Compugen Ltd., a clinical-stage therapeutic discovery and development company, identifies novel drug targets and new biological pathways to develop therapeutics in the field of cancer immunotherapy.
The company's innovative immuno-oncology pipeline consists of three clinical stage programs: COM701, COM902, and rilvegostomig, which target immune checkpoints discovered through computational methods. Two of these programs, COM701, a potential first-in-class anti-PVRIG antibody, and COM902, a poten...
Compugen Ltd., a clinical-stage therapeutic discovery and development company, identifies novel drug targets and new biological pathways to develop therapeutics in the field of cancer immunotherapy.
The company's innovative immuno-oncology pipeline consists of three clinical stage programs: COM701, COM902, and rilvegostomig, which target immune checkpoints discovered through computational methods. Two of these programs, COM701, a potential first-in-class anti-PVRIG antibody, and COM902, a potential best-in-class therapeutic anti-TIGIT antibody, are in Phase 1 clinical trials. They have been evaluated for the treatment of solid tumors both as monotherapies and in combination with dual (PVRIG/PD-1, PVRIG/TIGIT) and triple (PVRIG/PD-1/TIGIT) blockade. Based on data from the Phase 1 trials, it focuses on two specific tumor types for further clinical evaluation of COM701 and COM902, the company initiated two clinical trials in 2023. These trials are evaluating the triple combination treatment of COM701, COM902, and pembrolizumab, one in metastatic microsatellite stable colorectal cancer patients, and the other is in platinum-resistant ovarian cancer patients. Data from the metastatic microsatellite stable colorectal clinical trial is expected to be reported in the first half of 2024, and data from the platinum-resistant ovarian cancer trial is anticipated in the fourth quarter of 2024. Rilvegostomig, a novel anti PD-1/TIGIT bispecific antibody derived from COM902, is being developed by AstraZeneca under an exclusive license agreement and is being evaluated in multiple clinical trials, including a Phase 3 clinical trial for patients with biliary tract cancer. The company’s therapeutic pipeline of early-stage immuno-oncology programs consists of initiatives aimed at address various mechanisms of immune resistance. The company’s most advanced early-stage program, COM503, is currently in IND enabling studies and was licensed to Gilead in December 2023. COM503 is a potential first-in-class high-affinity antibody that blocks the interaction between IL-18 binding protein and IL-18, thereby freeing natural IL-18 in the tumor microenvironment to inhibit cancer growth.
Strategy
The company aims to transform patient lives by developing first-in-class therapeutics in cancer immunotherapy based on its computational target discovery capabilities. The company’s pipeline strategy for the development of potentially first-in-class cancer immunotherapies is differentiated in the competitive landscape of immuno-oncology as follows:
The company integrates computational capabilities with its groundbreaking immuno-oncology research and drug development expertise to discover novel drug targets and biological pathways that address the unmet needs of patients who are non-responsive to current cancer immunotherapies.
The company harness these capabilities to inform its drug development process.
The company identifies drug combinations and designs biomarker strategies for potential future patient selection.
In its clinical therapeutic pipeline, the company’s most advanced programs are:
COM701: This is the internal lead immuno-oncology pipeline program. COM701 is a humanized antibody that binds with high affinity to PVRIG, a novel immune checkpoint target candidate that blocks the interaction with its ligand, PVRL2. The company’s data suggests that the PVRIG pathway is parallel and complementary to TIGIT, an immune checkpoint discovered computationally in 2009. These two pathways intersect with DNAM-1, a costimulatory receptor on T cells and NK cells. The PD-1 pathway also intersects with DNAM-1. Phase 1 trials for COM701 were initiated in September 2018.
COM902: This is a high-affinity, fully human antibody targeting TIGIT, which blocks the interaction of TIGIT with PVR, its ligand. Phase 1 trials for COM902 were initiated in March 2020.
Rilvegostomig: This is a novel PD-1/TIGIT bispecific antibody derived from COM902, developed by AstraZeneca under an exclusive license agreement. AstraZeneca initiated its Phase 3 ARTEMIDE-Bil01 trial as adjuvant therapy for biliary tract cancer after resection in combination with chemotherapy at the end of 2023, dosing its first patient in December 2023. Additionally, AstraZeneca is running several Phase 1 and 2 trials with rilvegostomig in other indications.
