LGR6

Recently, Merus announced that the first patient has been dosed in the phase 3 clinical trial LiGeR-HN2, aimed at evaluating the efficacy of petosemtamab in the second-line and third-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (r/m HNSCC). LiGeR-HN2 is a randomized, open-label phase 3 clinical trial primarily assessing the safety and efficacy of petosemtamab compared to standard therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma. The trial will enroll patients who have previously received first-line treatment and whose disease has progressed. The primary endpoints of the study typically include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessments. Petosemtamab is a bispecific antibody developed by Merus that simultaneously targets both the epidermal growth factor receptor (EGFR) and LGR5 (Leucine-rich repeat-containing G protein-coupled receptor 5), receptors which are overexpressed in various types of cancer. By targeting these two receptors, petosemtamab aims to more effectively target and kill cancer cells while reducing the impact on healthy cells. Data presented by Merus at the 2024 American Society of Clinical Oncology (ASCO) showed that in patients with head and neck squamous cell carcinoma (HNSCC), when used in combination with Keytruda, six out of ten evaluable patients demonstrated a tumor response, achieving a response rate of 60%. Furthermore, Merus' latest public materials on their website also released mid-stage clinical updates of petosemtamab as a monotherapy for second-line and beyond HNSCC, which showed a response rate of 37% in 43 evaluable patients (2L+ HNSCC, ORR 37%), and mid-stage clinical updates of its combination with the PD-1 monoclonal antibody Keytruda for first-line HNSCC, which achieved a response rate of 67% in 24 evaluable patients (1L HNSCC, RR 67%). The company projects that by 2028, the global market size for HNSCC will exceed $5 billion, highlighting the substantial commercial potential of petosemtamab for this indication. The FDA has granted petosemtamab Breakthrough Therapy Designation (BTD) for the treatment of patients with recurrent or metastatic HNSCC who have experienced disease progression following platinum-based chemotherapy and anti-programmed cell death receptor-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) antibody therapy. Partnering with GileadIn early 2024, Gilead Sciences announced that it will pay Merus a $56 million upfront payment and make a $25 million equity investment in the biotech company. Through the partnership with Merus, Gilead Sciences aims to leverage Merus's expertise in the development of bispecific and multispecific antibodies to create innovative antibody therapies. The specific targets of the collaboration have not been disclosed. About LGR5LGR5, also known as GPR49, is a seven-transmembrane protein that belongs to the GPCR superfamily. Within this GPCR superfamily, LGR5, along with LGR4 and LGR6 which are part of the glycoprotein-receptor orphan subgroup, share a distinctive structural feature: a large extracellular domain containing 17 leucine-rich repeat sequences. When LGR5 binds to its ligand R-Spondin (RSPO), it collaborates with the Wnt receptors (Frizzled and LRP5/6) to enhance the Wnt/β-catenin signaling pathway. LGR5 regulates the Wnt/β-catenin signaling pathway in normal intestinal stem cells. For instance, during normal homeostasis of the intestine, the expression of LGR5 is restricted to the stem cell compartments located at the base of the crypts. As the progeny of the stem cells migrate upward through the proliferative zone and undergo differentiation, this expression of LGR5 is lost. Consistently, isolated single LGR5+ cells from the intestine can form self-organizing crypt/villus structures known as organoids, capable of reconstituting all differentiated epithelial lineages present in the intestine. The table below presents the pipeline status of clinical studies related to LGR5, all of which are for cancer-related indications. Merus clearly holds a leading position in this target competition. Next Indication: Colorectal CancerIn an interview with the CEO of Merus, it was also mentioned that the company is looking forward to evaluating petosemtamab in metastatic colorectal cancer (mCRC), which represents another significant potential opportunity. