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Angel Pharmaceuticals Presents Latest Research Findings from CPI-818 Clinical Trial at the 17th International Conference on Malignant Lymphoma (ICML) 2023
CPI-818 (ITK Inhibitor) Induces Th1 Polarization and CD8+ TEMRA-Mediated Host Antitumor Responses in Patients with Refractory T-Cell Lymphomas
Jiaxing, China and Burlingame, Calif., U.S.A. – June 16, 2023 – Angel Pharmaceuticals, a clinical-stage innovative drug company, today announced that the latest data on CPI-818, an ITK inhibitor, support its novel immunotherapeutic mechanism of action with broad potential for application in both solid tumors and hematologic malignancies. Updated interim analysis results from the Phase 1/1b clinical trial of CPI-818 continue to demonstrate its potential for ITK inhibition and biomarker absolute lymphocyte count (ALC) in T-cell lymphomas (TCL). These latest research findings were presented as a conference abstract and poster jointly by Angel Pharmaceuticals, Corvus, and Professor Ding Ning from Peking University Cancer Hospital at the 17th International Conference on Malignant Lymphoma (ICML) (Abstract #193). The poster can be viewed in the ICML exhibition hall and electronic poster display area.
Poster Highlights:
Phase I/Ib Trial Interim Analysis Data
A Phase 1/1b clinical trial of CPI-818 as monotherapy in patients with relapsed TCL is currently ongoing, with peripheral blood lymphocyte count (ALC) recently added to the enrollment criteria. Based on the current enrollment rate in the Phase 1/1b trial, the company believes that the number of subjects treated in this clinical trial will provide sufficient safety and preliminary efficacy data to support the design of a potential Phase 3 registrational randomized clinical trial. As of the updated interim analysis data cutoff on May 18, 2023 (waterfall plot shown below): A total of 30 subjects were enrolled in the Phase 1/1b trial at the optimal dose of 200 mg (BID), of whom 20 were evaluable for tumor response. There were 3 complete responses (CR), 3 partial responses (PR), with 1 PR subject showing durable tumor response. One CR and 2 PR subjects remain on treatment. A total of 10 subjects are still continuing treatment, of whom 6 have not yet undergone their first tumor assessment. Among subjects with peripheral blood ALC ≥ 0.90 × 10⁹/L, 6/14 achieved objective responses (CR+PR) and 12/14 achieved disease control (CR+PR+stable disease [SD]). Among 6 subjects with peripheral blood ALC < 0.90 × 10⁹/L, no objective responses were observed.
As of the updated interim analysis data cutoff on May 18, 2023, serial tumor biopsy samples were available from one subject receiving CPI-818 treatment. Single-cell RNA sequencing analysis of baseline and on-treatment specimens showed an increase in tumor-infiltrating CD8+ T cells compared to baseline, as well as an increase in cytolytic effector molecules such as granzymes and perforin in T cells. An increase in T effector memory cells (TEMRA cells), which are T cells that respond to antigens and are capable of mediating effector functions such as tumor cell destruction, was also observed. In addition, flow cytometry analysis of paired peripheral blood samples at baseline and on-treatment showed similar findings in both CD8 T cells and CD4 T cells. These results are consistent with preclinical data and provide supporting evidence for a novel immunotherapeutic mechanism of selective ITK inhibition based on Th1 polarization and the resulting immune effector responses capable of eliminating tumor cells. Further studies demonstrated that CPI-818 treatment reverses the expression of T-cell exhaustion markers. T-cell exhaustion is considered a resistance mechanism to checkpoint inhibitors.
The waterfall plot shows the percentage of best tumor response in 18 subjects evaluable by CT scan (out of 20 evaluable subjects). The other 2 subjects presented with skin and peripheral blood involvement, with 1 PR and 1 progressive disease.
