STAT5A

Recently, Hope Medicine (HopeMed) announced positive interim results from a Phase 2 study of HMI-115 in women with moderate to severe endometriosis-associated pain. HMI-115 is a monoclonal antibody targeting the prolactin receptor (PRLR) with a globally unique therapeutic mechanism. The company plans to quickly advance to a global Phase 3 trial so that patients can benefit from HMI-115 treatment as soon as possible. Latest Research DataThe Phase 2 study is an international, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of HMI-115 in women with moderate to severe endometriosis-associated pain over a 12-week treatment period. The study involved 142 female patients from the United States, Poland, and China. The interim analysis showed: ·Compared to the baseline, the 240 mg q2w group experienced a 42% reduction in average dysmenorrhea pain scores ·A 50% reduction in average non-menstrual pelvic pain scores.  ·Most patients reported normal menstruation.  ·No typical perimenopausal symptoms were reported.  ·There were no significant changes in bone mineral density and sex hormone levels, including estradiol, LH, FSH, and progesterone. About HMI-115HMI-115 non-competitively blocks PRLR-mediated signaling and has been granted Breakthrough Therapy Designation by the National Medical Products Administration (NMPA) in China for the treatment of moderate to severe pain associated with endometriosis. Initially developed by Bayer, Hope Medicine signed a global exclusive licensing agreement for the development and commercialization of HMI-115 (BAY 1158061) across multiple indications.  Beyond the endometriosis indication, the company has completed a Phase Ib study assessing the safety, tolerability, and efficacy of HMI-115 in treating androgenic alopecia. The study showed that the average non-vellus target area hair count (TAHC) increased by 14 hairs/cm² from baseline in two male patients, and the drug was safe and well-tolerated. About PRLR DrugsThe prolactin receptor (PRLR) is part of the class 1 cytokine/hematopoietic receptor superfamily and is widely expressed in the immune system, including monocytes, lymphocytes, macrophages, NK cells, granulocytes, and thymic epithelial cells. Research indicates that PRL is associated with autoimmune diseases, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and endometrial cancer. Upon ligand binding, PRLR undergoes conformational changes that activate multiple downstream signaling pathways, including the Jak2/Stat5 and Jak1/Stat3 pathways. Activation through Src family kinases and focal adhesion kinase (FAK) can also lead to the induction of PI3K/Akt and Raf/MEK/ERK pathways in cancer cell lines. According to incomplete statistics, fewer than ten PRLR-targeted drugs are currently under development. About EndometriosisEndometriosis is a common condition among women of reproductive age and is characterized as a hormone-dependent disease. Its clinical manifestations are diverse, with pain (often related to menstrual cycles) and infertility being the most significant and impactful. Endometriosis substantially affects patients' physical, psychological, sexual, social, and reproductive well-being, imposing a heavy burden on families, society, and national economies. It is estimated that approximately 190 million women worldwide have endometriosis, representing a market size of around $200 billion.  Current treatment options for endometriosis mainly include surgery and medication, neither of which can offer a fundamentally effective, safe, and long-term treatment. Surgical treatments can remove visible lesions, but due to the unclear pathogenesis of the disease, postoperative recurrence rates remain high (with an annual increase of 10% and an accumulated five-year recurrence rate of 50%). Surgery may also lead to bowel, urinary tract, and vascular complications. Available medications (common drugs include NSAIDs, combination oral contraceptives, progestins, and GnRH agonists) have various shortcomings, and patients may discontinue treatment due to inadequate efficacy or intolerance to side effects, leading to uncontrolled and recurrent disease. About Hope MedicineHope Medicine is a science-driven, clinical-stage innovative biopharmaceutical company. It is built upon the deep understanding and decades of research achievements in translational medicine by Professor Xiaoruiping, Dean of the College of Future Technology at Peking University, and his team. The company is dedicated to the research, development, and commercialization of first-in-class drugs aimed at addressing common and major diseases that pose significant threats to human health. 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!

