Immuno-oncology

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, today announced that clinical data from the SHRINK and alloSHRINK Phase 1 trials, evaluating the safety of NKG2D-based autologous and allogeneic CAR-T candidates, CYAD-01 and CYAD-101, respectively, will be presented at the upcoming European Society for Medical Oncology (ESMO) 21^st World Congress on Gastrointestinal Cancer (WCGIC) to be held on July 3-6, 2019, in Barcelona, Spain.

 “We are delighted for the opportunity to present updated data at the upcoming WCGIC from both our autologous and allogeneic NKG2D-based clinical candidates for the treatment of refractory metastatic colorectal cancer” noted Frédéric Lehmann, Head of Global Clinical Development and Medical Affairs at Celyad. “We continue to build upon our clinical experience in the treatment of solid tumors with these novel immunotherapies and the oral presentation at WCGIC represents a special milestone to highlight preliminary data from the industry’s first trial investigating an ‘off-the-shelf ‘ CAR-T candidate for the treatment of solid tumors. In addition, the comparable trial designs between SHRINK and alloSHRINK as well as the similar CAR constructs provide insight into autologous and allogeneic approaches in an advanced solid tumor indication.”

Presentation Details:

Abstract #631:  Phase 1 studies assessing the safety and clinical activity of autologous and allogeneic NKG2D-based CAR-T therapy in metastatic colorectal cancer

Session:           Short Oral Presentation

Background on CYAD-01 and CYAD-101

CYAD-01 is an investigational CAR-T therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) based on NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells. CYAD-101 is an investigational, non-gene edited, allogeneic (donor derived) CAR-T therapy that co-expresses the NKG2D CAR of CYAD-01 and the novel inhibitory peptide TIM (T cell receptor [TCR] Inhibiting Molecule). The expression of TIM reduces signalling of the TCR complex which is responsible for Graft versus Host Disease (GvHD).

Background on SHRINK and alloSHRINK Trials

SHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and activity of CYAD-01 administered concurrently with FOLFOX (combination of 5-fluorouracil, leucovorin and oxaliplatin) chemotherapy in patients with metastatic colorectal cancer (mCRC). Patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-01 every two weeks.

alloSHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of CYAD-101 administered concurrently with FOLFOX chemotherapy in patients with refractory mCRC.  Similar to the SHRINK trial for CYAD-01, patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-101 every two weeks.

• shRNA platform complements Company’s all-in-one-vector approach in the design, discovery and development of next-generation CAR-T candidates
• Allogeneic T-cells derived by shRNA targeting show distinctive profile compared to CRISPR-Cas9 gene edited cells in preclinical assays
• Plans to initiate several Phase 1 trials to evaluate lead candidates, including next generation, autologous NKG2D-based CYAD-02 and three first-in-class, shRNA-based, non-gene edited allogeneic CAR-T therapies from the CYAD-200 series

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, today presented at R&D Day in New York the continued progress of the its pipeline of proprietary CAR-T therapies for the treatment of hematological malignancies and solid tumors, based on its short hairpin RNA (shRNA) platform.

“We are very pleased with the recent progress of our preclinical CAR-T pipeline,” noted Dr. Christian Homsy, CEO of Celyad. “Together with CYAD-101, our next generation allogenic shRNA platform should allow us to leapfrog the competition in the allogeneic CAR-T landscape. In addition, CYAD-02 has shown encouraging preclinical data of increased CAR-T cell expansion, persistence and anti-tumor efficacy. We continue to tap into our deep expertise and knowledge in cell therapy manufacturing and our all-in-one vector approach provides tremendous flexibility, versatility and efficiency in the design of novel, CAR-T therapies.“

Corporate Updates

• Lead asset CYAD-01 continues to advance in clinical trials for the treatment of patients with relapsed/refractory (r/r) acute myeloid leukemia (AML). The Company reported that additional dosing and schedule optimization are under evaluation in the THINK Phase 1 trial. In addition, the Company reported that interim data from the DEPLETHINK Phase 1 trial evaluating CYAD-01 following preconditioning chemotherapy shows the CAR-T cell therapy is well-tolerated at the initial dose levels following preconditioning chemotherapy. Future clinical updates from the Phase 1 THINK and DEPLETHINK trials are anticipated by mid-2019. 
• Company also highlighted its operational excellence for 2018 including a 94% manufacturing success rate and a twofold increase year-over-year in the number of patients treated.

shRNA Platform

• In October 2018, Celyad announced it had entered into an exclusive agreement with Horizon Discovery Group for the use of its shRNA technology to generate a novel, next-generation, non-gene-edited allogeneic platform for CAR-T therapies. Horizon Discovery’s SMARTvector technology to express shRNA optimized by Celyad provides an alternate method to knockout the TCR complex in allogeneic CAR-T therapies compared to gene editing techniques as well as the specificity to target a broad range of proteins.
• Utilization of the shRNA platform allowed the Company to develop the next generation of autologous, NKG2D-based CAR-T candidate, CYAD-02, and the novel, non-gene edited allogeneic CYAD-200 series of CAR-T candidates.
• In addition, the shRNA platform complements the Company’s strong intellectual property of six U.S. patents related to allogeneic T-cell technology and producing TCR deficient cells expressing a CAR construct.

