Frontotemporal Dementia With Motor Neuron Disease

TPN-101 is the first PSP treatment to reduce NfL and IL-6 levels, key biomarkers of neurodegeneration and neuroinflammation in PSP Participants treated with TPN-101 for the entire 48-week study in PSP showed a stabilization of their clinical symptoms as measured by the PSPRS In the Phase 2 study of C9orf72-related ALS/FTD, TPN-101 showed effects on key biomarkers of neurodegeneration, neuroinflammation and microglial activation, including NfL, Tau, UCHL1, YKL-40 and osteopontin TPN-101 also showed a clinical effect on Vital Capacity, an objective respiratory measure that correlates with mortality in patients with ALS Transposon plans to advance TPN-101 to a Phase 3 registration study for PSP and is expanding the development of TPN-101 into Alzheimer's disease SAN DIEGO, Feb. 12, 2024 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases including Alzheimer's disease, today announced final results from its Phase 2 study of TPN-101 for the treatment of progressive supranuclear palsy (PSP). The company also announced interim results from its Phase 2 study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD). Transposon will present final results from its Phase 2 study in PSP in a poster presentation at the hybrid AD/PD™ 2024: 18th International Conference on Alzheimer's and Parkinson's Diseases. The meeting will take place online and in Lisbon, Portugal, from March 5-9, 2024. Final Phase 2 PSP Study Results Final 48-week results from the Phase 2 study in PSP confirm and extend the 24-week interim results that showed TPN-101 is the first treatment for PSP to reduce levels of neurofilament light chain (NfL), a key biomarker of neurodegeneration in tauopathies such as PSP and Alzheimer's disease. Participants treated with placebo from weeks 1 to 24 and then switched to 400 mg TPN-101 at week 24 experienced a reduction of NfL in the cerebrospinal fluid (CSF) from weeks 24 to 48 that was similar to that observed in the group of participants receiving the 400 mg dose from weeks 1 to 24. Participants treated with 400 mg TPN-101 for the entire 48-week treatment period showed no increase of NfL levels in the CSF from weeks 1 to 48. In contrast, NfL levels in the CSF are reported to increase by 9-18% annually in natural history studies of PSP. The 48-week results also showed further dose-related reductions in interleukin 6 (IL-6) cytokine levels, as well as reductions in levels of osteopontin. IL-6 is a biomarker of neuroinflammation that is elevated in PSP and correlates with disease progression and severity. Osteopontin levels correlate with cognitive deficit in Alzheimer's disease patients and lowering of osteopontin may predict cognitive improvement. Participants treated with TPN-101 for the entire 48-week trial duration showed a stabilization of their clinical symptoms as measured by the PSP Rating Scale (PSPRS) between weeks 24 and 48. In contrast, participants who had been on placebo from weeks 1 to 24 continued to show a worsening of the PSPRS between weeks 24 and 48, suggesting a delay of clinical benefit onset of at least 24 weeks after start of drug treatment, and lagging behind the early effects on biomarkers seen in weeks 1 to 24. "There are no effective treatments for PSP, a uniformly fatal disease that is similarly prevalent to ALS," said Adam Boxer, M.D., Ph.D., Endowed Professor in Memory and Aging in the Department of Neurology at the University of California, San Francisco and principal investigator in the Phase 2 study of TPN-101 for PSP. "The effects of TPN-101 on CSF NfL concentrations, as well as other exploratory CSF biomarkers, have not previously been observed in any PSP trial and support further investigation of clinical treatment effects in a larger study." Interim Phase 2 C9orf72-Related ALS/FTD Study Results Results from the pre-defined interim analysis of the Phase 2 study in C9orf72-related ALS/FTD demonstrated the impact of TPN-101 treatment on key biomarkers of neurodegeneration, neuroinflammation, and microglial activation including NfL, tau, UCHL1, YKL-40, and osteopontin from baseline to 24 weeks. The data also showed a clinical effect on Vital Capacity, an objective respiratory measure that correlates with mortality in patients with ALS. Notably, C9orf72-related ALS/FTD is a TDP-43 protein pathology associated with nuclear displacement of TDP-43 in the central nervous system. TDP-43 pathology also occurs in about 50% of patients with Alzheimer's disease. "Transposon's founding mission was to establish human proof-of-concept that dysregulation of retrotransposable elements in neurodegenerative diseases such as PSP, ALS and Alzheimer's disease can be addressed with a new class of LINE-1 reverse transcriptase inhibitors," stated Eckard