On December 10, 2017 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported that updated clinical results from HGB-206, the company’s ongoing Phase 1 multicenter study of its LentiGlobin gene therapy product candidate in patients with severe sickle cell disease (SCD), will be discussed in an oral presentation during the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, bluebird bio, DEC 10, 2017, View Source [SID1234522485]). In addition, a poster on the feasibility and potential benefits of plerixafor-mediated peripheral blood stem cell collection and drug product (DP) manufacturing in patients with SCD was presented yesterday at ASH (Free ASH Whitepaper).

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"The promising early results from the first two patients treated under the amended HGB-206 study protocol indicate that the manufacturing and patient management changes we implemented may have a meaningful impact on patient outcomes," said Dave Davidson, chief medical officer, bluebird bio. "These two patients have maintained higher levels of gene-marked cells in the blood following treatment compared to the previous patients in HGB-206. This improvement corresponds with increased production of the anti-sickling hemoglobin, HbAT87Q, made from LentiGlobin. We are hopeful that this high-level expression of HbAT87Q will lead to a sustained clinical benefit for these patients. The next group of patients in the study will be treated using LentiGlobin made from stem cells obtained from plerixafor-mobilized peripheral blood. Plerixafor mobilization in place of direct bone marrow harvest is less burdensome for patients, and our results suggest that this approach may be able to obtain a greater quantity of higher quality cells."

Interim Results from a Phase 1/2 Clinical Study of LentiGlobin Gene Therapy for Severe Sickle Cell Disease (Oral Abstract #527)
Presenter: Julie Kanter, M.D., Medical University of South Carolina, Charleston, SC
Date & Time: Sunday, December 10 at 5:30 p.m.
Location: Bldg C, Level 1, C101 Auditorium

"People with sickle cell disease have a genetic disease that causes the protein in red blood cells, called hemoglobin, to be misshapen. As a result of this abnormal hemoglobin, many affected individuals live with low blood counts and severe, recurrent pain crises that lead to organ damage and shortened life spans," said Dr. Kanter. "It is also a disease that has been historically under-researched and under-resourced, with few treatment options beyond pain management. These early results with the revised study protocol indicate that gene therapy with LentiGlobin may allow people with SCD to produce substantial levels of normal, anti-sickling, adult hemoglobin. We are hopeful about the possibility that this could substantially reduce the painful and damaging crises that are a hallmark of this disease, potentially allowing patients to live longer, healthier lives."

HGB-206 is an ongoing, open-label study designed to evaluate the safety and efficacy of LentiGlobin DP in the treatment of adults with severe SCD. Patients in this study are divided into three cohorts: A, B and C. Patients in Group A were treated under the original study protocol. Patients in Group B were treated under an amended study protocol that included changes intended to increase DP vector copy number (VCN) and improve engraftment of gene-modified stem cells. Patients in both Group A and B had DP made from stem cells collected using bone marrow harvest. Patients in Group C are also treated under the amended study protocol, but receive LentiGlobin made from stem cells collected from peripheral blood after mobilization with plerixafor rather than via bone marrow harvest. As of November 30, 2017, ten patients had been treated in the study and follow‑up data were available on nine patients from groups A and B, with a median of 21 (6-27) months since transplantation. Key results include:

Group A
N=7

Median (min-max)

Group B
N=2

Patient 1312 Patient 1313
Transduced CD34+ cells (%) 25 (8-42)
951, 901

46, 831
Drug product Cell Dose (x106 CD34+ cells) 2.1 (1.6-5.1) 3.2 2.2
Drug product VCN (copies per diploid genome) 0.6 (0.3-1.3) 2.91, 5.01 1.4, 3.31
VCN in peripheral blood (copies per diploid genome at last measurement) 0.1 (0.1-0.2) 2.5 (M6) 0.5 (M9)
HbAT87Q (g/dL at last measurement) 0.7 (0.5-2.0) 6.4 (M6) 3.0 (M9)
HbAT87Q (% of total, at last measurement) 7.9 (5.3-18.2) 51% (M6) 28% (M9)

1 LentiGlobin DP manufactured using refined process

Both patients in Group B were treated with two DP lots. Information from each of these LentiGlobin DP lots is reflected in the chart above.
Patient 1313 received LentiGlobin manufactured using a combination of the original and the refined manufacturing processes.
Patient 1312 received LentiGlobin manufactured entirely using the refined manufacturing process.
LentiGlobin DP has been manufactured for four patients in Group C:
Median transduced CD34+ cells: 80%
Median DP cell dose: 6.9 x106 CD34+ cells
Median DP VCN (copies per diploid genome): 3.3
The first patient treated with LentiGlobin (Group C) made using plerixafor-mobilized stem cells had a VCN in peripheral blood of 2.5 at one month.
The toxicity profile observed from drug product infusion to latest follow-up was generally consistent with myeloablative conditioning with single-agent busulfan.
Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease (Poster Abstract #990)
Presenter: John Tisdale, M.D., National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD
Date & Time: Saturday, December 9 at 5:30 p.m.
Location: Bldg A, Level 1, Hall A2

