TDP43

Results from this analysis were published in Free Radical Biology and Medicine JERSEY CITY, N.J., March 25, 2025 /PRNewswire/ -- Mitsubishi Tanabe Pharma America, Inc. (MTPA) today announced the publication of new preclinical research in Free Radical Biology and Medicine, highlighting the role of edaravone in mitigating TDP-43 mislocalization, a hallmark feature observed in more than 97% of sporadic amyotrophic lateral sclerosis (ALS) cases. The study, conducted using induced pluripotent stem cell (iPSC)-derived motor neurons from a single patient with ALS, demonstrated that edaravone significantly reduced the abnormal cytoplasmic accumulation of TDP-43, restoring its nuclear localization. This mislocalization is a key driver of neuronal dysfunction and degeneration in ALS, and suggests that edaravone may offer a varied therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways. "These findings help build upon our understanding of edaravone's potential effects in ALS," said Gustavo A. Suarez Zambrano, M.D., Vice President of Medical Affairs at MTPA. "By modulating TDP-43 pathology and engaging molecular pathways linked to neurodegeneration, edaravone may play a broader role in ALS management than previously understood and should continue to be studied." "This study provides preclinical evidence that edaravone's MOA in ALS extends beyond its known antioxidant properties," said Satsuki Mikuriya, Research Scientist at MTPA and lead author of the study. Key findings from the study include: In ALS patient-derived neurons from a patient with ALS harboring a TDP-43 mutation, edaravone significantly reduced the cytoplasmic accumulation of TDP-43, restoring its nuclear localization. Unlike vitamin C, edaravone preserved neurite structures and reduced neurotoxicity, supporting a unique mechanism of action. Edaravone treatment induced significant changes in gene expression as early as six hours post-treatment, with key pathways related to protein degradation and neuroprotection. Edaravone's effects were associated with modulation of the SIRT1-XBP1 pathway, a key regulator of cellular stress responses, suggesting a broader role in ALS neuroprotection. This preclinical study was conducted using iPSC-derived motor neurons from a single ALS patient with a specific TDP-43 mutation (A382T) in an in vitro setting. Additional research in animal models and clinical settings (including those with other ALS-related mutations and patients with sporadic ALS) is needed to confirm these findings. Additionally, recent research has highlighted not only the toxic gain of function caused by TDP-43 aggregation but also the pathological sequences of TDP-43 loss of function due to its nuclear depletion. Further studies are required to explore how edaravone influences the loss of TDP-43 function. While the study provides important new insights into edaravone's potential role in ALS treatment, further research is needed to confirm its effects in larger, more diverse ALS models and to explore its long-term impact on disease progression. This analysis was funded and conducted by MTPA. Additional results can be found in the publication, titled, "Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway." About Mitsubishi Tanabe Pharma America, Inc. Based in Jersey City, N.J., Mitsubishi Tanabe Pharma America, Inc. (MTPA) is a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC). It was established by MTPC to develop and advance our pipeline as well as commercialize approved pharmaceutical products in North America. For more information, please visit or follow us on X (formerly Twitter), Facebook and LinkedIn. About Mitsubishi Tanabe Pharma Corporation Mitsubishi Tanabe Pharma Corporation (MTPC), the pharma arm of Mitsubishi Chemical Group (MCG), is one of the oldest pharmaceutical companies in the world, founded in 1678, and focusing on ethical pharmaceuticals. MTPC is headquartered in Doshomachi, Osaka, the birthplace of Japan's pharmaceutical industry. MTPC sets the MISSION of "Creating hope for all facing illness". To that end, MTPC is working on the disease areas of central nervous system, immuno-inflammation, diabetes and kidney, and cancer. MTPC is focusing on "precision medicine" to provide drugs with high treatment satisfaction by identifying patient populations with high potential for efficacy and safety. In addition, MTPC is working to develop "around the pill solutions" to address specific patient concerns based on therapeutic medicine, including prevention of diseases, pre-symptomatic disease care, prevention of aggravation and prognosis. For more information, go to Media inquiries: [email protected] SOURCE Mitsubishi Tanabe Pharma America WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