Weber, M.D., Founder and Chief Innovation Officer of Transposon. "The results obtained with TPN-101 in both PSP and ALS/FTD show for the first time that neurodegenerative diseases that involve LINE-1 dysregulation are treatable with a specific inhibitor of this important novel target. We look forward to advancing the development of TPN-101 into registration studies to address this devastating and rapidly growing disease category." "Given the large unmet needs in PSP and ALS, these promising results highlight the therapeutic potential of TPN-101 for both disorders," added Murali Doraiswamy, MBBS, FRCP, Professor of Psychiatry and Geriatrics at Duke University and chair of Transposon's clinical advisory board. "These data also provide key validation of targeting LINE-1 to treat other tauopathies such as Alzheimer's disease." "Based on the groundbreaking study results shown by TPN-101 in both PSP and ALS/FTD, we plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of PSP, and potentially ALS/FTD as well, pending final confirmatory study results," said Dennis Podlesak, Chairman and Chief Executive Officer of Transposon. "Importantly, the totality of the results across both studies also provides compelling scientific rationale for targeting LINE-1 to treat Alzheimer's disease. Based on these findings, we are expanding our development efforts into Alzheimer's disease with the goal of bringing a novel drug treatment to patients that remain in dire need of an effective new therapeutic option." About AD/PD 2024 The hybrid AD/PD 2024: 18th International Conference on Alzheimer's and Parkinson's Diseases will take place online and in Lisbon, Portugal, from March 5-9, 2024. Transposon will present final results from its Phase 2 study in PSP in a poster presentation (abstract #433) at AD/PD 2024 entitled: "A Phase 2a Study of TPN-101, a Nucleoside Reverse Transcriptase Inhibitor, in Patients with Progressive Supranuclear Palsy." For more information, please visit the AD/PD 2024 website. About the Phase 2 Study in PSP The Phase 2 study in PSP is a multi-center, randomized, double-blind, placebo-controlled, parallel-group, 4-arm study with an open-label treatment phase in patients with PSP. Participants (n=42) were randomized to receive daily doses of 100 mg, 200 mg or 400 mg of TPN-101, or placebo. The study includes a 6-week screening period, a 24-week double-blind treatment period, a 24-week open label treatment period, and a follow-up visit 4 weeks post-treatment. All phases of the study, including the 24-week open label treatment period, have been completed. Further information on the study can be accessed at ClinicalTrials.gov. About the Phase 2 Study in C9orf72-related ALS/FTD The Phase 2 study in C9orf72-related ALS/FTD is multi-center, randomized, double-blind, placebo-controlled parallel-group, 2-arm study with an open-label treatment phase in patients with C9orf72-related ALS and/or FTD. Participants (n=42) were randomized to receive daily doses of 400 mg of TPN-101 or placebo. Similar to the Phase 2 study in PSP, this study includes a 6-week screening period, a 24-week double-blind treatment period, a 24-week open-label treatment period, and a follow-up visit 4 weeks post-treatment. The predefined interim analysis was performed after all patients completed the 24-week double-blind portion of the study. The open-label extension of the study is ongoing, with subjects and investigators blinded to the original treatment assignment. Further information on the study can be accessed at ClinicalTrials.gov. About TPN-101 TPN-101 specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication. LINE-1 elements are a class of retrotransposable elements that in humans are uniquely capable of replicating and moving to new locations within the genome. When this process becomes dysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 DNA, triggering innate immune responses that contribute to neurodegenerative, autoimmune and aging-related disease pathology. About PSP PSP is a rare and fatal tauopathy with no approved treatment options. PSP mainly affects people in their mid- to late-60s and is characterized by early postural instability and falls, vertical gaze palsy, akinesia, rigidity, pseudobulbar palsy, and frontal dysfunction with cognitive and behavioral changes. The mean survival for individuals with PSP is 6 to 7 years. About ALS and FTD ALS is a neurodegenerative disease characterized by progressive muscle weakness, loss of ability to speak, eat, move or breathe. FTD is a progressive frontal / temporal cortex disease associated with behavior and personality changes, emotional problems, and difficulty walking, communicating or working. With onset commonly in middle age or earlier, patients with ALS have a mean survival of only 3 years. Patients with FTD have a mean survival of 9 years. About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. Dr. Doraiswamy chairs the company's clinical advisory board and has received compensation/stock options for his role. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 rorr@transposonrx.com View original content to download multimedia: SOURCE Transposon Therapeutics

