB-modified CD19-specific CAR+ T cells appear to provide long-term cancer control when infused after hematopoietic stem-cell transplantation (HSCT) for patients with advanced CD19+ malignancies and could be detected years after administration in some recipients. All seven patients with advanced CD19+ non-Hodgkin’s lymphoma (NHL) that received autologous T cells were alive at a median survival of 40 months since infusion, with progression-free survival (PFS) reported at 86% and overall survival (OS) at 100%. For 19 patients with advanced CD19+ acute lymphoblastic leukemia (ALL) and NHL infused with allogeneic T cells following HSCT, nine patients were alive with a median survival of 31 months. The PFS rate and OS rates are 32% and 49%, respectively. Of the subset of eight patients who received donor-derived T cells after haploidentical HSCT, PFS and OS rates are 50% and 63%, respectively. Persistence of circulating SB-modified CAR+ T cells was demonstrated at two years in an autologous and allogeneic patient and for four years in two autologous patients.

Oral Presentation: "Shortening the Time to Manufacture CAR+ T Cells with Sleeping Beauty System Supports T-Cell Engraftment and Anti-Tumor Effects in Patients with Refractory CD19+ Tumors"

Dr. Kebriaei presented interim data from an ongoing second-generation trial demonstrating that the manufacture of SB-modified T cells could be shortened from four weeks to two weeks and that autologous T cells infused after lymphodepleting chemotherapy could be detected, and exhibited anti-tumor effects and an encouraging safety profile in patients with relapsed/refractory CD19+ malignancies. Complete responses at one month were reported in four of eight patients with either ALL (n=5), chronic lymphocytic leukemia (n=1), or diffuse large B-cell lymphoma (n=2), with two morphologic complete responses at three months. Follow up blood tests demonstrated sustained persistence of infused T cells and targeting of malignant and normal B cells. There were no dose limiting toxicities with only grade 1 or 2 adverse events being reported. T-cell dose escalation continues.

Poster Presentation, "CD19-Specific Chimeric Antigen Receptor-Modified T Cells with Safety Switch Produced Under ‘Point-Of-Care’ Using the Sleeping Beauty System for the Very Rapid Manufacture and Treatment of B-Cell Malignancies"

Rutul Shah, interim Head of Operations, Intrexon Human Therapeutics, presented preclinical findings showing T cells expressing CD19-specific CAR, mbIL15, and control (safety) switch were generated under P-O-C using the SB system. These T cells were manufactured in less than two days and did not require ex vivo activation or propagation and demonstrated potent anti-tumor effect and sustained CAR+ T-cell persistence in mice. These data support clinical evaluation of genetically modified T cells very rapidly manufactured using the SB system.

Poster Presentation, "Autologous T Cells Modified to Co-express CD33-Specific Chimeric Antigen Receptor and a Kill Switch for Treatment of CD33+ Acute Myeloid Leukemia"

Tim Chan, PhD, Senior Director, Intrexon Human Therapeutics, presented preclinical data supporting an ongoing Phase 1 study of CD33-specific CAR+ T-cell therapy for the treatment of relapsed or refractory acute myeloid leukemia. In vitro analyses demonstrated that CAR+ T cells exhibited redirected specificity for CD33. Co-expression of a kill switch was shown to eliminate CAR+ T cells by cetuximab-mediated antibody-dependent cellular cytotoxicity both in vitro and in vivo.

On December 10, 2017 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported the presentation of the results from the Phase 3 DUO study evaluating the efficacy and safety of duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Annual Meeting held December 9-12, 2017 in Atlanta (Press release, Verastem, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321965 [SID1234522500]). Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma which is currently being developed for the treatment of CLL/SLL and follicular lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including peripheral T cell lymphoma (PTCL).

