阿茲海默症治療大盤點 143種藥物172項臨床試驗開發中

撰文記者 劉馨香
日期2022-09-04
圖:取自研究
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