**2. Therapeutics for Alzheimer's disease: past, present and future**

In a 20-year period from 1998 to 2017, a total of 146 drugs in clinical trials were halted or had not received approval by the FDA [17]. In that same time, four cognitive-enhancing therapeutics had been approved, giving some hope that there is a chance to identify a therapeutic for AD. Therapeutics in the AD clinical trial pipeline are split into two major classes of mechanism of action (MOA): symptomatic treatments and disease-modifying therapies (DMTs). Symptomatic treatments aim to alleviate symptoms that are present with the onset of the disease easing the burden on the affected individuals. There are currently five therapies that have been approved for use in patients that exhibit symptoms derived from neurotransmitter disturbance in mild to severe cases of AD. Suppressing symptoms such as memory loss and cognitive decline do not address the underlying nature of the disease [18]. Symptomatic treatments are beneficial for family and friends, demonstrating modest and consistent benefits for cognition. However, the underlying cause of the disease remains unchanged in these therapies where the disease progresses into a more severe state. DMTs are treatments that alter the pathology of the disease, changing the long-term course of the disease. A large proportion of DMTs targets the major hallmarks of AD, NFTs and Aβ formation. Other DMTs are present that target alternative aspects of the disease; however, these alternative targets are mostly downstream effects of NFTs or Aβ plaques. Of major interest are DMTs that target the amyloid cascade, their primary goal is to reduce plaque load, clear plaque depositions, or reduce inflammation. The nature of this MOA is of a neuroprotective stance, theoretically with the ability to reduce the amount of neurodegeneration that occurs due to chronic inflammation from Aβ seeding in the extracellular space.

As of February 2019, 132 therapeutics were in clinical trials for AD, 96 of those classed as DMTs presenting an increase of 25 DMTs from 2018 [19, 20]. Therapeutics labelled as neuroprotective, anti-inflammatory and anti-amyloid in the 2019 cohort of clinical trials will be described as neuroprotective DMTs as they all target the amyloid cascade as the priming step of neuroinflammation. Neuroprotective DMTs are described as either prophylactic treatments or diseaseclearing treatments. Prophylactic treatment of AD aims at preventing the onset

of the disease by targeting the steps prior to amyloid deposition aiming to prevent the activation of microglia and subsequent neuroinflammation. Disease-clearing therapeutics target plaques deposited into the extracellular space. They focus on removing plaques and debris to prevent chronic inflammation. There is no clear current trend in neuroprotective DMTs, with a broad selection of therapeutics covering different targets from amyloid clearance using antibodies or vaccines to mark areas for the immune system, anti-aggregation of Aβ fibrils, or preventing the production of Aβ fragments by targeting BACE1 or alpha secretase.

## **2.1 Lessons from previous clinical trials**

With such a broad range of therapeutics in clinical trials, it would be easy to assume that we are close to finding a treatment for AD, but we are not. In the 20 years spanning 1998 to 2017, almost 150 therapeutics in clinical development had stopped or not received regulatory approval [17]. The FDA approved only four therapeutics in that time leaving a lot to learn from past failures. Neuroprotective DMTs made up 34% of the therapeutics discontinued in this time, leaving in their wake a plethora of lessons that can be applied to upcoming therapeutics [21]. A shift in development from the conventional small molecule drug (SMD) to a biological approach has shown benefits. Increased knowledge on the effects of more potent and specific therapeutics has led to the identification of new targets for therapeutic development, specifically the amyloid cascade. Of the therapeutics active in clinical trials in the 15 years from 2005 to 2019, 79 targeted the amyloid cascade in a diseasemodifying mechanism (**Table 1**). Moreover, of the 79 clinical trials, 20 have been discontinued (**Table 1**).

#### *2.1.1 Types of therapeutics*

A shift in the type of therapeutic used in AD has given insights into how targets respond to certain molecules. A common issue encountered with amyloid targeting therapeutics is specificity, with off-target effects halting a few large-scale trials [22]. There are two major molecular classes present in amyloid targeting DMTs: small molecule, low molecular weight entities including chemical drugs and peptides, and biologics, larger structures such as proteins and antibodies.

#### *2.1.1.1 Small molecular entities*

Thought of as the traditional form of therapeutic, small molecular entities (SMEs) are typically chemical in nature and mostly target molecules with deep catalytic channels or clefts such as enzymes or receptors [23]. The nature of these SMDs is to bind to the target and exert its effect, doing so until there is no more target available for binding or the drug is cleared from the body. This overzealous technique of SMDs poses the risk of long-term modulation on the target, whether it be positively or negatively, regardless of whether the disease state improves or not [24].

