It is likely that in one’s lifetime a friend or family member will be diagnosed with Alzheimer’s disease. As of 2018, approximately 50 million people worldwide are living with dementia and this number is expected to triple to 152 million by 2050.
Despite the increasing prevalence of the disease, no new drugs have been approved for the treatment of Alzheimer’s since 2003. An article recently published on PharmaTimes proclaims, “The search for a cure for Alzheimer’s is far from over.”
In support of this claim, the article cites numerous Phase III trials that have been halted. Phase III trials of crenezumab (Genentech – subsidiary of Roche), lanabecestat (AstraZeneca/Eli Lilly), and most recently aducanumab (Biogen) have been discontinued. Furthermore, drug giant Pfizer announced in January 2018 that it was pulling out of neuroscience research. (Admittedly, in October 2018, Pfizer teamed up the investment firm Bain Capital to create a new company, Cerevel Therapeutics, composed of its neuroscience assets.)
In light of these trends, it is easy to question the future of Alzheimer’s disease research and this is the topic explored in this blog.
Recently Discontinued Trials
A survey of AdisInsight provides additional details on discontinued trials for various drugs for the treatment of Alzheimer’s disease and dementia. The three previously mentioned drugs are examined below.
At the end of January 2019, Genentech discontinued the CREAD1 and CREAD2 phase III trials of its amyloid beta-protein inhibitor drug in Alzheimer’s disease in over 40 countries due to unfavourable efficacy results and the unlikeliness that the drug would meet the primary endpoint of change in Clinical Dementia Rating-Sum of Boxes.
In June 2018, AstraZeneca announced that Phase III trials of this oral inhibitor of β-secretase cleaving enzyme for the treatment of Alzheimer’s disease were being discontinued. Similar to the reason cited above for the discontinuation of the crenezumab trials, the decision to discontinue the AMARANTH, AMARANTH extension, and DAYBREAK-ALZ trials was based on a recommendation by an independent data monitoring committee that concluded the trials were not likely to meet primary endpoints upon completion. The primary endpoint of the trials was change from baseline on the 13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale. The AMARANTH trial was for early Alzheimer’s disease and the DAYBREAK-ALZ trial was for mild Alzheimer’s disease dementia.
The phase III ENGAGE and EMERGE trials of Biogen’s aducanumab, an amyloid beta-protein inhibitor, in patients with early Alzheimer’s disease were discontinued in March 2019. Aducanumab was previously granted fast track designation by the US FDA in 2016 for the treatment of early Alzheimer’s disease. Again, rather than being discontinued for safety concerns, the trials were halted due to the results of an analysis by an independent data monitoring committee that determined the trials were unlikely to meet the primary endpoint of change from baseline in Clinical Dementia Rating-Sum of Boxes upon completion. The long term-term extension trial of the phase I PRIME trial in Australia, Belgium, and the USA and the phase II EVOLVE trial in Spain and the USA for Alzheimer’s disease were also discontinued in March 2019.
The Future of Alzheimer’s Research
There seems to be a theme emerging in terms of the clinical trials that were discontinued – these drugs inhibit amyloid beta-proteins or amyloid precursors, in accordance with the amyloid hypothesis. The beta-amyloid hypothesis suggests that accumulation of the peptide amyloid-β is the main cause of Alzheimer’s; when this peptide accumulates to form deposits in the brain, neurodegenerative processes that lead to the loss of memory and cognitive ability are activated.
If the amyloid hypothesis does not prove to be viable, where do we go from here in the fight against Alzheimer’s disease?
One such avenue of exploration is the link between neurological diseases and the immune system. The basis of this research is founded on the tau protein, which was discovered in 2000. The tau protein is involved in the formation of neuro-fibrillar tangles that are characteristic of neurological disease like Alzheimer’s and other forms of dementia. 