JERSEY CITY, N.J., March 12, 2025 /PRNewswire/ -- Mitsubishi Tanabe Pharma America, Inc. (MTPA) today announced the presentation of eleven abstracts covering research in amyotrophic lateral sclerosis (ALS) at the 2025 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference being held in Dallas, Texas, March 16-19. "We are looking forward to presenting our latest ALS research, including an innovative study exploring how clinical algorithms may aid in the diagnosis of ALS," said Gustavo A. Suarez Zambrano, M.D., Vice President of Medical Affairs, MTPA. "We remain dedicated to advancing ALS research and fostering scientific dialogue at medical meetings and congresses on our mission to provide meaningful treatment options and help improve the lives of those affected by this disease." RADICAVA ORS® (edaravone) Studies: Final efficacy and safety results from two multi-center, Phase 3b, double-blind, parallel group studies will be presented, including a comparison of daily dosing of RADICAVA ORS® (edaravone) with the FDA-approved on/off regimen, assessed at 48 weeks (MT-1186-A02) and its extension study (MT-1186-A04). Safety data from a Phase 3 open-label safety extension study for up to 96 weeks (MT-1196-A03) will also be shared. An additional presentation will examine the long-term function and survival of patients treated with RADICAVA ORS using data from propensity score-matched patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. Phase 3b Study MT-1186-A02 to Investigate the Superiority of Daily Dosing vs the FDA-approved On/Off Regimen of Oral Edaravone in Patients with ALS (Alejandro Salah, M.D., Ph.D., MBA, MHA; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Phase 3, Open-Label, Safety Extension Study of Oral Edaravone Administered Over 96 Weeks in Patients with ALS (MT-1186-A03) (Stephen Apple, M.D.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Phase 3b Study MT-1186-A04 Extension Study to Evaluate the Continued Efficacy and Safety of Radicava ORS® (Oral Edaravone) for up to an Additional 48-Weeks in Patients With Amyotrophic Lateral Sclerosis (Alejandro Salah, M.D., Ph.D., MBA, MHA; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Analysis of Long-term Function and Survival of Radicava ORS® (Oral Edaravone)-Treated Patients With Amyotrophic Lateral Sclerosis vs Propensity Score–Matched PRO-ACT Historical Controls (Stephen Apple, M.D.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Real World Data: Presentations will highlight a clinical algorithm designed to analyze electronic medical record (EMR) data of neurologists, which aims to reduce delays in ALS diagnosis and treatment. Findings from the ALS/Motor Neuron Disease National History Consortium database will provide insights into the survival, treatment patterns and clinical outcomes of patients treated for ALS. In addition, studies examining referral patterns for ALS diagnosis, as well as demographics and healthcare resource utilization (HCRU) trends across specialty and non-specialty treatment centers, will be shared. Further, two studies will explore point-of-care quality classifications and at-home telespirometry assessments, evaluating forced vital capacity as well as erect and supine slow vital capacity in individuals with ALS. Smartphone Application-Mediated Supervised At-Home Telespirometry Erect and Supine Slow Vital Capacity (eSVC/sSVC) Measurements in Subjects With Amyotrophic Lateral Sclerosis Identify Statistically Significant Differences in eSVC/sSVC Decline as Function of Non-Invasive Ventilation Treatment Status [NCT05106569] (Stephen Apple, M.D.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Smartphone Application–Mediated, Supervised, At-Home Telespirometry Vital Capacity Measurements in Amyotrophic Lateral Sclerosis: Comparison of American Thoracic Society/European Respiratory Society Point-of-Care Quality Assessment Algorithms Implemented for Slow Vital Capacity and Forced Vital Capacity [NCT05106569] (Stephen Apple, M.D.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Referral Patterns for Patients With Amyotrophic Lateral Sclerosis Enrolled in a US-Based Administrative Claims Database (Malgorzata Ciepielewska, M.S.