In addition to the clinical therapeutic pipeline, bapotulimab, an antibody targeting ILDR2, a drug target discovered by the company, which was licensed for further research and development to Bayer, under a research and discovery collaboration and license agreement (RDCLA). Bapotulimab has been evaluated in Phase 1 clinical trials in naïve head and neck squamous cell carcinoma patients. As of February 27, 2023, the license granted to Bayer was terminated, and the rights previously licensed to Bayer reverted to the company, which also exercised its right to obtain a license for certain intellectual property rights developed by Bayer under the license agreement. The company retains the right to continue the development and commercialization of bapotulimab, should it choose to do so.
In its preclinical therapeutic pipeline, the company’s most advanced program is:
COM503: This is a potential first-in-class high-affinity antibody that blocks the interaction between IL-18 binding protein and IL-18, thereby freeing natural IL-18 in the tumor microenvironment to inhibit cancer growth. The "interleukin-18 binding protein and interleukin-18 complex" represents a potential dominant immunosuppressive mechanism used by tumors to escape the immune system. The inflammasome-induced pro-inflammatory cytokine, interleukin-18, is present at high levels in the tumor microenvironment, where it is expected to activate anti-tumor effector cells, such as T and NK cells. However, IL-18 is one of the rare cytokines that is naturally blocked by an endogenous high-affinity inhibitor, known as IL-18 binding protein.
Biomarker Driven Strategy
The company recognizes that one of the major limitations of current immunotherapy approaches is the lack of tools to predict patient responses. Through informed biomarker-driven strategies based on newly discovered biological pathways, the company aims to identify biomarkers that can help predict which patients are most likely to respond to its novel therapies. This long-term approach also seeks to improve the probability of success of clinical studies.
The company employs three approaches in its biomarker strategy:
Computational Analysis: The company analyzes omics data to identify tumor indications where the target pathway is elevated. This analysis is validated experimentally, and the validated data is used for indication selection in clinical trials. This approach was used for COM701 to select tumor types for inclusion in cohort expansion studies, further supporting the biomarker-informed approach and predictive discovery capabilities.
Identification of Potential Biomarkers: This approach is used for the COM701 program, both as a stand-alone and in combination, utilizing various cutting-edge technologies and methodologies on biopsies, liquid biopsies, and blood samples. Technologies include immunohistochemistry, transcriptomic, genomic, and proteomic analysis. Data generated by these technologies also inform the suggested mechanism of action of COM701. Currently, the company is evaluating the correlation between the expression of PDL-1 and the PVRIG pathway with clinical response through immunohistochemistry analysis.
Pharmacodynamic Biomarker Approach: The company measures immune modulation induced by COM701 and combinations in peripheral and tumor patient samples obtained before and during treatment. This analysis includes measuring both protein and sequence analytics, such as cytokine analysis, immune phenotyping, proteomic changes, transcriptomics analysis, and TCR clonality. This serves both to identify potential biomarkers and to inform the suggested mechanism of action of COM701.
At SITC 2023, the company presented new translational data and initial biomarker data from platinum-resistant ovarian cancer studies evaluating COM701 + nivolumab ± BMS anti-TIGIT, as well as in a small breast cancer cohort treated with COM701 +/- nivolumab. Both studies support a COM701-mediated clinical benefit and provide initial data suggesting PVRL2 as a potential biomarker for patients who may benefit from COM701 combinations.
Early-Stage Pipeline
Immuno-oncology represents a paradigm shift in cancer treatment, with biological drugs blocking immune checkpoint targets resulting in long-term patient survival in certain cancer types. Despite their potential, current checkpoint inhibitors are limited to a few targets and are only effective in certain patients and cancers.
The company's early-stage programs, discovered using its discovery capabilities, consist of drug targets with the potential to address various mechanisms of immune resistance.
The most advanced early-stage program, COM503, was licensed to Gilead in December 2023 and is currently being advanced towards IND clearance, which is expected to take place in 2024.
