阿茲海默症是全球性的健康危機，卻也是藥物開發領域中難以攻克的領域。根據美國阿茲海默症協會(Alzheimer’s Association, AA)，分析全球臨床試驗資料庫ClinicalTrials.gov在2022年1月25日之資料，開發中的阿茲海默症藥物共有143種，分布於172項臨床試驗。

就藥物的目標分類，疾病緩解治療(Disease-modifying therapy, DMT)占大多數(83.2%)，其餘則是針對症狀的治療，包括認知增強治療(9.8)和神經精神病學治療(6.9%)。在疾病緩解治療中，有34%為生物製劑，66%為小分子藥物。

其中，有37%的藥物是已批准用於其他適應症的老藥新用。

所有臨床試驗中，有50%為生物製藥公司贊助，而臨床三期試驗的比例則來到68%。若全部的臨床試驗都招募到足夠的受試者，總共會有5萬人參與。

在臨床三期試驗階段，共有31個藥物和47項試驗；在臨床二期試驗階段，共有82個藥物和94項試驗；在臨床一期試驗階段，共有30個藥物和31項試驗。以下分別就臨床一、二、三期簡述代表性的藥物。


圖片來源：https://doi.org/10.1002/trc2.12295
 

臨床三期試驗

除了已獲得批准但極具爭議的Aduhelm (aducanumab)，百健(Biogen)和衛采(Eisai)共同研發的另一款藥物lecanemab，以及羅氏(Roche)子公司基因泰克(Genentech)的gantenerumab，和禮來(Eli Lilly)的donanemab，這三種藥物都是針對大腦中澱粉樣蛋白(Aβ)斑塊的單株抗體，預計在明年發布關鍵的臨床數據。

來自諾和諾德(Novo Nordisk)的第二型糖尿病藥物和減重藥物semaglutide，為GLP-1促效劑，則希望藉由改善神經細胞、發炎和血管健康，從而減緩阿茲海默症疾病的進展。Semaglutide有兩項三期研究，預計於2026年4月完成。

值得注意的還有Cassava Sciences的simufilam，該公司受到指控在早期的臨床前研究中操縱數據，調查過程還因此衍生案外案，一篇受引用超過兩千次的2006年《Nature》論文，遭踢爆疑似造假的醜聞。目前simufilam有兩項三期研究正在進行中，預計完成日期為2023年10月和2024年6月。

Quince Therapeutics (先前名為Cortexyme)的atuzaginstat，旨在減少牙齦卟啉單胞菌(Porphyromonas gingivalis)感染，該菌被認為與認知能力下降有關。然而，該療法的未來仍懸而未決，因為Atuzaginstat在2021年11月未達成一項臨床2/3期研究的主要終點，又在今年1月底被FDA臨床擱置；Cortexyme在更名為Quince後，該公司正在四處尋求收購或對外授權其神經科學和抗病毒資產。
 

臨床二期試驗

比利時跨國藥廠優時比(UCB Pharma)的bepranemab，針對的是另一種在大腦中積聚和纏結的蛋白質—tau蛋白，目前正在進行臨床二期試驗，治療患有輕度認知功能障礙(MCI)或輕度阿茲海默症的患者。

瑞士藥廠AC Immune和楊森(Janssen)同樣也在tau上押注了一些籌碼，雙方共同開發的阿茲海默症疫苗ACI-35，誘導免疫系統產生攻擊tau蛋白的抗體，其二期試驗預計在2023年10月完成。

Athira Pharma的fosgonimeton則是一種肝臟生長因子受體促效劑，在6月公布的二期試驗結果中，在主要試驗終點失敗，未能提高工作記憶和記憶處理速度。儘管如此，Athira仍指出該研究的亞組分析結果「非常令人鼓舞」，預計將據此調整臨床三期試驗的設計。
 

臨床一期試驗

禮來的Remternetug (LY3372993)為donanemab的後續產品，禮來稱為「次世代抗澱粉樣蛋白抗體」，預計於明年9月完成第一期臨床試驗。

乘著百健/衛采的Aduhelm在2021年6月獲得批准的浪潮，Acumen Pharmaceuticals在當時IPO籌集了1.6億美元，用於推動ACU193的臨床試驗。該藥物最初由Acumen與默沙東(MSD)在2003年到2011年間共同開發，為針對Aβ寡聚體的單株抗體。

參考資料：https://www.fiercebiotech.com/biotech/beyond-headlines-and-amyloid-alzheimers-pipeline-chugs-along
研究：
https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12295?af=R

(編譯/劉馨香)

