On January 7, Pfizer announced that it would stop development of all current new drugs for Alzheimer’s disease and Parkinson's disease, and lay off 300 employees in the next months.
On January 9, Takeda Pharmaceutical announced that it reached strategic cooperation with Denali, to jointly develop therapies for neurodegenerative diseases, with the total amount to exceed USD 1 billion, including 2 Alzheimer’s disease projects.
On January 10, Xinhua Pharmaceutical announced that it entered into the contract for "development of the innovative drug OAB-14 and preparations for Alzheimer’s disease" with Shenyang Pharmaceutical University, and would pay RMB 100 million for the development of Alzheimer’s disease drugs.
The pharmaceutical giants that entered early in the field have suffered R&D setbacks and quit, but this does not stop other companies from continuing to seek the light of victory.
Introduction
Alzheimer’s disease (AD) is a serious neurodegenerative disease. AD patients are forecast to reach above 115 million by 2050, with the resulting direct social costs second only to cancer treatment. There are only a few AD drugs available clinically. In the face of such huge market demands, pharmaceutical enterprises have been highly enthusiastic about R&D of new drugs for AD, however, the unknown pathogenesis and the disease characteristics lead to new drug R&D failure rate of up to 99%, and the field becomes the hardest-hit area to new drug R&D.
Pharmaceutical enterprises have made great efforts in developing new drugs for AD, however, there have been hundreds of compounds entering the clinical trials over the 15 years after the U.S. FDA approved memantine for AD in 2003, but none of them is approved for marketing, and even many drugs with immense potential suffered crushing defeats in Phase III clinical trials due to serious adverse reactions or insufficient treatment effectiveness. The new drug R&D for AD are highly challenging.
Lucky stars of patients—the approved AD drugs
The AD drugs currently approved include many acetylcholinesterase inhibitors and the memantine that affects the glutamatergic system, which can alleviate some symptoms of AD by strengthening cholinergic signal transduction and improving acetylcholine level, but cannot completely cure the disease or contain the dementia progression.
Drugs Approved for AD Treatment
|
Pharmaceutical product name
|
Type of action
|
Indication
|
Approval time
|
|
Memantine
|
N-methyl D-aspartate (NMDA) receptor antagonist
|
Moderate to severe AD
|
October 16, 2003
|
|
Tacrine
|
Acetylcholinesterase inhibitor
|
Moderate to severe AD
|
September 9, 1993
(Removed from market due to severe hepatotoxicity)
|
|
Rivastigmine
|
Acetylcholinesterase inhibitor
|
Mild to moderate AD/PD
|
April 21, 2000
|
|
Galanthamine
|
Acetylcholinesterase inhibitor
|
Moderate to severe AD
|
February 28, 2001
|
|
Donepezil
|
Acetylcholinesterase inhibitor
|
Mild, moderate and severe AD
|
November 25, 1996
|
|
Huperzine A
|
Acetylcholinesterase inhibitor
|
Improving dementia patients and dysmnesia caused by organic brain disease
|
May 16, 2003
|
|
Memantine hydrochloride/donepezil hydrochloride
|
Acetylcholinesterase inhibitor
|
Moderate to severe AD
|
January 27, 2017
|
Fallen stars—AD drugs that suffered serious defeats in the R&D
The R&D failure rate of AD drugs is extremely high. In the AD drug R&D field filled with sufferers, pharmaceutical giants like Eli Lilly, Pfizer, J&J, Roche, and GSK have suffered serious defeats, resulting in the loss of billions of U.S. dollars.
AD Drugs Discontinued Clinical Trials
|
Pharmaceutical product name
|
Discontinuation phase
|
Discontinuation time
|
Discontinuation reason
|
Company name
|
|
Idalopirdine
|
Phase III
|
2017
|
Failure to reach the primary efficacy endpoint
|
H. Lundbeck, Otsuka Pharmaceutical Co., Ltd.
|
|
Verubecestat
|
Phase III
|
2017
|
Lack of clinical efficacy for moderate to severe AD
|
Merck
|
|
Solanezumab
|
Phase III
|
2016
|
Failure to reach the primary endpoint
|
Eli Lilly & Co.
|
|
EVP-0962
|
Phase II
|
2016
|
Failure to reach the primary endpoint
|
FORUM Pharmaceuticals Inc.
|
|
Encenicline
|
Phase II
|
2015
|
Serious adverse reactions of gastrointestinal tract
|
FORUM Pharmaceuticals Inc.;
Mitsubishi Tanabe Pharma
|
|
BI 1181181
|
Phase I
|
2015
|
Low bioavailability, and low blood-brain barrier penetration
|
Boehringer Ingelheim, Vitae Pharmaceuticals
|
|
AD-02
|
Phase II
|
2014
|
No disclosure of trial results
|
AFFiRiS AG
|
|
LY2886721
|
Phase II
|
2013
|
Hepatotoxicity
|
Eli Lilly & Co.
|
|
RG7129
|
Phase I
|
2013
|
Hepatotoxicity
|
Roche
|
|
ACC-001
|
Phase II
|
2013
|
Eliciting a strong autoimmune response
|
Janssen
|
|
Epothilone D
|
Phase I
|
2013
|
No further study
|
Bristol-Myers Squibb
|
|
IVIG
|
Phase III
|
2013
|
Failure to reach the primary clinical efficacy
|
Baxter International Inc
|
|
GSK239512
|
Phase II
|
2012
|
Ineffectiveness to cognitive impairment
|
GlaxoSmithKline
|
|
Semagacestat
|
Phase III
|
2012
|
Failure to reach the primary endpoint; occurrence of adverse reactions such as skin cancer and infection
|
Eli Lilly & Co.