On April 22, 2024, ImmunityBio announced that the FDA has approved Anktiva (N-803) in combination with Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. The drug is expected to be available in the United States by mid-May 2024. Nogapendekin alfa inbakicept-pmln(N-803)N-803 (nogapendekin alfa inbakicept-pmln) is an interleukin-15 (IL-15) superagonist complex composed of a mutated variant of IL-15 (IL-15N72D) fused with the IL-15Rα sushi domain and an IgG1 Fc fusion protein. The IL-15Rα sushi domain allows for activation of downstream signaling pathways without the requirement for trans-presentation, as is necessary for natural IL-15, while the IgG1-Fc fragment significantly extends the drug's half-life. Previously, the FDA granted N-803 Fast Track designation and Breakthrough Therapy designation, and in October 2023, accepted the resubmission of the Biologics License Application (BLA) for N-803 in combination with BCG. In a single-arm, multi-center Phase 2 trial, 77 patients with high-risk non-muscle invasive bladder cancer (NMIBC) who were unresponsive to BCG and who had undergone transurethral resection with or without Ta/T1 papillary lesions were enrolled; patients received N-803 induction followed by intravesical instillation of Bacillus Calmette-Guérin (BCG), with maintenance therapy lasting up to 37 months. For up to 2 years, tumor status was evaluated every three months via cystoscopy and urinary cytology, with biopsies performed (randomly or under cystoscopic guidance) within the first 6 months after treatment initiation. The primary efficacy endpoints were the complete response (CR) at any time and the duration of complete response (DOR). CR is defined as a negative cystoscopy (with TURBT/biopsy where applicable) and negative urinary cytology. The results showed a CR rate of 62% (95 CI: 51, 73); 58% of patients with CR had a DOR of ≥12 months, and 40% had a DOR of ≥24 months. The most common adverse reactions (≥15%) included laboratory abnormalities such as increased creatinine, dysuria, hematuria, urinary frequency, urinary urgency, urinary tract infections, elevated potassium, musculoskeletal pain, chills, and fever. Beyond non-muscle-invasive bladder cancer (NMIBC), N-803 has also shown promising therapeutic potential in pancreatic cancer. At the 2022 ASCO GI, Immunity Bio revealed phase II data for N-803 combined with standard-of-care chemotherapy, albumin-bound paclitaxel, and PD-L1 t-haNK as a third-line treatment for pancreatic cancer. The results indicated a median overall survival (mOS) of 6.3 months, doubling compared to historical data. Regarding safety, grade 3 or higher adverse events mainly included anemia, neutropenia, and thrombocytopenia. Additionally, preclinical data published in the journal Science suggested that in combination with broadly neutralizing antibodies, N-803 might enable the immune system to control human immunodeficiency virus (HIV) without the need for antiretroviral therapy. IL-15IL-15, as a T cell growth factor, is mainly produced by monocytes and macrophages. It binds to the IL-15 receptor (IL-15R) on responsive cells, mediating the proliferation and activation of T cells, NK cells, and B cells, and inducing the generation of cytotoxic T lymphocytes (CTLs). IL-15 principally employs two distinct mechanisms for signal delivery: cis-presentation and trans-presentation. In cis-presentation, IL-15 binds to the transmembrane or soluble forms of IL-15Rα before associating with IL-15Rβγ. In trans-presentation, IL-15Rα is expressed on the surface of IL-15 producing cells, such as dendritic cells and macrophages, delivering IL-15 in a trans manner to responder cells carrying the IL-15Rβ/γc receptor, such as NK or memory CD8+ T cells. This may play a key role in coordinating the innate and adaptive branches of the immune system. The specific binding of IL-15 to its receptor IL-5R can activate the JAK-STAT5 signal transduction molecule, which then leads to the cascade activation of multiple signaling pathways including PI3K/Akt and Ras/Raf/MAPK, ultimately exerting its biological effects. Additionally, IL-15Rα can also shed from the membrane and exist in a free form after binding to IL-15, activating the IL-15Rβ/γc receptor at a distance. Due to IL-15’s ability to promote the activation and proliferation of immune cells, it plays a very important role in immunotherapy. IL-15 does not induce apoptosis in activated T cells and can maintain the survival of memory T cells, thereby achieving the goal of long-term treatment. However, the application of IL-15 in immunotherapy also faces some challenges. For example, excessive secretion of IL-15 may lead to an over-activation of the immune system, which can induce