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"In the Phase 3 DUO study, oral duvelisib monotherapy achieved a statistically significant improvement in Progression-Free Survival (PFS) versus the approved standard of care treatment ofatumumab, along with a well characterized and manageable safety profile, in patients with previously treated CLL/SLL," said Ian Flinn, MD, PhD, Director of the Blood Cancer Research Program at Sarah Cannon Research Institute and lead investigator of the DUO study. "Similar PFS advantages were also observed across all analyzed patient subgroups, including patients with 17p deletion, a genotype that historically correlates with poorer clinical outcomes. Duvelisib also achieved a statistically significant improvement in Overall Response Rate (ORR) and significantly reduced lymph node burden in the vast majority of patients. These data are encouraging for patients with CLL/SLL who progress or relapse following initial treatment."
"CLL/SLL mostly affects elderly patients and many are unable or unwilling to be hospitalized or come into the clinic for frequent IV infusions. The CLL/SLL treatment landscape therefore is moving away from chemotherapies and toward more targeted, preferably oral regimens," said Diep Le, MD, PhD, Chief Medical Officer of Verastem. "While patients are living longer many will be intolerant to, or relapse following, their initial therapy emphasizing the need for new options. Oral duvelisib is the first PI3K inhibitor to show efficacy as an oral monotherapy in a randomized Phase 3 study in patients with relapsed or refractory CLL/SLL and may offer an appealing alternative for patients who have progressed or relapsed. We remain on track to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) during the first quarter of 2018 requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL)."

DUO Efficacy Results
The DUO study met its primary endpoint with oral duvelisib monotherapy achieving a statistically significant improvement in median PFS (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL per a blinded Independent Review Committee (IRC) using iwCLL or revised IWG Response Criteria (modified iwCLL/IWG; 13.3 months vs 9.9 months, respectively; HR=0.52; p<0.0001), representing a 48% reduction in the risk of progression or death. Similar efficacy of duvelisib was observed regardless of whether patients had 17p deletion (del[17p]). The primary outcome of mPFS via IRC review in the del[17p] subpopulation significantly favored duvelisib over ofatumumab (12.7 months vs 9.0 months, respectively; HR=0.41; p=0.0011), representing a 59% reduction in the risk of progression or death. Per investigator assessment, duvelisib demonstrated a mPFS of 17.6 months, compared to 9.7 months for ofatumumab (HR=0.40, p<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed as a subset of pre-specified sensitivity analyses.

The secondary efficacy outcome of ORR via IRC assessment according to modified iwCLL/IWG, significantly favored duvelisib over ofatumumab (73.8% vs 45.3%, respectively; p<0.0001), and reduced lymph node burden >50% in most patients vs ofatumumab (85% vs 16%). In the del[17p] subpopulation of patients, ORR was also significantly higher for duvelisib compared to ofatumumab, 70.0% versus 43.0%, respectively (p=0.0182). The Overall Survival (OS) in the ITT population was similar for those randomized to duvelisib and to ofatumumab during the study (HR=0.99; p=0.4807), demonstrating no detrimental effect on OS and was likely due to other available therapies following progression. Patients who progressed in the DUO study were given option to enroll in a crossover study to receive the opposite treatment. In the optional crossover study, 89 patients who were previously treated with ofatumumab in DUO and experienced disease progression were subsequently treated with duvelisib monotherapy. As in the parent DUO study, duvelisib demonstrated robust clinical activity in this crossover study with an ORR of 73%, a median duration of response of 12.7 months and a mPFS of 15 months by investigator assessments.

DUO Safety Results
Duvelisib monotherapy demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in patients with advanced hematologic malignancies in previous studies. For duvelisib-treated patients, the median time on treatment was 50.3 weeks (range, 0.9 – 160.0) compared to 23.1 weeks (range, 0.1 – 26.1) for ofatumumab. The most common Grade ≥3 treatment-emergent hematologic adverse events (occurring in >10% of patients) were neutropenia (30%) and anemia (13%). The most common Grade ≥3 non-hematologic treatment-emergent adverse events (occurring in >10% of patients) were diarrhea (15%), pneumonia (14%) and colitis (12%). The rate of severe opportunistic infections was 6%, including 2 patients (1%) with Pneumocystis jirovecii pneumonia (PJP), neither of whom was on prophylaxis for PJP at the time of the event. 35% of patients discontinued duvelisib treatment due to an adverse event; ~40% of patients treated with duvelisib remained on treatment for over 18 months, with a median total follow-up of nearly 2 years. Adverse Events of Interest infrequently led to discontinuation of duvelisib treatment (e.g., diarrhea (5.1%), colitis (5.1%), pneumonitis (1.9%), neutropenia (1.3%), pneumonia (1.3%), transaminase elevations (0.6%), and rash (0.6%). Duvelisib treatment-related AEs leading to death (n=4) include general physical health deterioration (n=1); pneumonia staphylococcal (n=2) and sepsis (n=1)).