"Historically, harvesting stem cells from people with SCD required bone marrow harvest, a painful approach for obtaining cells that often yields a suboptimal dose level and cell quality," said Dr. Tisdale. "The data we presented at ASH (Free ASH Whitepaper) suggest that not only is this new approach using plerixafor mobilization generally tolerable for patients, but it may enable us to obtain a larger cell dose with a higher concentration of primitive stem cells. Cells with this primitive phenotype are more likely to become long-term sources of gene-modified red blood cells. We believe that providing more primitive hematopoietic stem cells that carry more copies of the gene therapy vector may be critical to realizing the full promise of gene therapy for people with SCD, and we look forward to getting more data on this new cohort of patients in the coming months."

Results as of November 30, 2017:

Bone Marrow Harvest Plerixafor
Number of Patients 9 (26 BMHs) 7 (10 mobilization cycles)
Adverse Events
17 Grade 3 AEs following BMH in 5 patients, 4 were SAEs (1 procedural pain, 3 SCD pain crisis)

5 Grade 3 events included 2 non-serious (hypomagnesemia and non-cardiac chest pain) and 3 SAEs (1 patient each) of SCD pain crisis
CD34+ cells collected per harvest, median (min-max) cells/kg 5.0 (0.3-10.8) x 106 10.4 (5.1-20.0) x 106

Webcast Information
bluebird bio will host a webcast at 8:30 p.m. ET today, December 10, 2017. The webcast can be accessed under "Calendar of Events" in the Investors and Media section of the company’s website at www.bluebirdbio.com.

About SCD
Sickle cell disease (SCD) is an inherited disease caused by a mutation in the beta-globin gene, that produces βS-globin. High levels of HbS in patients with SCD are responsible for the characteristic chronic anemia, vaso-occlusive crises, and other acute and chronic manifestations of SCD which lead to significant morbidity and early mortality.

Where adequate medical care is available, common treatments for patients with SCD largely revolve around prevention of infection and management and prevention of acute sickling episodes. Chronic management may include hydroxyurea and, in certain cases, chronic transfusions. Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only available option to address the underlying genetic cause of SCD, though it carries significant risk. Complications of allogeneic HSCT include a risk of treatment-related mortality, graft failure, graft versus host disease (GvHD) and opportunistic infections, particularly in patients who undergo non-sibling-matched allogeneic HSCT.

On December 10, 2017 Incyte Corporation (Nasdaq:INCY) reported new 208-week (4-year) follow-up data from the ongoing, global, multi-center, open-label Phase 3 RESPONSE study of Jakafi (ruxolitinib) comparing the efficacy and safety of Jakafi with best available therapy (BAT) in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU) (Press release, Incyte, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321950 [SID1234522490]). The pre-planned data analysis showed a durable primary response to Jakafi in patients with PV who are resistant to or intolerant of HU and the overall safety profile for Jakafi remained consistent with previously reported 80-week RESPONSE data.1 The results were shared in an oral presentation today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2017 in Atlanta, Georgia.

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"With 30 months of additional follow-up, the four-year RESPONSE data analysis presented today at ASH (Free ASH Whitepaper) further reinforces the potential of Jakafi as a long-term option for patients with PV," said Peg Squier, M.D., Ph.D., Head of U.S. Medical Affairs at Incyte. "Given the few treatment options available to treat this chronic and progressive blood cancer, these long-term safety and efficacy data are meaningful to patients with uncontrolled PV."

The 80-week follow-up results from RESPONSE confirmed that among patients who initially responded to Jakafi treatment, the probability of maintaining primary and hematocrit (Hct) responses for ≥ 80 weeks was 92% and 89%, respectively, and hence Jakafi could be an effective long-term treatment option for patients with PV who are HU-resistant or intolerant.

At the week 208 analysis, the overall long-term safety profile remained consistent with the 80-week data analysis and the response was durable. In both the Jakafi arm and the crossover population, around 30% of patients completed the study treatment and 37% of patients were still receiving treatment.

