A recent review, in Nature Reviews Neurology, has provided an overview of the promising compounds for clinical trials in individuals with Alzheimer’s disease. It also highlights emerging evidence on the use of transcriptional signatures to identify novel candidates for repurposing.
More than 40 million people worldwide have Alzheimer’s disease (AD). Scientists expect that this will increase to more than 100 million by 2050 due an increasingly ageing population. AD is a devastating neurodegenerative disorder that has both a personal and financial impact on sufferers, families and society.
The main pathological mechanism of AD is the buildup of amyloid plaques and neurofibrillary tangles. Other mechanisms implicated, include neuroinflammation, protein misfolding, mitochondrial dysfunction and clearance of abnormal proteins. Within the past 20 years, only two new pharmacological therapies have become available. In fact, China is the only country to have licensed one of these therapies – oligomannate.
Drug repurposing in Alzheimer’s disease
The aim of drug repurposing is to identify new indications for agents, other than the indications that they were originally intended for. Drug repurposing offers an attractive way of enhancing traditional drug development and accelerating arrival of new treatments. Phase II trials assessing repurposed agents must consider the most suitable target population for the candidate treatment and its mechanism of action.
In this review, authors performed a systematic review of the literature and evidence available from repurposing routes to identify the best candidate compounds for AD treatment. They also performed a Delphi consensus with a series of experts to evaluate the evidence and rank the candidates. This methodology was an update on the systematic review and Delphi consensus published in 2012. Authors excluded priority candidates from the 2012 census from the second one.
The 2012 Delphi consensus
In 2012, the Delphi consensus prioritised five classes of compounds for AD repurposing. These classes include: tetracycline antibiotics, calcium channel blockers, angiotensin receptor blockers (ARBs), glucagon-like peptide 1 (GLP1) analogues and retinoid therapy. All of these classes of compounds, apart from retinoid therapy, have now been taken into clinical trials. Unfortunately, evidence from the completed trials of the tetracycline antibiotic minocycline, the calcium channel blocker nilvadipine and the ARB losartan showed no significant benefits. The emerging evidence for the use of GLP1 analogues has been more encouraging than the other prioritised compounds, particularly in preventing incident dementia in people with diabetes. As a result, they remain a high priority candidate for repurposing.
New priority compounds
In the 2018-2019 Delphi consensus, experts nominated a total of five compounds for further consideration. These included: ACE inhibitors, antiviral drugs, disease-modifying antirheumatic drugs (DMARDs), fasudil and phenserine. After several round of prioritisation, the panel regarded fasudil, antiviral drugs and phenserine as the highest priority candidates (summarised below).
Fasudil is a selective inhibitor of rho kinase (ROCK) 1 and 2. It is a potent vasodilator, particularly of the cerebral vasculature. Japan and China have approved fasudil for the treatment of cerebral vasospasm following subarachnoid haemorrhage. In 2009, the use of fasudil in AD became apparent, when studies showed that administration of fasudil associated with protection against age-related memory impairment in rats. Results from various preclinical studies have suggested that fasudil targets classic AD neuropathology. It achieves this by targeting amyloid burden and other pathological mechanisms, such as inflammation and synaptic damage.
Scientists initially developed phenserine as a cholinesterase inhibitor. However, evidence has emerged that suggests it may be able to reduce neuronal and synaptic loss. Overall, preclinical evidence has shown that phenserine has biological effects that are important in the treatment of AD and other nondegenerative conditions. Importantly, it has shown a newly identified influence on apoptosis. While phase II studies have been promising, the authors suggest that the results should be interpreted with caution due to small sample sizes and short trial durations. Evidence has also shown that phenserine has a good clinical safety profile.
In 1991, scientists hypothesised that herpes simplex virus (HSV) was a risk factor in the development AD. Since then, evidence, particularly from post-mortem studies, have revealed that HSV-1 may promote accumulation of amyloid plaques. In vitro studies using antiviral drugs have also resulted in reduction in amyloid beta and tau accumulation as well as levels of HSV-1. Other epidemiological research has shown that participants with HSV-1 treated with anti-herpetic medication have a significantly lower risk of developing dementia than those who were not treated. The existing evidence suggests that antiviral drugs may be more effective at diminishing the risk of AD or delaying onset, than as a treatment for individuals who have already developed AD.
Experts selected prioritised drugs in this review based on the drugs established mechanisms of action. A key strategy for identifying novel compounds for preclinical testing and clinical trials is transcriptional profiling. The authors believe that researchers could apply this approach to identify drugs for repurposing. They propose that as disease or injury can alter gene expression, creating a transcriptional signature, then a drug that alters gene expression in an opposing manner could have therapeutic effects.
Several projects, such as the CMAP and LINCS, have collated transcriptional signatures induced by several compounds. There are widely available transcriptional profiles for early, middle and late stages of AD. Signatures from early and mild AD have been probed in both CMPA AND LINCS data, identifying 78 drugs that inversely correlated with the AD signature. Out of these, 19 were found to significantly reduce AD-associated changes. This approach could substantially increase the scale of identification of candidate compounds.
Complementing traditional drug discovery approaches with drug repurposing reduces costs and results in faster drug approval. Nevertheless, the need for novel methodologies to identify and screen new candidates, like transcriptomic approaches, is critical. The authors note that expanding funding to streams that prioritise this work and providing better commercial incentives for repurposing will also be essential.