West China Second Hospital of Sichuan University

Discovery led by experts at Cincinnati Children's reveals potential treatment for multiple sclerosis (MS), age-related cognitive deficits, and other rare neural diseases CINCINNATI, May 2, 2024 /PRNewswire/ -- When treated with a novel protein function inhibitor called ESI1, mice that mimic the symptoms of multiple sclerosis (MS) and lab-prepared human brain cells both demonstrated the ability to regenerate vital myelin coatings that protect healthy axon function. This breakthrough, published May 2, 2024, in Cell, appears to overcome difficulties that have long frustrated previous attempts to reverse a form of nerve damage that robs people with MS of motor control and gradually blunts cognitive functions for many people as they age. Continue Reading In human organoid cells, ESI1 treatment strengthened myelin sheath production, as shown by the thick, long green strands. in this confocal microscope image. "Currently, there are no effective therapies to reverse myelin damage in devastating demyelinating diseases such as MS," says corresponding author Q. Richard Lu, PhD, a top brain research expert at Cincinnati Children's. "These findings are significant as they offer new pathways for treatment that potentially shift the therapeutic focus from just managing symptoms to actively promoting repair and regeneration of myelin." Promoting healing by clearing a roadblock A critical insight driving the new findings was observing that brain regions damaged by MS still possessed a type of cell needed to repair myelin damage, but the disease activates other cell types and signals that combine forces to silence the repair function. These useful cells in the brain, called oligodendrocytes, are responsible for producing myelin sheaths that wrap around cable-like parts of nerve cells called axons, much like the plastic insulation around a wire. When the protective myelin gets damaged, be it by disease or the wear and tear of age, nerve signaling gets disrupted. Depending on where the damaged nerves lead, the disruptions can affect movement, vision, thinking and so on. Essentially, the research team found a way to unsilence the silenced repair process, setting the oligodendrocytes (OLs) free to do their jobs. Pinning down the genetic changes and signals involved in the repair silencing process and finding a small molecule compound that can reverse the silencing was a complex undertaking. The project, which spanned over five years, involved four co-first authors and 29 contributing co-authors from Cincinnati Children's, the University of Cincinnati, and 14 other institutions including universities in Australia, China, Germany, India, Singapore, and the United Kingdom. Among the team's key findings: Identifying the mechanism preventing myelin production in MS Analysis of stored autopsy tissues revealed that OLs within MS lesions lacked an activating histone mark called H3K27ac, while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity. Finding a compound that can reverse the silencing The research team scoured a library of hundreds of small molecules known to target enzymes that could modify gene expression and influence the silenced OLs. The team determined that the compound ESI1 (epigenetic-silencing-inhibitor-1) was nearly five times more powerful than any other compounds they considered. The compound tripled the levels of the desired H3K27ac histone mark in OLs while sharply reducing levels of the two repressive histone marks. Additionally, the research reveals a new way in which ESI1 promotes the creation of special membrane-less regulatory hubs known as "biomolecular condensates" within the cell nucleus that control fat and cholesterol levels. These hubs act as central points to boost the production of essential fats and cholesterol needed to make myelin, a crucial component of nerve fibers. Demonstrating benefits in mice and lab-grown human tissue In both aging mice and mice mimicking MS, the ESI1 treatment prompted myelin sheath production and improved lost neurological function. Testing included tracking gene activation, measuring the microscopic new myelin sheaths surrounding axons, and observing that treated mice were quicker at navigating a water maze. Then the team tested the treatment on lab-grown human brain cells. The team used a type of brain organoid, myelin organoids, that is far more simplified than a full brain but still produces complex myelinating cells. When the organoids were exposed to ESI1, the treatment extended the myelin sheath of myelinating cells, the study reports. Implications and next steps MS is the most common and best known of several major neurodegenerative diseases. The new findings may spark a new approach to stopping the degenerative effects of these conditions, Lu says. Myelin regeneration treatment also could be helpful for people recovering from brain and spinal cord injuries. But the most far-reaching implication of the study is the possibility of using ESI1, or similar compounds, to help slow or even reverse cognitive losses that often occur during aging. Many studies have shown that myelin loss plays a role in age-related loss of cognitive function, Lu says. However, more research is needed to determine whether human clinical trials can be launched to evaluate ESI1 as a potential treatment. For example, the effects of ESI1 may need to be modulated by adjusting the dose, treatment duration, or using "pulsed therapy" during specific time windows. More study also is needed to determine whether even more effective compounds than ESI1 might be designed from scratch. "This study is a beginning," Lu says. "Prior to finding ESI1, most scientists believed that remyelination failure in MS was due to the stalled development of precursors. Now we show a proof of concept that reversing the silencing activity in OLs present in the damaged brain can enable myelin regeneration." About the study These researchers contributed equally as co-first authors: Xuezhao Liu, Dazhuan Eric Xin, Xiaowen Zhong and Chuntao Zhao, all with Cincinnati Children's. Xuelian He, of West China Second University Hospital, Sichuan, China, was a co-corresponding author. Co-authors from Cincinnati Children's included Liguo Zhang, Arman Bayat, Eva Nicholson, William Seibel, Mei Xin, Adam Dourson, Jason Tchieu, and Michael Jankowski. Bingfang Yan, of the Division of Pharmaceutical Sciences at the University of Cincinnati also contributed. Funding sources for this study include the National Multiple Sclerosis Society and the National Institutes of Health (R01NS113965, R01NS105715, R01AA030486, R01AI172959, and R35NS097303) and the National Key R&D Program of China (2022YFA1105500). The authors declare no conflict of interest. SOURCE Cincinnati Children's Hospital Medical Center

