Med Res Rev. 2017 Sep;37(5):1186-1225. doi: 10.1002/med.21434.

Drugs in clinical trials for Alzheimer’s disease. The major trends

Sergey O. Bachurin*, Elena V. Bovina, Aleksey A. Ustyugov

Institute of Physiologically Active Compounds of the Russian Academy of Sciences. 142432 Russia, Moscow region, Chernogolovka, Severny proezd, 1

*Corresponding author: Sergey O. Bachurin, e-mail: bachurin@ipac.ac.ru, Tel/Fax +7(496)5249508

Elena V. Bovina, e-mail: bovina_e@ipac.ac.ru, Tel/Fax +7(496)5249508

Aleksey A. Ustyugov, e-mail: alexey@ipac.ac.ru, Tel/Fax +7(496)5249508 

 

Abstract

Alzheimer’s disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade more than 50 drug candidates have successfully early phases clinical trials, but failed to reach the market. Here, we summarize data on “anti-Alzheimer’s” agents currently in clinical trials based on available information in the Thomson Reuters «Integrity» database as well as public websites www.clinicaltrials.gov and Alzforum.org. We outline major trends in AD drug discovery: (1) compounds with the disease-modifying properties that could potentially slow the development of structural and functional abnormalities in the CNS providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. (2) Focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease. (3) Finally, the repositioning of old drugs to fit new “anti-Alzheimer’s” application offering a very attractive approach to facilitate successful completion of clinical trials.

PMID: 28084618

 

Supplement

Research and development of efficient therapeutic agents for the treatment of neurodegenerative diseases (NDD) is one of the most risky and challenging problems of modern medicinal chemistry. At the same time, the socioeconomic importance of the development of such medicines outweighs any possible risks and development costs. For example, in the US alone in 2010-2011, the economic damages from Alzheimer’s disease (AD) exceeded 215 billion dollars [1]. A review by Cammings J. et al, reports that 413 clinical trials of 244 potential drugs proposed for the treatment of AD were conducted during 2002-2012, of which 124 studies entered phase I, 206 were in phase II and 83 in phase III. However, despite the enormous efforts and costs in search for new and effective agents for AD treatment in the past decade, there are still no new drugs on the market.

In general terms, AD is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood, yet it is clear that advanced age is the main risk. There are various theories and hypotheses depicting the causal factors, all of which lead to the conclusion that AD is a multifactorial disease and hence there could not be just one curative agent to battle the progression of the pathology [2]. The majority AD of drug targets as well as the mechanisms are summarized in Fig. 1.

 

Figure 1. A schematic illustration of interrelation of possible molecular targets used for discovery of innovative drugs for AD treatment and prevention.

 

 

In order to identify major trends in the discovery of novel “anti-Alzheimer’s” drugs, we analyzed available data on agents that are currently at various phases of clinical trials for AD treatment. The following review summarizes findings available in the «Integrity» database (Thomson Reuters), Alzforum.org as well the public website www.clinicaltrials.gov that tracks clinical trials since 2007. In June 1 2016, there were 34 (28%) drugs at Phase I, 57 (47%) compounds were in Phase I/II and II, and 30 (25%) reached phase III clinical trials on Alzheimer’s disease patients. All these drugs could be subdivided into several groups according to the main targets or pathways of their action (Fig. 2).

 

 

Figure 2. Distribution of drug mode of action by phases (based on data available in June 2016 in the Thomson Reuters «Integrity» database, www.clinicaltrials.gov and Alzforum.org websites). Due to multitarget action of some compounds, some might be involved in more than one group.

