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Dr. Christian Homsy – CEO of Celyad

Dear Celyad Shareholders,

We entered into the very promising field of immuno-oncology in 2015 with the goal of offering truly transformational treatment options to patients and emerging as a world leader in cell therapy. We were pleased to announce this past Monday, July 11, that we have taken a significant step in achieving these objectives by entering into a collaboration with ONO Pharmaceutical to enhance the development of our innovative Natural Killer Receptor (NKR) based T-Cell platform.

Our license agreement with ONO Pharmaceutical Co., Ltd: an opportunity to expand Celyad’s reach globally.

We are thrilled that one of the preeminent immuno-oncology companies in the world is as excited as we are about the potential of our NKR-2 program and the opportunity this presents us to expand Celyad’s reach globally. The license agreement with ONO grants them the exclusive right to develop and commercialize our allogeneic NKR-2 T-Cell immunotherapy in Japan, Korea and Taiwan. In exchange for receiving a license in these countries, ONO will pay Celyad up to $311.5 million (plus double-digit royalties on net sales) in development and commercial milestones, including an upfront payment of $12.5 million. ONO’s impressive experience in developing and launching drugs in Asian countries, including the blockbuster PD-1 inhibitor Opdivo, significantly accelerates our progress in these new markets, which account for 10% of the world population that have access to advanced medical care, and ensures that our program is in the best position to succeed worldwide. Having such a strong regional partner allows us to concentrate on the continued development of NKR-2 for the largest opportunities in the US and EU, where we maintain full ownership and development of the entire
NKR platform. In addition to the monetary and regional benefits of the agreement, we look forward to the clinical expertise that will be shared amongst our teams, which should lead to us exploring the full potential of NKR-2 T-Cell immunotherapies worldwide. Collectively, we will also be capable of conducting global registration and combination trials.

To read the full Letter to Celyad shareholders, please click here.

Pour lire l’intégralité de la Lettre aux actionnaires de Celyad en français,cliquez ici.

• Celyad grants an exclusive license to ONO for the development and commercialization of Celyad’s unique allogeneic NKR-2 T-cell in Japan, Korea and Taiwan.
• Celyad also grants to ONO an exclusive option to license its autologous NKR-2 T cell product in the above ONO territories.
• Total deal value of up to 31.325 JPY B (€282 million or $311.5 million) plus double digit royalties on net sales in ONO territories.

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of cell therapies, today announced an exclusive license agreement with the leading Japanese immuno-oncology company, ONO Pharmaceutical Co., Ltd. (TSE: 4528), for the development and commercialization of Celyad’s allogeneic NKR-2 T-cell immunotherapy in Japan, Korea and Taiwan. This license agreement opens new markets to Celyad and expands the global footprint of its NKR-2 T-cell cancer immunotherapy treatment and potentially for other disease conditions.

Celyad will receive an upfront payment of 1.25 JPY B (€11.25 million or $12.5 million) and is eligible of up to 30.075 JPY B (€270.75 million or $299 million) in development and commercial milestones. Celyad will also receive double digit royalties based on net sales of the licensed product in ONO’s territories.

Under the terms of the agreement, Celyad will continue developing its allogeneic NKR-2 T-cell immunotherapy in the EU and US territories, and ONO will be responsible for future development and commercialization in ONO’s territories (Japan, Korea and Taiwan). Both companies will also explore the opportunity to collaborate to collectively run global registration trials and combination trials. In addition, Celyad grants to ONO an exclusive option to license for development and commercialization of its autologous NKR-2 T cell product in the above ONO territories.

Dr. Christian Homsy, CEO of Celyad, said: “We are very pleased to collaborate with ONO and to activate the development of our NKR-2 T-cell allogeneic platform in Japan, Korea and Taiwan. This license agreement is a great opportunity for Celyad to expand the scope of its immuno-oncology clinical programs and bring this breakthrough science to numerous patients around the world. Further, this license agreement with ONO, the leader in immuno-oncology in Asia, validates our NKR-2 approach and its tremendous potential.”

