Tuesday June 2nd 2020

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Celyad, a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, today announced updates from the company’s allogeneic programs.

Celyad, a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, today announced updates from the company’s allogeneic programs, including additional data from the Phase 1 alloSHRINK trial evaluating the T cell receptor (TCR) inhibitory molecule (TIM)-based, non-gene edited allogeneic CAR-T  candidate, CYAD‑101, for the treatment of metastatic colorectal cancer (mCRC), and the company’s short hairpin RNA (shRNA) platform underpinning the next-generation, non-gene edited CYAD-200 series of CAR-T candidates. These data were presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program from May 29-31, 2020.

Dr. Frédéric Lehmann, VP of Clinical Development at Celyad, commented“The latest safety and clinical activity data from the alloSHRINK trial in metastatic colorectal cancer patients further demonstrate CYAD-101’s differentiated profile as an allogeneic CAR-T candidate. The absence of clinical evidence of graft-versus-host-disease (GvHD) for CYAD-101, which co-expresses the NKG2D receptor with our novel, TIM technology used to knockdown signalling of the TCR complex, confirms the potential of non-gene edited approaches for the development of allogeneic CAR-T  candidates. Taking these positive clinical data into account, we have decided to broaden the program to include evaluating CYAD-101 following FOLFIRI chemotherapy in refractory patients as an expansion cohort of the alloSHRINK trial. Overall, treatment of advanced metastatic colorectal cancer patients beyond second line regimens remains a high unmet medical need, and we believe CYAD-101 could offer a unique immunotherapeutic approach to treat this incurable disease.”

Dr. David Gilham, CSO of Celyad, stated, “CYAD-101 has pioneered the potential for non-gene edited approaches for the development of allogeneic CAR-T  candidates, and we are excited to build upon this strong position with our shRNA technology platform. Preclinical data reported during ASCO over the past few days confirm the ability of a single shRNA hairpin to provide prolonged TCR knockdown, which our first shRNA-based allogeneic candidate, CYAD-211. In addition, the data demonstrated the breadth and depth of the shRNA platform, including the concurrent knockdown of up to four genes. We believe combining the knockdown potential of the platform with additional construct enhancements provides tremendous therapeutic optionality to our non-gene edited CYAD-200 series of CAR-T candidates.”

alloSHRINK Phase 1 Trial Update

Background

  • To date, a total of 15 patients with relapsed/refractory mCRC who progressed after previous treatment with oxaliplatin-based or irinotecan-based chemotherapies have been enrolled in the dose-escalation, alloSHRINK Phase 1 trial evaluating three consecutive dose levels of CYAD-101 administered concurrently with FOLFOX chemotherapy. The number of prior therapies received by patients enrolled in the trial ranged from one to six with a mean of three.

  • All 15 patients were dosed from a single cell bank of CYAD-101 that was generated in advance from two manufacturing runs each using a fraction of an apheresis from a single healthy donor.

Safety and Tolerability

  • No clinical evidence of GvHD has been observed following 44 injections of CYAD-101. We believe these data continue to support the ability of the company’s novel inhibitory peptide TIM to reduce signaling of the TCR complex through a non-gene edited approach.

  • Treatment with CYAD-101 following FOLFOX preconditioning chemotherapy was observed to be well-tolerated. Seven of the 15 patients enrolled in the trial reported at least one treatment-related adverse event (AE), however, all AEs reported were grade 1 or 2, including one patient who experienced cytokine-release syndrome (grade 1). No patient discontinued treatment due to AEs.

Clinical Activity

  • Encouraging anti-tumor activity was observed in the trial with two patients who achieved a confirmed partial response (PR) according to RECIST 1.1 criteria, including one patient with a KRAS-mutation, the most common oncogenic alteration found in all human cancers. In addition, nine patients achieved stable disease (SD), with seven patients demonstrating disease stabilization lasting more than or equal to three months of duration.

  • No correlation was observed between clinical responses and the degree of human leukocyte antigen (HLA) matching between patients and CYAD-101 donor cells, indicating that CYAD-101 can be used in a broad patient population regardless of the HLA haplotype.

Next Steps

  • An expansion cohort of alloSHRINK trial will evaluate CYAD-101 following FOLFIRI (combination of 5-fluorouracil, leucovorin and irinotecan) preconditioning chemotherapy in refractory mCRC patients, at the recommended dose of one billion cells per infusion. Enrollment in the expansion cohort of the trial is expected to begin during the fourth quarter of 2020.

shRNA Platform and CYAD-200 Series

Background

  • In October 2018, the company announced 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 was optimized by Celyad to knockdown the TCR complex in allogeneic CAR-T therapies as well as to target a broad range of proteins.

shRNA Platform

  • shRNA platform coupled with company’s all-in-one vector approach is designed to provide flexibility, versatility and efficiency in designing novel, allogeneic CAR-T candidates through single step engineering process.

  • Lead shRNA-based allogeneic candidate CYAD-211, targeting B-cell maturation antigen (BCMA) for the treatment of relapsed/refractory multiple myeloma, which uses a single hairpin to knockdown the CD3ζ component of the TCR complex, is expected to enter clinical trials by year-end 2020.

  • Next-generation candidates exploring two shRNA knockdowns are currently under development.

  • Continued preclinical evaluation of the shRNA platform demonstrates proof-of-principle that the concurrent knockdown of four genes using an optimized framework is feasible.

  • Combining shRNA knockdown with additional functional components should offer therapeutic optionality to non-gene edited allogeneic CYAD-200 series of product candidates.

About CYAD-101 and alloSHRINK Trial

CYAD-101 is an investigational, non-gene edited, allogeneic (healthy donor derived) CAR-T  candidate engineered to co-express a chimeric antigen receptor based on NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands and the novel inhibitory peptide TIM (TCR Inhibitory Molecule). The expression of TIM reduces signalling of the TCR complex, which is responsible for graft-versus host disease.

alloSHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of three consecutive administrations of CYAD-101 every two weeks administered concurrently with FOLFOX (combination of 5-fluorouracil, leucovorin and oxaliplatin) chemotherapy in patients with refractory mCRC. In the expansion cohort of the trial, CYAD-101 will be administered concurrently with FOLFIRI.

About shRNA Platform and CYAD-200 Series

The company is focused on the development of its proprietary non-gene edited allogeneic short hairpin RNA (shRNA) SMARTvector technology platform through the CYAD-200 series of candidates. The company is currently evaluating several shRNA-based allogeneic CAR-T candidates, including CYAD-211, an allogeneic CAR-T candidate targeting B-cell maturation antigen for the treatment of relapsed/refractory multiple myeloma.

About Colorectal Cancer

Colorectal cancer is the third most common type of cancer among both men and women worldwide and is the fourth most common in terms of mortality. In 2018, approximately 1.8 million people were diagnosed with colorectal cancer, with about 140,000 and 500,000 diagnoses in the United States and Europe, respectively. According to data from ASCO, approximately 40% of patients are diagnosed with early-stage, localized-stage disease. The five-year survival rate of localized disease is approximately 90%. In patients where the cancer has spread to distant parts of the body, as in metastatic colorectal cancer, the five-year survival rate drops to approximately 15%.