Alzheimer’s drug discovery: Leaving no stone unturned

March 7, 2019 0 By S Harachand

A large number of potential therapeutic candidates have been studied for Alzheimer’s disease for the last two decades with very few reaching the final stage of commercialisation.

As per the National Institutes of Health registry of the US, 244 drugs for Alzheimer’s were tested in clinical trials registered in the decade of 2002-2012. However, only one — memantine — could win approval from the US FDA.

Traditionally, the drug discovery for Alzheimer’s has been riddled with impeding factors like the slow pace of clinical study recruitment, the inability of animal models to reliably predict whether an experimental treatment will work in humans and the relatively long time needed to observe whether an investigational treatment affects disease progression.

Today, the Alzheimer’s drug discovery pipeline consists around 120 potential therapies at various stages of development, according to the data provided by Alzheimer’s Drug Discovery Foundation, a non-profit organisation based in New York, which supports drug discovery for Alzheimer’s. The studies explore various targets implicated in the development and the progression of the disease as biological processes go awry with age. They include impaired clearance of toxic misfolded proteins of amyloid and tau, chronic systemic inflammation and neuroinflammation, mitochondrial and metabolic dysfunctions, vascular problems, loss of synapses, epigenetic changes, ApoE gene and neuroprotection mechanisms.


Misfolded protein targets

Nearly two-dozen drugs are in advanced phase 3 clinical trials. The later-phase trials are dominated by drugs targeting beta-amyloid and tau, the classic pathological hallmarks of Alzheimer’s disease. While 52% are targeting amyloid or tau, other strategies are gaining ground and are in phase 1 or 2 trials.

One of the most notable candidate molecules is Eisai’s BAN2401, which has been found to reduce amyloid in the brain of 81% of patients and slow cognitive decline in 30%. BAN2401’s was the first late-stage study data that successfully demonstrated potential disease-modifying effects on both clinical function and amyloid beta accumulation in the brain, and provides compelling evidence to support the amyloid hypothesis as a therapeutic target for Alzheimer’s disease, Eisai said.

However, the additional clinical data from a sub-trial in prodromal and mild Alzheimer’s patients presented by the company in the 11th Clinical Trials on Alzheimer’s Disease Conference (CTAD) in Barcelona in October 2018 showed no significant difference in the rate of cognitive decline for placebo patients, based on the presence of ApoE- e4 allele, a genetic risk factor for Alzheimer’s.

Beside BAN2401, which came out of a strategic research alliance between Eisai and BioArctic, the Japanese drugmaker has three more product candidates for Alzheimer’s in the clinical stage . These are -site amyloid precursor protein cleaving enzyme (BASE) inhibitor elenbecestat and anti-Aß antibody aducanumab — both in Phase 3 — and anti-tau antibody E2814, which is currently under preparation for Phase 1, said a spokesperson from Eisai.

”We have three candidates targeting Aß, as such BAN2401, aducanumab and elenbecestat. The accumulation of Aß is considered to accelerate the tau pathology and might be the cause of neuronal cell death, resulting from the accumulation of tau. The accumulation of aggressive factors such as Aß and tau is the potential target of Alzheimer’s disease treatment”, she said.

Two Phase 3 studies for elenbecestat in patients with early Alzheimer’s disease are ongoing. According to Eisai, the Phase 2 study conducted in the U.S. was the first study of a BACE inhibitor to show a statistically significant difference in amyloid beta in the brain while also suggesting a delay in the decline of clinical symptoms in exploratory endpoints.

Regarding aducanumab, two Phase 3 studies are ongoing, and patient enrolment was completed in July 2018.

The Swiss drug giant Roche currently has two phase 3 programmes for Alzheimer’s – crenezumab and gantenerumab, both targeting beta-amyloid. They have another monoclonal antibody in phase 2, targeting tau, according to World Alzheimer Report 2018 by Alzheimer’s Disease International, UK.


Repurposed candidates

Some of the existing drugs are also being tested for their potential in Alzheimer’s treatment through what is called repurposing. Repurposing involves the testing of a drug that is effective in one field to see if it’s effective in another.