The main target of an SME is commonly found in biological processes where a high amount of regulation is required, in the form of either enzymes or receptors [25]. The interaction that SMEs target is between an enzyme or receptor and its respective substrate, all of which are proteins. Referred to as protein–protein interactions (PPIs), they have gained popularity as a target for therapeutic intervention due to the control these interactions have on biological processes. Many PPIs have been identified as candidates targeting diseases similar to AD where a biological process has been altered resulting in disease [25].

**21**

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease*

Pravastatin

ISCOMATRIXTM

**NCT number Drug name Phase Status Start date Completion date**

NCT00479219 GSI-953 I C 05/2007 10/2007 NCT00765115 LY450139 I C 07/2006 09/2007 NCT0083808 LY2811376 I C 12/2008 06/2009 NCT00733642 PF-04360365 I A, NLR 08/2008 07/2009 NCT01125631 PF-04360365 I C 05/2010 08/2011 NCT01148498 Solanezumab II C 08/2010 08/2012 NCT01482013 HPP854 I D 10/2011 03/2012

NCT00411580 CAD106 I C 06/2005 12/2008 NCT00945672 PF-04360365 II C 08/2009 06/2011 NCT01547169 Insulin detemir II C 03/2011 12/2012 NCT00500500 EGb 761 II D 07/2005 04/2008 NCT00739037 PAZ-417 I D 08/2008 12/2008 NCT01568086 Affitope AD03 I D 12/2011 10/2013 NCT01661673 EVP 0962 II C 11/2012 10/2013 NCT00812565 Immune Globulin II C 02/2009 09/2010 NCT00857506 Florbetapir F 18 II C 01/2009 12/2011 NCT00397891 Bapineuzumab I C 10/2006 02/2010 NCT01035138 Semagacestat III C 12/2009 04/2011 NCT01669876 Anatabine II D 08/2012 02/2015 NCT01978548 Atabecestat I C 12/2013 04/2015 NCT02061878 Bexarotene I C 08/2014 11/2014 NCT00486044 Simvastatin II C 02/2005 06/2009

IV C 08/2002 04/2005

I C 03/2007 01/2012

I C 11/2008 04/2010

I C 10/2009 07/2010

I D 07/2011 11/2013

I C 02/2008 09/2009

I C 12/2014 02/2016

*DOI: http://dx.doi.org/10.5772/intechopen.91065*

NCT00303277 Simvastatin &

NCT00464334 V950 and

NCT00711321 Affitope AD02 &

NCT01093664 Affitope AD02 &

NCT01357629 Affitope AD02 &

NCT00633841 Affitope AD02 &

NCT02323334 LY3202626 &

Aluminium hydroxide

Aluminium hydroxide

Aluminium hydroxide

Aluminium hydroxide

Itraconazole

NCT01782742 Bexarotene II C 02/2013 12/2014

NCT00722046 Ponezumab II C 12/2008 08/2011 NCT00956410 Amilomotide II C 09/2009 06/2011 NCT00762411 Semagacestat III C 09/2008 04/2011 NCT01097096 Amilomotide II C 03/2010 12/2012 NCT01928420 Pinitol II C 04/2007 06/2014 NCT00329082 Solanezumab II C 05/2006 05/2008


*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.91065*

*Neuroprotection - New Approaches and Prospects*

**2.1 Lessons from previous clinical trials**

discontinued (**Table 1**).

*2.1.1 Types of therapeutics*

*2.1.1.1 Small molecular entities*

of the disease by targeting the steps prior to amyloid deposition aiming to prevent the activation of microglia and subsequent neuroinflammation. Disease-clearing therapeutics target plaques deposited into the extracellular space. They focus on removing plaques and debris to prevent chronic inflammation. There is no clear current trend in neuroprotective DMTs, with a broad selection of therapeutics covering different targets from amyloid clearance using antibodies or vaccines to mark areas for the immune system, anti-aggregation of Aβ fibrils, or preventing the

With such a broad range of therapeutics in clinical trials, it would be easy to assume that we are close to finding a treatment for AD, but we are not. In the 20 years spanning 1998 to 2017, almost 150 therapeutics in clinical development had stopped or not received regulatory approval [17]. The FDA approved only four therapeutics in that time leaving a lot to learn from past failures. Neuroprotective DMTs made up 34% of the therapeutics discontinued in this time, leaving in their wake a plethora of lessons that can be applied to upcoming therapeutics [21]. A shift in development from the conventional small molecule drug (SMD) to a biological approach has shown benefits. Increased knowledge on the effects of more potent and specific therapeutics has led to the identification of new targets for therapeutic development, specifically the amyloid cascade. Of the therapeutics active in clinical trials in the 15 years from 2005 to 2019, 79 targeted the amyloid cascade in a diseasemodifying mechanism (**Table 1**). Moreover, of the 79 clinical trials, 20 have been