【臨床三期試驗列表】

Agent	Sponsor	CADRO mechanism class	Mechanism of action	Therapeutic purpose	Estimated end date
Aducanumab	Biogen	Amyloid	Monoclonal antibody directed at Aβ plaques and oligomers	DMT	2023/10/1
AGB101 (low-dose levetiracetam)	AgeneBio, NIA	Synaptic Plasticity/Neuroprotection	SV2A modulator; to reduce Aβ-induced neuronal hyperactivity	DMT	2022/12/1
Atuzaginstat (COR388)	Cortexyme	Synaptic Plasticity/Neuroprotection	Bacterial protease inhibitor targeting gingipain produced by P. gingivalis to reduce neuroinflammation and hippocampal degeneration	DMT	2022/12/1
AVP-786	Avanir	Neurotransmitter receptors	Sigma 1 receptor agonist; NMDA receptor antagonist	Neuropsychiatric symptoms agent (agitation)	2022/7/1
	Avanir				2023/10/1
	Avanir				2024/12/1
	Avanir				2024/12/1
AXS-05	Axsome therapeutics	Neurotransmitter receptors	NMDA receptor antagonist; combination of dextromethorphan and bupropion	Neuropsychiatric symptoms agent (agitation)	2022/12/1
	Axsome therapeutics				2023/6/1
Blarcamesine (ANAVEX2-73)	Anavex life sciences	Synaptic plasticity/neuroprotection	Sigma-1 receptor agonist, M2 autoreceptor antagonist; to ameliorate oxidative stress, protein misfolding, mitochondrial dysfunction, and inflammation	DMT	2022/6/1
	Anavex life sciences				2024/6/1
BPDO-1603	Hyundai pharmaceutical	Undisclosed	Undisclosed	Cognitive enhancer	2023/3/1
Brexpiprazole	Otsuka	Neurotransmitter receptors	Atypical antipsychotic; D2 receptor partial agonist; serotonin-dopamine modulator	Neuropsychiatric symptoms agent (agitation)	2022/8/1
	Otsuka				2022/7/1
	Otsuka				2022/4/1
Caffeine	University Hospital, Lille	Neurotransmitter receptors	Adenosine antagonist; non-specific phosphodiesterase inhibitor	Cognitive enhancer	2024/11/1
Donanemab	Eli Lilly	Amyloid	Monoclonal antibody specific for pyroglutamate form of Aβ	DMT	2025/8/1
	Eli Lilly				2027/11/1
Donanemab & Aducanumab	Eli Lilly	Amyloid	Monoclonal antibody specific for pyroglutamate form of Aβ (donanemab); monoclonal antibody directed at plaques and oligomers (aducanumab); given in separate arms of the trial	DMT	2023/6/1
Donepezil	Assistance Publique – Hôpitaux de Paris	Neurotransmitter receptors	Acetylcholinesterase inhibitor	Cognitive enhancer	2024/7/1
Escitalopram	Johns Hopkins University, NIA	Neurotransmitter receptors	Selective serotonin reuptake inhibitor	Neuropsychiatric symptoms agent (agitation)	2022/8/1
Gantenerumab	Roche	Amyloid	Monoclonal antibody directed at Aβ plaques and oligomers	DMT	2026/10/1
	Roche				2023/8/1
	Roche				2023/4/1
	Roche				2024/12/1
Gantenerumab & Solanezumab	Washington University, Eli Lilly, Roche, NIA, Alzheimer's Association	Amyloid	Monoclonal antibody directed at Aβ plaques and oligomers (gantenerumab); Monoclonal antibody directed at Aβ monomers (solanezumab); given in separate arms of the trial	DMT	2022/7/1
Guanfacine	Imperial College London, UK National Institute of Health Research	Neurotransmitter receptors	Alpha-2 adrenergic agonist	Cognitive enhancer	2022/12/1
GV-971	Shanghai Greenvalley	Gut-brain axis	Algae-derived acidic oligosaccharides; changes microbiome to reduce peripheral and central inflammation	DMT	2026/10/1
Hydralazine	Shahid Sadoughi University, Iran	Oxidative stress	Free radical scavenger	DMT	2023/12/1
Icosapent ethyl (IPE)	VA Office of Research and Development, University of Wisconsin, Madison	Oxidative stress	Purified form of the omega-3 fatty acid EPA; to improve synaptic function and reduce inflammation	DMT	2023/1/1
Lecanemab (BAN2401)	Eisai, Biogen	Amyloid	Monoclonal antibody directed at Aβ protofibrils	DMT	2024/8/1
	Eisai, Biogen, ACTC, NIA				2027/10/1
Losartan & Amlodipine & Atorvastatin + exercise	University of Texas Southwestern	Vasculature	Angiotensin II receptor blocker (losartan), calcium channel blocker (amlodipine), cholesterol agent (atorvastatin)	DMT	2022/1/1
Metformin	Columbia University, NIA	Metabolism and bioenergetics	Insulin sensitizer to improve CNS glucose metabolism	DMT	2025/4/1
Nabilone	Sunnybrook Health Sciences Center, ADDF	Neurotransmitter receptors	Synthetic cannabinoid	Neuropsychiatric symptoms agent (agitation)	2025/10/1
NE3107	Neurmedix	Inflammation	MAPK-1/3 inhibitor; reduces proinflammatory NFκB activation	DMT	2023/1/1
Nilotinib BE	KeifeRx	Proteostasis/Proteinopathies	Tyrosine kinase inhibitor; autophagy enhancer; promotes clearance of Aβ and tau	DMT	2026/6/1
Octohydro-aminoacridine Succinate	Shanghai Mental Health Center	Neurotransmitter receptors	Acetylcholinesterase inhibitor	Cognitive enhancer	2021/2/1
Omega-3 (DHA+EPA)	University Hospital, Toulouse	Oxidative stress	Antioxidant	DMT	2023/12/1
Semaglutide	Novo Nordisk	Metabolism and bioenergetics	GLP-1 agonist; reduces neuroinflammation and improves insulin signaling in the brain	DMT	2026/4/1
	Novo Nordisk				2026/4/1
Simufilam (PTI-125)	Cassava sciences	Synaptic Plasticity/Neuroprotection	Filamin A protein inhibitor; stabilizes amyloid-alpha-7 nicotinic receptor interaction	DMT	2023/10/1
	Cassava sciences				2024/6/1
Solanezumab	Eli Lilly, ATRI	Amyloid	Monoclonal antibody directed at Aβ monomers	DMT	2023/6/1
Tricaprilin	Cerecin	Metabolism and bioenergetics	Caprylic triglyceride; induces ketosis and improves mitochondrial and neuronal function	DMT	2024/2/1
TRx0237	TauRx Therapeutics	Tau	Tau protein aggregation inhibitor	DMT	2023/3/1
Valiltramiprosate (ALZ-801)	Alzheon, NIA	Amyloid	Prodrug of tramiprosate; inhibits Aβ aggregation into toxic oligomers	DMT	2024/5/1