For Chinese translation click here
点击此处查看中文翻译
TauRx Therapeutics Management Ltd today announced results from its Phase III LUCIDITY trial evaluating the efficacy and safety of hydromethylthionine mesylate (HMTM) in the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) have been published in The Journal of Prevention of Alzheimer's Disease.
The trial reports that participants with MCI who received HMTM 16 mg/day experienced statistically significant cognitive improvement over 18 months, with no significant cognitive or functional decline observed over a period of two years.
Professor Claude Wischik, TauRx Co-Founder and Chairman, who is lead author of the paper, said: “These results show HMTM has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient or physician burden.
“The study also found starting HMTM treatment early in the disease process is important for preservation of cognitive function and that it impacts the underlying disease process in AD.
“This study confirms results from earlier trials showing that HMTM has a benign safety profile, with headache (1.5%) and diarrhoea (1.2%) reported as the most frequent adverse effects.”
The trial evaluated the safety and efficacy of HMTM in 598 participants with MCI and mild to moderate dementia due to Alzheimer’s disease (AD). All participants were amyloid β-PET positive, with 44% (263) meeting the clinical criteria for MCI due to Alzheimer’s disease, and 56% (335) diagnosed with mild to moderate dementia due to AD.
The paper, entitled Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer’s disease, reports on the trial which was conducted at 82 sites across Canada, the European Union, United Kingdom, and United States.
It compared 16 mg/day and 8 mg/day doses of HMTM with 4 mg twice weekly doses of methylthioninium chloride (MTC). MTC was required as a urinary colourant to preserve blinding due to possible urinary discolouration caused by HMTM.
In the trial, HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all patients receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Unexpected initial symptomatic activity in the MTC arm interfered with the intended primary outcome analyses at 52 weeks, but not with longer-term outcomes in participants with MCI.
MCI participants receiving HMTM 16 mg/day showed statistically significant differences in cognitive decline (ADAS-cog13) at 78 weeks and 104 weeks in analyses specified prior to the 104-week database lock. Those starting HMTM 16 mg/day after a 52-week delay could not catch up with those starting earlier due to ongoing neurodegeneration during the first 52 weeks in those receiving MTC.
The benefit of HMTM 16 mg/day has been confirmed in a further study utilising closely matched external placebo arm cases from a well-documented trial database to provide true placebo controls not confounded by the blinding problem.
In the early start MCI group receiving HMTM 16 mg/day, statistically significant cognitive improvement over baseline score was sustained for 78 weeks, with no significant cognitive or functional decline over 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change in blood at 52 weeks in both the whole and MCI populations. This was consistent with significant reductions in progression of brain atrophy in scans at 52 and 104 weeks, and a reduction in progression of tau pathology (measured by pTau217 change in blood) in MCI.
The study confirms the results from earlier trials showing that HMTM has a benign safety profile, with headache (1.5%) and diarrhoea (1.2%) reported as the most frequent adverse effects at the 16 mg/day dose.
HMTM is an investigational drug and a Marketing Authorisation Application from TauRx Therapeutics Management Ltd is currently being evaluated by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
《阿尔茨海默病预防杂志》刊发临床试验成果：口服药物HMTM或为早期阿尔茨海默病患者提供治疗新选择
TauRx Therapeutics Management Ltd（以下简称“TauRx公司”）今日宣布，其针对甲磺酸氢甲硫堇（HMTM）用于治疗阿尔茨海默病源性轻度认知障碍的有效性与安全性的LUCIDITY III期临床试验结果，已在国际学术期刊《阿尔茨海默病预防杂志》正式发表。
试验数据显示，每日服用16毫克HMTM的轻度认知障碍受试者，在18个月内认知功能获得统计学意义的显著改善，并在为期两年的观察期内未出现明显的认知或功能衰退。
该论文第一作者、TauRx公司联合创始人兼董事会主席Claude Wischik教授表示：“该结果表明，HMTM有望成为一种安全性良好、口服便利、对医患双方负担较小的治疗选择。研究还发现，在疾病早期阶段启动HMTM治疗对维持认知功能至关重要，且该疗法能够干预阿尔茨海默病的潜在病理进程。本次试验也再次验证了HMTM良好的安全性特征，最常见的不良反应为头痛（1.5%）和腹泻（1.2%）。”
本项III期临床试验共纳入598名β-淀粉样蛋白PET检测呈阳性的受试者，其中包括263例（44%）符合阿尔茨海默病源性轻度认知障碍临床标准的患者，以及335例（56%）被诊断为阿尔茨海默病源性轻度至中度痴呆的患者。试验在加拿大、欧盟、英国和美国的82个临床中心开展。
研究采用了改良的延迟启动设计：前52周比较每日16毫克或8毫克HMTM与每周两次、每次4毫克的氯化甲硫堇（MTC）的疗效与安全性；之后所有受试者均转为每日16毫克HMTM治疗，直至104周。MTC在此设计中作为维持双盲的尿路染色对照剂。
尽管MTC组在前52周出现非预期的症状改善，对预设的主要终点分析造成干扰，但这并未影响对轻度认知障碍人群的长期疗效评估。
根据104周数据库锁定前预设的分析方案，每日服用16毫克HMTM的轻度认知障碍受试者，在第78周和第104周通过ADAS-cog13量表评估的认知衰退情况，均显示出统计学显著差异。延迟52周启动每日16毫克MTC治疗的受试者，因其对照组在前52周已发生持续的神经退行性变化，认知水平未能追赶上早期治疗组。
每日16毫克HMTM的疗效进一步通过一项外部对照研究得到验证。该研究采用来自完善临床试验数据库、经高度匹配的外部安慰剂组数据作为对照，提供了不受原试验双盲设计干扰的真实世界安慰剂比较结果。
在早期启动治疗的轻度认知障碍组中，每日16毫克HMTM治疗带来的认知功能改善（相对于基线）可持续至78周，且在104周内未出现显著的认知或功能衰退。全人群及轻度认知障碍人群的血液神经丝轻链蛋白（NFL）水平变化均显示，第52周时神经退行性病变进展显著减缓。这一结果与第52周及104周影像学检查中观察到的脑萎缩延缓，以及轻度认知障碍患者血液磷酸化Tau217蛋白水平变化所提示的Tau病理进展减缓相一致。
本研究再次证实HMTM安全性良好，每日16毫克剂量下最常见的不良反应为头痛（1.5%）和腹泻（1.2%）。
目前，HMTM仍处于临床研究阶段，尚未获批上市。TauRx公司已向英国药品和健康产品管理局提交上市许可申请，相关评审工作正在进行中。
