CD63

SAN DIEGO, SHANGHAI and SYDNEY, April 28, 2023 /PRNewswire/ -- Inmagene Biopharmaceuticals ("Inmagene") today announced positive topline results from a Phase 1 study evaluating IMG-004 in healthy participants. IMG-004 is a potent, non-covalent, reversible, and brain permeable third-generation Bruton's tyrosine kinase (BTK) inhibitor. Inmagene is developing the drug candidate to potentially treat immunological diseases. The study was a single ascending dose design with dose levels of 30 mg to 600 mg. The objectives of the study were to evaluate the safety, pharmacokinetic, and pharmacokinetic effects of IMG-004 in healthy participants. A total of 40 participants were randomized in the study, with 30 participants receiving IMG-004 and 10 receiving placebo. Additional details can be found at clinicaltrials.gov, using identifier NCT05349097. IMG-004 was well tolerated, with no dose-limiting or serious adverse events. It was rapidly absorbed following the oral administration with peak concentrations occurring around 2 hours post-treatment and was eliminated with a terminal half-life ranging from 26 to 37 hours. In an ex vivo basophil CD63 activation assay, IMG-004 showed robust and dose-dependent target engagement. A maximum (approximately 95%) inhibition of basophil activation was observed at a dose level as low as 100 mg, up to 600 mg. Sustained inhibition (80-90%) of basophil activation was observed at 100mg up to 600mg, for at least 72 hours post-treatment. "BTK remains an attractive target for autoimmune diseases but many BTK inhibitors have been limited by serious safety risks due to their molecular features," commented Dr. Yufang Lu, Chief Medical Officer of Inmagene. "Designed specifically as a non-covalent, reversible, and brain permeable BTK inhibitor, IMG-004 has demonstrated a longer half-life and pharmacodynamic effect than most leading BTK inhibitors. It presents the best-in-class potential as a therapeutic candidate for autoimmune diseases." Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED commended, "Autoimmune diseases are often chronic, requiring long-term care and monitoring. We understand and value the desire for safety, convenience and quality of life for this group of patients. Our teams are committed to the discovery and development of novel treatment options to address the high unmet medical needs." About IMG-004 Designed specifically for inflammatory and autoimmune diseases that usually require long-term treatment, IMG-004 is potent, highly selective and brain permeable. It was originally discovered by HUTCHMED, with Inmagene assuming the development responsibility at the candidate stage. Inmagene has an exclusive option to in-license IMG-004's global rights for the treatment of immunological diseases. About Inmagene Inmagene is a global clinical-stage biotechnology company focused on developing novel therapeutics for immunology-related diseases. Inmagene's most advanced drug candidate is IMG-020 (izokibep), which has successfully met the protocol endpoints in global Phase 2 studies for both psoriasis and psoriatic arthritis (PsA). It has received the IND approval from China's Center for Drug Evaluation (CDE) for Phase 3 studies in plaque psoriasis. In addition, IMG-007, a monoclonal antibody (mAb) against OX40 with a silenced antibody-dependent cell-mediated cytotoxicity (ADCC) function, is entering two global Phase 2 clinical trials. IMG-004 is in Phase 1 development. Moreover, IMG-008, a long-acting mAb against IL-36 receptor (IL-36R), has been cleared by the FDA via an IND-application for Phase 1 clinical development. Believing in "Borderless Innovation", the Inmagene team strives to integrate efficient resources worldwide to develop novel therapeutics for global patients. Based on its proprietary QuadraTek® platform, Inmagene creates and develops several novel drug candidates with global rights. Inmagene also in-licenses drug candidates and, together with its partners, carries out global development activities, including global multi-center clinical trials. Inmagene has formed strategic partnerships with multiple partners, such as HUTCHMED and Affibody AB, to develop highly innovative drug candidates. For more information, please visit: About HUTCHMED HUTCHMED is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has more than 4,600 personnel across all its companies, at the center of which is a team of about 1,700 in oncology/immunology. Since inception it has advanced 12 cancer drug candidates from in-house discovery into clinical studies around the world, with its first three oncology drugs now approved and marketed in China. For more information, please visit: –med.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Inmagene's and/or HUTCHMED's current expectations regarding future events, including expectations regarding the therapeutic potential of IMG-004 for the treatment of patients with immunological diseases, the further clinical development of IMG-004, expectations as to whether clinical studies of IMG-004 would meet their primary or secondary endpoints, and expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding IMG-004's potential to successfully advance in clinical studies and to eventually gain approvals in any jurisdiction, the safety profile of IMG-004, the timing of these events, and the impact of the COVID-19 pandemic on general economic, regulatory and political conditions. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of various risks applicable to HUTCHMED, see HUTCHMED's filings with the U.S. Securities and Exchange Commission, on AIM and with The Stock Exchange of Hong Kong Limited. Neither Inmagene nor HUTCHMED undertakes to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. SOURCE Inmagene

