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REDWOOD CITY, Calif., May 08, 2024 (GLOBE NEWSWIRE) -- Coherus BioSciences, Inc. (Coherus; Nasdaq: CHRS) today announced that the Cancer Research Institute (CRI) and its Immunotherapy Platform Study in Platinum-Resistant High-Grade Serous Ovarian Cancer (IPROC) Drug Selection Committee (DSC) have selected LOQTORZI (toripalimab-tpzi), anti-PD-1 antibody, to explore in combination with ENB-003, a first-in-class small molecule inhibitor of endothelin B receptor (ETBR), for the treatment of drug-resistant cancers in the iPROC platform study. Endothelin B receptor is implicated in tumorigenesis and tumor immune suppression for several solid tumors, including melanoma, ovarian, and pancreatic cancers. “The iPROC DSC is pleased to have access to this next-generation PD-1 inhibitor and advance this combination supported by preclinical and clinical data in this study in ovarian cancer,” said John Stagg, Ph.D., Professor, Faculty of Pharmacy at the University of Montreal and Principal Investigator, Centre Hospitalier de l’Université de Montréal (CHUM) and its affiliated Cancer Institute of Montreal. Dr. Stagg continued, “The iPROC study DSC brings together a group of scientific experts within the CRI community to select promising combinations and rapidly advance them to clinical trials. Importantly, the DSC is not confined by a pipeline but looks to work with companies with drugs that have a strong data package. For this multiparty platform study to succeed, it requires science-driven, highly collaborative, and engaged companies. Coherus and ENB Therapeutics are two such partners, and we are excited to advance this clinical study.” “CRI is an established and preeminent organization leading immunotherapy discovery and advancement through its global network of scientific experts, and we are excited that the CRI network has selected LOQTORZI for this study to gain more insight into the potential clinical benefit that LOQTORZI might have when combined with novel mechanisms such as ENB Therapeutics’ ETBR blocker, particularly in this underserved patient population,” said Rosh Dias, M.D., Chief Medical Officer at Coherus. “There is a large body of clinical evidence for LOQTORZI, including positive phase 3 studies published in top-tier scientific journals, showing efficacy and safety in multiple tumor types,” said Jay Campbell, Managing Director, Clinical Accelerator and Venture Fund at CRI. “This level of scientific evidence is what we are looking for when selecting immunotherapies to bring into our network, with the goal of advancing clinically meaningful solutions to patients. We are grateful to have the opportunity to collaborate with Coherus and ENB Therapeutics on this study and excited to be working with them on this novel combination that we hope will lead to improved outcomes in these patient populations.” Dr. Sumayah Jamal, CEO of ENB Therapeutics, added, “We are honored to be collaborating with CRI and Coherus to further accelerate the development of innovative immunotherapy solutions and expand the pool of patients benefitting from this approach to harness the immune system to fight cancer.” Under the terms of a clinical supply agreement with the Cancer Research Institute (CRI), Coherus will supply toripalimab-tpzi for combination treatment with ENB-003 to be investigated in the iPROC platform study. About the IPROC Platform TrialThe IPROC clinical trial uses an adaptive platform study design that utilizes a single master protocol to evaluate multiple immunotherapy combinations. This allows multiple treatments to be evaluated in different groups of patients, or cohorts, from the same patient population. Such a study design offers flexibility in that different treatments can be evaluated in different cohorts, treatment regimens can be modified between cohorts, and treatment selection criteria can be customized for a specific cohort. The trial, titled Immunotherapy Platform Study in Platinum-Resistant High-Grade Serous Ovarian Cancer (IPROC) (NCT04918186), has two ongoing cohorts. About LOQTORZI (toripalimab-tpzi)LOQTORZI is an anti-PD-1 monoclonal antibody that blocks PD-L1 binding to the PD-1 receptor at a unique site with high affinity and activates anti-tumor immunity. LOQTORZI is indicated in the United States in combination with cisplatin and gemcitabine for first-line treatment of adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC) and as a single agent for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after platinum-containing chemotherapy. For more information about LOQTORZI, including the