Design of Phase Three of KYSA-6, a Global Open-label, Randomized, Controlled Study of KYV-101, a Fully Human CD19 Chimeric Antigen Receptor (CAR) T-cell Therapy, Versus Ongoing Standard-of-Care (SOC) Immunosuppressive Therapy in Generalized Myasthenia Gravis (gMG)
Sri Mupiddi1, Michael C Hunter2, Sarah Hoffmann3, Tobias Hegelmaier4, Jeremias Motte5, Ralf Gold5, Dimitrios Mougiakakos6, Charlotte Schubert7, Stefanie Schreiber8, Ali Habib9, Christian Geis10, Olimpia Carbunar11, Sheetal Shroff12, Marinos Dalakas13, Achim Berthele14, Perry Shieh15, Alexandru Barboi16, Livia Dutra17, Alanood Alsolaihim18, Edward Needham19, Fiona Norwood20, Gary R Cutter21, Brad Hunter22, Justin Chou23, Baodong Xing23, Dominic Borie23, Naji Gehchan23, Aiden Haghikia4
1Stanford, 2Intermountain Medical Center, 3Charité-Universitätsmedizin Berlin, 4Hannover Medical School, 5Ruhr University Bochum, 6Otto von Guericke University Magdeburg, 7University Medical Center Hamburg-Eppendorf, 8Otto-von-Guericke University Magdeburg, 9University of California, Irvine, 10Jena University Hospital, 11University Of Miami, 12Houston Methodist Hospital, 13Thomas Jefferson University, 14School of Medicine, Technical University Munich, Klinikum rechts der Isar, Dept., 15University of California Los Angeles, 16Indiana University Health, 17Instituto do Cérebro do Hospital Israelita Albert Einstein, 18King Faisal Specialist Hospital and Research Center, 19University of Cambridge, 20Kings College Hospital, 21University of Alabama, 22Intermountain Health, 23Kyverna Therapeutics Inc.
Objective:
Assess the efficacy of KYV-101 in generalized myasthenia gravis (gMG) compared with standard-of-care (SOC) treatment.
Background:
Patients with myasthenia gravis (MG) can have substantial disability despite available treatments. KYV-101 is an autologous, fully human CD19 CAR T-cell therapy with CD28 costimulation designed for potency and tolerability that has the potential to achieve deep B-cell depletion and immune reset to deliver durable, disease-free, drug-free remission, with a single dose. Compassionate use of KYV-101 in 3 patients with refractory gMG resulted in up to 24 months of ongoing remission with acceptable safety.
Design/Methods:
The Phase 3 portion of KYSA-6 (NCT06193889) is a global randomized 2-arm superiority trial. Approximately 60 patients aged 18–75 years, with gMG (MGFA class II–IV), AChR or MuSK autoantibodies, MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) total scores ≥6 and ≥11, respectively, and failure of treatment with ≥2 immunosuppressant(s)/immunomodulator(s), are eligible. All patients will undergo apheresis to enable KYV-101 manufacturing and then resume SOC treatment. Patients will be randomized 1:1 to KYV-101 or continued SOC, stratified by prior biologics use. Patients in the KYV-101 arm will undergo SOC washout, lymphodepletion, and KYV-101 dosing (1×108 CAR T cells). Co-primary endpoints are change in MG-ADL and QMG scores from baseline to week 24 with KYV-101 versus SOC. The key secondary endpoint is change in MG composite score. Other secondary endpoints include safety and autoantibody levels. Patients receiving SOC will have the opportunity to cross over to receive KYV-101 at Week 24.
Results:
Phase 3 of KYSA-6 is open and enrolling.
Conclusions:
KYV-101 is a novel therapy with the potential to change the treatment paradigm through deep B-cell depletion and immune reset with a single dose in patients with autoimmune diseases. The phase 3 portion of KYSA-6 is intended as a registrational study for patients with gMG.
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