CytoAgents’ Drug for Management of CAR-T-associated CRS Gets FDA IND Clearance

CTO1681, which is designed to lower NF-kB signaling without eliminating it altogether, was previously evaluated for safety in a phase 1 clinical trial in healthy adults.

CytoAgents’ CTO1681 (GP1681), an investigational small molecule drug intended to manage cytokine release syndrome (CRS), has received clearance of an investigational new drug (IND) application by the FDA.1

CTO1681 is directed at the NF-kB signaling pathway and is intended to reduce inflammation via the modulation of cytokine production.2 The drug is meant to decrease NF-kB signaling without eliminating it completely; CytoAgents expects that sufficient signaling for immune system function will remain. The company has developed CTO1681 with the expectation that it could be used to manage a broad range of CRS indications, including CRS caused by chimeric antigen receptor T-cell (CAR-T) therapy, bispecific antibody therapy, COVID-19, and other respiratory diseases.1 The new IND clearance specifically relates to evaluation of CTO1681 for the management of CRS in patients receiving CAR-T therapy for lymphoma. CytoAgents noted that it expects to initiate a phase 1b/2a clinical trial for this indication in the summer of 2023.

“We are thrilled to advance CTO1681 into the clinic and excited about how our novel therapeutic will potentially prevent and/or treat CRS,” Teresa Whalen, RPh, the CEO of CytoAgents, said in a statement.1 “The FDA’s clearance to advance our clinical program for CTO1681 in the United States is another important milestone for our company.”

CTO1681 was previously evaluated for safety and tolerabilityin a phase 1 clinical trial that enrolled healthy adults.3 The randomized, double-blind, placebo-controlled trial, which evaluated multiple ascending doses, was initiated in October 2020.3,4 It was conducted in Australia with the collaboration of Novotech and CMAX Clinical Research. Upon the trial’s completion in August 2021, CytoAgents reported that the drug had shown “a strong safety profile” and that the results supported further evaluation of the drug in clinical trials.

“As someone who has dedicated my life to cancer treatment, patient advocacy and innovation, I’m highly motivated to solve the CRS problem associated with CAR T-cell therapy” Stanley Marks, MD, the chairman of UPMC Hillman Cancer Center and the chief of the Division of Hematology and Oncology at UPMC Shadyside Hospital, and a member of CytoAgents’ board of directors, said in an August 2021 statement.4 “GP1681 could not only treat but perhaps prevent CRS altogether. Reducing this life-threatening side effect will allow us to treat and cure more patients with CAR T-cell therapy.”

CytoAgents is not the only company developing a treatment with the potential for management of CRS related to CAR-T. In May 2023, Enlivex received a European patent that provides protection until at least 2037 related to the use of its cell therapy Allocetra for purposes of preventing or managing CRS in patients being treated with CAR-T for cancer.5 Allocetra is an investigational allogeneic cell therapy intended to reprogram macrophages back into a homeostatic state and is comprised of non-HLA matched peripheral blood mononuclear cells derived from a healthy human donor that have been induced into an apoptotic stable state.6 It is being evaluated in clinical trials for the treatment of patients with solid tumors (NCT05581719), patients with peritoneal metastasis (NCT05431907), patients with COVID-19 (NCT04659304, NCT04922957), and patients with sepsis (NCT04612413).

1. CytoAgents Announces FDA Acceptance of IND Application for CTO1681 to Treat Cytokine Release Syndrome in Oncology. News release. CytoAgents, Inc. May 11, 2023. Accessed May 12, 2023.
2. Our science. CytoAgents, Inc. Website. Accessed May 12, 2023.
3. Cytoagents launches clinical trials for GP1681, treatment of COVID-19 cytokine storm. News release. CytoAgents, Inc. October 13, 2020. Accessed May 12, 2023.
4. Cytoagents’ phase 1 trial results show “cytokine release syndrome” drug candidate safe. News release. CytoAgents, Inc. August 10, 2021. Accessed May 12, 2023.
5. Enlivex announces issuance of European patent covering the use of Allocetra to prevent cytokine release syndrome (CRS) resulting from CAR t-cell therapy. News release. Enlivex Therapeutics Ltd. May 8, 2023. Accessed May 12, 2023.
6. Enlivex receives Israeli Ministry of Health approval for the initiation of a phase I/II trial evaluating Allocetra alone and in combination with a PD1 checkpoint inhibitor in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. August 17, 2022. Accessed May 12, 2023.
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