U.S. Prescribing Information and important safety information, please visit www.loqtorzi.com. About ENB-003ENB-003, a small-molecule drug candidate targeting the ETBR, is expressed in solid tumors and plays a role in tumorigenesis and immune evasion. ETBR, a G-protein-coupled receptor, is overexpressed in a variety of tumor cell types and plays a key role in tumor cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and angiogenesis. It also plays a role in tumor immunosuppression and blocks T-cell trafficking. As reported in November 2023, preliminary results from the ENBOLDEN-101 demonstrated that ENB-003 in combination with KEYTRUDA® (pembrolizumab) demonstrated encouraging objective responses, disease control, and progression-free survival in patients with metastatic platinum refractory/resistant ovarian cancer (PROC). About the Cancer Research InstituteThe Cancer Research Institute, established in 1953, is the preeminent U.S. nonprofit organization dedicated to saving more lives by fueling the discovery and development of powerful immunotherapies for all cancers. Guided by a world-renowned Scientific Advisory Council that includes four Nobel laureates and 35 members of the National Academy of Sciences, CRI has invested over $517 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. Learn more at cancerresearch.org. About Coherus BioSciences Coherus is a commercial-stage biopharmaceutical company focused on researching, developing, and commercializing innovative cancer treatments. Coherus is developing an innovative immuno-oncology pipeline that is expected to synergize with its proven commercial capabilities in oncology. Coherus’ immuno-oncology pipeline includes multiple antibody immunotherapy candidates focused on enhancing the innate and adaptive immune responses to enable a robust antitumor immunologic response and enhance outcomes for patients with cancer. Casdozokitug is a novel IL-27 antagonistic antibody currently being evaluated in two ongoing clinical studies: a Phase 1/2 study in advanced solid tumors and a Phase 2 study in hepatocellular carcinoma. CHS-114 is a highly selective, competitively positioned, cytolytic anti-CCR8 antibody currently in a Phase 1 study in patients with advanced solid tumors. CHS-1000, a novel ILT4-targeted antibody, is a preclinical candidate targeting immune-suppressive mechanisms via the pathway ILT4. Coherus markets LOQTORZI® (toripalimab-tpzi), a novel next-generation PD-1 inhibitor, UDENYCA® (pegfilgrastim-cbqv), a biosimilar of Neulasta®, and YUSIMRY® (adalimumab-aqvh), a biosimilar of Humira®. About ENB TherapeuticsENB Therapeutics is a clinical-stage biopharmaceutical company developing a novel class of medicines, ETBR inhibitors, to overcome resistance to CAR-T in solid tumors and immune-based therapies such as immune checkpoint inhibitors. ETBR causes uncontrolled cancer growth, drives cancers to spread through the body, and prevents the immune system from detecting and killing cancer cells. ENB’s lead product candidate, ENB-003, specifically blocks the ETBR and can potentially drive the efficacy of CAR-T and anti-PD1 therapies in solid tumors. ENB-003 is being investigated in an ongoing Phase 1/2 clinical trial in collaboration with Merck. Forward-Looking Statements Except for the historical information contained herein, the matters set forth in this press release are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Coherus’ ability to identify synergies between its I-O pipeline and its commercial capabilities; Coherus’ expected initiating clinical trials for CHS-1000; Coherus’ expectations to be able to advance its candidates through clinical trials; and Coherus’ expectations that its immunotherapy candidates will enhance outcomes for patients with cancer. Such forward-looking statements involve substantial risks and uncertainties that could cause Coherus’ actual results, performance, or achievements to differ significantly from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the risks and uncertainties inherent in the preclinical and clinical drug development process; risks related to Coherus’ existing and potential collaboration partners; risks of Coherus’ competitive position; the risks and uncertainties of the regulatory approval process, including the speed of regulatory review and the timing of Coherus’ regulatory filings; the risks of competition; the risk that Coherus is unable to complete commercial transactions; and the risks and uncertainties of possible litigation. All forward-looking statements contained in this press release speak only as of the date of this press release. Coherus undertakes