Predictive Computational Discovery Approach
The company has demonstrated the applicability of its discovery approach in computationally identifying multiple in-silico targets, including PVRIG, TIGIT, and ILDR2. The first two now serve as targets for therapeutic antibodies currently being evaluated in the clinic by the company and others. The antibodies designed to block these targets have been evaluated in Phase 1 clinical trials by the company (COM701 and COM902) or by its partners (bapotulimab and rilvegostomig). More recently, the company identified IL-18BP as a dominant tumor-associated macrophages immune resistance mechanism and, based on this biological understanding, developed COM503, a potential first-in-class antibody that is licensed to Gilead under a license agreement dated December 18, 2023, and is currently being advanced towards IND clearance.
Business Strategy and Partnerships
Gilead License
On December 18, 2023, the company entered into a License Agreement, granting Gilead an exclusive license under its preclinical antibody program against IL-18 binding protein and all associated intellectual property rights. This license allows Gilead to use, research, develop, manufacture, and commercialize products, including COM503 and additional products.
Under the License Agreement, Gilead paid a $60 million upfront license payment and is also eligible to pay the company $30 million as a milestone payment upon the clearance of the IND application for COM503. The company is also eligible to receive up to approximately $758 million in additional milestone payments upon achieving certain development, regulatory, and commercial milestones, as well as single-digit to low double-digit tiered royalties on worldwide net sales of licensed products. The company is required to make certain upstream payments to service providers with respect to the licensed products.
During the term of the License Agreement, the company is prohibited from researching, developing, making, or commercializing any compounds, molecules, products, or treatment methods directed at IL-18 or any companion diagnostics for an IL-18 product.
AstraZeneca License
In March 2018, the company entered into an exclusive license agreement with AstraZeneca to enable the development of bi-specific and multi-specific immuno-oncology antibody products.
Under the terms of the license agreement, the company granted AstraZeneca an exclusive license to use its monospecific antibodies that bind to TIGIT, including COM902, for the development of bi-specific and multi-specific antibody products, excluding those that also bind to PVRIG, PVRL2, and/or TIGIT. AstraZeneca has the right to create multiple products under this license and is solely responsible for all research, development, and commercial activities under the agreement. In connection with this license agreement, AstraZeneca developed rilvegostomig, a novel PD-1/TIGIT bispecific antibody derived from COM902, which entered the clinic in September 2021 and initiated Phase 3 with first patient dosing in December 2023.
The company received a $10 million upfront payment and is eligible to receive up to $200 million in development, regulatory, and commercial milestones for the first product, as well as tiered royalties on future product sales. The company accrued $2 million in 2020 as a preclinical milestone, $6 million in 2021 as a clinical milestone (triggered by the dosing of the first patient in a Phase 1/2 trial evaluating rilvegostomig), an additional $7.5 million in 2022 as a clinical milestone (triggered by the dosing of the first patient in the ARTEMIDE Phase 2 trial), and another $10 million in 2023 as a clinical milestone (triggered by the dosing of the first patient in the ARTEMIDE-Bil01 Phase 3 trial). If additional products are developed, further milestones and royalties would be due to the company for each product. The company retains all other rights to its entire pipeline of programs as monotherapies and in combination with other products.
Bayer Collaboration
On August 5, 2013, the company entered into a collaboration with Bayer, or the Bayer Collaboration, for the research, development, and commercialization of antibody-based therapeutics against two novel Compugen-discovered immune checkpoint regulators, CGEN 15001T/ILDR2 and CGEN 15022.
Under the terms of the Bayer Collaboration, the company received an upfront payment of $10 million, and following the return of the CGEN 15022 program, it became eligible to receive over $250 million in potential milestone payments for bapotulimab (formerly known as BAY1905254), not including approximately $23 million in milestone payments received to date. Additionally, the company is eligible to receive mid-to-high single-digit royalties on global net sales of any approved products under the collaboration.
In 2014 and 2015, the company achieved several preclinical milestones with respect to bapotulimab. Pursuant to the terms of the Bayer Collaboration, this program was transferred to Bayer for further preclinical and clinical development activities, and worldwide commercialization under milestone and royalty-bearing licenses from the company. In September 2018, the program achieved the fourth milestone, following the dosing of the first patient in the Phase 1 clinical trial of bapotulimab.
