TPN-101

▎药明康德内容团队编辑今日，Transposon Therapeutics公布其在研逆转录酶抑制剂TPN-101治疗进行性核上性麻痹（PSP）患者临床2期研究的最终结果。Transposon同时公布TPN-101用于治疗肌萎缩侧索硬化（ALS）和/或额颞叶痴呆（FTD）患者2期试验的中期结果，这些患者的C9orf72基因具有六核苷酸重复扩增（C9orf72相关的ALS/FTD）。分析显示，TPN-101能够稳定PSP患者的临床症状。根据新闻稿，该药物是首个降低关键生物标志物神经丝轻链（NfL）和白细胞介素-6（IL-6）水平的PSP治疗药物。TPN-101亦显示改善ALS患者的肺活量。根据这些积极结果，Transposon计划将TPN-101推进到PSP的3期试验，并将TPN-101的临床开发扩展到阿尔茨海默病。PSP临床2期试验的最终结果该试验的最终48周结果与之前所公布的24周中期结果一致，从第1周到第24周接受安慰剂治疗，然后在第24周改用400 mg TPN-101的受试者，从第24周到第48周，脑脊液（CSF）中的NfL减少，这与从第1周到第24周接受TPN-101治疗受试者所显示的结果相似。而在整个48周治疗期间，全程接受400 mg TPN-101治疗的受试者，其从第1周到第48周的脑脊液NfL水平没有增加。相比之下，PSP自然历史对照患者脑脊液中的NfL水平每年增加9-18%。此外，48周的结果还显示，IL-6细胞因子以及骨桥蛋白（osteopontin）水平进一步降低，并呈现剂量相关性。采用PSP评定量表（PSPRS）进行评估的结果显示，在为期48周的试验中，接受TPN-101治疗的受试者在第24周至第48周期间的临床症状稳定性得到了维持。与此相对，初期使用安慰剂（第1周至第24周）的受试者在第24周至第48周期间PSPRS评分持续下降，说明TPN-101的治疗效果至少延迟了24周，并且落后所见的生物标志物早期效果。C9orf72相关ALS/FTD中期2期试验结果该2期试验的预定中期分析结果显示，从基线到24周，TPN-101治疗影响神经变性、神经炎症和小胶质细胞激活的关键生物标志物，包括NfL、tau、UCHL1、YKL-40、和骨桥蛋白。数据还显示TPN-101可能改善患者的肺活量，肺活量是一种与ALS患者死亡率相关的客观呼吸测量指标。值得注意的是，C9orf72相关的ALS/FTD是一种与中枢神经系统中TDP-43蛋白核移位相关的疾病。TDP-43相关病变也发生在大约50%的阿尔茨海默病患者中。▲Transposon管线图（图片来源：Transposon Therapeutics公司官网） TPN-101（censavudine）是一款潜在“first-in-class”、每日一次的口服LINE-1逆转录酶抑制剂，用于治疗神经退行性疾病和自身免疫性疾病。在一项对220多名艾滋病患者进行的为期48周的研究中，TPN-101显示具有良好的耐受性。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Transposon Announces Final Results from a Phase 2 Study of its LINE-1 Reverse Transcriptase Inhibitor TPN-101 for the Treatment of Progressive Supranuclear Palsy and Interim Results from a Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia. Retrieved February 13, 2024 from https://www.prnewswire.com/news-releases/transposon-announces-final-results-from-a-phase-2-study-of-its-line-1-reverse-transcriptase-inhibitor-tpn-101-for-the-treatment-of-progressive-supranuclear-palsy-and-interim-results-from-a-phase-2-study-of-tpn-101-for-the-treatmen-302060254.html免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

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