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Investigating Application of a Clinical Algorithm on Real-World Electronic Medical Record Data for Earlier Detection of Amyotrophic Lateral Sclerosis (Dung Pham, Ph.D.; MTP-CA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Treatment of Amyotrophic Lateral Sclerosis in General and Specialist US Healthcare Settings: Results From a Real-World Survey (Malgorzata Ciepielewska, M.S.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Survival Benefits and Treatment Patterns of Edaravone–Treated People With Amyotrophic Lateral Sclerosis in the ALS/MND Natural History Consortium (Malgorzata Ciepielewska, M.S.; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 Preclinical Data: Data from a preclinical study examining the effects of edaravone on spinal motor neurons derived from an ALS patient carrying the A382T mutation in TDP-43, as analyzed through a comprehensive transcriptomic approach, will be presented. Transcriptomic Signature Induced by Edaravone in Motor Neurons From an ALS Patient With a TDP-43 Mutation (Alejandro Salah, M.D., Ph.D., MBA, MHA; MTPA) Poster Session: 6:00 p.m. – 8:00 p.m. CT, March 16 – March 18, 2025 About RADICAVA® (edaravone) and RADICAVA ORS® (edaravone) The U.S. Food and Drug Administration (FDA) approved RADICAVA® (edaravone) on May 5, 2017, and the oral formulation RADICAVA ORS® (edaravone) on May 12, 2022, for the treatment of amyotrophic lateral sclerosis (ALS). In 2024, the FDA recognized RADICAVA ORS with Orphan Drug Exclusivity based on the major contribution to patient care of the innovative oral formulation. RADICAVA is administered in 28-day cycles by intravenous (IV) infusion. It takes 60 minutes to receive each 60 mg dose. For the initial cycle, the treatment is infused daily for 14 consecutive days, followed by a two-week drug-free period. All cycles thereafter are infused daily for 10 days within a 14-day period, followed by a two-week drug-free period. RADICAVA ORS is taken daily for 14 consecutive days followed by a 14-day drug-free period for the initial treatment cycle. For subsequent treatment cycles, RADICAVA ORS is taken for 10 days within a 14-day period followed by a 14-day drug-free period. RADICAVA ORS should be taken in the morning after overnight fasting. Patients should not eat or drink (except water) within one hour after taking RADICAVA ORS.1 Edaravone was discovered and developed for ALS by Mitsubishi Tanabe Pharma Corporation (MTPC) and commercialized in the U.S. by Mitsubishi Tanabe Pharma America, Inc. (MTPA). The MTPC group companies began researching ALS in 2001 through an iterative clinical platform over a 13-year period. In 2015, edaravone was approved as RADICUT® for the treatment of ALS in Japan and South Korea. Marketing authorizations were subsequently granted in Canada (October 2018), Switzerland (January 2019), Indonesia (July 2020), Thailand (April 2021), Malaysia (December 2021) and Brazil (February 2024). Marketing authorization for RADICAVA® Oral Suspension was granted in Canada (November 2022) and Switzerland (May 2023), and RADICUT® Oral Suspension 2.1% was granted regulatory approval in Japan in December 2022. To date, in the U.S., RADICAVA and RADICAVA ORS have been used to treat over 16,000 people with ALS, with over 2.0-million days of therapy, and have been prescribed by over 2,400 HCPs.2-4 IMPORTANT SAFETY INFORMATION Hypersensitivity Reactions RADICAVA (edaravone) and RADICAVA ORS (edaravone) are contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients of this product. Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have occurred with RADICAVA. Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue RADICAVA or RADICAVA ORS, treat per standard of care, and monitor until the condition resolves. Sulfite Allergic Reactions RADICAVA and RADICAVA ORS contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but occurs more frequently in asthmatic people. Adverse Reactions The most common adverse reactions (≥10%) reported in RADICAVA-treated patients were contusion (15%), gait disturbance (13%), and headache (10%). In an open label study, fatigue was also observed in 7.6% of patients receiving RADICAVA ORS. Pregnancy Based on animal data, RADICAVA and RADICAVA ORS may cause fetal harm. To report suspected adverse reactions or product complaints, contact Mitsubishi Tanabe Pharma America, Inc., at 1-888-292-0058. You may also report suspected adverse reactions to the FDA at 1-800-FDA-1088 or . INDICATION RADICAVA and RADICAVA ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS). For more