AcuraStem Leverages iNeuroRx® Platform to Drive Innovative SYF2 and UNC13A Treatments Forward Toward Clinical Trials PASADENA, Calif., Jan. 30, 2024 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company advancing treatments for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, announced today that it has successfully raised nearly $7 million in grant funding for ALS / FTD research from the National Institutes of Health (NIH) and the Department of Defense (DOD). This latest achievement—building upon the recent licensing agreement with Takeda worth $580 million to develop and commercialize AcuraStem's PIKFYVE targeted therapeutics including AS-202—enables the company to advance multiple programs towards clinical trials. "We are thrilled to receive continued support from NIH and the DOD," said Sam Alworth, MS, MBA, AcuraStem co-founder and CEO. "Leaders from the scientific community selected AcuraStem for these awards through a rigorous peer-review process, which demonstrates the excellence of our research." AcuraStem has made a significant advancement in understanding the pathophysiology of ALS, focusing on the crucial role of UNC13A. An overwhelming majority of ALS cases, and roughly half of FTD cases, are characterized by TDP-43 pathology. TDP-43, a RNA-binding protein typically found in the nucleus, is mislocalized to the cytoplasm in affected neurons, leading to RNA processing errors. These errors result in the incorporation of a cryptic exon into the UNC13A messenger RNA, causing a loss of UNC13A protein. This loss is further exacerbated by a risk variant in the UNC13A gene, closely linked to the TDP-43 binding site and associated with reduced survival in ALS and FTD patients. AcuraStem's iNeuroRx® platform has successfully replicated UNC13A pathology in patient neurons, enabling the rapid development and testing of antisense oligonucleotides (ASOs). These ASOs effectively suppress the cryptic exon and restore normal UNC13A function, offering a promising therapeutic approach for TDP-43 proteinopathies and a deeper understanding of UNC13A's role in disease progression. Additionally, AcuraStem has made a pivotal discovery with its focus on SYF2, a novel target in TDP-43 pathology. In collaboration with co-founder Dr. Justin Ichida's lab at USC, AcuraStem's extensive research on patient neurons via the iNeuroRx® platform, coupled with a comprehensive bioinformatic analysis, identified SYF2 as a key therapeutic target. SYF2, a pre-mRNA splicing factor, plays a crucial role in the regulation of splicing affected by the depletion of nuclear TDP-43, a common feature in most ALS cases (Linares GR et al Cell Stem Cell 2023). AcuraStem's findings highlight that SYF2 can address both the toxic aggregation of TDP-43 in cytoplasm and also counter the widespread gene dysregulation, including critical genes like UNC13A and STMN2, caused by TDP-43's absence from the nucleus. Targeting SYF2 could offer a more direct and potentially effective therapeutic strategy compared to addressing each dysregulated gene individually. Funding from NIH and the DOD was awarded through rigorous peer-reviewed processes, suggesting the award matches the health-related missions established by each agency. For additional information, please visit AcuraStem at acurastem.com and follow on LinkedIn, Facebook and X. Disclaimer This project will be supported by an NIH grant (R44AG085411). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, or the U.S. Army Medical Research Acquisition Activity at the U.S. Army Medical Research and Development Command, in the amount of $839,898.40 through the ALSRP under Award No. HT9425-23-1-0469. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Muscular Dystrophy Association, Department of Defense and the National Institute of Neurological Disorders and Stroke. Contact: Kissy Black [email protected] 615.310.1894 SOURCE AcuraStem - Patient-Based Therapeutics