A study published in February 2019 in Nature Neuroscience, details the discovery that the brain cells of Alzheimer’s patients are unable to effectively dispose of damaged mitochondria through the process of mitophagy; accumulation of waste material leads to cell death and the development and progression of Alzheimer’s disease.  The combination of compromised mitophagy and build-up of damaged mitochondria negatively impacts neurons, as well as microglia, which act as the brain’s macrophages by removing neurotoxic components and release pro-inflammatory and anti-inflammatory cytokines that regulate immune responses. 
One specific company exploring the immune system route is Alector. Alector operates on the hypothesis that the immune system plays a significant role in the development of all neurodegenerative diseases and believes that by harnessing the body’s immune system it will be possible to cure neurodegenerative diseases like Alzheimer’s. By utilizing microglia, the body’s innate immune system, Alector hopes to counteract multiple pathologies, such as amyloid beta aggregates and tau tangles.  This is in contrast to the current therapeutic approaches to curing Alzheimer’s and other neurodegenerative diseases, which only target tau tangles or amyloid beta aggregates. 
In the words of Arnon Rosenthal, Ph.D., co-founder and CEO of Alector, “At Alector, we believe that Alzheimer’s disease is caused by a dysfunctional brain immune system that due to aging or genetic mutations, fails to clear pathological proteins, nourish nerve and glial cell, and promote neuronal connections.”
According to AdisInsight, Alector has three drugs in development for neurodegenerative diseases; one is for dementia (AL 001) and the other two are for Alzheimer’s (AL 002, AL 003). Alector is also collaborating with companies like Janssen, AbbVie, and GigaGen on research programs aimed at developing drugs for neurodegenerative disorders.
In August 2018, the US FDA granted orphan drug status to AL 001 for the treatment of frontotemporal dementia. Recruitment is currently underway for a first-in-human phase I study in healthy volunteers and in patients with frontotemporal dementia with granulin mutation to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL 001.
A first-in-human phase I study for AL 003 is also planned. AL 003 is a monoclonal antibody that targets Siglec-3 and is being developed in collaboration with AbbVie.  This multicenter, randomized, double-blind, placebo-controlled, dose escalation study in healthy adults and in patients with mild-to-moderate Alzheimer’s disease is designed to assess the safety, immunogenicity, tolerability, pharmacokinetics, and pharmacodynamics of AL 003.
AL 002, an antibody targeting a triggering receptor expressed on myeloid cells 2, is the result of collaboration with AbbVie. The phase I trial INVOKE of AL 002 is currently recruiting. This first-in-human study in healthy adults and in patients with mild-to-moderate Alzheimer’s disease will assess the safety, immunogenicity, tolerability, pharmacokinetics, and pharmacodynamics of the drug. This multicenter, randomized, double-blind, placebo-controlled, dose escalation study will be conducted in two phases: single ascending dose and multiple-dose.
On the topic of the INVOKE trial, Robert Paul, M.D., Ph.D., Chief Medical Officer at Alector stated, “AL002 is designed to address multiple brain pathologies in parallel by modulating immune function. We believe that TREM2 is one of the most promising, new therapeutic targets for the treatment of Alzheimer’s disease and other neurodegenerative disorders, and we look forward to further understanding its potential through this trial.” 
A search of Alzheimer’s on AdisInsight indicates that there are numerous research programs and drugs of varying mechanisms in development, including mechanisms that diverge from directly targeting amyloid beta-protein and tau protein.
Despite the discontinuation of initially promising clinical studies, the outlook for a cure to Alzheimer’s is in no way dismal. An examination of the Alzheimer’s disease drug development pipeline that concluded in January 2018 indicated that there is an increase in non-amyloid mechanism of action in earlier phases of development.  In 2018 there were 112 agents in the pipeline: 26 agents in 35 trials in phase III, 63 agents in 75 trials in phase II, and 23 agents in 25 trials in phase I.  Researchers appear to now be even more motivated to find a cure. As a result, innovative therapies will be explored that could potentially uncover previously unknown information about the nervous system and neurodegenerative diseases.
To learn more about Alzheimer’s drugs and to stay up to date on ongoing clinical trials please visit AdisInsight. 
Image credit: Emily Morter – Unsplash