SAN FRANCISCO and SUZHOU, China, July 31, 2022 /PRNewswire/ -- Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, autoimmune, metabolic, ophthalmology and other major diseases, and Laekna Therapeutics, a clinical-stage biotechnology company dedicated to bringing ground-breaking therapies to cancer and liver fibrosis patients worldwide, jointly announced that the first patient has been dosed in a Phase 1/2 clinical trial (clinicaltrials.gov, NCT05383482) of a three-drug combination therapy (afuresertib + sintilimab + chemotherapy) in patients with specific solid tumors who were resistant to anti-PD-1/PD-L1 therapy at the West China Second Hospital of Sichuan University. This marks a key milestone on the first anniversary of the clinical research partnership established between Innovent and Laekna in July 2021. The study is a multi-center, single-arm, open-label, dose-escalation Phase 1/2 clinical study, assessing recommended Phase 2 dose (RP2D), safety, tolerability and anti-tumor activity of afuresertib in combination with sintilimab and chemotherapy (nab-paclitaxel or docetaxel) in patients with solid tumors who were resistant to prior anti-PD-1/PD-L1 therapy. The principal investigator of the study is Professor Lin Shen, Director of the Department of Gastrointestinal Oncology of Beijing Cancer Hospital. The primary endpoints of the Phase 1 dose escalation study are maximum tolerated dose (MTD) and RP2D, and the primary endpoint of the Phase 2 study is overall response rate (ORR). The study is planned to be extended as a multi-regional clinical trial at the pivotal stage. The clinical trial assesses five types of solid tumors, including non-small cell lung cancer (NSCLC), gastric cancer/gastroesophageal junction cancer (GC/GEJC), esophageal cancer (EsC), cervical cancer (CC) and endometrial cancer (EC). The study focuses on the AKT inhibitor, a potential new therapy for drug resistant-cancer, to address the unmet medical needs in cancer immunotherapy resistance and bring hope to solid tumor patients who have received prior anti-PD-1/PD-L1 treatments. The combination therapy consists of Laekna's afuresertib (LAE002), a highly selective ATP competitive AKT inhibitor in pivotal clinical trials with favorable clinical efficacy and safety profile, and Innovent's PD-1 inhibitor sintilimab (TYVYT®), which has been approved for six indications in China with the first four included in the National Reimbursement Drug List (NRDL). The subject who received the first dose was a patient with cervical cancer. Professor Rutie Yin, investigator of the center where the first patient was dosed and Director of the Department of Chemoradiotherapy Oncology at the West China Second Hospital of Sichuan University, said, "Cervical cancer is the fourth most common cancer globally in women1. In 2020, China reported about 110,000 new cases and about 60,000 death cases of cervical cancer2. Patients are faced with limited treatment options and the prognosis is poor3,4. Immunotherapy plays an increasingly important role in the treatment of recurrent or metastatic cervical cancer, and there is huge unmet need. With the launch of new immunosuppressants, they've been applied to more patients and become essential for the treatment of cervical cancer. AKT inhibitor, a serine/threonine-specific protein kinase, is considered a potential new target for cancer treatment as results of multiple preclinical studies showed that inhibition of AKT could restore the sensitivity of cancer cells to anti-tumor therapies. We look forward to the progress of the clinical trial and hope it will bring new breakthroughs to the later-line treatment of cervical cancer in China." Professor Lin Shen, principal investigator of the study, Director of the Department of Gastrointestinal Oncology of from Beijing Cancer Hospital, stated, "Innovation never stops in oncology as we are always looking for new ways to treat cancer patients. Based on results from the preclinical and clinical studies, the combination of an immune checkpoint inhibitor, an AKT inhibitor and taxanes shows potential to be a new treatment option for patients who were resistant to immune checkpoint inhibitors5,6,7,8. The trial conducted by Laekna and Innovent aims to explore this innovative combination therapy and validate this new promising solution. There is a significant clinical need for patients with digestive system and gynecologic solid tumors in China; we hope to see that AKT-targeting therapy will prove to be an effective strategy to overcome drug resistance." Dr. Hui Zhou, Senior Vice President of Innovent, stated, "With the increasing prescription of immune checkpoint inhibitors (ICI) in first-line settings in various tumor types, many patients developed ICI resistance or have poor response rates in clinical practice. It is of great clinical value to explore potential treatments for this huge unmet medical need. Sintilimab is the first PD-1 inhibitor in China with first-line indications for 5 major types of cancers. Innovent hopes to continue to develop the potential of high-quality drugs, in this