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and the fourth leading cause of cancer-related deaths, with its burden expected to increase by 60% by 2030. Despite significant improvements in detection and treatment protocols, most advanced-stage cancer patients will die from recurrence of their disease. A widely recognized reason for CRC recurrence is the failure of existing therapies to eradicate subpopulations of cancer stem cells (CSCs) within the tumor. CSCs express a variety of markers, including CD133, CD44, CD166, ALDH, EphB2, and Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). These CSCs are capable of resisting therapeutic assaults and re-establishing tumor growth after treatment interventions, creating an urgent need for innovative, non-toxic targeted cancer therapies to induce sustained clinical remission. A key early event in the progression of colorectal cancer is the dysregulation of the Wnt/β-catenin signaling pathway, which is often constitutively activated by genetic mutations in APC or β-catenin. Under normal conditions, the lack of Wnt ligands leads to the constitutive phosphorylation of β-catenin, followed by proteasomal degradation, keeping Wnt target genes suppressed. When Wnt ligands bind to the Wnt receptors Frizzled and LRP5/6, the accumulation of β-catenin in the cytoplasm leads to its nuclear translocation, where it binds with the TCF/LEF family of transcription factors and activates oncogenic Wnt target genes such as c-myc, cyclinD1, and survivin. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

SEATTLE, Feb. 29, 2012 /PRNewswire/ -- Omeros Corporation (NASDAQ: OMER) today announced that it has identified compounds that functionally interact with each of the following six orphan G protein-coupled receptors (GPCRs): GPR17, GPR153, CCRL2, LGR4, LGR6 and OPN5. Without compounds that functionally interact with orphan GPCRs, developing drugs targeting those receptors is extremely difficult. Omeros has now unlocked 33 of them, representing over 40 percent of the Class A orphan GPCRs. There are approximately 120 orphan GPCRs and Omeros expects to unlock a large percentage of them, focusing first on Class A orphan GPCRs. GPR17 is a novel target tied to multiple sclerosis. GPR153 is associated with schizophrenia, and CCRL2 is connected to immunological disorders, such as rheumatoid arthritis. LGR4 is linked to cancer stem cells and the self-renewal and maintenance of adult stem cells. LGR4 is also tied to bone disorders, such as osteoporosis. LGR6 is expressed in the hair follicle stem cells and is involved in long-term wound repair, including the formation of new hair follicles. OPN5 is a recently discovered photoreceptor for ultraviolet light, but its physiological role is currently unknown. Omeros is in the process of filing broad patent applications around its unlocked orphan GPCRs and compound optimization efforts are in progress. "We continue to advance rapidly through the Class A orphans and, by the end of 2012, we plan to have screened them all using our proprietary Cellular Redistribution Assay," said Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. "For each of these receptors, the compounds uniquely identified by Omeros represent keys to drug development, and we believe that Omeros exclusively controls those keys. In parallel with our successful screening efforts, we are building our patent position for each of our unlocked orphans with the goal of protecting and capitalizing on our discoveries." Ongoing GPCR Program Omeros is screening orphan GPCRs against its small-molecule chemical libraries using its proprietary, high-throughput cellular redistribution assay (CRA). The CRA detects receptor antagonists, agonists and inverse agonists. Omeros has announced that it has identified and confirmed sets of compounds that interact selectively with 33 orphan receptors linked to metastatic melanoma (GPR19), esophageal squamous cell carcinoma and obesity-related type-2 diabetes (GPR39), hepatocellular carcinoma (GPR80), squamous cell carcinoma (GPR87), pancreatic cancer (GPR182), acute lymphoblastic leukemia (P2Y8/P2RY8), ovarian and prostate cancer (OGR1), arterial stiffness (GPR25), sleep disorders (OPN4), cognitive disorders (GPR12), torpor or "suspended animation" (GPR50), anxiety disorders (GPR31), schizophrenia (GPR52, GPR153), bipolar disorder and schizophrenia (GPR78), psychotic and metabolic disorders (GPR27, GPR85, GPR173), cognitive impairments (MAS1), inflammatory responses (GPR32), obesity and diabetes (GPR21), appetite control (GPR101), immunological disorders (CCRL2), rheumatoid arthritis and HIV-mediated enteropathy (GPR15), respiratory and immune disorders (GPR141), multiple sclerosis (GPR17), motor control (GPR139), congenital cataracts