Autologous CAR-T candidate: CYAD-02

• CYAD-02 incorporates shRNA technology to target NKG2D ligands MICA/MICB. In preclinical AML models, CYAD-02 shows an encouraging increase in in vitro proliferation and in vivo persistence and anti-tumor activity. The Company plans to generate additional preclinical proof-of-concept data for the program throughout 2019 and plans to submit an Investigational New Drug (IND) application for CYAD-02 in first half 2020.

Non-gene edited allogeneic CAR-T candidates: CYAD-200 series

• Celyad utilizes two technologies based on non-gene edited approaches to modulate the T-cell receptor (TCR) complex to generate allogeneic CAR-T therapies. The first approach utilizes our TCR-inhibitor molecule (TIM) and is tailored to our NKG2D-based CAR-T clinical candidate CYAD-101. The second approach leverages shRNA technology exclusively licensed from Horizon Discovery to target the CD3ζ component to knockdown the expression of the TCR/CD3 complex on the surface of the T-cell.
• In vivo data demonstrate that shRNA targeting of CD3ζ effectively protects against Graft-versus-Host Disease (GvHD) to a level equivalent to CRISPR-Cas9 based knock-out.  Furthermore, results from preclinical tests show significant increase in persistence of allogeneic T cells using shRNA targeting when compared to gene editing technologies, such as CRISPR-Cas9.
• Celyad announced plans to develop three disruptive first-in-class non-gene-edited allogenic CAR-T candidates leveraging the shRNA SMARTvector platform, including:
  • CYAD-211: B-cell maturation antigen (BCMA) targeting CAR-T therapy for the treatment of multiple myeloma, which is expected to enter the clinic by mid-2020.
  • CYAD-221: CD19 targeting CAR-T therapy for the treatment of B-cell malignancies, which is expected to enter the clinic by late 2020.
  • CYAD-231: Dual specific CAR-T targeting NKG2D and an undisclosed membrane protein, which is expected to enter the clinic by early 2021.
• In addition, the company continues to investigate additional undisclosed targets using the shRNA platform to pair with CARs to develop, differentiated next-generation cell therapies for the treatment of both hematological malignancies and solid tumors.

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD) a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, today announced the successful injection of the first patients in the SHRINK trial and the LINK trial, both targeting metastatic colorectal patients.

Celyad achieves important milestone in CYAD-01 treatment evaluation of metastatic colorectal cancer: ​

• No toxicity observed to date in first patient enrolled in the SHRINK[1] trial (concurrent administration of CYAD-01 with standard chemotherapy)
• No toxicity observed to date in first patient enrolled in the LINK[2] trial (hepatic transarterial administrations)

Dr. Christian Homsy, CEO of Celyad commented: “The infusion of a first patient in a new trial is always an important moment. CYAD-01, concurrently administered with standard chemotherapy FOLFOX in SHRINK, or administered through hepatic transarterial injections in LINK appears to have been well–tolerated to date. We are particularly satisfied with the lack of on-target/off-tumor toxicity observed to date in the context of the combination of CYAD-01 with chemotherapy. This bolstered our belief that, based on a careful and exhaustive clinical development plan, our product candidate will lead the path towards a therapy for cancer patients.”

After the promising signals of clinical activity of CYAD-01 reported in 2017 and validation of the use of the NKG2D receptor, Celyad designed a clinical development plan which aims at defining the best of the following approaches for CYAD-01 in patients with Acute Myeloid Leukemia (AML) and colorectal (CRC) cancers:

– CYAD-01 as a stand-alone investigational therapy, currently being evaluated in the THINK trial with relapsed refractory AML and CRC patients. Results have already been reported: the world’s first complete response by a CAR-T cell therapy in a patient with refractory and relapsed AML as well as stable diseases reported in colorectal and ovarian cancer patients.

– CYAD-01 administered concurrently with standard of care treatments. The SHRINK trial was initiated with CRC patients earlier in 2018. We expect that the EPITHINK trial will be initiated soon with AML patients.

– CYAD-01 administered after preconditioning of the patients using lymphodepletion. We expect trials in AML (DEPLETHINK AML) and CRC (DEPLETHINK CRC) patients to be initiated in the coming weeks.