A copy of the DUO oral presentation will be available here following the conclusion of the session.
Regulatory Plan

Verastem plans to submit a NDA to the U.S. FDA requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory FL. The Company expects to submit the duvelisib NDA during the first quarter of 2018. Along with the clinical data from the DUO study, the duvelisib NDA submission will also contain the results from the Phase 2 DYNAMO study in patients with indolent non-Hodgkin’s lymphoma that are double-refractory to both rituximab and chemotherapy or radioimmunotherapy.

About the Phase 3 DUO Study Design
In the Phase 3 DUO study, 319 patients were randomized 1:1 to receive either duvelisib 25mg orally twice daily or ofatumumab monotherapy, an approved standard of care treatment for use in CLL/SLL, per its label with an initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg. In addition to the primary endpoint of PFS per IRC in the ITT population, additional analyses to evaluate the outcome in several patient subgroups, including those with 17p deletion CLL/SLL, a known poor prognostic subgroup, were also conducted. PFS and other efficacy endpoints were analyzed using response determinations per the IRC using modified iwCLL/IWG criteria.

Verastem to Host R&D Event and Webcast at ASH (Free ASH Whitepaper) 2017
On Sunday, December 10, 2017, Verastem will host a Research and Development event, which will feature a slide presentation and moderated panel discussion with recognized experts in the treatment of hematologic malignancies, including CLL/SLL, in a live Q&A session. Confirmed key opinion leader speakers include:
Ian Flinn, MD, PhD, Sarah Cannon Research Institute
Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center
Lori Kunkel, MD, Verastem Clinical and Scientific Advisory Board; former CMO, Pharmacyclics
In addition, Steve Bloom, Verastem’s Chief Strategy Officer, will also participate, and Robert Forrester, Verastem’s President and Chief Executive Officer will moderate.
The event will take place during the ASH (Free ASH Whitepaper) 2017 annual meeting and interested parties can access a live webcast of the event beginning Sunday, December 10, 2017 at 8:15 p.m. ET on the "Presentations" page of the company’s website at View Source;p=irol-calendar. A replay of the webcast will be archived on the company’s website for 90 days following the event.

About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints and Verastem intends to submit a New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed by Verastem for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On December 10, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported initial clinical data from its ongoing Phase 2 trial of SY-1425, its first-in-class oral, selective retinoic acid receptor alpha (RARα) agonist, in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Press release, Syros Pharmaceuticals, DEC 10, 2017, View Source [SID1234522499]). The data are being presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"I’m encouraged with the single-agent activity and tolerability of SY-1425 in difficult-to-treat leukemia and MDS patients who have few treatment options," said Joseph G. Jurcic, Professor of Medicine at Columbia University Medical Center and Director of the Hematologic Malignancies Section of the Division of Hematology/Oncology. "We saw improved blood counts and reduced blast counts in conjunction with differentiation of cancer cells in genomically defined patients. These data, along with the mechanistic and preclinical data supporting combinations with azacitidine and with daratumumab, suggest SY-1425 could be a meaningful combination agent with the potential to address a substantial unmet need for patients with AML and MDS."

"The biologic and clinical activity seen in patients selected by our proprietary RARA and IRF8 biomarkers provide validation of our platform’s ability to enrich for patients most likely to respond to gene control therapies," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "These data support continued development of SY-1425 in combination, which will be our focus going forward. Our preclinical data showing the tumor-killing activity of SY-1425 in combination with azacitidine and with daratumumab support the ongoing development of SY-1425 in combination with these therapies, and we plan to present initial clinical data on these two combinations in 2018."