case by combination therapy with Laekna's innovative AKT inhibitor. We look forward to the results of clinical trial to bring clinical benefits to patients with specific solid tumors." Dr. Yong Yue, Chief Medical Officer of Laekna, said, "It took less than six months to complete the journey from IND approval to dosing of first patient, showing robust strategic execution of Laekna's global clinical team. There are three main considerations in selecting the five types of solid tumors: PD-1/PD-L1 inhibitors have been approved as the standard-of-care treatments for those cancers in multiple countries; higher rates of biomarkers that activate the AKT pathway in patients with resistance to anti-PD-1/PD-L1 therapy were observed in those cancers; and the incidence rates and death rates are relatively high in China. We hope this innovative three-drug combination therapy will benefit patients with these solid tumors." About Afuresertib (LAE002) Afuresertib (LAE002) is an investigational highly selective adenosine triphosphate (ATP) competitive AKT inhibitor. Laekna in-licensed afuresertib from Novartis in 2018 and are conducting five combination therapy clinical trials for the treatment of ovarian cancer, prostate cancer, breast cancer, and PD-1/PD-L1-resistant solid tumors. Prior to Laekna's in-licensing agreement, over 10 clinical trials had been conducted to demonstrate the safety and efficacy profiles of afuresertib. In the Phase Ib study conducted by Novartis, afuresertib showed potential anti-tumor efficacy in platinum-resistant ovarian cancer (PROC) patients with an overall response rate (ORR) of 32.1% and progression-free survival (PFS) of 7.1 months9. In pre-clinical studies, afuresertib has demonstrated its ability to restore platinum/paclitaxel sensitivity in PROC cell lines. After the in-licensing agreement, Laekna also identified the therapeutic potential of combining afuresertib and LAE001 (an investigational potential first-in-class next-generation androgen synthesis inhibitor that simultaneously inhibits both CYP17A1 and CYP11B2) and observed their synergistic anti-tumor efficacy in our completed Phase 1 and ongoing Phase 2 studies in metastatic castration-resistant prostate cancer (mCRPC) patients as second- to fourth-line treatments. According to Frost & Sullivan, afuresertib is one of the three AKT inhibitors worldwide that have entered pivotal clinical trials10. About Sintilimab Sintilimab, marketed as TYVYT® (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody jointly developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells11. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials. In China, sintilimab has been approved for six indications as below, with the first four included in the National Reimbursement Drug List (NRDL), including: The treatment of relapsed or refractory classic Hodgkin's lymphoma after two lines or later of systemic chemotherapy; In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of non-squamous non-small cell lung cancer lacking EGFR or ALK driver mutations; In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer; In combination with BYVASDA® (bevacizumab biosimilar injection) for the first-line treatment of unresectable or advanced hepatocellular carcinoma; In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma; In combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-mutated non-squamous NSCLC following EGFR-TKI treatment under review in the China's NMPA. Additionally, two clinical studies of sintilimab have met their primary endpoints: Phase 2 study as second-line treatment of esophageal squamous cell carcinoma; Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy. About Innovent Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune, metabolic, ophthalmology and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK. Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 32 valuable assets in the fields of cancer, autoimmune, metabolic, ophthalmology and other major therapeutic areas, with 7 products approved for marketing in China – TYVYT® (sintilimab injection), BYVASDA® (bevacizumab biosimilar injection), SULINNO® (adalimumab biosimilar injection), HALPRYZA® (rituximab biosimilar injection) , Pemazyre® (pemigatinib oral inhibitor) and olverembatinib (BCR-ABL TKI) and Cyramza® (ramucirumab) , 3 asset under NMPA NDA review, 3 assets in Phase 3 or pivotal clinical trials, and an additional 19 molecules in clinical studies. Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Adimab, Incyte, MD Anderson Cancer Center, Hanmi and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: www.innoventbio.com. and www.linkedin.com/company/innovent-biologics/. About Laekna Founded in 2016, Laekna is a clinical-stage biotechnology company, dedicated to bringing ground-breaking therapies to cancer and liver fibrosis patients worldwide. Laekna has two potential core products: LAE002 is an investigational highly selective adenosine triphosphate (ATP) competitive AKT inhibitor for the treatment of ovarian cancer, prostate cancer, breast cancer and PD-1/PD-L1 drug-resistant solid tumors. The other core product LAE001 is an investigational potential first-in-class next-generation androgen synthesis inhibitor that simultaneously inhibits both CYP17A1 and CYP11B2 for the treatment of prostate cancer. Laekna's robust infrastructure has already enabled the rapid development of 14 innovative product candidates, including one pivotal clinical trial and another five clinical trials for it's potential core products. Among these six clinical trials, three multi-regional clinical trials (MRCTs) are designed to address urgent yet unmet global medical needs in the standard of care (SOC)-resistant cancers. Laekna's internal drug discovery primarily focuses on coordinating the human immune system to treat cancer and liver fibrosis. For more information, please visit: https://www.laekna.com/ or https://www.linkedin.com/company/74110713/