On June 6, 2019 AstraZeneca reported positive results from the Phase III ELEVATE-TN trial of Calquence (acalabrutinib) in patients with previously-untreated chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults (Press release, AstraZeneca, JUN 6, 2019, View Source [SID1234536914]).1 This is the second Calquence pivotal trial in CLL to meet its primary endpoint early, following the positive results of the ASCEND trial, announced in May.

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The trial met its primary endpoint; Calquence in combination with obinutuzumab demonstrated a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) when compared with the chemotherapy-based combination of chlorambucil and obinutuzumab.

The trial also met a key secondary endpoint showing Calquence monotherapy achieved a statistically-significant and clinically-meaningful improvement in PFS compared to the chemotherapy and obinutuzumab regimen.

The safety and tolerability of Calquence was consistent with its established profile.

José Baselga, Executive Vice President, Oncology R&D said: "These findings confirm the superiority of Calquence as a monotherapy and also in combination over standard-of-care treatments for chronic lymphocytic leukaemia. The positive results from both the ELEVATE-TN and ASCEND trials will serve as the foundation for regulatory submissions later this year."

AstraZeneca plans to present detailed results from ELEVATE-TN at a forthcoming medical meeting. Additionally, AstraZeneca will present full results from the Phase III ASCEND clinical trial in relapsed or refractory CLL as a late-breaking abstract at the upcoming European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress on 16 June 2019 (Abstract #LB2606).

Calquence is currently approved for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL) in the US, Brazil, the UAE, and Qatar and is being developed for the treatment of CLL and other blood cancers.

About ELEVATE-TN

ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence alone or in combination with obinutuzumab vs. chlorambucil in combination with obinutuzumab in previously-untreated patients with CLL. In the trial, 535 patients were randomised (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg twice daily until disease progression) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg twice daily until disease progression).2

The primary endpoint is PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.2

About Calquence

Calquence (acalabrutinib) was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Calquence is an inhibitor of Bruton tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.3 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 26 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenstrom macroglobulinaemia, follicular lymphoma, and multiple myeloma and other haematologic malignancies. Several Phase III clinical trials in CLL are ongoing, including ASCEND, ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating acalabrutinib vs. ibrutinib in patients with previously-treated high-risk CLL, and ACE-CL-311 evaluating acalabrutinib in combination with venetoclax and with/without obinutuzumab in patients with previously-untreated CLL without 17p deletion or TP53 mutation.

About chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults, with an estimated 191,000 new cases globally and 20,720 new cases in the US annually, and prevalence that is expected to grow with improved treatment.1,4,5,6 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.1 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.1 This could result in anaemia, infection and bleeding.1 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

In October 2018, AstraZeneca and Innate Pharma announced a global strategic collaboration that included Innate Pharma licensing the US commercial rights of Lumoxiti (moxetumomab pasudotox-tdfk), and with support from AstraZeneca, will continue EU development and commercialisation, pending regulatory submission and approval.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On June 6, 2019 GRAIL, Inc., a healthcare company whose mission is to detect cancer early, when it can be cured, reported that Hans Bishop has been appointed as Chief Executive Officer, effective immediately (Press release, Grail, JUN 6, 2019, View Source [SID1234536933]). He succeeds Jennifer Cook, who has stepped down from the Board and her role as Chief Executive Officer for family health reasons. Mr. Bishop has served on GRAIL’s Board of Directors since August 2018 and will continue to serve as a Director on the GRAIL Board.

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GRAIL also announced the appointment of Joshua Ofman as Chief of Corporate Strategy and External Affairs. In addition, Maykin Ho has joined GRAIL’s Board as an Independent Director. The company also announced that Renée Galá has decided to step down from her role as Chief Financial Officer.

During her tenure as Chief Executive Officer, Ms. Cook led the company through the transition from discovery-stage research to advancing an investigational multi-cancer early detection test into clinical development and toward commercialization. In addition, the company has fully enrolled two of its population-scale clinical studies with approximately 115,000 participants, and initiated a third 50,000-participant clinical study.

"We are very grateful to Jennifer for her important contributions to the company, resulting in the pivotal milestone of the recently presented impressive data from CCGA that support advancement of GRAIL’s investigational multi-cancer early detection test toward commercialization. While we are disappointed to see Jennifer go, we respect and support her decision," said Catherine Friedman, Chair of the GRAIL Board of Directors. "We are thrilled that Hans is stepping into the CEO role to continue building upon this positive trajectory. Hans is a widely respected corporate leader with significant experience building successful companies and guiding novel products through commercialization."

