Preclinical study demonstrates that adding LYMPHIR to anti-PD-1 treatment augments anti-tumor activity and improves overall survival compared to monotherapy alone by transiently depleting Tregs in the tumor microenvironment

CRANFORD, N.J., Oct. 31, 2023 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR) today announced 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. 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.

"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

1. 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).

About Citius Pharmaceuticals, Inc.

Citius Pharma is a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products, with a focus on oncology, anti-infectives in adjunct cancer care, unique prescription products, and stem cell therapies. The Company's diversified pipeline includes two late-stage product candidates. Mino-Lok®, an antibiotic lock solution for the treatment of patients with catheter-related bloodstream infections, is enrolling patients in a Phase 3 Pivotal superiority trial and was granted Fast Track designation by the FDA. Citius Pharma is preparing to resubmit the Biologics License Application for LYMPHIR, a novel IL-2R immunotherapy for an initial indication in CTCL, in early 2024, and announced plans to form Citius Oncology, a standalone publicly traded company with LYMPHIR as its primary asset. LYMPHIR received orphan drug designation by the FDA for the treatment of CTCL and PTCL. In addition, at the end of March 2023, Citius Pharma completed enrollment in its Phase 2b trial of CITI-002 (Halo-Lido), a topical formulation for the relief of hemorrhoids. For more information, please visit www.citiuspharma.com.

Forward-Looking Statements

This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price.  Factors that could cause actual results to differ materially from those currently anticipated are: risks relating to the results of research and development activities, including those from existing and new pipeline assets; our need for substantial additional funds; our ability to commercialize our products if approved by the FDA; our dependence on third-party suppliers; our ability to procure cGMP commercial-scale supply; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; uncertainties relating to preclinical and clinical testing; the early stage of products under development; market and other conditions; our ability to attract, integrate, and retain key personnel; risks related to our growth strategy; patent and intellectual property matters; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by Covid-19 and could be impacted by any future public health risks. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings which are available on the SEC's website at www.sec.gov, including in our Annual Report on Form 10-K for the year ended September 30, 2022, filed with the SEC on December 22, 2022, and updated by our subsequent filings with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Investor Contact:

Ilanit Allen
ir@citiuspharma.com
908-967-6677 x113

Media Contact:

STiR-communications
Greg Salsburg
Greg@STiR-communications.com 

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