Malignant melanoma is a relatively aggressive type of skin cancer. When detected early, it is usually treatable by surgical resection only, but metastases develop often spreading to distant areas. Currently, tumor thickness and the presence of ulceration are some of the known prognostic factors used as indicators of malignant melanoma. Therefore, the discovery of valuable markers to assess the malignant potential of melanoma more accurately may be necessary to develop appropriate treatments. Cross talk between cancer cells and surrounding stromal cells is believed to orchestrate cancer progression through a variety of mechanisms. Cancer-associated fibroblasts (CAFs) - key factors in the tumor microenvironment - in particular have been implicated in cancer cell progression. It has also been reported that the exosomes, a type of small vesicles, produced by CAFs play an important role in cancer progression. A research group led by Naho Fujii, M.D., and Professor Hisashi Motomura from Osaka Metropolitan University Graduate School of Medicine investigated the effect of CAF-derived exosomes on the growth of malignant melanoma cells. The group found that the transmembrane proteins CD9 and CD63 were mainly present on CAF-derived exosomes, and that among the exosomes, the CD9-positive ones inhibited the growth of malignant melanoma cells. "As a plastic surgeon, usually I provide surgical treatment for skin cancer, but I have wanted to study other treatment methods for a long time," explained Fujii, M.D. "This study suggests that CD9-positive exosomes inhibit the growth of malignant melanoma, so CD9-positive exosomes may be a useful marker to evaluate the malignant grade of melanoma. We expect further research will lead to the development of new treatments in that line." Fujii N, Yashiro M, Hatano T, Fujikawa H, Motomura H. CD9-positive Exosomes Derived from Cancer-associated Fibroblasts Might Inhibit the Proliferation of Malignant Melanoma Cells. Anticancer Res. 2023 Jan;43(1):25-33. doi: 10.21873/anticanres.16130

Multiple types of beta cells produce insulin in the pancreas, helping to balance blood sugar levels. Losing a particularly productive type of beta cell may contribute to the development of diabetes, according to a new study. Multiple types of beta cells produce insulin in the pancreas, helping to balance blood sugar levels. Losing a particularly productive type of beta cell may contribute to the development of diabetes, according to a new study by Weill Cornell Medicine investigators. In the study, published March 16 in Nature Cell Biology, Dr. James Lo, associate professor of medicine at Weill Cornell Medicine, and colleagues measured gene expression in individual beta cells collected from mice to determine how many different types of beta cells exist in the pancreas. The team discovered four distinct beta cell types, including one that stood out. The cluster 1 group of beta cells produced more insulin than other beta cells and appeared better able to metabolize sugar. The study also showed that loss of this beta cell type might contribute to type 2 diabetes. "Before this, people thought a beta cell was a beta cell, and they just counted total beta cells," said Dr. Lo, who is also a member of the Weill Center for Metabolic Health and the Cardiovascular Research Institute at Weill Cornell Medicine and a cardiologist at NewYork-Presbyterian/Weill Cornell Medical Center. "But this study tells us it might be important to subtype the beta cells and that we need study the role of these special cluster 1 beta cells in diabetes." Drs. Doron Betel, Jingli Cao, Geoffrey Pitt and Shuibing Chen at Weill Cornell Medicine teamed up with Dr. Lo to carry out the study. The investigators used a technique called single-cell transcriptomics to measure all the genes expressed in individual mouse beta cells and then used that information to group them into four types. The cluster 1 beta cells had a unique gene expression signature that included high expression of genes that help cellular powerhouses called mitochondria to break down sugar and power them to secrete more insulin. Additionally, they could distinguish the cluster 1 beta cells from the other beta cell types by its high expression of the CD63 gene, which enabled them to use the CD63 protein as a marker for this specific beta cell type. "CD63 expression provided us a way to identify the cells without destroying them and allowed us to study the live cells," he said. When the team looked at both human and mouse beta cells, they found that cluster 1 beta cells with high CD63 gene expression produce more insulin in response to sugar than the three other types of beta cells with low CD63 expression. "They are very high-functioning beta cells," Dr. Lo said. "We think they may carry the bulk of the workload of producing insulin, so their loss might have profound impacts." In mice fed an obesity-inducing, high-fat diet and mice with type 2 diabetes, the numbers of these insulin-producing-powerhouse beta cells decreased. "Because the numbers of cluster 1/high CD63 cells went down, you may have less insulin production, which may play a major role in diabetes development," he said. Transplanting beta cells with high CD63 production into mice with type 2 diabetes restored their blood sugar levels to normal. But removing the transplanted cells caused high blood sugar levels to return. Transplanting low CD63 production beta cells into the mice didn't restore blood sugar to normal levels. The transplanted low CD63 beta cells instead appeared dysfunctional. The discovery may have important implications for the use of beta cell transplants to treat diabetes, Dr. Lo said. For example, it may be better to transplant only high CD63- beta cells. He noted that it might also be possible to transplant fewer of these highly productive cells. Dr. Lo's team also found that humans with type 2 diabetes had lower levels of high CD63 beta cells compared to those without diabetes. Next, Dr. Lo and his colleagues would like to find out what happens to the high CD63-producing beta cells in mice with diabetes and how to keep them from disappearing. "If we can figure out how to keep them around longer, surviving and functional, that could lead to better ways to treat or prevent type 2 diabetes," he said. They would also like to study how existing diabetes treatments affect all types of beta cells. GLP-1 agonists, which help increase the release of insulin in people with diabetes, interact with high and low CD63-producing beta cells. "Our study also shows that GLP-1 agonists might also be a way to get the low CD63-producing beta cells to work better," Dr. Lo said.