Ms. Friedman continued: "In addition, we are delighted to welcome Josh, an accomplished industry expert in health economics, market access, and health policy with deep experience integrating innovation into healthcare systems, and Maykin, a distinguished biotech leader with unparalleled expertise in healthcare strategy and finance, to GRAIL."

"GRAIL is guided by its bold vision to improve cancer survival rates by creating a single blood test that can detect multiple deadly cancer types at one time," said Mr. Bishop. "For much of my career, I’ve been involved in the fight against cancer, and during that time, I have seen real progress for patients. However, cancer is still the second leading cause of death globally, and I believe early detection is key to changing that. I’m excited to step into the CEO role at a time where the team at GRAIL has delivered such exciting results. I look forward to working with the Board and the entire GRAIL team in this new role to ensure a smooth transition as we advance our test toward commercialization."

Mr. Bishop has more than 30 years of experience in the biotechnology industry. He will continue to serve as the Executive Chair of the Sana Board of Directors and as a Director of Celgene, Agilent Technologies, and Lyell Immunopharma. Mr. Bishop founded Juno Therapeutics in 2013 and served as its President and Chief Executive Officer until the company was acquired by Celgene in March 2018. Prior to this, he served as an Executive in Residence at Warburg Pincus. Earlier, he was Executive Vice President and Chief Operating Officer for Dendreon, Inc. He also previously served as President of Specialty Medicine at Bayer Healthcare, Senior Vice President of Global Commercial Operations at Chiron Corporation, and Vice President and General Manager of European Biopharmaceuticals. Mr. Bishop holds a bachelor’s degree in chemistry from Brunel University in London.

Joshua Ofman, MD, MSHS, joins GRAIL from Amgen where he spent 16 years in several roles, most recently as Senior Vice President, Global Health Policy. Prior to joining Amgen in 2003, Dr. Ofman was a member of the academic faculty in the Department of Medicine and Health Services Research, University of California, Los Angeles (UCLA) School of Medicine, Cedars-Sinai Medical Center. Dr. Ofman also served as Senior Vice President of Zynx Health Inc., a healthcare IT company and subsidiary of the Cerner Corp. Dr. Ofman obtained his undergraduate degree from the University of California, Berkeley and his MD from the University of California, Irvine, School of Medicine. He conducted his internship and residency in internal medicine and fellowship in digestive diseases at the UCLA Department of Medicine. In addition, Dr. Ofman completed a RAND/VA/UCLA fellowship in ambulatory care and health services research, specializing in technology assessment, and obtained his MSHS from the UCLA School of Public Health. He is widely published in health economics and technology assessment, public health program evaluation, and health policy analysis.

Maykin Ho, PhD, has more than 30 years of experience in the healthcare and finance industries. She is a venture partner of Qiming Venture Partners and a member of the Biotech Advisory Panel of the Stock Exchange of Hong Kong. She is also a retired partner of the Goldman Sachs Group, where she served as senior biotechnology analyst, co-head of healthcare for global investment research, and advisory director for healthcare investment banking. Prior to Goldman Sachs, Dr. Ho held various managerial positions in licensing, strategic planning, marketing, and research at DuPont-Merck Pharmaceuticals and DuPont de Nemours & Company. Dr. Ho serves on the Board of Directors for FibroGen, Agios Pharmaceuticals, Parexel International Corporation, the Aaron Diamond AIDS Research Center, and the Institute for Protein Innovation. She was a postdoctoral fellow at Harvard Medical School. Dr. Ho received a PhD in Microbiology and Immunology and a BS from the State University of New York, Downstate Medical Center.

On June 6, 2019 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that it has enrolled the first patient in the TELLOMAK Phase II study of IPH4102 in patients with different subtypes of T-cell lymphoma (TCL) (Press release, Innate Pharma, JUN 6, 2019, View Source [SID1234536915]). IPH4102 is Innate Pharma’s wholly-owned first-in-class anti-KIR3DL2 antibody, developed for the treatment of T-cell lymphoma.

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"The start of the TELLOMAK study is an important milestone in advancing IPH4102 towards potential registration in Sézary syndrome. The Phase I results demonstrated strong clinical activity, a favorable safety profile and a substantial improvement in quality of life. Based on these data, IPH4102 has the potential to become the treatment of choice in later lines of Sézary syndrome therapy, where there are currently limited effective treatment options and where toxicity is remaining an area of great concern with currently approved drugs", said Pierre Dodion, Chief Medical Officer of Innate Pharma. "Moreover, we are excited about exploring the activity of IPH4102 in larger subsets of T-cell lymphoma, such as Mycosis fungoides (MF) and Peripheral T-cell lymphoma (PTCL) where patients suffer from a significant medical need and to broaden the potential use of IPH4102."