inflammatory responses, autoimmune diseases, infectious diseases, and tumors. Because the IL-15 signaling pathway requires the sushi domain of IL-15Rα, it is limited by the expression level of IL-15Rα within the body. Moreover, the short half-life of IL-15 (less than 1 hour in humans) and strict post-transcriptional regulation significantly limit IL-15's clinical applications. The most common strategies to address this include increasing the molecular size to reduce renal elimination, or fusion with the neonatal Fc receptor (FcRn). Additionally, considering IL-15's unique ability to maintain the homeostasis and proliferation of memory CD8+ T cells, applying it in CAR-T engineering also promises to achieve stronger antitumor efficacy. According to incomplete statistics, there are currently only approximately 200 IL-15 drugs under research globally, with about 90 having entered the clinical stage. Apart from N-803, other drugs worth paying attention to include SOT101, a subcutaneous formulation developed by SOTIO, SHR-1501 by Jiangsu Hengrui Pharmaceuticals, ASKG315 by Aosaikang Pharmaceutical, and BJ-001 by BJ Bioscience. Regarding Non-Muscle Invasive Bladder CancerBladder Urothelial Carcinoma (UC) is the 13th most common cancer worldwide by incidence and is divided into two main categories: non-muscle invasive bladder cancer (NMIBC), which accounts for 70%, and muscle-invasive bladder cancer (MIBC), which accounts for 30%. The peak incidence age of this disease is between 50 and 70 years old, with the incidence rate of urothelial carcinoma in men being 3 to 4 times that in women. In 2020, there were 516,000 cases of urothelial carcinoma globally, and it is projected to reach 586,000 by 2025 and 663,000 by 2030. In China, there were about 77,000 new cases of urothelial carcinoma in 2020, and the number is expected to rise to 91,000 by 2025 and to reach 106,000 by 2030. NMIBC refers to bladder malignancies that are confined to the mucosal layer (Ta) and lamina propria (T1), with no invasion into the muscular layer. This includes Ta, T1, and Tis stages, with Ta accounting for 70%, T1 representing 20%, and Tis making up 10%. Based on the different risks of recurrence and prognosis, NMIBC is divided into low-risk NMIBC, intermediate-risk NMIBC, high-risk NMIBC, and very high-risk NMIBC. Treatment options, intravesical instillation, and follow-up plans are chosen according to the grouping of risk levels. The standard treatment for NMIBC is transurethral resection of bladder tumor (TURBT). Due to the high recurrence rate of NMIBC postoperatively, adjuvant intravesical instillation therapy is recommended for all NMIBC patients. Commonly used chemotherapeutic agents for instillation include mitomycin, gemcitabine, and epirubicin, and there is no evidence that maintenance instillation schemes using different chemotherapy drugs significantly differ in effectiveness. Despite guidelines recommending chemotherapy instillation and BCG intravesical therapy, about 50% of patients still experience tumor recurrence within five years. The standard treatment for patients after tumor recurrence is radical cystectomy, which makes patients lose their normal urine storage and voiding functions, severely affecting their quality of life and psychological health. Therefore, the development of new drugs is crucial for NMIBC patients who do not respond to chemotherapy and BCG. Representative drugs approved in recent years include: In January 2020, the FDA approved pembrolizumab ("Drug K") as a monotherapy for treating BCG-unresponsive, high-risk NMIBC patients with CIS, with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy. In December 2022, the FDA approved Ferring's gene therapy, nadofaragene firadenovec-vncg (commercial name Adstiladrin), for treating high-risk NMIBC patients unresponsive to BCG therapy, with CIS, with or without papillary tumors. ImmunityBioImmunityBio is a clinical-stage immunotherapy company headquartered in California, United States, dedicated to the development of a new generation of treatments that harness immunogenic mechanisms for the treatment of cancer and infectious diseases. In January 2024, Oberland Capital provided ImmunityBio with up to $320 million in royalty monetization and equity financing, with total proceeds of $210 million due on December 29, 2023. This additional financing provides the company with significant financial resources to accelerate its commercialization efforts, in anticipation of regulatory approval, and to expand its product line in the broader field of urologic oncology. The raised funds will also support ongoing business operations and clinical trials, extending the indications of N-803 to multiple solid tumors.