A shift in the type of therapeutic used in AD has given insights into how targets respond to certain molecules. A common issue encountered with amyloid targeting therapeutics is specificity, with off-target effects halting a few large-scale trials [22]. There are two major molecular classes present in amyloid targeting DMTs: small molecule, low molecular weight entities including chemical drugs and peptides, and

Thought of as the traditional form of therapeutic, small molecular entities (SMEs) are typically chemical in nature and mostly target molecules with deep catalytic channels or clefts such as enzymes or receptors [23]. The nature of these SMDs is to bind to the target and exert its effect, doing so until there is no more target available for binding or the drug is cleared from the body. This overzealous technique of SMDs poses the risk of long-term modulation on the target, whether it be positively or negatively, regardless of whether the disease state improves or

The main target of an SME is commonly found in biological processes where a high amount of regulation is required, in the form of either enzymes or receptors [25]. The interaction that SMEs target is between an enzyme or receptor and its respective substrate, all of which are proteins. Referred to as protein–protein interactions (PPIs), they have gained popularity as a target for therapeutic intervention due to the control these interactions have on biological processes. Many PPIs have been identified as candidates targeting diseases similar to AD where a biological

biologics, larger structures such as proteins and antibodies.

process has been altered resulting in disease [25].

production of Aβ fragments by targeting BACE1 or alpha secretase.

**20**

not [24].


**23**

*2.1.1.2 Biologics*

**Table 1.**

models.

AD and other diseases.

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease*

Therapy-Longeveron

therapy-Anterogen

*as amyloid targeting as of January 9, 2020, according to https://adisinsight.springer.com.*

Analysis of SMEs targeting PPIs has shown that they do not observe standard drug-like properties, specifically surrounding their size, hydrophobicity and specificity [26, 27]. These properties all show mild increases, compared to conventional SMDs, proving that the chemistry of PPIs requires molecules to be selected more

NCT03402659 Neflamapimod II C 12/2017 07/2019

*Abbreviations: A, Active; NLR, no longer recruiting; C, Completed; D, Discontinued. NOTE: 79 trials were identified* 

**NCT number Drug name Phase Status Start date Completion date** NCT03036280 Elenbecestat III D 12/2016 11/2023 NCT02245737 Lanabecestat II/III D 09/2014 10/2018 NCT03443973 Gantenerumab III R 08/2018 03/2023 NCT03444870 Gantenerumab III R 06/2018 03/2023 NCT00299988 Immune Globulin II D 02/2006 04/2010

I A, NLR 10/2016 09/2020

I/II C 04/2017 06/2019

Biologics fill the void of the upper end of the molecular weight scale, made up of antibodies, proteins and enzymes. Biological therapeutics like antibodies and vaccines aim to modulate the immune system to clear various threats from the body. Other therapies involve the replacement of an important molecule in a biological process, such as hormone replacement therapy (HRT) or lactose intolerance. Replacement therapies use therapeutics that mimic proteins in a healthy individual, usually using recombinant technology to produce the protein in different biological

The PPIs mentioned above have important regulatory roles in biological processes, keeping them in check as cell signalling molecules [28]. Biological intervention with molecules that mimic or stop these interactions enables control over biological pathways similar to SMDs, however, giving the pathway some control over feedback [24]. Antibodies are an excellent example of controlling the immune system in AD to remove the build-up of deposited plaques, while allowing the body to exert control over the reaction of the immune response to these antibodies. This shows the benefit of using biologics in the development of therapeutic options for

A common issue that has arisen in the therapeutic development of biologics is the bioavailability and half-life of the therapeutic. Biologics are not well known for high bioavailability, particularly where the oral route is concerned, an issue that can be overcome using other forms of administration [29]. Following administration, biologics are subjected to proteases and harsh conditions in the stomach or other accessory organs that reduces the half-life dramatically [30]. Intravenous and intramuscular administration has improved the half-life of biologics; however,

carefully rather than selecting the molecule with the highest potency.

