**3. Treatments that failed in clinical trials**

Only four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) and an *N*-methyl-d-aspartate (NMDA) receptor AD antagonist (memantine) are approved for the treatment of AD. These five drugs are all symptomatic treatments. No new drugs have been approved for treatment of AD since 2003. Disease modifying drugs (DMD) is the real goal in AD treatment. However, success rate is extremely low for Alzheimer treatment research. Until today, anti-inflammatory (NSAİD, steroids), antioxidant (selenium, vitamin E), anti-ischemic (statin, aspirin), cholinergic (lecithin), nutrients (Omega-3, vitamins B, folic acid), monoclonal antibody (bapineuzumab, solanezumab) treatments have failed (**Table 1**). The overall failure rate was 99.6% (0.4% success) in the decade spanning from 2002 to 2012 [20]. Many explanations have been proposed for the failures of trials of DMD for AD, including starting therapies at the late phase of disease, wrong or nonspecific treatment targets, incorrect doses, the lack of homogeneity of individuals (genetic, ethical, temporal and medical grounds), nonspecific or blunt trial design [21, 22]. On the other hand, pathological changes may not correlated with cognitive deficits


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manifestations.

*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

Piracetam Multiple complex

Bapineuzumab Humanized, N-terminal

Solanezumab Humanized monoclonal

antibody

Tarenflurbil(Rflurbiprofen)

**Table 1.**

mechanisms

Semagacestat γ-Secretase inhibition Serious adverse events

specific anti-Aβ monoclonal

IgG1 antibody directed against the mid-domain of

the Aβ peptide

in AD, measuring cognitive abilities is a reductionist approach as the disease is too complex and transgenic animal models are not capable of mimicking the various pathophysiological mechanisms in humans. Several new chemical entities claiming to have potential benefits in AD have been developed by researchers all over the globe. However, the evolution of a definite disease modifying therapy for AD is

**Agent Proposed mode of action Reason Reference**

The evidence does not support the use of piracetam in the treatment of people with dementia or cognitive

(weight loss, skin cancers and infections), worsening of cognition and functioning

the loss of daily living activities

No significant improvement in cognition, serious side effects,

No significant improvement in

Flicker and Evans [38]

Doody et al. [39]

Green et al. [40]

Abushouk et al.

Honig et al. [42]

[41]

impairment

in mild AD

cognition

vasogenic edema

γ-Secretase inhibition No effect on cognitive decline or

Alzheimer's disease (AD) is a neurodegenerative disorder resulting from progressive pathological changes characterized by protein deposits in the form of amyloid plaques (APs) and neurofibrillary tangles (NFTs), which cause synaptic and neuronal loss. According to generally accepted hypothesis AD starts with abnormal processing of amyloid precursor protein (APP) [2]. Excess production or reduced clearance of β-amyloid peptide monomers, which is produced by the amyloidogenic cleavage of the membrane-spanning protein APP are the two main mechanisms of this abnormal deposition process, which causes aggregation of β-amyloid (Aβ) fibrils in extracellular APs. Second core pathophysiological mechanism of the disease is the

intraneuronal deposition of hyperphosphorylated tau (pT) within NFTs [5].

Synaptic dysfunction, mitochondrial and oxidative changes, neuroinflammation, gliosis, and finally apoptosis and neuronal loss are known neurodegenerative consequences of AD, which are reflected in the macroscopical level as the regional cortical atrophy starting from limbic regions of the brain and then traveling trans synaptically to paralimbic, heteromodal and finally to unimodal association cortices. These changes and dysfunctions of the neurotransmitter systems such as acetylcholine, serotonin, glutamate, noradrenaline, dopamine cause clinical

All these pathological changes are the targets of ongoing clinical trials for the treatment of AD. The term "disease-modifying strategies in AD" primarily connotes

constantly under the threat of chasing the wrong pathology [22].

*The anti-AD drug candidates for which the clinical trials have been failed or suspended.*

**4. Ongoing clinical trials for Alzheimer's disease**

*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*


**Table 1.**

*Geriatric Medicine and Gerontology*

Ganstigmine Acetylcholinesterase inhibitor

Metrifonate Cholinesterase inhibition (irreversible)

Lecithin Major dietary source of choline

Rofecoxib Cyclo-oxygenase-2

Selegiline Monamine oxidase

inhibition

inhibition

Pravastatin Lowers plasma cholesterol and lipoprotein

Vitamins B Methionine-synthase

mediated conversion of homocysteine to methionine, antioxidant, nerve growth and repair

Activity at cholinergic neurons, membrane stabilization and enhancing mitochondrial function