- Pioneering compounds believed to be the first orally administered reversible inhibitors to bind to and inhibit the SH2 domain potently and selectively - Proprietary STAT3 inhibitors are differentiated in several ways from alternative approaches, including potency, selectivity, reversibility and oral bioavailability Recludix Pharma, a leader in platform approaches to discover inhibitors of challenging targets for inflammatory disease and cancer, announced that in a presentation given today titled “Drugging the Undruggable,” Recludix’s senior vice president of biology, Paul Smith, Ph.D., discussed the first application of the company’s platform capabilities to target the Src Homology 2 (SH2) domain, as well as reviewed preclinical data on an early STAT3 inhibitor that was internally discovered through the platform. The presentation is available on the company’s website under the section titled “Events.” “We have had tremendous success in developing oral STAT inhibitors by targeting the SH2 domain, which has been previously considered undruggable,” said Nancy Whiting, PharmD, CEO of Recludix. “In this presentation, we highlight data from one of our earlier STAT3 discovery compounds showing its highly selective STAT3 inhibition with demonstrated potency in biochemical and cellular assays. We have continued to refine our lead STAT3 inhibitors and are in the final stages of confirming a STAT3 development candidate to move into clinical testing. We believe this could be a first- and best-in-class approach to selectively inhibit Th17-driven inflammatory diseases, such as psoriasis, rheumatoid arthritis, ulcerative colitis and Crohn's disease.” Recludix has generated potent and selective small molecule STAT3 inhibitors for Th17-driven inflammation. In T cell functional assays, Recludix’s STAT3 inhibitor potently and selectively impaired the Th17 phenotype, while still enabling the T cell to continue to perform robustly against viruses, bacteria, extracellular pathogens, and parasites. This is in contrast to the family of JAK or TYK2 inhibitors, which can be associated with changes in immune surveillance and hematopoiesis, leading to dose limiting safety concerns. Data demonstrate that targeting STAT3 spares interferon-driven anti-viral gene transcription and avoids STAT5 signaling, which is important for hematologic homeostasis and is differentiated from JAK/TYK2 inhibition. In a preclinical model of multiple sclerosis, proof-of-concept was established that STAT3 inhibition modulates in vivo Th17 diseases as measured by mean clinical score compared to vehicle control, exhibiting greater preclinical disease control than the JAK inhibitor baricitinib. Activity for STAT3 was found to be dose-dependent in both prophylactic and therapeutic preclinical models. Selective STAT3 inhibition was also evaluated in an imiquimod-induced (Th17-dependent) model of psoriasis which demonstrated that STAT3 inhibition modulates disease as measured by the PASI score and skin thickness, and it does so comparably to a supra-maximal efficacious dose of the JAK inhibitor tofacitinib (30 mg/kg). About STAT3 The interleukin cytokines IL-23 and IL-6 signal through STAT3 and promote the generation and function of pathogenic T helper type-17 (Th17) cells, a type of immune cell that is pro-inflammatory. Th17 cells are considered pivotal players in certain inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others. Inhibiting STAT3 can also offer potential efficacy beyond Th17 / IL-17 driven diseases in clinical indications where blocking the IL-6 pathway is clinically validated. Furthermore, clinical trials inhibiting oncostatin M (OSM) and IL-22, both STAT3 dependent cytokines, have been reported as efficacious in inflammatory disease. A selective, oral STAT3 inhibitor has potential to replace JAK/TYK2 inhibitors and biologics for multiple inflammatory diseases. STAT3 inhibitors may also have significant opportunity in cancer settings, as STAT3 is activated in greater than 70% of human cancers. About Recludix Recludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders and founding scientific team members of Seagen and Blueprint Medicines. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease, as well as numerous cancer types, such as multiple leukemias and lymphomas. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases and oncology indications, as well as additional programs. For more information, please visit the company’s website at https://recludixpharma.com. The content above comes from the network. if any infringement, please contact us to modify.