ON July 2, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported several strategic updates to its relapse/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) program, including its lead autologous NKG2D-based CAR-T therapy, CYAD-01, as well as the next-generation NKG2D-based CAR-T candidate, CYAD-02 (Press release, Celyad, JUL 2, 2019, View Source [SID1234537363]). The Company’s management team will host a conference call tomorrow, July 2nd, at 2 p.m. CEDT / 8 a.m. EDT, to discuss each of the updates and future milestones for the program.
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Filippo Petti, CEO of Celyad noted "Over the past few years Celyad has made great strides in evaluating our NKG2D-based CAR-T therapy for the treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. We have observed that targeting NKG2D ligands with our lead CAR-T candidate CYAD-01 drives anti-leukemic activity and is well tolerated. Today marks a milestone event as we announce that the FDA has accepted our Investigational New Drug application to commence clinical trials for our next-generation, CAR-T candidate, CYAD-02, and that the FDA and FAMHP have accepted our proposal to utilize our new, proprietary ‘OptimAb’ manufacturing process for both CYAD-01 and CYAD-02. Given the recent updates to our relapsed/refractory AML program, we believe we are well-positioned to improve upon the initial signals we’ve observed to date for CYAD-01 in this difficult to treat and rapidly progressing patient population."
Overview of CYAD-01 r/r AML and MDS Clinical Program
To date, results from the Phase 1 THINK trial evaluating CYAD-01 without prior preconditioning chemotherapy for the treatment of r/r AML and MDS have shown the NKG2D-based CAR-T to be well tolerated with encouraging preliminary anti-leukemic activity in six of thirteen patients (46%) evaluable per protocol.
The company is currently evaluating the potential for CYAD-01 in the treatment of r/r AML and MDS in multiple clinical trials including the Schedule Optimization cohorts of the THINK trial, which is assessing a more frequent dosing schedule of CYAD-01, and in the Phase 1, dose-escalation DEPLETHINK trial, which is assessing CYAD-01 following the preconditioning chemotherapy cyclophosphamide and fludarabine, or CyFlu. CyFlu is the preconditioning therapy typically used with other hematological malignancies evaluating CAR-T cell therapies.
In June 2019, preliminary data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) meeting demonstrated that a denser schedule of infusions of CYAD-01 without preconditioning in Cohort 10 (Schedule Optimization) of the THINK trial and a single infusion of low dose (1×108 cells) CYAD-01 following preconditioning chemotherapy in the DEPLETHINK trial was well tolerated and led to better time-averaged engraftment of the CAR-T cells.
Strategic Drivers Aimed to Enhance NKG2D-based CAR-T for r/r AML and MDS
Based on the initial clinical data and tolerability profile for CYAD-01 from the r/r AML and MDS clinical program, Celyad aims to increase the potency of the NKG2D-based CAR-T therapy to potentially deepen the breadth, frequency and duration of clinical responses in this patient population. In particular, Celyad is focused on: 1) the optimization of treatment conditions, including denser dosing schedule or exploiting preconditioning chemotherapy; 2) optimization of the manufacturing process, including enrichment of T cells with memory-like phenotype; and 3) improving the persistence of CAR-T cell therapies through RNA interference using short hairpin RNA (shRNA) technology.
Recent Developments for r/r AML and MDS Program
CYAD-01 – Enriching Early Memory T cells in our First-in-Class, NKG2D-based CAR-T Candidate by Leveraging the OptimAb Manufacturing Process
Celyad recently submitted Chemistry, Manufacturing, and Control ("CMC") amendments to the U.S. Food and Drug Administration (FDA) and Belgium’s Federal Agency for Medicines and Health Products (FAMHP) related to "OptimAb", a modified manufacturing process for CYAD-01.
OptimAb, is designed as an iterative improvement of Celyad’s first two manufacturing processes for CYAD-01 (the LY and mAb processes) and builds upon key characteristics of both. OptimAb utilizes a shortened eight-day cell culture and incorporates a selective PI3K inhibitor. Combined with the manufacturing optimizations previously developed by the company, the OptimAb process results in a product that is enriched for T cells with a memory-like phenotype while maintaining the high level of manufacturing reliability required to support clinical development. The amendment filed with the regulatory agencies is based upon our in-house research focused on the development of a manufacturing process to enrich for T cells with memory-like phenotype.