Figure 1: Waterfall Plot of Best Response in Target Tumor Lesions in the 200 mg Cohort of the Phase 1/1b Trial of CPI-818 in T-Cell Lymphomas
Preclinical Data Support the Novel Immunotherapeutic Mechanism of CPI-818
CPI-818 has the potential to treat solid tumors and hematologic malignancies through a novel mechanism of action involving ITK inhibition, which can modulate T-cell differentiation, enhance antitumor immune responses through Th1 polarization, increase T-cell cytolytic capacity, and reduce T-cell exhaustion. CPI-818 monotherapy demonstrated statistically significant tumor growth inhibition in tumor models (EL4 T-cell lymphoma, A20 B-cell lymphoma, and CT26 colon cancer). In the EL4 TCL model, CPI-818 induced increased infiltration of CD8+ T cells into tumor tissue. Furthermore, these CD8+ T cells highly expressed perforin, an effector molecule produced by cytotoxic T cells involved in killing tumor cells. In the CT26 colon cancer model, CD8 cell depletion attenuated the efficacy of CPI-818, indicating that its mechanism of action is dependent on the presence of normal CD8+ T cells. In the CT26 colon cancer model, CPI-818 reduced the expression of T-cell exhaustion markers. T-cell exhaustion is observed in tumors and chronic inflammation, where prolonged exposure to antigens leads to T-cell exhaustion or inactivation, rendering them unable to eliminate tumors or inflammation. In other mouse studies using T cells repeatedly pre-stimulated with antigens, CPI-818 reduced the development of T-cell exhaustion and could reverse exhaustion in already exhausted T cells. These reactivated T cells restored their ability to kill tumor cells. These results indicate that CPI-818-mediated ITK inhibition leads to alterations in the tumor microenvironment. These alterations promote antitumor immune responses, creating an environment unfavorable for tumor growth.
"Data presented at ICML demonstrate the potential of ITK inhibition as a novel immunotherapeutic mechanism of action for the treatment of cancer," said Dr. Richard Miller, Co-founder of Angel Pharmaceuticals. "The biology and immune-enhancing mechanisms mediated by selective ITK inhibition have shown consistent and comprehensive results across preclinical and clinical studies, including the modulation of normal T-cell differentiation to enhance the immune system's antitumor activity against lymphomas and solid tumors. In the interim analysis data, we observed tumor regression in the majority of patients treated with the optimal dose of CPI-818 at 200 mg (BID). Notably, ITK is not classified as an immune checkpoint in terms of oncology targets, but rather a kinase that can regulate T-cell differentiation into antitumor or pro-inflammatory cells. This positioning and the supporting research have laid a solid foundation for the development of CPI-818 as monotherapy and in combination regimens. We are confident that CPI-818 has the potential to become a cornerstone of novel tumor immunotherapy upon approval."
The International Conference on Malignant Lymphoma (ICML) is the world's largest international conference on malignant lymphoma, dedicated to presenting and discussing the latest basic, translational, and clinical research findings on the treatment of lymphomas. The 17th International Conference on Malignant Lymphoma (17-ICML 2023) was held from June 13 to 17, 2023, in Lugano, Switzerland.
About Angel Pharmaceuticals
Angel Pharmaceuticals is an innovative drug company dedicated to oncology and autoimmune diseases. With the mission of benefiting Chinese patients, Angel is committed to bringing globally top-tier innovative drugs for serious diseases such as cancer and autoimmune disorders to China. In October 2020, Angel Pharmaceuticals completed its Series A financing round, co-invested by Beta Fund, Hisun Pharmaceuticals, Tigermed, and Puhua Investment, and established a strategic partnership with Corvus Pharmaceuticals (CRVS) of the U.S. For more information, please visit www.angelpharma.com.
About Corvus Pharmaceuticals
Corvus Pharmaceuticals is a clinical-stage biopharmaceutical company. Corvus's lead product candidate is CPI-818, an oral, selective ITK inhibitor currently being evaluated in a multicenter Phase 1/1b clinical trial in patients with various T-cell lymphomas. Its second clinical program is ciforadenant (CPI-444), an oral small molecule inhibitor of the A2A receptor. Its third clinical program, mupadolimab (CPI-006), is a humanized anti-CD73 monoclonal antibody that has demonstrated immunomodulatory activity and immune cell activation in preclinical studies. For more information, please visit www.corvuspharma.com.