no obligation to update or revise any forward-looking statements. For a further description of the significant risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Coherus’ business in general, see Coherus’ Annual Report on Form 10-K for the fiscal year ended December 31, 2023 filed with the Securities and Exchange Commission on March 15, 2024, including the section therein captioned “Risk Factors” and in other documents Coherus files with the Securities and Exchange Commission. UDENYCA®, YUSIMRY®, and LOQTORZI®, whether or not appearing in large print or with the trademark symbol, are trademarks of Coherus, its affiliates, related companies, or its licensors or joint venture partners unless otherwise noted. Trademarks and trade names of other companies appearing in this press release are, to the knowledge of Coherus, the property of their respective owners. Neulasta® is a registered trademark of Amgen, Inc.Humira® is a registered trademark of AbbVie Inc. Coherus Contact Information:For Investors:Jami TaylorHead of Investor RelationsIR@coherus.com For Media:Jodi SieversVP, Corporate Communicationsmedia@coherus.com

On March 20th, the Swiss pharmaceutical company Idorsia announced that the U.S. FDA has approved TRYVIO™ (aprocitentan) for use in combination with other antihypertensive medications to treat adult hypertension, in order to lower blood pressure levels in the adult patient population whose blood pressure has not been effectively controlled. Hypertension is a common chronic condition characterized by persistently high blood pressure readings (140/90 mmHg or higher). Lowering high blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, with stroke and myocardial infarction being the primary concerns. ·TRYVIO acts by targeting endothelin-1 (ET-1), which is a potent vasoconstrictor closely associated with the mechanisms leading to hypertension. It mitigates the detrimental effects of ET-1 by preventing its binding to ETA and ETB receptors, thereby reducing the vasoconstrictive, fibrotic, cellular proliferative, and inflammatory responses induced by ET-1. ·TRYVIO tablets are required to be taken only once daily and can be ingested with or without food. ·TRYVIO comes with a black box warning, indicating its teratogenic toxicity. It is contraindicated for use in pregnant women. Effective contraceptive measures must be taken before starting treatment, throughout the course of treatment, and for one month after discontinuation. ·Warnings and precautions associated with TRYVIO include risks of hepatotoxicity, fluid retention, decrease in hemoglobin, and reduced sperm count. Common adverse reactions comprise edema/fluid retention and anemia. The following is a retrospective review of TRYVIO's R&D milestones over the past 10 years at various time points: 2023: Submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). 2022: Filed a New Drug Application (NDA) with the U.S. FDA, and in the same year, presented the work as a late-stage breakthrough study at an American Heart Association (AHA) meeting, with relevant Phase III clinical trial data published in the prestigious medical journal The Lancet. 2022: Successfully completed Phase III clinical studies, demonstrating the drug's safety and efficacy in the targeted patient population. 2018: Initiated Phase III clinical trial, a crucial step in validating the drug's therapeutic effectiveness and safety in a large population. 2017: The dose-response study yielded positive results, confirming the pharmacodynamic response of Aprocitentan at different dosages, laying the foundation for subsequent research. 2015: Began Phase II dose-response relationship studies aimed at further exploring the optimal dosage range of the drug and its response in humans. 2014: Launched Phase I clinical trial program, marking the first step for Aprocitentan to move from laboratory to human clinical testing, primarily to assess the drug's safety, tolerability, and preliminary pharmacokinetic characteristics in humans. Hypertension Medication Returned by Johnson & JohnsonOn January 26, 2017, Johnson & Johnson announced a proposal to acquire the Swiss pharmaceutical company Actelion in an all-cash tender offer, at a price of $280 per share (totaling $30 billion in cash) for all of Actelion's outstanding shares. As part of the transaction, Actelion will spin off its drug research and early-stage clinical development assets into a newly formed Swiss biopharmaceutical company called Idorsia. Idorsia will be listed on the Swiss Stock Exchange, and Johnson & Johnson will initially hold a 16% stake in the newly established R&D company. In