Georges Rawadi, VP Business Development of Celyad, said: “Celyad surrounds itself with the best immuno-oncology experts in the world to develop its NKR T-cell platform. This is why we have entered this agreement with ONO. Through this commercial license agreement, Celyad aims to expand the clinical and commercial potential of its allogeneic NKR-2 T-cell immunotherapies worldwide.”

Gyo Sagara, President, Representative Director and CEO of ONO, said: “We are very delighted to collaborate with the leading cell therapy company, Celyad, for its distinct immuno-oncology candidates. Celyad’s NKR-2 is backed by cutting-edge science and we believe that it can be a new therapeutic option for patients who are not cured with existing therapies.”

Conference Call Details

A conference call will be held on Monday, July 11, 2016 at 2:00pm (CEST) / 8:00am (EDT) to review the licensing agreement with ONO Pharmaceutical. Christian Homsy, Chief Executive Officer, will deliver a brief presentation followed by a Q+A session.

Participants are asked to call the assigned numbers approximately five minutes before the conference call begins.

The call can be accessed by dialing the numbers below and using the passcode: 30423803

International:                                +44 (0) 1452 584233
Belgium:                                            024003425
France:                                               0800947325
UK:                                                        08002795994
US:                                                        1 866 629 0057

About Celyad’s NKR Platform

Celyad is developing a unique Natural Killer Receptor (NKR) based T-Cell platform to target a wide range of solid and hematological tumors. Unlike traditional CAR-T cell therapy, which target only one tumor antigen, Natural Killer (NK) cell receptors enable a single receptor to recognize multiple tumor antigens.

Celyad’s lead candidate, NKR-2, is a T-Cell engineered to express the human NK receptor, NKG2D, which is an activating receptor that triggers cell killing through the binding of NKG2D to any of eight naturally occurring ligands that are known to be overexpressed on more than 80% of tumors.

Preclinical results indicate that NKR-2 has multiple mechanism of actions and goes beyond direct killing by signifying that its encoded T-Cells attack the tumor cells, inhibit the mechanisms that enable tumors to evade the immune system, activate and recruit anti-tumor immune cells and disrupt the blood supply to the tumor. These mechanisms promote the induction of adaptive immunity, meaning the body develops a long-term cell immune memory against specific tumor antigens of the targeted tumor.

In contrast to traditional CAR-T therapeutic approaches, and based on strong preclinical evidence, Celyad’s current NKR-2 program does not employ patient lymphodepleting pre-conditioning, thereby avoiding the toxicities associated with chemotherapy and allowing the immune system to remain intact.

Celyad is developing both autologous and allogeneic NKR-2 administrations. For autologous NKR-2, Celyad collects the patient’s own T-Cells and engineers them to express NKG2D in order to target cancer cells effectively. Celyad’s allogeneic platform engineers the T-Cells of healthy donors, that also express TCR Inhibitory Molecules (TIMs), to avoid having the engineered donor cells be rejected by the patient’s normal tissues.

The preclinical research underlying this technology was originally conducted at Dartmouth College by Dr. Charles Sentman and has been published extensively in peer-reviewed publications.

NKR-2 is currently being tested in a Phase I trial in acute myeloid leukemia and multiple myeloma patients. The trial is designed to assess the safety and feasibility of NKR-2, with secondary endpoints including clinical activity. Key research investigations include understanding the persistence of NKR-2 cells within the patient.

About ONO PHARMACEUTICAL CO., LTD.
ONO PHARMACEUTICAL CO., LTD., headquartered in Osaka, Japan, is an R&D-oriented pharmaceutical company committed to create innovative medicines in specific areas. It focuses especially on the oncology and diabetes areas. For more information, please visit the company’s website at http://www.ono.co.jp/eng/index.html

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, today announced the infusion of the first patient enrolled in the fourth dose level of its Phase I/IIa clinical trial. The study is evaluating the safety and feasibility of its NKR-2 T-cell therapy using T-cells with NKG2D receptor in cancer patients suffering from Acute Myeloid Leukemia (AML) or Multiple Myeloma (MM).