Lowers plasma cholesterol

Vitamin E Vitamin E, selenium There is no evidence that

and lipoprotein

Simvastatin, pravastatin

Omega-3 polyunsaturated fatty acids

Vitamin E, selenium

Acetyl-lcarnitine

Ibuprofen Anti-inflammatory, NSAİD No evidence yet exists

Aspirin, steroid Anti-inflammatory No significant improvement in

Latrepirdine Antihistamine drug There is no effect of latrepirdine

**Agent Proposed mode of action Reason Reference**

Side effects (headache, nausea,

Side effects (neuromuscular dysfunction, respiratory

There is no significant benefit of lecithin for Alzheimer's disease or Parkinsonian

ibuprofen is efficacious in Alzheimer's disease

No significant differences between treatments were found for the ADAS-cog score

cognitive decline for aspirin and

on cognition and function in mild-to-moderate AD patients

The evidence of benefit using standardised global cognitive scales was extremely limited. There is not yet enough evidence to recommend its use

Pravastatin had no significant effect on cognitive function or

There is no evidence that statins prevent cognitive decline or

evidence for the efficacy of omega-3 PUFA supplements in the treatment of mild to

Racchi et al. [23]

Arrieta et al. [24]

Higgins and Flicker [25]

Tabet and Feldman [26]

Reines et al. [27]

Jaturapatporn et al. [28]

Chau et al. [29]

Birks and Flicker

Shepherd [31]

McGuinness et al. [32]

Burckhardt et al.

Kryscio et al. [34]

Farina et al. [35]

Li et al. [36]

Hudson [37]

[33]

[30]

vomiting, anorexia)

failure)

dementia

steroid

in practice

disability

dementia

moderate AD

or AD

not prevent dementia

vitamin E prevents dementia, or that it improves cognitive function in people with MCI

There is no adequate evidence of an effect of vitamins B on general cognitive function, executive function

There is no evidence of benefit of improvement in cognition or

functional ability

Essential dietary nutrient There is not convincing

Antioxidant supplement Antioxidant supplements did

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*The anti-AD drug candidates for which the clinical trials have been failed or suspended.*

in AD, measuring cognitive abilities is a reductionist approach as the disease is too complex and transgenic animal models are not capable of mimicking the various pathophysiological mechanisms in humans. Several new chemical entities claiming to have potential benefits in AD have been developed by researchers all over the globe. However, the evolution of a definite disease modifying therapy for AD is constantly under the threat of chasing the wrong pathology [22].

### **4. Ongoing clinical trials for Alzheimer's disease**

Alzheimer's disease (AD) is a neurodegenerative disorder resulting from progressive pathological changes characterized by protein deposits in the form of amyloid plaques (APs) and neurofibrillary tangles (NFTs), which cause synaptic and neuronal loss. According to generally accepted hypothesis AD starts with abnormal processing of amyloid precursor protein (APP) [2]. Excess production or reduced clearance of β-amyloid peptide monomers, which is produced by the amyloidogenic cleavage of the membrane-spanning protein APP are the two main mechanisms of this abnormal deposition process, which causes aggregation of β-amyloid (Aβ) fibrils in extracellular APs. Second core pathophysiological mechanism of the disease is the intraneuronal deposition of hyperphosphorylated tau (pT) within NFTs [5].

Synaptic dysfunction, mitochondrial and oxidative changes, neuroinflammation, gliosis, and finally apoptosis and neuronal loss are known neurodegenerative consequences of AD, which are reflected in the macroscopical level as the regional cortical atrophy starting from limbic regions of the brain and then traveling trans synaptically to paralimbic, heteromodal and finally to unimodal association cortices. These changes and dysfunctions of the neurotransmitter systems such as acetylcholine, serotonin, glutamate, noradrenaline, dopamine cause clinical manifestations.

All these pathological changes are the targets of ongoing clinical trials for the treatment of AD. The term "disease-modifying strategies in AD" primarily connotes treatment strategies aiming at the prevention of and/or clearance of pathological Aβ and tau. Neurotransmitter-based strategies and others, such as combatting against oxidative stress or neuroinflammation are generally classified as "symptomatic treatments". In this section, current disease-modifying and symptomatic treatment strategies will be reviewed.

#### **4.1 Amyloid-focused ongoing clinical trials**

According to the amyloid cascade hypothesis, AD begins with the accumulation of Aβ, years before its clinical onset. APP is a transmembrane protein whose physiological function is not completely understood. In a healthy brain, APP is metabolized by three proteolytic enzymes, namely α, β and γ secretases [43]. Proximally, γ-secretase cleaves the protein in its membrane-spanning domain solely by itself, forming an intracellular carboxy-terminal fragment (CTF), which is probably pro-plastic by translocating into the neuronal nucleus and playing a role in pro-plastic signaling. However distally, APP is cleaved alternatively, either by α-secretase or by β-secretase (BACE) on its two different sites in the extracellular domain close to the amino terminal of APP. The former cleavage is nonamyloidogenic since it produces an inert peptide called p3 in the mid-segment and another one, which is called sAPPα containing the N-terminus and probably having some neurotrophic functions. However, the latter cleavage is amyloidogenic, since it produces the anti-plastic and deposition-prone Aβ fragment in the mid-segment and sAPPβ in the N-terminus. The resulting Aβ will either be cleared by lysosomal-proteasomal mechanisms or will oligomerize and start to induce its pathophysiological functions. Now it is known that soluble oligomers of Aβ are more toxic than its more downstream moieties that are insoluble protofibrils and fibrils [44, 45].