information, including full Prescribing Information, please visit . About Mitsubishi Tanabe Pharma America, Inc. Based in Jersey City, N.J., Mitsubishi Tanabe Pharma America, Inc. (MTPA) is a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC). It was established by MTPC to develop and advance our pipeline as well as commercialize approved pharmaceutical products in North America. For more information, please visit or follow us on X (formerly Twitter), Facebook and LinkedIn. About Mitsubishi Tanabe Pharma Corporation Mitsubishi Tanabe Pharma Corporation (MTPC), the pharma arm of Mitsubishi Chemical Group (MCG), is one of the oldest pharmaceutical companies in the world, founded in 1678, and focusing on ethical pharmaceuticals. MTPC is headquartered in Doshomachi, Osaka, the birthplace of Japan's pharmaceutical industry. MTPC sets the MISSION of "Creating hope for all facing illness". To that end, MTPC is working on the disease areas of central nervous system, immuno-inflammation, diabetes and kidney, and cancer. MTPC is focusing on "precision medicine" to provide drugs with high treatment satisfaction by identifying patient populations with high potential for efficacy and safety. In addition, MTPC is working to develop "around the pill solutions" to address specific patient concerns based on therapeutic medicine, including prevention of diseases, pre-symptomatic disease care, prevention of aggravation and prognosis. For more information, go to Media inquiries: [email protected] 1 RADICAVA and RADICAVA ORS Prescribing Information. Jersey City, NJ: Mitsubishi Tanabe Pharma America, Inc.; 2022. 2 Data on file. Mitsubishi Tanabe Pharma America, Inc. 3 Data on file. Mitsubishi Tanabe Pharma America, Inc. 4 Data on file. Mitsubishi Tanabe Pharma America, Inc. SOURCE Mitsubishi Tanabe Pharma America WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

In a note to clients, William Blair analysts described the latest updates on DNL343 as “disappointing but largely expected following the previous update on the failed study.”\n Denali Therapeutics’ amyotrophic lateral sclerosis (ALS) drug has racked up another clinical miss this year, leaving the company to mull the asset’s future.The therapy, dubbed DNL343, is designed to activate the protein complex eIF2B, protecting neurons by preventing further aggregation of the TDP-43 protein. A phase 2/3 readout from a Massachusetts General Hospital trial at the start of the year showed that DNL343 was unable to slow ALS progression compared to placebo after 24 weeks or improve secondary outcomes like muscle strength and respiratory function.At the time, Denali pinned its hopes on additional analyses of the trial data assessing the drug\'s effect on neurofilament light (NfL)—a biomarker of neuronal damage—as well as specific subgroups of patients and longer-term treatment data.But the biotech announced in a Securities and Exchange Commission filing March 5 that these additional analyses hadn’t demonstrated a treatment effect on NfL in either the 24-week trial or in a 28-week open-label treatment extension.As a result, Denali is moving to halt the extension arm of the trial, with the data to be presented at a future medical meeting.The company isn’t quite ready to abandon the drug, however. For now, the biotech said it “intends to assess potential future development opportunities for DNL343.” Denali isn’t the only company to struggle in ALS. The same Massachusetts General Hospital trial also evaluated AbbVie and Calico’s eIF2B agonist, called fosigotifator, which was equally unsuccessful.The continuing failure of DNL343 may have implications for Bristol Myers Squibb, which paid Evotec a $20 million option fee to license an eIF2B candidate in 2021. BMS’ phase 1 pipeline includes an eIF2B activator that is in development in Alzheimer’s disease.In a note to clients, William Blair analysts described the latest updates on DNL343 as “disappointing but largely expected following the previous update on the failed study.”The analysts are more focused on Denali’s Hunter syndrome enzyme replacement therapy, tividenofusp alfa (tivi), also known as DNL310. A phase 1/2 study last month showed the treatment met its primary safety endpoints and reduced key biomarkers of the disease.“Much more relevant to our investment thesis will be updates in 2025 on the accelerated approval BLA filing (still on track for early 2025) for tivi to treat Hunter syndrome and potential acceptance and approval in late 2025 or early 2026,” the analysts added.