Dr. Christian Homsy, CEO of Celyad, commented: “We are pleased to have enrolled the first patient in the fourth dose level cohort of this study on track and are encouraged that no adverse safety signals have been observed so far for the nine patients already treated with
NKR-2. We are actively working on the recruitment of the two next patients for this new dose level and we look forward to the data that are expected in the next few months”

Dr. Frédéric Lehmann, Head of Immuno-Oncology at Celyad:«The infusion of the 10^th patient demonstrates good progress in our first-in-human NKR-2 Phase I/IIa study. This technology has great potential in multiple cancer indications and we look forward to completing this Phase I/IIa and moving to the next stage in clinical development.”

About Celyad’s NKR-T program

NKR stands for Natural Killer Cell Receptor. NKG2D CAR T-cells are now called NKR-2 T-cells and the product development name is NKR-2.

Existing CAR-T cells are engineered using constructs encoding an antibody single chain variable fragment, the signalling domain of CD3 zeta and one or more co-stimulatory domain(s). In contrast to existing CAR-T cells, Celyad’s lead immuno-oncology product candidate, NKR-2, is a T-Cell encoded to express the human Natural Killer activating receptor, NKG2D and the signalling domain of CD3 zeta. Using the human Natural Killer cell receptor, unlike traditional CAR technologies, NKR-2 has the potential to:

• Bind to 8 different ligands that are expressed by a vast majority of cancer cells, both hemaetological and solid malignancies.
• Target and kill tumors as well as the blood vessels that feed them and also express the ligands of the NKG2D receptor.
• Act on the immunosuppressive microenvironment within tumors resulting in the inhibition of the mechanisms which enable tumor to evade the immune system.
• Induce adaptive auto-immune response resulting in the creation of a long term cell memory against the targeted tumor.

The research underlying this technology was originally conducted by Dartmouth College Professor Charles Sentman, and has been published in numerous peer-reviewed publications. NKR-2 has an active Investigational New Drug (IND) application with the FDA for a Phase I clinical trial. The trial is designed to assess the safety and feasibility of NKR-2 in acute myeloid leukemia and multiple myeloma patients, with secondary endpoints including clinical activity.

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, with clinical programs in cardiovascular diseases and immuno-oncology, today announced that an oral presentation titled “Validation of Manufacturing NKG2D Chimeric Antigen Receptor T Cells for a First-in Human Trial in AML/MDS and Multiple Myeloma” will be made at the American Society of Gene & Cell Therapy (ASGCT) 19^th Annual Meeting May 4-7 in Washington DC.

Dr. Frédéric Lehmann, Head of Immuno-Oncology at Celyad: “We are pleased that the application to present the validation of our cell manufacturing process was selected for an oral presentation.  It highlights the importance and interest in our NKR-2 clinical program marking a positive step forward.  This technology has great potential and we are looking forward to completing the Phase I.”

About Celyad’s NKR-T program

NKR stands for Natural Killer Receptor. NKG2D CAR T-cells are now called NKR-2 T-cells and the product development name is NKR-2.

Existing CAR-T cells are engineered using constructs encoding an antibody single chain variable fragment, the signaling domain of CD3 zeta and one or more co-stimulatory domain(s). In contrast to existing CAR-T cells, Celyad’s lead immuno-oncology product candidate, NKR-2, is a T-Cell encoded to express the human Natural Killer activating receptor, NKG2D. Using the human Natural Killer cell receptor, unlike traditional CAR technologies, has the potential to:

• Bind to 8 different ligands that are expressed by a vast majority of cancer cells, both hemaetological and solid malignancies.
• Target and kill tumors as well as the blood vessels that feed them and also express the ligands of the NKG2D receptor.
• Target and kill the inhibitory mechanisms preventing the tumor from evading the immune system.
• Induces adaptive auto-immune response thanks to the creation of a long term cell memory against the targeted tumor.