On November 29, 2022, Bayer notified the company that it resolved to terminate the 2013 research and development collaboration and license agreement, effective February 27, 2023.
Bristol Myers Squibb Collaboration
On October 10, 2018, the company entered into the MCTC with Bristol Myers Squibb to evaluate the safety and tolerability of COM701 in combination with Bristol Myers Squibb’s PD-1 immune checkpoint inhibitor Opdivo (nivolumab) in patients with advanced solid tumors.
Under the terms of the MCTC, as amended from time to time, the company conducted triple combination clinical trials to evaluate the safety, tolerability, and antitumor activity of COM701 in combination with Opdivo and Bristol Myers Squibb’s investigational antibody targeting TIGIT known as BMS-986207 in patients with advanced solid tumors, as well as dual combination clinical trials to evaluate the dual combination of COM701 and Opdivo in patients with advanced solid tumors. The company sponsored all clinical trials while Bristol Myers Squibb provided Opdivo and BMS-986207 at no cost.
The MCTC granted Bristol Myers Squibb the right to negotiate a license for commercialization and provided certain exclusivity rights.
In conjunction with the signing of the MCTC in October 2018, Bristol Myers Squibb made a $12 million investment in the company, followed by an additional $20 million investment in November 2021. In both investments, the share price paid represented a 33% premium over the closing price of the company’s ordinary shares on the last trading day prior to the execution of the applicable securities purchase agreement. The company issued a total of 4,757,058 ordinary shares to Bristol Myers Squibb in these two investments.
On August 3, 2022, in response to challenging market conditions, the company decided to focus on prioritized indications and wind down its broad Phase 1 cohort expansion program. Consequently, it entered into a letter agreement with Bristol Myers Squibb, terminating the MCTC as of that date, and all ongoing clinical trials at the time of termination entered a winding down process.
Intellectual Property Rights
As of February 1, 2024, the company held a total of 61 issued and allowed patents, including 17 U.S. patents, 8 European patents, and additional 36 patents in other territories. The company’s issued and allowed patents are set to expire between 2028 and 2038. As of February 1, 2024, the company had over 138 pending patent applications filed in the United States, Europe, and other territories, as well as pending applications filed under the Patent Cooperation Treaty for which the countries of filing have not yet been designated. The patents for COM701 and COM902 issued in the U.S. and Europe between 2017 and 2023 are expected to expire no earlier than 2036.
In October 2020, two parties, including GSK (following an assignment), filed oppositions in the European Patent Office (EPO) requesting the revocation of the company's granted European patent related to anti-PVRIG antibodies, which expires in 2036. Following various proceedings, on July 11, 2023, the opposition division of the EPO ruled in favor of maintaining the broad claims in the patent as granted to the company. The opponents retain the right to appeal this decision. In January 2023, another opposition was filed by GSK, requesting the revocation of the company's granted European patent concerning the method of screening for inhibitors of the binding association of PVRIG polypeptide with PVRL2, to which the company has already responded. In May 2023, two additional oppositions were filed by GSK and another party requesting the revocation of the company's granted European patent concerning anti-PVRIG antibodies competing with COM701.
Manufacturing
The company relies on contract manufacturing organizations (CMOs), advisors, and third-party contractors to generate formulations and produce both small-scale and large-scale amounts of GLP, cGMP clinical and commercial drug substances and products required for clinical trials in the foreseeable future. It also contracts with CMOs and third-party contractors for the labeling, packaging, storage, and distribution of investigational drug products.
The company has entered into agreements with certain CMOs for the manufacturing and respective analytics of COM701, COM902, and COM503. Its manufacturing strategy is currently structured to support the clinical development of COM701 and COM902, as well as the preclinical development and future clinical development of COM503.
Government Regulation
The company is subject to laws and regulations in the U.S., European Union, and Israel governing the use, storage, handling, and disposal of all materials and resulting waste products.
Research and Development
Research and development expenses during 2023 totaled approximately $34.5 million.
History
Compugen Ltd. was incorporated in 1993.
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