Preclinical data based on conditions where the dose of CYAD-01 produced with the mAb manufacturing process is reduced to have minimal activity indicate that cells produced using the OptimAb manufacturing process drive improved anti-tumor activity in an aggressive AML model.
Following feedback from the FDA and FAMHP, the CMC amendments were accepted and now in effect with regulators under the current Investigational New Drug (IND) application for CYAD-01. Celyad expects to treat the first patient using the recently accepted OptimAb manufacturing process for CYAD-01 in cohort 4 (1×109 cells) of the Phase 1 DEPLETHINK trial in August 2019. Based on regulatory feedback, Celyad expects to stagger treatment of the first three subjects treated with CYAD-01 cells manufactured by OptimAb.
CYAD-02 – Next-Generation, NKG2D-based CAR-T Candidate
At the company’s R&D Day held in March 2019, management unveiled its novel shRNA platform to develop next-generation autologous and allogeneic CAR-T cell therapies, including CYAD-02, a next-generation, autologous NKG2D-based CAR-T candidate that incorporates shRNA technology to target the NKG2D ligands MICA and MICB. The single shRNA modulates the expression of both ligands which translates to encouraging increases in in vitro proliferation, in vivo engraftment and anti-tumor activity. CYAD-02 also incorporates the OptimAb manufacturing process thereby enriching for T cells with memory-like phenotype.
In late June 2019, the FDA accepted the IND application for CYAD-02 and permitted it to go into effect. The company plans to begin enrollment of a Phase 1 dose-escalation trial evaluating the safety and clinical activity of CYAD-02 with the preconditioning chemotherapy CyFlu for the treatment of r/r AML and MDS in early 2020.
The CYAD-02 Phase 1 trial will be the first CAR-T cell therapy clinical trial employing the optimized shRNA SMARTvector technology licensed from Horizon Discovery and represents the output of a strong collaboration with the company’s partner.
Upcoming Milestones for r/r AML and MDS Program based on OptimAb Manufacturing Process
Initial clinical data from cohort 4 of the Phase 1 DEPLETHINK trial for CYAD-01 using the OptimAb manufacturing process are expected by year-end 2019. Full results from cohort 4 of the DEPLETHINK trial are anticipated in first quarter 2020.
Initiate the Phase 1 dose-escalation trial evaluating CYAD-02, following preconditioning chemotherapy for the treatment of r/r AML and MDS in early 2020. Preliminary data from the Phase 1 trial are expected by mid-2020.
Conference Call and Webcast Details
Celyad will host a conference call to discuss the update to the r/r AML and MDS program on Tuesday, July 2nd, 2019 at 2 p.m. CEDT / 8 a.m. EDT. The conference call can be accessed through the following numbers:
United States: +1 877 407 9208
International: +1 201 493 6784
Conference ID: 13692100
The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events & Webcasts" section of the Company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.
Background on Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS)
Acute myeloid leukemia (AML) is an aggressive (fast-growing) form of leukemia characterized by the abnormal growth of myeloid cells, that spread in the bone marrow, blood stream and occasionally to other organs. AML is most commonly diagnosed in males aged 65-74 years old.
With about 40,000 new cases diagnosed each year in aggregate in the United States and Europe, AML is the most common type of aggressive leukemia in adults. The five-year survival rate for people 20 and older with AML is approximately 24%. For people younger than 20 diagnosed with AML, the survival rate is 67%. It has one of the lowest survival rates of all types of leukemia.
AML can develop either de novo in a healthy individual or in patients with a predisposing disease called myelodysplastic syndrome (MDS). Myelodysplastic syndrome (MDS) can be considered a premalignant disease that affects myeloid cells. Approximately 1,400 individuals in the United States are diagnosed each year with MDS.
Standard therapies for AML include chemotherapy (cytarabine) or hypomethylating agents (azacytidine or decitabine). If these therapies fail patients will receive a blood stem cell transplant. In addition, some patients are not eligible for transplant due to a poor general health condition. Despite these treatments, most patients relapse. As such, new or improved therapies for the treatment of AML are urgently needed.