The research underlying this technology was originally conducted by Dartmouth College Professor Charles Sentman, and has been published in numerous peer-reviewed publications. NKR-2 has an active Investigational New Drug (IND) application with the FDA for a Phase I clinical trial. The full data readout from the Phase I dose escalation trial is expected in mid-2016. The trial is designed to assess the safety and feasibility of NKR-2 in acute myeloid leukemia and multiple myeloma patients, with secondary endpoints including clinical activity. The safety follow-up period post-infusion has been decreased to 21 days after approval by the U.S. Food and Drug Administration (FDA) and Institutional Review Board (IRB).

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, with clinical programs in cardiovascular disease and immuno-oncology, today announced that the EMA has issued a certification for C-Cure^®non-clinical data.

C-Cure^® (C3BS-CQR-1) is a cardiovascular lineage-committed cell therapy product being developed for the treatment of ischemic heart failure, currently in a pivotal phase III clinical trial in Europe and Israel. The EMA certification announced today is the second of three modules, following the certification of quality data obtained in May 2014, made in preparation for a marketing application. The certification provides confirmation that the Committee for Advanced Therapies (CAT), recognizes that the C-Cure^® development program continues to meet the rigorous standards set by the EMA for a successful development and submission package.

Dr. Jean-Pierre Latere, Head of Cardiovascular Franchise at Celyad, commented: “This certification acknowledges the rigor of our work and we continue to execute on our plans to make C-Cure® available to patients with ischemic heart failure.  We are optimistically awaiting the CHART 1 Phase III results which are expected end of June 2016.”

Dr. Richard Mountfield, Head of Regulatory Affairs and Clinical Operations at Celyad, commented: “Through constructive collaboration with CAT, the issuing of this certification for the non-clinical data for C-Cure^® further reflects the positive Regulatory environment for our Marketing Authorization Application.”

European Regulation on ATMPs

ATMPs (Advanced Therapy Medicinal Product) are at the forefront of biotechnology and medical innovation. Because of their novelty and complexity, evaluating the quality, safety, and efficacy of ATMPs often requires the development of alternative approaches that go beyond what is needed for conventional medicines.

The European Regulation (EC) No 1394/2007 provides a consolidated framework for this innovative class of products, including a procedure allowing SMEs (Small to Medium Enterprises) to voluntarily apply for the certification of the pharmaceutical quality and the pre-clinical data of an ATMP. The aim is to offer an early dialogue with the EMA, to clarify regulatory requirements and provide feedback on the quality and completeness of data submitted. 

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, with clinical programs in cardiovascular diseases and immuno-oncology, today announced appointment of Dr. Hinrich Abken, Dr. Scott Antonia, Dr. Marco Davila, Dr. Stéphane Depil, Dr. Marc Ernstoff, Dr. David Edward Gilham, Dr. Sebastian Kobold, Dr. Daniel Olive, Dr. Charles Sentman and Dr. Jeffrey S. Weber to the Company’s Scientific Advisory Board.

Dr. Christian Homsy, CEO of Celyad: “We are proud to have gathered such an accomplished team of international immuno-oncology experts to our Scientific Advisory Board. Each member has dedicated their career to landmark scientific achievements that have advanced the field of immunotherapy for cancer treatment. It is of paramount importance for Celyad to surround itself with thought leaders that will help the Company translate pioneering technology into transformative therapies that will change the lives of cancer patients”.

Dr. Frédéric Lehmann, Head of Immuno-Oncology at Celyad:“We are honored to collaborate with these internationally renowned specialists and to cross-fertilize their scientific expertise in immuno-oncology, in clinical development and in cell therapy to develop our NKR-T platform. Their collective knowledge and guidance will contribute to make the most of Celyad’s unique therapeutic approach and potentially open the path to new treatment options for cancer patients”.