November 2017, the newly formed Idorsia announced a collaboration with Janssen Biotech, a subsidiary of Johnson & Johnson, focusing on Aprocitentan. As part of the agreement, Idorsia will receive about $230 million in milestone payments; Idorsia and Janssen Biotech will share the development costs of aprocitentan during the Phase III clinical trials; and Idorsia will be entitled to royalty fees on potential future net sales. On September 6th, 2023, Idorsia announced that the company had reached an agreement with Janssen Biotech, a subsidiary of Janssen Pharmaceuticals, to reacquire the rights to Aprocitentan. It was reported that, although Phase 3 clinical trial results of the drug showed a significant reduction in blood pressure compared to placebo, they also revealed an issue where 18% of patients on high doses experienced mild to moderate fluid retention. Johnson & Johnson deemed that the drug might not meet their commercial development objectives and therefore decided to return the rights. In return, Idorsia will pay Janssen Biotech approximately 306 million Swiss francs, contingent upon the approval of Aprocitentan's marketing application by the US FDA and the European EMA. Additionally, Idorsia is currently exploring the best approach to maximize the value of aprocitentan." Aprocitentan is a novel oral dual endothelin receptor antagonist currently being developed by Idorsia Pharmaceuticals. It effectively inhibits the binding of ET-1 to both ETA and ETB receptors. It is reported that the potential for drug-drug interactions with Aprocitentan is low, and its mechanism of action is highly suitable for the pathophysiology of resistant hypertension. The Latest Clinical Data on AprocitentanIn November 2022, the team from Idorsia and Johnson & Johnson published an article in The Lancet journal, presenting Phase 3 clinical study data of aprocitentan for the treatment of resistant hypertension. The results indicated that aprocitentan was well-tolerated in patients with resistant hypertension, showing a superior blood pressure-lowering effect compared to placebo at week 4 and sustained efficacy at week 40. The data demonstrated that among the 730 patients enrolled in the study, the least squares mean changes in systolic blood pressure after the first 4 weeks of treatment were -15.3 mm Hg for aprocitentan 12.5 mg, -15.2 mm Hg for aprocitentan 25 mg, and -11.5 mm Hg for placebo. The differences compared to placebo were -3.8 mm Hg and -3.7 mm Hg, respectively. Four weeks after discontinuation of the medication, systolic blood pressure significantly increased by 5.8 mm Hg compared to placebo. The most common adverse events were mild to moderate edema or fluid retention, leading to discontinuation of aprocitentan treatment in 7 patients. There were 11 cases of sudden death during the trial, which the researchers considered unrelated to the treatment. Based on this positive Phase 3 clinical data, Idorsia and Johnson & Johnson submitted marketing authorization applications for Aprocitentan to the United States in December 2022 and to the European Union in January 2023. About Endothelin (ET)Endothelin (ET) is a potent peptide vasoconstrictor, discovered in 1988 by Japanese scientist Yanagisawa and colleagues. It regulates blood pressure through its actions on blood vessels, the heart, and kidneys. The ET peptide family consists of three members: ET-1, ET-2, and ET-3. These ET peptides are each 21 amino acids in length and their overall structure is constrained by two disulfide bonds. The carboxyl-terminal sequence is essential for their activity. Taking ET-1 as an example, the translated ET-1 exists in the form of a precursor. Under the action of endothelin-converting enzyme (ECE), it undergoes proteolytic processing from an inactive precursor to a mature peptide, providing a potential pathway for inhibiting the production and action of ET-1. From, DOI: 10.1038/s41569-019-0176-3Humans have two types of ET receptors, the ETA receptor (ETA) has a higher binding affinity with ET-1 and ET-2 than with ET-3; the ETB receptor (ETB) has comparable binding affinity with all three isoforms. The figure below shows the relative mRNA expression levels of the ETA receptor and ETB receptor in 41 types of adult mouse tissues. The ETA receptor is highly expressed in the cardiovascular and pulmonary tissues, whereas the ETB receptor is highly expressed in the brain tissue. From,DOI: 10.1038/s41569-019-0176-3About Endothelin Receptor AntagonistsEndothelin receptors are widely known for their involvement in the physiological regulation of vascular tone due to their potent vasoconstrictive