Agreement enables the development of therapeutics, including AcuraStem's AS-202 Candidate, an antisense oligonucleotide that suppresses levels of the PIKFYVE kinase MONROVIA, Calif., Sept. 25, 2023 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company pioneering how treatments are developed for neurodegenerative diseases, announced today that it has entered into a license agreement with Takeda to develop and commercialize AcuraStem's PIKFYVE targeted therapeutics including AS-202, an innovative antisense oligonucleotide (ASO) for the treatment of Amyotrophic Lateral Sclerosis (ALS). Continue Reading PIKFYVE is a novel therapeutic target for ALS and may also be relevant for treating additional TDP-43 proteinopathies such as Frontotemporal Dementia (FTD). AcuraStem's therapeutic strategy for PIKFYVE focuses on addressing neurodegeneration by expelling toxic protein aggregates and protecting healthy neuronal function. "We are delighted to have secured a partner in Takeda...to deliver on our mission," Sam Alworth, AcuraStem CEO. Tweet this This novel therapeutic mechanism was initially discovered at the lab of AcuraStem's co-founder, Justin Ichida, PhD, using patient-derived disease models, is exclusively licensed to AcuraStem by the USC Stevens Center for Innovation, and was further developed on AcuraStem's iNeuroRx® disease modeling platform (Shi Y et al Nat Med 2018, Hung S-T et al Cell 2023). The AcuraStem researchers further demonstrated that ASO-mediated suppression of PIKFYVE can restore motor function, reduce neurodegeneration, and improve survival in multiple in vivo models of both ALS and FTD. Under the terms of the agreement, Takeda will receive an exclusive, worldwide license to AcuraStem's PIKFYVE program. AcuraStem will receive an upfront and milestone payments totaling up to approximately $580 million if all future clinical, regulatory, and commercial milestones are achieved during the term of the agreement plus tiered royalties on potential net sales of any commercial products resulting from this license. "Our mission at AcuraStem is to get our promising therapeutics to the patients who need them as quickly as possible," said Sam Alworth, MS, MBA, CEO of AcuraStem. "We are delighted to have secured a partner in Takeda who has the world class clinical development and commercial capabilities to deliver on our mission." AcuraStem will be responsible for certain activities to help advance AS-202 IND enabling studies and characterizing potential backup ASOs. Takeda will be responsible for all other development activities including clinical development, regulatory affairs, and global commercialization. "We aim to develop transformative treatments for some of society's most debilitating neurological diseases including ALS. Whilst recent treatment advances have brought new hope to some patients, there remains a significant unmet need," said Sarah Sheikh, BM BCh, MSc, MRCP, Head, Neuroscience Therapeutic Area Unit at Takeda. "We believe AS-202 has the potential to address this unmet need through its unique dual mechanism of action, which addresses TDP-43 aggregation and improves TDP-43 function, the pathological hallmark of ALS and other TDP-43 proteinopathies including certain forms of dementia. We look forward to building on AcuraStem's work to progress this exciting science into development and to patients." AcuraStem, co-founded by Alworth, Ichida, Paul August, PhD, and Qing Liu, PhD, in 2016, remains committed to continually improving its patient-based iNeuroRx® technology platform, discovering ever more effective therapeutic approaches across neurodegenerative indications, and rapidly advancing its therapeutic programs to patients including its existing SYF2 and UNC13A programs for ALS and FTD. "I'm very pleased that AcuraStem is partnering with Takeda around their PIKFYVE program," said Justin Ichida, PhD. "We originally identified PIKFYVE as a novel therapeutic target for ALS using nerve cells derived from patient stem cells, and this illustrates the power of using this modern approach. I am grateful for the funding and help we received from philanthropic and government agencies that enabled us to better understand the therapeutic potential of targeting PIKFYVE. AcuraStem has done an outstanding job of generating best-in-class molecules to target PIKFYVE in humans, and I am excited to see this move forward." Destum Partners acted as transaction advisor to AcuraStem, and Foley Hoag acted as legal counsel to AcuraStem. For more information about AcuraStem and their iNeuroRx® platform go to acurastem.com. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Department of Defense and the National Institute of Neurological Disorders and Stroke. About AS-202 AcuraStem identified clinical candidate AS-202 through screening on its iNeuroRx® patient-based technology platform. AS-202 is an intrathecally delivered ASO that potently suppresses PIKFYVE in the central nervous system and addresses neurodegeneration by expelling toxic protein aggregates and restoring healthy neuronal function in in vivo preclinical models. Contact: Kissy Black Director of Communications, AcuraStem [email protected] 615.310.1894 SOURCE AcuraStem - Patient-Based Therapeutics