|
|
Avagacestat
|
Phase II
|
2012
|
Adverse reactions such as cerebral microbleeds, dose-dependent glycosuria, and nonmelanoma skin cancer
|
Bristol-Myers Squibb
|
|
Bapineuzumab
|
Phase III
|
2012
|
Failure to reach the effectiveness endpoint
|
Janssen, Pfizer
|
|
GSK933776
|
Phase I
|
2012
|
Failure to prove the clinical benefits of antibodies
|
GlaxoSmithKline
|
|
ABT-288
|
Phase II
|
2011
|
Without clinical efficacy
|
AbbVie
|
|
LY2811376
|
Phase I
|
2008
|
Hepatotoxicity
|
Eli Lilly & Co.
|
|
Flurizan
|
Phase III
|
2008
|
Failure to reach the effectiveness endpoint
|
Myriad Genetics & Laboratories
|
|
Rember
|
Phase II
|
2007
|
Adverse reactions including diarrhea, urgent micturition, and odynuria
|
TauRx Therapeutics Ltd
|
|
Alzhemed
|
Phase II
|
2007
|
Failure to reach the effectiveness endpoint
|
Neurochem, Inc.
|
|
Ibuprofen
|
Phase IV
|
2005
|
No significant improvement of cognitive function; occurrence of adverse reactions including nausea and vomiting
|
--
|
|
AN-1792
|
Phase II
|
2002
|
Occurrence of serious meningitis
|
Janssen, Pfizer
|
Future stars—the AD drugs in development that have entered the clinical phases
AD’s characteristic is neuronal death, and the neuropathological changes relating thereto include acetylcholine deficiency, glutamate excitotoxicity, extracellular plaque deposits of the β-amyloid peptide (Aβ), neurofibrillary tangles (NTFs) caused by accumulations of hyper-phosphorylated tau protein, and nerve inflammation, etc., which become the targets of AD drugs.
AD Drugs that Have Entered the Clinical Phases
|
Type of action
|
Pharmaceutical product name
|
Clinical phase
|
Company name
|
|
Acetylcholinesterase inhibitor
|
Intepirdine
|
II/III
|
Axovant Sciences Ltd.
|
|
SUVN-G3031
|
I
|
FORUM Pharmaceuticals Inc.; Mitsubishi Tanabe Pharma
|
|
L-clausenamide tablets
|
II
|
Qingdao Huanghai Pharmaceutical; Guangzhou Nuohao Pharmaceutical Technology Co., Ltd.; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
|
|
AD-35 tablets
|
I
|
Zhejiang Hisun Pharmaceutical Co., Ltd.
|
|
N-methyl D-aspartate (NMDA) receptor antagonist
|
Riluzole
|
II
|
Sanofi
|
|
Beta-secretase (BACE) inhibitor
|
E2609
|
III
|
Biogen, Eisai Co., Ltd.
|
|
AZD3293
|
III
|
AstraZeneca, Eli Lilly & Co.
|
|
CNP520
|
II/III
|
Amgen, Inc., Novartis
Pharmaceuticals Corporation
|
|
JNJ-54861911
|
II/III
|
Janssen, Shionogi Pharma
|
|
γ-secretase inhibitor
|
NIC5-15
|
II
|
Humanetics Pharmaceuticals Corporation
|
|
Aβ scavenger
|
CAD106
|
II/III
|
Novartis Pharmaceuticals Corporation
|
|
AAB-003
|
I
|
Janssen, Pfizer
|
|
Crenezumab
|
III
|
AC Immune SA, Genentech, Hoffmann-La Roche
|
|
Gantenerumab
|
III
|
Chugai Pharmaceutical Co., Ltd., Hoffmann-La Roche
|
|
BAN2401
|
II
|
Biogen, Eisai Co., Ltd.
|
|
Aducanumab
|
III
|
Biogen
|
|
ACI-24
|
II
|
AC Immune SA
|
|
971 capsules
|
III
|
Shanghai Green Valley Pharmaceutical Co., Ltd.
|
|
Tau protein microtubule stabilizer
|
TPI287
|
I
|
Cortice Biosciences
|
|
Tau protein aggregation inhibitor
|
TRx0237
|
III
|
TauRx Therapeutics Ltd
|
|
P-Tau scavenger
|
AADvac-1
|
II
|
Axon Neuroscience SE
|
|
ACI-35
|
I
|
AC Immune SA, Janssen
|
|
Microglial activation inhibitor
|
Azeliragon
|
III
|
Pfizer, TransTech Pharma, Inc., vTv Therapeutics LLC
|
|
CHF 5074
|
II
|
CereSpir™ Incorporated, Chiesi Pharmaceuticals Inc.
|
|
Insulin (nasal delivery)
|
Humulin® R U-100
|
II/III
|
Impel NeuroPharma
|
|
Calcium channel blocker
|
Nilvadipine
|
III
|
Prof Brian Lawlor
|
About Author
Erxiao, Master of Pharmacy, pharmaceutical industry practitioner, engaged in imported drug and new drug registration, and focused on registration regulations and new drug dynamics.
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