Therefore, current studies aim to agonize α-secretase activity (ADAM10 activators), inhibit β-secretase (BACE inhibitors), and inhibit or modulate γ-secretase (GSIs and GSMs). Also enhancing clearance of Aβ with active or passive immunotherapies or prevention of aggregation of APs are the treatment focuses of ongoing trials. Monoclonal antibodies bind different epitopes which are N-terminal, C-terminal or mid-domain of Aβ and different conformations of Aβ which are monomer, oligomer and fibril [46].

#### *4.1.1 Reducing Aβ production*

Two secretases, namely α and γ are seemingly no longer the focus of drug development efforts for AD, as a result of many failures in clinical trials and concerns that their interaction with other substrates may trigger diseases like cancer. Specific ADAM10 activators that will act only in the brain thus preventing its potential role in breast cancer is yet to be developed [47] In a recent review it was stated that "the future of γ-secretase inhibition as an AD treatment strategy may depend on the development of GSMs, which aim to cause a shift from Aβ1-42 species toward the shorter and less pathogenic forms of Aβ, while also sparing Notch" [48].

β-Secretase is an aspartic acid protease belongs to the pepsin family. β-Site APP cleaving enzyme 1 (BACE1) plays role in Aβ production. BACE1 inhibition strategies do not share the same concerns for interfering with the other secretases. Therefore BACE1 inhibition is one of the strategies to interfere with amyloid cascade. There are ongoing trials with E 2609 (NCT03036280, NCT02956486), CNP520 (NCT02565511, NCT03131453) and JNJ-54861911 (NCT02569398, NCT01760005) [49].

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*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

The first experience of active vaccine trial was with AN1792 and ended occurrence of T-cell mediated meningoencephalitis [50]. Now the only ongoing active vaccine trial is CAD-106 that generates anti-Aβ antibodies to N-terminus [51, 52]. Crenezumab is a humanized IgG4 monoclonal antibody (mAb) that binds the mid-domain of the Aβ peptide (residues 13–24) and binds multiple conformations of Aβ (monomers, oligomers, fibrils) [53, 54]. Patients with mild to moderate Alzheimer Disease and also Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers are involved in ongoing trials of Crenezumab (NCT03491150,

Gantenerumab is a first fully human IgG1 mAb binds an N-terminal [3–12] and central [18–27] amino acids of the Aβ peptide. It binds monomers weaker than oligomers and fibrils [46]. Gantenerumab is being evaluated in phase 2 and 3 trials in individuals with prodromal and early AD and individuals at risk for and with early-stage autosomal-dominant AD (NCT02051608, NCT03444870,

Aducanumab is a fully human IgG1 mAb binds the N-terminus (residues 3–6) of Aβ peptide. It recognizes oligomers and fibrils but it does not react to the monomers [18]. Ongoing Aducanumab trials involve prodromal, early and mild AD patients

Solanezumab is a humanized IgG1 mAb, binds the mid-domain of Aβ (residues 16–26). It specifically recognizes monomers [58]. There are two ongoing prevention

In addition to abovementioned strategies, there are some other anti-amyloido-

(NCT02547818) [59]. Posiphen is another anti-amyloidogenic drug that currently in

Update of selected anti-Alzheimer's disease drugs in clinical trials including

Tau is a microtubule-associated protein (MAP) in neurons which regulates the axonal transport [63]. Although tau pathology proved to be more correlated with clinical symptoms than amyloid mechanisms, tau-based therapeutic strategies are relatively new. Beta-folded oligomers of abnormal phosphorylation of tau are the main component of NFTs. Post-translational modifications such as phosphorylation, acetylation and truncation play a major role in tau function [64]. Modulating tau phosphorylation, targeting other tau post-translational modifications, microtubule stabilizers, tau aggregation inhibitors, anti-tau immunotherapy are the mechanisms targeted by clinical trials. Current clinical trials focusing on tau are

Salsalate is a nonsteroidal anti-inflammatory drug that has been shown to inhibit acetyltransferase p300-induced tau acetylation in frontotemporal dementia (FTD) mouse model [75]. There is a phase I clinical trial in patients with prodromal to mild

genic compounds with diverse mechanisms. ALZT-OP1 prevents Aβ aggregation and neuroinflammation and is being evaluated in phase III clinical trial

NCT03114657, NCT02353598, NCT01998841, NCT02670083).

NCT03443973, NCT01224106, NCT01760005) [46, 55, 56].

trials with solanezumab (NCT01760005, NCT02008357).

*4.1.3 Other anti-amyloidogenic compounds*

phase I/II clinical trial (NCT02925650) [60].

**4.2 Tau-focused ongoing clinical trials**

summarized in **Table 3**.

anti-amyloid strategies are summarized in **Table 2**.

*4.2.1 Targeting tau-post-translational modifications*

(NCT03639987, NCT02484547, NCT02477800, NCT01677572) [46, 57].

*4.1.2 Aβ clearance*