action. Excessive secretion of endothelin in the lungs can lead to pulmonary arterial hypertension. Endothelin autoregulates itself through physical and chemical factors such as blood flow, mechanical stretch, or pH changes and triggers the production of growth factors. Moreover, chronic endothelin stimulation has been shown to be associated with a variety of human cardiovascular, inflammatory, fibrotic, and neoplastic diseases. Additionally, endothelin may also play a role in conditions such as heart failure, renal insufficiency, septic shock, atherosclerosis, and hemorrhage-associated cerebrovascular diseases. Therefore, drugs that act on endothelin receptors may be beneficial in the treatment of a multitude of diseases. Source: DOI: 10.3390/jcm9030824Currently, several companies are screening antagonists targeting the ETA and ETB receptors, including selective antagonists for the ETA receptor, selective antagonists for the ETB receptor, or dual antagonists. Multiple endothelin receptor antagonists have been approved for the treatment of this disease. Current Status of Drug Development According to statistics from the Synapse database, there are a total of 5 endothein receptor antagonists (ETA or ETB antagonists) approved by the FDA, including Bosentan (2001, dual antagonist), Sitaxentan (2006, withdrawn), Ambrisentan (2007, ETA receptor selective), Macitentan (2013, dual antagonist), and Sparsentan (2023, ETA+AT1R dual antagonist). In February 2023, a dual antagonist targeting the inner ETA receptor and angiotensin II (Ang II) type 1 receptor (AT1R) named Filspari (Sparsentan) was approved by the FDA for marketing. The pharmaceutical is indicated for adults with primary immunoglobulin A nephropathy who are at risk of rapid disease progression and aims to reduce proteinuria. In May 2023, an ETA receptor selective agonist developed by the biopharmaceutical company Pharmazz, Sovateltide injectable solution, was approved for marketing in India for the treatment of patients with acute ischemic stroke. On September 14, Pharmazz entered into a licensing agreement with the Indian pharmaceutical company Sun Pharma. Under this agreement, Sun Pharma will have the rights to sell Sovateltide in India under the brand name Tyvalzi™. Pharmazz will be entitled to upfront and milestone payments, including royalties. Regarding Endothelin and Antitumor Drugs Aside from the symptoms of hypertension, endothelin receptors have multiple functions related to fundamental cellular processes such as cell proliferation and apoptosis. Aberrant expression of ET1 or overexpression of endothelin receptors or their associated signaling pathways can promote the occurrence and development of tumors through autocrine and paracrine mechanisms. These altered mechanisms can originate from genetic and epigenetic changes. In addition, a complex crosstalk network between ET1 signaling and other growth factor pathways propels tumor progression. This includes the interactions between endothelin receptors and receptors for epidermal growth factor and vascular endothelial growth factor. The ET1 signal can promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), angiogenesis, immune cell responses, and drug resistance, with its mechanisms of action depending on specific contexts. Consequently, endothelin receptors have become key targets in cancer therapy. The figure below shows the expression of endothelin receptors in some human malignancies. According to statistics from the Synapse database, there are currently several clinical candidate drugs globally targeting ETA or ETB receptors for research into various types of solid tumors. This includes the ETB receptor antagonist VRP-1620, developed by the University of Illinois for breast cancer research, and ENB Medical's selective ETB receptor small molecule antagonist ENB-003, both of which are in clinical research stages. Chinese innovative pharmaceutical company Gmax Biopharm LLC is conducting research on GMA202, a bispecific M-Body molecule consisting of an antibody targeting the ETA receptor and an antibody fragment targeting CD3. Reportedly, GMA202 achieves a unique and precise tumor immunotherapy effect by pairing activated T cells with ovarian cancer cells that highly express the ETA receptor. RG-7636 (DEDN6526A) is an ADC product developed by Genentech, which uses the ETB receptor as the mAb target linked to MMAE. Preclinical studies have shown that RG-7636 exhibits dose-dependent antitumor activity against xenografts expressing the ETB receptor. Phase 1 clinical trials have demonstrated that RG-7636 has antitumor activity in patients with melanoma.