CTO1681 to prevent and mitigate cytokine release syndrome in multiple myeloma patients receiving CAR T-cell therapy

Abstract
CytoAgents is developing CTO1681 for the prevention and treatment of cytokine release syndrome (CRS)
associated with chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy has emerged as a very
promising treatment option for patients with relapsed or refractory (R/R) hematologic malignancies. However,
CAR T-cell therapy can also result in a high incidence of severe and potentially life-threatening immune-mediated
toxicity, including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is a systemic
inflammatory response that has been reported as one of the most frequent and dangerous adverse events
following CD19-directed CAR T-cell therapy. CRS is thought to be mediated by an initial release of
proinflammatory cytokines, which activate bystander immune cells and endothelial cells, which in turn activate
more immune cells, culminating in a cytokine storm. Because CytoAgents’ novel approach is focused on
reducing the transcription of multiple proinflammatory cytokines, its compound is expected to mitigate,
and in some cases even prevent, CRS. CTO1681 is an orally available, stable compound identical to beraprost
sodium-314d (BPS-314d), the stereoisomer of the racemate beraprost sodium (BPS) that accounts for nearly all
of BPS’s pharmacological activity. Because BPS can modulate the release of cytokines from human peripheral
blood mononuclear cells, CytoAgents has investigated the use of BPS and its active isomer CTO1681 as a
treatment for moderate virus-induced CRS, specifically influenza and COVID-19. All of the results to date indicate
that CTO1681 has strong potential to reduce the CRS response, leading to better patient outcomes regardless
of CRS etiology. Overall, BPS, BPS-314d, and CTO1681 formulations have been found to be well tolerated and
to not completely suppress cytokine levels in healthy volunteers with normal serum levels. CytoAgents is
currently conducting a Phase 1b trial of CTO1681, a multicenter, open-label, dose-escalating safety and
pharmacokinetic (PK) MAD study in patients with diffuse large B cell lymphoma (DLBCL) receiving CD19-
directed CAR T-cell therapy. This Direct to Phase II project will support additional drug manufacturing and
initiation of an open-label Phase 2a trial in multiple myeloma (MM) patients. The company will undertake three
specific aims: 1) Determine the preliminary efficacy of CTO1681 in preventing or reducing CRS or ICANS
compared to historical data; 2) Determine the expanded safety profile of CTO1681 in patients with R/R MM
receiving CAR T-cell therapy; 3) Investigate the potential impact of CTO1681 on antitumor activity of CAR T-cell
therapy compared to historical data. This project will help support clinical assessment of CTO1681 in CAR T-cell
therapy recipients, advancing a novel treatment with the potential to reduce hospitalization, intensity of
supportive care, and mortality and to improve patients’ quality of life. Moreover, this therapeutic may allow more
patients with R/R hematologic malignancies to have access to potentially life-saving CAR T-cell treatment.

Grant Number: 1R44CA295189-01A1
NIH Institute/Center: NIH
Principal Investigator: ARTHUR BERTOLINO