Our objective is to continue with the above approach that offers the best observed safety/efficacy profile and to move forward in later phase clinical trials in both AML and CRC indications.

Dr. Frédéric Lehmann, VP Clinical Development and Medical Affairs at Celyad added: “Today’s announcement reflects Celyad’s commitment to develop the potential of CYAD-01 and is the result of our strong collaborations with key academic institutions in both the USA and Europe. Our clinical strategy aims to build on the favorable tolerability profile of CYAD-01 observed to date, and evaluate CYAD-01 in multiple settings to find the best approach for cancer patients. We are making good progress and look forward to sharing further results on SHRINK, LINK and other trials.“

SHRINK is an open-label Phase I trial evaluating the safety and clinical activity of multiple doses of CYAD-01, administered concurrently with the neoadjuvant FOLFOX treatment in patients with resectable liver metastases from colorectal cancer. The dose escalation design of SHRINK includes three dose levels: 1×10⁸, 3×10⁸ and 1×10⁹ of CYAD-01. At each dose, the patients will receive three successive administrations, two weeks apart at the specified dose. No adverse events have been reported in the first injection of the first patient enrolled.

LINK is an open-label Phase I trial evaluating the safety and clinical activity of multiple doses of CYAD-01, adopting a loco-regional approach in treating patients with CYAD-01 administration through multiple hepatic transarterial injections to colorectal cancer patients diagnosed with unresectable liver metastases. The dose escalation design of LINK includes three dose levels: 3×10⁸, 1×10⁹ and 3×10⁹ of CYAD-01. At each dose, the patients will receive three successive administrations, two weeks apart at the specified dose. No  adverse events have been reported in the first patient enrolled, who has received his three consecutive CYAD-01 administrations at the first dose level.

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[1] Standard CHemotherapy Regimen and Immunotherapy with NKG2D

[2] Loco-regional Immunotherapy with NKG2D

Mont-Saint-Guibert, Belgium – Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, today announces that first data analysis of the NKR-2 Phase I trial shows encouraging results which will be presented during a poster session at the 58th American Society of Hematology (ASH) Annual Meeting, taking place on December 3-6, 2016, in San Diego, CA.

The NKR-2 Phase I trial is a single infusion, dose escalation study evaluating the safety and feasibility of NKR-2 T-cells in Acute Myeloid Leukemia and Multiple Myeloma patients. This study was completed in September 2016 with a successful safety follow-up for all dose level cohorts. There were no cases of cytokine release syndrome, cell-related neurotoxicity, auto-immunity, or CAR-T related death. 

Based on recent analysis, encouraging clinical update and correlative analysis, including post-infusion immunophenotyping, will be presented at the poster session of the ASH Annual Meeting:

• Title: Safety Data from a First-in-Human Phase 1 Trial of NKG2D Chimeric Antigen Receptor-T Cells in AML/MDS and Multiple Myeloma (Poster Presentation)
• Abstract: 4052
• Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
• Presentation: Monday, December 5, 2016, 6:00pm – 8:00pm PST
• Location: San Diego Convention Center, Hall GH

Dr. Christian Homsy, CEO of Celyad commented: “NKR-2 Phase I trial was a safety study with the primary objective of ensuring that there was no on-target, off-tumor toxicity. We are positively surprised at reports of unexpected clinical benefit, while testing just one single infusion dosed between 50 and 1,000 times lower than our expected efficacious dose extrapolated from animal experiments. Our exceptionally strong animal data was obtained with three injections of human equivalent doses of 1 to 2 billion cells per injection, while the highest dose tested in the NKR-2 study was 30 million cells in a single infusion. These results are therefore encouraging and we look forward to triggering the next phase of our NKR-T program once European agencies and the FDA have approved our THINK trial protocol”.

Dr. Frédéric Lehmann, VP Immuno-Oncology at Celyad: “We are excited to present these data at ASH and to explore the full potential of our NKR-2 autologous therapy in our next development phase. The THINK trial will evaluate the clinical activity and safety in seven indications, in both hematologic malignancies and solid tumors. It is our hope that this study will be the foundation of a robust approach to treating patients with advanced tumors.”

Dr. David Gilham, VP Research and Development at Celyad: “NKR-2 CAR T cell therapy was designed to act like a drug with short term persistence and multiple injections in order to provide a better controlled and more predictable safety profile than that of other traditional CAR-T products. The primary objective is to avoid uncontrolled in-vivo cell expansion and long term persistence thereby replacing this paradigm with well controlled pharmacokinetics.  We are re-assured to note that the safety outcome of this Phase I study confirms the pre-clinical animal data generated to date.”