Data from the Ongoing Phase 2 Clinical Trial
The ongoing Phase 2 clinical trial of SY-1425 is assessing the safety and efficacy as both a single agent and a combination agent in AML and MDS patients who are positive for either the RARA or IRF8 biomarkers, or both. The data being presented at ASH (Free ASH Whitepaper) are from two of the five cohorts in the ongoing trial. As of the data cutoff at the end of October 2017, 58 patients had been treated with SY-1425 in two single-agent cohorts, consisting of 29 patients in the relapsed or refractory AML and higher-risk MDS cohort and 29 patients in the lower-risk transfusion-dependent MDS cohort.

The relapsed or refractory AML and higher-risk MDS cohort had a median age of 72 years with more than half the patients having poor risk cytogenetics and 45% having two or more prior therapies, and the lower-risk MDS cohort had a median age of 76 years. Target enrollment has been reached in both cohorts.

Initial Safety Data

Chronic daily dosing of SY-1425 administered at 6 mg/m2 orally divided in two doses was generally well-tolerated, with a median treatment duration of 80 days, and patients treated up to eight months and remaining on study.
The majority of adverse events (AEs) were Grade 1 or Grade 2.
Across all grades and causality, the most commonly reported AEs included hypertriglyceridemia (36%), fatigue (31%), and dermatologic effects (28%).
The most common Grade 3 or 4 AE was hypertriglyceridemia (16%).
Initial Clinical Activity Data

As of the data cutoff, 48 patients were evaluable for response assessment, including 23 patients in the relapsed or refractory AML and higher-risk MDS cohort and 25 patients in the lower-risk transfusion-dependent MDS cohort.

Ten of the 23 (43%) evaluable relapsed or refractory AML and higher-risk MDS patients and two of the 25 (8%) evaluable transfusion-dependent lower-risk MDS patients had evidence of clinical activity, including:.
Nine with improvements in hematological parameters. Of those, four achieved hematological improvement lasting at least eight weeks, as defined by Revised International Working Group (IWG) criteria.
Five with reductions in bone marrow blasts. Of those, one relapsed or refractory higher-risk MDS patient achieved a marrow complete response as defined by IWG criteria. The patient had been on treatment 238 days and remained on treatment as of the data cutoff.
13 of the 23 (57%) evaluable relapsed or refractory AML and higher-risk MDS patients had stable disease.
11 of 13 (85%) of patients with pre- and post-treatment immunophenotyping samples showed increased expression of CD38, a marker of cell differentiation, on bone marrow blasts after one 28-day cycle of treatment.
No patients with lower-risk MDS achieved transfusion independence.
Additionally, myeloid cell differentiation in the bone marrow, as measured by morphologic evaluation, FISH analysis and immunophenotyping, was observed, consistent with the underlying mechanism of action of SY-1425 as a differentiating agent. The induction of CD38 observed in bone marrow blasts from patients treated with SY-1425 supports the combination cohort with daratumumab recently added to the Phase 2 trial.

As presented at the European School of Haematology’s 4th International Conference on Acute Myeloid Leukemia in October 2017, approximately 40% of 201 patients screened for the clinical trial as of the end of August 2017 were biomarker-positive, including approximately one-third of relapsed or refractory AML and higher-risk MDS patients. In blood samples taken from patients upon screening and treated ex vivo with SY-1425, a positive biomarker status was significantly correlated with SY-1425 induced myeloid cell differentiation, supporting the predictive value of the biomarker test for patient selection.

Preclinical Combination Data for SY-1425
SY-1425 has shown synergistic tumor-killing activity in combination with azacitidine, a standard-of-care therapy in AML and MDS, as well as with daratumumab, an anti-CD38 antibody approved to treat multiple myeloma, in preclinical models of RARA biomarker-positive AML. In combination with azacitidine, SY-1425 demonstrated greater clearance of tumor cells in bone marrow and other tissues and greater depth and duration of tumor response, compared to either azacitidine or SY-1425 alone. In combination with daratumumab, SY-1425 triggered robust immune cell-mediated tumor death. Notably, AML cells do not normally express high levels of CD38. Syros has shown that by inducing CD38 expression, SY-1425 sensitizes biomarker-positive AML models to the tumor-killing effects of daratumumab.