"These are clinically relevant long-term safety and efficacy results, and further support the use of Jakafi in PV patients who have an inadequate response to or are intolerant of hydroxyurea," said Srdan Verstovsek, M.D., Ph.D., medical oncologist and professor, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas.

About the RESPONSE Trial

RESPONSE is an ongoing, global, multi-center, open-label, Phase 3 trial comparing the efficacy and safety of Jakafi (ruxolitinib) with BAT in 222 patients (Jakafi, 110; BAT, 112) with PV who are resistant to or intolerant of hydroxyurea (HU).2

The primary response was a composite endpoint of the proportion of patients who achieved both hematocrit (Hct) control (defined as no phlebotomy eligibility from week 8 through week 32, with no more than 1 post-randomization phlebotomy eligibility up to week 8) and a spleen volume reduction of at least 35% from baseline at week 32. Phlebotomy eligibility was defined as an Hct >45% and at least 3 percentage points greater than baseline or an Hct >48%. Patients randomized to BAT could crossover (CO) to ruxolitinib at week 32 if they did not meet the primary endpoint, or after week 32 in case of disease progression (PBT eligibility, splenomegaly progression, or both).2

The primary endpoint of the RESPONSE study was achieved, demonstrating that Jakafi was superior to BAT at controlling Hct and reducing spleen volume at week 32.2 The 80-week follow-up results from RESPONSE have been published previously and confirmed that ruxolitinib could be an effective long-term therapy option for HU-resistant/intolerant (R/I) patients with PV.3

Durability of the primary response, overall clinicohematologic (CLHM) response (defined as Hct control, platelet count ≤ 400 × 109/L, white blood cell count ≤ 10 × 109/L, and spleen volume reduction ≥ 35% by imaging), as well as long-term safety were updated at week 208.1

At week 208, the Kaplan-Meier (KM) estimate of duration of primary response was 0.73 (95% CI: 0.49, 0.87), and the KM estimate of duration of absence of PBT eligibility was 0.73 (95% CI: 0.60, 0.83). The KM estimate of duration of at least 35% reduction in spleen volume was 0.86 (95% CI: 0.61, 0.95). Median duration of primary and CLHM responses has not been reached.1

Out of the 70 patients (63.6%) in the Jakafi arm who achieved an overall CLHM response at week 32, 21 had progressed by week 208. The KM estimate of duration of complete hematological remission (defined as Hct control, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L) at 208-weeks was 0.54 (95% CI: 0.31, 0.72). RESPONSE data also demonstrated that the KM estimate for overall survival at 5-years was 90.6% (95% CI: 80.1, 95.7) for patients treated with Jakafi compared to 87.7% (95% CI: 74.8, 94.3) for patients treated with BAT.1

At the week 208 analysis, 41 patients (37%) originally randomized to the Jakafi arm were still receiving therapy (median exposure, 225 weeks) versus no patients on BAT (median exposure, 34 weeks). Among patients in the Jakafi arm, 29% completed the treatment as per protocol. Of the 98 patients who crossed over to Jakafi after week 32, 38% remained on Jakafi (median exposure, 189 weeks) and 31% completed treatment. Other main reasons for the study drug discontinuations (Jakafi + CO patients) were disease progression (11% + 8%), patient decision (6% + 6%), and adverse events (14% + 14%).1

The most common adverse events in the Jakafi randomized arm (week 208 vs week 80) per 100 patient-years of exposure were anemia (9.3 vs 13.2), pruritus (7.3 vs 9.7), diarrhea (7.1 vs 9.7), headache (6.1 vs 10.5), arthralgia (5.9 vs 6.1), increased weight (5.6 vs 7.5) and muscle spasms (5.4 vs 7.9).

The 208-week results (Abstract #322) were presented as a part of an oral session (#634) on Sunday, December 10, 2017, 7:30-9:00 AM Eastern Time (8:15 AM), Building C, Level 2, C208-C210.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and is typically characterized by elevated hematocrit, the percent volume of red blood cells in the blood, which can lead to a thickening of the blood and an increased risk of blood clots. An elevated white blood cell and/or platelet count may also be present.4 Patients with PV who fail to consistently maintain appropriate hematocrit levels have a four times higher risk of major thrombosis (blood clots) or cardiovascular death.5 Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body.6 Signs and symptoms of PV commonly include fatigue, itching, night sweats, bone pain, fever, and unexplained weight loss.7

Approximately 100,000 patients in the U.S. are living with PV.8 Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized in high-risk patients.9,10 Approximately one in four patients with PV are considered uncontrolled11,12 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in Cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: low platelet count, low red blood cell counts, bruising, dizziness, headache.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

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.