and birth defects of the brain and spinal cord (GPR161), cancer stem cells and the self-renewal and maintenance of adult stem cells (LGR4) and long-term wound repair, including the formation of new hair follicles (LGR6). In addition, Omeros has unlocked GPR20, GPR135 and OPN5, which have not yet been tied to any indications but are expressed preferentially in the gastrointestinal tract (GPR20), brain (GPR135) and eye, brain, testes and spinal cord (OPN5). About G Protein-Coupled Receptors GPCRs, which mediate key physiological processes in the body, are one of the most valuable families of drug targets. According to Insight Pharma Reports, GPCR-targeting drugs represent 30 to 40 percent of marketed pharmaceuticals. Examples include Claritin® (allergy), Zantac® (ulcers and reflux), OxyContin® (pain), Lopressor® (high blood pressure), Imitrex® (migraine headache), Reglan® (nausea) and Abilify® (schizophrenia, bipolar disease and depression) as well as all other antihistamines, opioids, alpha and beta blockers, serotonergics and dopaminergics. The industry focuses its GPCR drug discovery efforts mostly on non-sensory GPCRs. Of the 363 total non-sensory GPCRs, approximately 240 have known ligands (molecules that bind the receptors) with nearly half of those targeted either by marketed drugs (46 GPCRs) or by drugs in development (about 70 GPCRs). There are approximately 120 GPCRs with no known ligands, which are termed "orphan GPCRs." Without a known ligand, drug development for a given receptor is extremely difficult. Omeros uses its proprietary high-throughput CRA to identify small-molecule agonists and antagonists for orphan GPCRs, unlocking them to drug development. Omeros believes that it is the first to possess the capability to unlock orphan GPCRs in high-throughput, and that currently there is no other comparable technology. Unlocking these receptors could lead to the development of drugs that act at these new targets. There is a broad range of indications linked to orphan GPCRs including cardiovascular disease, asthma, diabetes, pain, obesity, Alzheimer's disease, Parkinson's disease, multiple sclerosis, schizophrenia, learning and cognitive disorders, autism, osteoporosis, osteoarthritis and several forms of cancer. About Omeros Corporation Omeros is a clinical-stage biopharmaceutical company committed to discovering, developing and commercializing products targeting inflammation, coagulopathies and disorders of the central nervous system. The Company's most clinically advanced product candidates are derived from its proprietary PharmacoSurgery™ platform designed to improve clinical outcomes of patients undergoing a wide range of surgical and medical procedures. Omeros has four ongoing clinical development programs. Omeros may also have the near-term capability, through its GPCR program, to add a large number of new drug targets and their corresponding compounds to the market. Behind its clinical candidates and GPCR platform, Omeros is building a diverse pipeline of protein and small-molecule preclinical programs targeting inflammation, coagulopathies and central nervous system disorders. Forward-looking Statements This press release contains forward-looking statements as defined within the Private Securities Litigation Reform Act of 1995, which are subject to the "safe harbor" created by those sections. These statements include, but are not limited to, statements regarding Omeros' expectation regarding its ability unlock orphan GPCRs and add a large number of new drug targets and their corresponding compounds to the market; the disorders that could potentially be treated by drugs that target unlocked orphan receptors, including GPR17, GPR153, CCRL2, LGR4, LGR6 and OPN5; Omeros' ability to obtain broad patent protection for the orphan GPCRs that it has unlocked; and the Company's ability to complete the screening of all Class A orphans by the end of 2012. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. Omeros' actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the risks, uncertainties and other factors described under the heading "Risk Factors" in the Company's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 8, 2011. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the Company assumes no obligation to update these forward-looking statements publicly, even if new information becomes available in the future. SOURCE Omeros Corporation Jennifer Cook Williams, Cook Williams Communications, Inc., Investor and Media Relations, +1-360-668-3701, jennifer@cwcomm.org