*DOI: http://dx.doi.org/10.5772/intechopen.91065*

NCT02600130 hMSC

NCT03117738 Adipose SC

*Amyloid targeting clinical trials from 2005 to 2019.*

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.91065*


*Abbreviations: A, Active; NLR, no longer recruiting; C, Completed; D, Discontinued. NOTE: 79 trials were identified as amyloid targeting as of January 9, 2020, according to https://adisinsight.springer.com.*

#### **Table 1.**

*Neuroprotection - New Approaches and Prospects*

NCT02614131 LY 2599666 &

NCT02565511 Amilomotide &

NCT01760005 Atabecestat &

Solanezumab

Umibecestat

Gantenerumab & Solanezumab

NCT02406027 Atabecestat II D 07/2015 06/2018 NCT02051608 Gantenerumab III A, NLR 03/2014 04/2021 NCT03114657 Crenezumab III D 03/2017 06/2019

NCT01224106 Gantenerumab III A, NLR 11/2010 08/2020 NCT01966666 TPI 287 I A, NLR 11/2013 11/2019 NCT00594568 Semagacestat III C 03/2008 05/2011 NCT02719327 E-EPA II/III R 06/2017 11/2021 NCT02956486 Elenbecestat III D 10/2016 11/2023

I D 12/2015 12/2016

II/III D 11/2015 03/2025

II/III D 12/2012 03/2021

**NCT number Drug name Phase Status Start date Completion date** NCT01600859 Elenbecestat I C 07/2012 10/2013 NCT01297218 hMSC Therapy I C 02/2011 12/2011 NCT01193608 AAB 003 I C 09/2010 10/2013 NCT02260674 Atabecestat II C 11/2014 06/2016 NCT02033668 GSK 933776 I C 01/2014 07/2014 NCT01424436 GSK 933776 I C 05/2010 12/2011 NCT02576639 Umibecestat II C 08/2015 03/2016 NCT00904683 Solanezumab III C 05/2009 06/2012 NCT02386306 GC 021109 I C 02/2015 10/2015 NCT01595646 Insulin detemir II C 11/2011 03/2015 NCT01561430 LY 2886721 I/II D 03/2012 Jun 2013 NCT02551809 UB 311 II C 10/2015 08/2018 NCT03417986 Thiethylperazine II A, NLR 11/2017 07/2021 NCT01056965 Davunetide I C 01/2010 12/2012 NCT01428453 Rilapladib II C 07/2011 02/2013 NCT02036645 MEDI 1814 I C 02/2014 09/2016 NCT01397578 Crenezumab II C 07/2011 04/2014 NCT01127633 Solanezumab III D 11/2010 02/2017 NCT02760602 Solanezumab III D 06/2016 05/2017 NCT01900665 Solanezumab III D 07/2013 02/2017 NCT02080364 Azeliragon III D 04/2015 06/2018 NCT01807026 LY 2886721 I C 03/2013 05/2013 NCT02462161 Insulin aspart I C 03/2015 04/2019 NCT02899091 CB-AC 02 I/II R 09/2016 12/2021

**22**

*Amyloid targeting clinical trials from 2005 to 2019.*

Analysis of SMEs targeting PPIs has shown that they do not observe standard drug-like properties, specifically surrounding their size, hydrophobicity and specificity [26, 27]. These properties all show mild increases, compared to conventional SMDs, proving that the chemistry of PPIs requires molecules to be selected more carefully rather than selecting the molecule with the highest potency.

#### *2.1.1.2 Biologics*

Biologics fill the void of the upper end of the molecular weight scale, made up of antibodies, proteins and enzymes. Biological therapeutics like antibodies and vaccines aim to modulate the immune system to clear various threats from the body. Other therapies involve the replacement of an important molecule in a biological process, such as hormone replacement therapy (HRT) or lactose intolerance. Replacement therapies use therapeutics that mimic proteins in a healthy individual, usually using recombinant technology to produce the protein in different biological models.

The PPIs mentioned above have important regulatory roles in biological processes, keeping them in check as cell signalling molecules [28]. Biological intervention with molecules that mimic or stop these interactions enables control over biological pathways similar to SMDs, however, giving the pathway some control over feedback [24]. Antibodies are an excellent example of controlling the immune system in AD to remove the build-up of deposited plaques, while allowing the body to exert control over the reaction of the immune response to these antibodies. This shows the benefit of using biologics in the development of therapeutic options for AD and other diseases.

A common issue that has arisen in the therapeutic development of biologics is the bioavailability and half-life of the therapeutic. Biologics are not well known for high bioavailability, particularly where the oral route is concerned, an issue that can be overcome using other forms of administration [29]. Following administration, biologics are subjected to proteases and harsh conditions in the stomach or other accessory organs that reduces the half-life dramatically [30]. Intravenous and intramuscular administration has improved the half-life of biologics; however, modification to the structure of the therapeutic may be required to reach the target from the blood stream or the tissue at the site of injection. Although there are common issues regarding ideal therapeutic properties of biologics, new technology is improving every day allowing therapeutic development of biologics to overcome what seems to be simple obstacles.

## *2.1.2 Targets of the amyloid cascade*
