Citius Pharmaceuticals Announces Publication in Frontiers of Immunology of Positive Results from Solid Tumor Study of LYMPHIR™ in Combination with Checkpoint Inhibitor

On October 31, 2023 Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR) reported that preclinical research on LYMPHIR ("denileukin diftitox" or "E7777") was published today in Frontiers in Immunology1, a leading peer-reviewed journal in the immunology field (Press release, Citius Pharmaceuticals, OCT 31, 2023, View Source [SID1234636582]). The article reported positive results from a preclinical study that showed that denileukin diftitox in combination with an anti-PD-1 checkpoint inhibitor was more effective in the treatment of solid tumors (liver and colon) than either therapy alone. Data from this study contributed to the design and dosing regimen of two Phase 1 investigator-initiated studies currently underway at the University of Pittsburgh and the University of Minnesota.

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"We are excited to share the published results of this important animal study with the broader scientific community. The compelling results of this study showed that LYMPHIR administered in combination with an anti-PD-1 inhibitor, either sequentially or concurrently, led to significantly increased anti-tumor activity and prolonged survival compared to either treatment alone. Based on the strong signal of the study, two ongoing Phase 1 trials were initiated by investigators at leading cancer research institutions. We intend to share interim data from these studies when it becomes available. Importantly, the results of the preclinical study highlight LYMPHIR’s additional potential as a combination therapy in the treatment of solid tumors, which may allow Citius to explore substantially larger market opportunities for LYMPHIR in the future," stated Leonard Mazur, Chairman and CEO of Citius.

In recent years, one of the most important advances in solid tumor management has been the use of anti-PD-1/PDL1 antibody therapy. However, the effectiveness of treatment has varied, with not all tumors or patients responding with equivalent sensitivity to the treatment. The primary role of Treg-targeted cancer immunotherapy is to transiently deplete Treg cells. It is believed that regulatory T cells (Tregs) in the tumor microenvironment play an important role in patient resistance to anti-PD-1 immunotherapy. Targeting Tregs with LYMPHIR during treatment with anti-PD1/PDL1 checkpoint inhibitors may change the dynamics of the immune microenvironment, including anti-PD-1 sensitivity, in situations where Tregs are prominent. Consequently, the innovative preclinical study evaluated whether adding LYMPHIR improved the efficacy of anti-PD-1 antibody therapy. Syngeneic murine solid tumor models in colon cancer CT-26 and liver cancer H22 were used to conduct the study.

"This landmark study demonstrated that an increase in T-reg cell infiltration induced by anti-PD-1 treatment can be counterbalanced by their depletion by LYMPHIR, suggesting potential synergistic activity in a solid tumor model," stated Dr. Myron Czuczman, Chief Medical Officer of Citius. "We look forward to future results of ongoing human studies evaluating the potential benefit of Treg depletion by LYMPHIR in combination with checkpoint inhibitors and other immunomodulatory agents."

Key Study Findings

Targeting Tregs using LYMPHIR combined with anti-PD-1 (either sequentially or concurrently) demonstrated significant anti-tumor activity, and consistently targeted and transiently depleted Tregs in the tumor microenvironment
Combination treatment was more effective than monotherapy with either drug alone
Combination therapy was well-tolerated and significantly enhanced long-term survival in solid tumor-bearing animals
Mahdi, H. Woodall-Jappe, M., Singh, P., Czuczman, S., Targeting Regulatory T cells by E7777 enhances CD8 T-cell-mediated anti-tumor activity and extends survival benefit of anti-PD-1 in solid tumor models. Frontiers in Immunology. (Published online ahead of print, 2023 October 27).
About the Investigator Initiated Trials

A Phase 1 Study is underway at the University of Pittsburgh Medical Center (UPMC), Hillman Cancer Center. This study is an open label, Phase 1/1b study to investigate the safety and efficacy of a combined regimen of pembrolizumab with T-regulatory cell depletion via denileukin diftitox in patients diagnosed with recurrent or metastatic solid tumors. (Title: The efficacy of T-regulatory cell depletion with E7777 combined with immune checkpoint inhibitor, pembrolizumab, in recurrent or metastatic solid tumors: Phase I/II Study. NCT05200559). The study consists of two parts. Part I is a dose escalation study of four cohorts (3,6,9,12 mcg of LYMPHIR) and is expected to enroll 18-30 patients. Part II is a dose expansion study of approximately 40 patients to evaluate the safety and tolerability of the recommended combination dose of LYMPHIR and pembrolizumab (to include ovarian cancer and MSI-H cancer cohorts). The study will also investigate the alteration of the immune microenvironment within tumors and peripheral blood. Secondary endpoints include the objective response (complete response plus partial response), progression-free survival, and overall survival.

A Phase 1 trial has also been initiated at the University of Minnesota, Masonic Cancer Center. This study is a single-arm open-label trial which has an estimated enrollment of 20 participants who will be administered denileukin diftitox prior to receiving Chimeric Antigen Receptor (CAR-T) therapies. The Phase 1 study consists of two components: dose finding to establish a maximum tolerated dose (MTD) of denileukin diftitox in combination with CAR-T therapies and an extension component to provide an estimate of efficacy at that MTD. (Title: Phase I/II Trial Using E7777 to Enhance Regulatory T-Cell Depletion Prior to CAR-T Therapy for Relapsed/Refractory B-Cell Lymphoma (DLBCL) NCT04855253).