On June 6, 2019 bluebird bio, Inc. (Nasdaq: BLUE) reported that the company will host a live webcast to review new data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting, and to discuss the approval of ZYNTEGLO (autologous CD34+ cells encoding βA-T87Q-globin gene) on Friday, June 14 at 8:00 a.m. ET (Press release, bluebird bio, JUN 6, 2019, View Source [SID1234536934]).

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Investors may listen to the call by dialing (844) 825-4408 from locations in the United States or +1 (315) 625-3227 from outside the United States. Please refer to conference ID number 2189283.

To access the live webcast of bluebird bio’s presentation, please visit the "Events & Presentations" page within the Investors & Media section of the bluebird bio website at View Source Replays of the webcast will be available on the bluebird bio website for 90 days following the event.

On June 6, 2019 Astex Pharmaceuticals, Inc. a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., reported top-line results from the ASCERTAIN phase 3 study evaluating cedazuridine and decitabine fixed-dose combination (ASTX727) vs decitabine IV in adults with intermediate and high-risk MDS or CMML (Press release, Astex Pharmaceuticals, JUN 6, 2019, View Source [SID1234536935]).

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The study met its primary endpoint of decitabine exposure equivalence of 5-day dosing between orally administered ASTX727 and IV decitabine as per the protocol analysis plan. Safety and clinical activity were similar to that observed in a previous phase 1/2 study. The full data will be presented at an upcoming scientific meeting.

Astex plans to file an NDA with the US FDA by the end of 2019.

"We are delighted with the outcome of the ASCERTAIN trial, and the demonstration that the fixed dose combination of cedazuridine with decitabine enables successful oral delivery of decitabine, alleviating the significant burden of five days of monthly IV infusions for patients who may continue to benefit from the drug for several months or even years," said Mohammad Azab, Astex Pharmaceuticals’ president and chief medical officer. "Subject to regulatory review and approvals, ASTX727 could bring a new treatment option to patients with these deadly diseases. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to this effort."

About Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727)

ASTX727 is a novel, orally administered fixed dose combination of cedazuridine, an inhibitor of cytidine deaminase, with the anti-cancer DNA hypomethylating agent, decitabine.1 By inhibiting cytidine deaminase in the gut and the liver, ASTX727 allows for oral delivery of the approved DNA hypomethylating agent, decitabine at exposures which are equivalent to the approved intravenous form of decitabine administered over 5 days.

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study in patients with MDS and CMML to define appropriate doses of the individual components of ASTX727 (cedazuridine and decitabine) so that decitabine exposure after oral administration of ASTX727 is similar to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 20 mg/m2 (see View Source NCT02103478). This study demonstrated that ASTX727 allowed decitabine to be delivered orally at a dose that emulates parenteral pharmacokinetics, as measured by 5-day area-under-the-curve (AUC).3 The drug’s safety profile was similar to that of IV decitabine. Of particular note was the low level of gastrointestinal adverse events.3

The concept of using cedazuridine to block the action of cytidine deaminase is also being evaluated in a low dose formulation of cedazuridine and decitabine for the treatment of lower risk MDS (see View Source NCT03502668). ASTX727 may also have potential in all-oral combination regimes for the treatment of a range of different tumor types.

Astex is also expanding the evaluation of cedazuridine – decitabine combinations through a program of investigator-sponsored trials.

ASTX727 is an investigational compound and is not currently approved in any country.

About the ASCERTAIN Study

The ASCERTAIN study was designed to demonstrate that the cedazuridine and decitabine fixed-dose combination (ASTX727) could deliver orally a pharmacokinetically equivalent exposure of decitabine compared to IV decitabine in adults with previously untreated or treated MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, int-2, or high-risk MDS. (see View Source NCT03306264). The study was designed as a randomized, open-label cross-over study in which patients were randomized in a 1:1 ratio to receive ASTX727 daily x 5 in the first 28-day cycle followed by IV decitabine daily x 5 in the second 28-day cycle, or the converse order. Following completion of the first two cycles, patients continued to receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or the subject decided to discontinue treatment or withdrew from the study. The primary endpoint of the study was total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine as measured across the first two cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, secondary PK parameters, clinical responses, red blood cell transfusion independence, leukemia-free survival, and overall survival. The study was conducted in 138 patients at 46 sites in the US and Canada.

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. US incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.4,5 The prevalence has been estimated to be from 60,000 to 170,000 in the US.6 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.7 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML. CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the US is approximately 1,100 new cases per year,8 and CMML may transform into AML in 15% to 30% of patients.9 The hypomethylating agents decitabine and azacitidine are effective treatment modalities for hematologic cancers and are FDA-approved for the treatment of higher risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.