Clinical Development Plans for SY-1425
Syros plans to focus its ongoing Phase 2 clinical trial on assessing the safety and efficacy of SY-1425 in combination with other therapies. Syros is continuing to enroll patients in a cohort evaluating SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. Syros recently added a cohort in relapsed or refractory AML and higher-risk MDS patients to evaluate SY-1425 in combination with daratumumab and expects to begin enrolling patients in that cohort in early 2018. All patients enrolled or to be enrolled in the trial are prospectively selected using the Company’s RARA or IRF8 biomarkers. Syros expects to report initial clinical data from each combination cohort in 2018. Syros does not plan to pursue further development of SY-1425 as a single agent and is stopping enrollment in the single-agent cohort in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

Investor Event and Webcast Information
Syros will host an investor event on Monday, December 11 beginning at 12:00 p.m. ET in Atlanta to discuss the initial SY-1425 clinical data presented at ASH (Free ASH Whitepaper). The event can be accessed by dialing 866-595-4538 (domestic) or 636-812-6496 (international) and providing the passcode 8887999. A live webcast will also be available and can be accessed under "Events & Presentations" in the Investors section of the Company’s website at View Source A replay of the webcast will be available approximately two hours after the event and will be available for 30 days following the event.

On December 10, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported that new preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor currently in a Phase 1 clinical trial in advanced solid tumors, show anti-tumor activity in in vitro and in vivo models of blood cancers (Press release, Syros Pharmaceuticals, DEC 10, 2017, View Source [SID1234522498]). Additionally, the data point to a potential biomarker of response to SY-1365 and synergistic activity with a BCL2 inhibitor in preclinical models of acute myeloid leukemia (AML). These data are being presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"We believe SY-1365 represents a promising therapeutic approach across a number of solid tumors and blood cancers," said Eric R. Olson, Ph.D., Chief Scientific Officer of Syros. "These new preclinical data underscore the power of our gene control platform to elucidate the underlying biology and mechanism of action of SY-1365, furthering our ability to identify biomarkers to select the patients most likely to respond and to identify rational combination approaches with the potential to provide a profound benefit for patients."

Syros scientists analyzed the anti-tumor activity of SY-1365 in a broad panel of leukemia and lymphoma cell lines, as well as in primary cell cultures from leukemia patients. They then grouped the cell lines according to sensitivity to SY-1365 and looked for markers of response using Syros’ gene control platform. Based on the findings, Syros evaluated SY-1365 in combination with venetoclax, a BCL2 inhibitor, in preclinical studies. The data showed that:

SY-1365 inhibited proliferation in vitro in leukemia and lymphoma cells, as well as in leukemia cells from primary patient cultures.
SY-1365 induced cell death in the majority of AML, leukemia and lymphoma cell lines tested.
SY-1365 inhibited tumor growth, including inducing tumor regression, using biweekly dosing in preclinical mouse models of AML.
Sensitivity to SY-1365 was associated with low expression of the mitochondrial apoptosis antagonist BCL2L1 in AML and other leukemia cell lines.
SY-1365 lowered expression of MCL1, a gene in the mitochondrial apoptosis pathway that is known to inhibit apoptosis.
SY-1365 synergized with venetoclax in AML cell lines in vitro and increased tumor growth inhibition when combined with venetoclax, compared to either SY-1365 or venetoclax alone.
The Phase 1 trial of SY-1365 is a multi-center, open-label trial enrolling patients with advanced solid tumors. The primary objective of the trial is to assess the safety and tolerability of escalating doses of SY-1365, with the goal of establishing a maximum tolerated dose and a recommended Phase 2 dose and regimen. The dose-escalation phase is open and expected to enroll approximately 35 solid tumor patients for whom standard curative or palliative measures do not exist or are no longer effective. Following the dose-escalation phase, expansion cohorts are planned to further evaluate the safety and anti-tumor activity of SY-1365 in patients with transcriptionally driven tumors and to enroll patients with tumors of any histology in a cohort focused on analyzing biopsied tumor tissue. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov. Syros expects to present initial clinical data from this study in 2018.