 

Analysis of modern approaches in research and development of new efficient drugs for treatment of AD identifies the following key trends:

  1. Development of compounds acting on the main stages of pathogenesis of the disease – Disease-modifying drugs

These drugs could potentially slow the development of structural and functional abnormalities in the CNS providing sustainable improvements of cognitive functions (in the case of AD) persisting even after the drug withdrawal. In the case of AD treatments, the main directions include the search for drugs that are aimed at reducing and promoting removal of the main pathological structures – beta-amyloid aggregates and neurofibrillary tangles formed by hyperphosphorylated Tau. Of considerable interest is the development and validation of new molecular targets and pathways that are involved in the pathogenesis of the disease. Major attention is drawn to molecular targets and enzymes causing the formation and degradation of beta-amyloid peptide (beta-, gamma- and alpha-secretases) as well as the enzymes involved in the phosphorylation of Tau (Cdk-5, GSK3b, JNK, and others). The possibilities of pharmacological correction of the ApoE system as a way of removing pathogenic beta-amyloid oligomers are particularly compelling. A rise of promising approaches of pharmacological correction of AD has emerged in past years. These include stabilization of mitochondrial function (mitoprotectors), inhibition of pathological protein aggregation in neurodegenerative diseases (drugs preventing proteinopathy), activation of endogenous cell clearance systems by stimulating autophagy and neurogenesis. As a result, several different potent groups of compounds were proposed utilizing these mechanisms in model systems. Most such compounds are still in the very early stages of clinical trials or on preclinical trials.

  1. Multitargeted drugs

The multifactor nature of AD is commonly recognized, implying the involvement of a number of neurobiological targets (including the Aβ peptide and tau protein) in the formation of this neurodegenerative disease. In this context, the concept of multi-target drugs having an integrated action on a number of biological targets involved in pathogenesis of the disease appears to be highly promising in the design of drugs for treating AD. It can be expected that these drugs would be able not only to compensate for or restore the lost cognitive functions, but also to suppress further development of the neurodegenerative process. These include the combinational approaches where a single structure possess inhibitory properties of cholinesterase and monoamine oxidase, antioxidant and metallo-chelate properties, the ability to act as ligands for multiple receptors as well as incorporation of additional NO-generating fragments into the ligand core structure.

  1. Repositioning of old drugs

Research and development of new drugs is a long-term (10-15 years), expensive (hundreds of millions of dollars) and risky process. In the field of AD treatments, over the last decade more than 50 drug candidates have successfully passed phase II but none have passed phase III. The main reasons are believed to be a lack of knowledge of the mechanism(s) of disease development (which are often a close group of pathologies with different etiology) as well as obstacles of modeling complex human neurodegenerative diseases in animals. In this regard, opportunities for use of existing drugs for new applications are opening a very attractive approach to facilitate completion of clinical trials. Such a “repositioning” of the existing medications appears extremely efficient from the investment point of view as it minimizes the risk of unknown side effects shortening total time of clinical trials due to known safety characteristics of these medicines [3]. Interestingly, the successful application of known drugs for the treatment of neurodegenerative diseases sometimes leads to the discovery of new pharmacological targets as in the case of Bexarotene or Dimebon.

Another, quite unexpected reason is also linked to the problem of heterogeneous patient population in trials, lies in different sensitivity to specific agents of patients that have been treated before or non treated by another drug. In clinical trails with LMTX (Leucomethylthioniniumsalt) initiated by TauRx company it was noted that the subset of patients who were not taking other AD drugs performed better on LMTX. “It turned out the drug only worked if people were not taking other drugs,” TauRx’s chief executive, Claude Wischik, said in an interview [4]. Even different gender ratio in groups of patients could lead to deviations in results of clinical trials as it was recently noted that women’s better verbal memory skills may mask early signs of AD. The important problem that hamper development of efficient agents for treatment of AD lies in a limited number and narrow application of animal models recapitulating major features of AD. An Alzheimer’s expert at the Mayo Clinic, Mayo’s D. Knopman, stated that such models “have not been very good at predicting a drug’s effect, and none of them is appropriate for late-onset Alzheimer’s” as opposed to the uncommon early-onset form that results from rare genetic mutations. A quite exhausted list of challenges and problems in clinical trials for AD are summarized in the review by Mangialasche and co-authors [5].

Notwithstanding the fact that no new drugs for AD treatment have been launched on the market in the past 12 years, the active research for promising new structures that are capable of preventing the progression of the disease is still ongoing. A number of radically new approaches for targeting key stages in AD pathogeneses were proposed, giving hope for success in developing new therapeutics for AD treatments in the coming years.

 

Acknowledgments

This work was supported by the grant from the Russian Scientific Foundation №14-23-00160-P.

 

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