The new members of the Scientific Advisory Board include:

• Dr. Hinrich Abken is Professor for Genetics & Immunology at CMMC (Center for Molecular Medicine Cologne) at the University of Cologne and Dept of Internal Medicine, Oncology?Hematology at the University Hospital Cologne where he is working towards the development of adoptive cell therapy of malignant diseases using engineered
  T-cells. Dr. Abken’s group is internationally leading in pre?clinical research of adoptive therapy with T-cells engineered with chimeric antigen receptors.
• Dr. Scott Antonia is the Department Chair of the Thoracic Oncology Department at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. He is also a Professor of Oncologic Sciences at the University of South Florida College of Medicine in Tampa. 
  Dr. Antonia’s work focuses on translational research. Using his molecular biology and cellular background in the development of immunotherapeutic strategies for the treatment of cancer patients, he has developed strategies designed to thwart the immunosuppressive mechanisms used by tumors to evade T-cell mediated rejection.
• Dr. Marco Davila is a medical oncologist that specializes in both clinical and laboratory research in the treatment of patients with hematologic malignancies.  He is Associate Member in the Blood and Marrow Transplantation and Immunology Departments at the Moffitt Cancer Center, University of South Florida. Dr. Davila’s laboratory develops gene-engineered cell therapies that target and kill cancerous cells in animal models of hematologic malignancies and was the Principal Investigator of a clinical trial using genetically engineered T cells targeted against malignant B cells. 
• Dr. Stéphane Depil is onco-hematologist at Léon Bérard Cancer Center and Associate Professor at University Claude Bernard Lyon I, adjunct Professor at UCBL and CEO of Netris Pharma.  Dr Depil has significant expertise in conducting pre-clinical and clinical development in oncology as the former head of Oncology R&D at Servier.
• Dr. Marc Ernstoff is a medical oncologist, professor and chief of the Division of Hematology/Oncology in the Department of Medicine in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo (UB). Over the past 30 years, Dr. Ernstoff has focused his research on expanding understanding of the immunobiology of human cancer and the development of new immune therapies for melanoma, renal cell carcinoma and glioblastoma multiforme.
• Dr. David Edward Gilhamis Senior Lecturer Clinical and Experimental Immunotherapy Group Director of the Institute of Cancer Sciences, Manchester.  His group focuses upon developing immunotherapies for the treatment of cancer which include the exploitation of chimeric antigen receptors and recombinant T cell receptors to re-direct the effector functions of T cells, which are then used in adoptive transfer studies.
• Dr. Sebastian Koboldis Professor at the Medical Center of the University of Munich and Senior Academic Assistant. He is also Deputy Head of the Immunopharmacology group at Ludwig-Maximilians University of Munich. His research aims to develop new proteins that are intended to modulate the function of T-cells of the human immune system and enable them to destroy specifically and efficiently cancer cells.
  • Dr. Daniel Olive is Professor of Immunology at Aix Marseille University; he is also in charge of the « Immunity and Cancer » research team of INSERM UMR1068 of Marseille Cancer Research Center (Institut Paoli Calmettes). He is the head of the first IBiSA Platform dedicated to Cancer Immunomonitoring Platform and has been a pioneer and leader in the co-signalling field since 1990. His work is dedicated to tumor immunology with a major emphasis on innate immunity and co-signalling molecules.
  • Dr. Charles L. Sentman is a Professor of Microbiology & Immunology and the Director of the Center for Synthetic Immunity at the Geisel School of Medicine at Dartmouth. In addition to academic research, he is a Scientific Founder for Celdara Medical LLC (Lebanon, NH) and inventor of CM-CS1. He has expertise in natural killer cell biology, T cells, immunotherapy, chimeric antigen receptors, bispecific antibodies, and immuno-oncology.
  • Dr. Jeffrey S. Weber is Deputy Director at the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center and professor of Medicine at NYU and head of Experimental Therapeutics at the Perlmutter Cancer Center. He is a translational clinician-scientist and clinical trialist with an interest in Immuno-Oncology and the development of new treatment strategies for patients with melanoma. Dr. Weber was the principal investigator of the first trial that demonstrated benefit for PD-1 blocking antibodies in melanoma patients that had failed ipilimumab. He was also the first investigator who demonstrated that PD-1 blocking antibodies had encouraging activity in resected melanoma patients.