Trial for CytoAgents’ Drug for Management of CAR-T-Associated CRS Begins Enrolling Participants

CytoAgents has begun enrolling patients in its phase 1b/2a clinical trial (NCT05905328; CTA-2101) evaluating CTO1681, its small molecule drug intended to treat cytokine release syndrome (CRS, also known as cytokine storm) associated with treatment with chimeric antigen receptor T-cell (CAR-T) therapy.¹

The company noted that the first patient will be enrolled at UPMC Hillman Cancer Center, the first of multiple locations to be activated for the trial. In total, the study is expected to recruit approximately 54 patients aged 18 years or older who are scheduled to be treated with a CD19-targeted CAR-T therapy for the treatment of diffuse large B-cell lymphoma.

“We were early adopters of CAR T-cell therapy and remain committed to providing this treatment for our patients in the safest way possible,” Robert L. Ferris, MD, PhD, a physician-scientist and the director of UPMC Hillman Cancer Center, said in a statement.¹ “We are dedicated to solving the CRS problem associated with CAR T-cell therapy and to be a part of this clinical trial at our institution.”

The investigational new drug application for the trial was cleared by the FDA in May 2023.² CTO1681 is directed at the NF-kB signaling pathway and is intended to reduce inflammation via the modulation of cytokine production.³ The drug is meant to decrease NF-kB signaling without eliminating it completely; CytoAgents expects that sufficient signaling for immune system function will remain. Although the current trial is specifically testing the drug for CRS in patients receiving CAR-T for lymphoma, CytoAgents expects that CTO1681 has potential to treat CRS resulting from a variety of causes, such as bispecific antibody therapy, COVID-19, and other respiratory diseases. 

“We are thrilled to advance CTO1681 into the clinic to establish key insights into the safety and efficacy of our novel therapeutic,” Teresa Whalen, RPh, the CEO of CytoAgents, added to the statement.² “Dosing our first patients in the lymphoma population is an important step forward for the company and the patients who may benefit. We look forward to continued enrollment with data anticipated in 2024.”

CytoAgents stated that it hopes CTO1681 could make receiving advanced therapeutics like CAR-T and bispecific antibody therapy safer and more accessible options for patients who are in need of effective treatments for their diseases.¹ Thus, the drug could help these advanced modalities to become more widely adopted for clinical use.

“This clinical trial addresses an area of great unmet medical need as the majority of patients receiving CAR T-cell therapy experience the toxicities of CRS and associated neurotoxicity,” Arthur P. Bertolino, MD, PhD, MBA, the chief medical officer of CytoAgents, added to the statement.¹

CytoAgents is not the only company developing a small molecule drug intended to address CRS in patients receiving CAR-T for cancer. In January 2023, Poolbeg Pharma announced that it was beginning preclinical work to explore whether POLB 001, its small molecule p38 MAP kinase inhibitor originally developed to address hypercytokinemia in severe influenza, could be applied to manage CRS in patients being treated with CAR-T for hematological malignancies.^4-6 In light of data gathered during the research for the severe influenza indication, which Poolbeg Pharma described as specific to the immune response in patients receiving CAR-T, the company submitted a patent application related to the use of p38 inhibitors for this indication. At the time, the company stated that it expects to be able to initiate a relevant clinical trial in 2024.

"Hyperinflammation as a driver of disease severity in influenza is also fundamental to CRS, which can severely complicate CAR-T cell therapy of patients with blood cancers,” Brendan Buckley, a scientific advisory board member at Poolbeg Pharma, said in a January 2023 statement.⁴ “By reducing runaway inflammation associated with CRS, POLB 001 has the potential to significantly reduce the serious adverse effects that many CAR-T cell patients suffer... With oncology clinical trial enabling activities for POLB 001 underway, we look forward to updating the market as to the progress of this exciting program."

REFERENCES
1. CytoAgents announces initiation of patient enrollment in phase 1b/2a clinical trial to treat cytokine release syndrome in CAR t-cell therapy. News release. CytoAgents, Inc. October 17, 2023. Accessed October 19, 2023. https://www.businesswire.com/news/home/20231017178717/en/CytoAgents-Announces-Initiation-of-Patient-Enrollment-in-Phase-1b2a-Clinical-Trial-to-Treat-Cytokine-Release-Syndrome-in-CAR-T-cell-Therapy
2. 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. https://firstwordpharma.com/story/5738638
3. Our science. CytoAgents, Inc. Website. Accessed May 12, 2023. https://cytoagents.com/our-science/
4. Poolbeg announces strategic expansion of POLB 001 into oncology. News release. Poolbeg Pharma. January 16, 2023. https://polaris.brighterir.com/public/poolbeg_pharma/news/rns_widget_home/story/xel2nzr
5. Positive initial data analysis in POLB 001 LPS challenge trial. News release. Poolbeg Pharma. January 9, 2023. https://polaris.brighterir.com/public/poolbeg_pharma/news/rns/story/w69767w
6. Poolbeg Pharma. POLB 001 – severe influenza. Website Accessed January 16, 2023. https://www.poolbegpharma.com/pipeline/polb-001/