The cholesterol-lowering drug gemfibrozil can be effective in reducing the levels of amyloid and brain inflammation in preclinical studies conducted in mice, showed the result of a study presented at Alzheimer’s Association International Conference (AAIC). Gemfibrozil, a micro-RNA pathways modulator, works as an agonist of the peroxisome proliferator-activated receptor a (PPARa). An early pre-clinical study of the repurposed gemfibrozil is underway to understand its effect on amyloid plaque pathology, neuroinflammation and memory in subjects with intact cognition and mild cognitive impairment.

The BEACON (Blocking Endothelial Activation to Curb the Onset of Neurodegeneration) trial is evaluating the efficacy of dabigatran, a direct thrombin inhibitor, to slow down the harmful cascade in the early stages of Alzheimer’s disease. Dabigatran is currently approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the treatment and to reduce the risk of reoccurrence of deep venous thrombosis and pulmonary embolism. Research has shown that factors such as high blood pressure, diabetes and stroke can injure blood vessels in the brain, resulting in inflammation that could cause damage to or the death of brain cells that occurs in Alzheimer’s disease. The Phase I study will look into the possible role of the brain’s blood vessels in Alzheimer’s disease and the effects of the drug dabigatran in a repurposed use.

Nabilone, a synthetic cannabinoid antiemetic used in chemotherapy, is another potential repurposed candidate being investigated. Researchers from Sunnybrook Research Institute, University of Toronto, recently presented the results of a safety and efficacy study of nabilone in patients with moderate to severe AD. The data showed that nabilone significantly improved agitation in a trial of 39 moderate-to-severe Alzheimer’s patients. Improvements were observed with nabilone as early as two weeks. Some patients experienced sedation with nabilone, though 53 percent of the patients tolerated the highest dose (2 mg/day). As the pilot study showed positive results, a larger Phase 3 study is being planned. Agitation is a common and persistent symptom in those with Alzheimer’s disease and current pharmacotherapies have modest efficacy and poor safety. This study is funded by the ADDF and the Alzheimer’s Society of Canada.

Rotigotine, a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson’s disease (PD) and restless leg syndrome, is under investigation as a potential cognitive enhancer for Alzheimer’s. Recently, preliminary findings from the DOPAD trial, which tests the dopaminergic therapy, were presented. The trial in 94 mild Alzheimer’s patients tested whether rotigotine improved cognitive function, including executive function, and activities of daily living after six months of treatment.


Focus on synapses

The focus of a few of the clinical studies are synapses, the junctions between nerve cells, which are important for memory and cognition. Current treatments increase levels of the neurotransmitter acetylcholine with modest impact on Alzheimer’s symptoms.

Researchers from Vanderbilt University Medical Center reported preliminary results from a Phase 1 study of novel drug compound VU319 that modulates muscarinic (M1) synaptic receptors. So far, a total number of five doses of VU319 have been tested in patients and they have been well-tolerated. After analysing the data from a multiple-ascending dose study to assess the safety and tolerability of seven consecutive-day dosing, the researchers are aiming a Phase 2a VU319 study in people with mild cognitive impairment in the latter half of 2019. It will be a proof-of-concept, double-blind, placebo-controlled study to assess the ability of VU319 to modulate brain networks. Previous drugs targeting M1 produced improvement in cognitive performance and behavioural disturbances in Alzheimer’s patients, but failed in Phase 3 trials due to intolerable (cholinergic) side effects, as per ADDF data.

Other candidates targeting synaptic activity and neurotransmitters include Takeda’s TAK-071 (Phase 1) as a combination treatment with donepezil, a palliative treatment for Alzheimer’s, Agenebio Inc’ s AGB101 (Phase2/3), Heptares’ HTL0009936 (Phase 1), H Lundbeck/Otsuka’s Lu AE58054 (idalopirdine) 5-HT6 receptor antagonist and Boehringer Ingelheim’s BI 409306 phosphodiesterase 9A inhibitor (Phase 2).


ApoE approach & cell therapy

Several gene therapy and stem cell approaches for dementia are in the experimental stage. Among the genes, ApoE4 is the most targeted genetic risk factor for Alzheimer’s disease. People with two copies of the ApoE -e4 variant of the gene are up to 12 times more likely to develop Alzheimer’s and to get it at younger ages. Dr Ronald Crystal of Weill Cornell Medicine uses ApoE- e2, the protective variant of the gene delivered to the brain, to counteract the negative effects of ApoE -e4. Dr Crystal recently received FDA approval to proceed to the first human clinical trials with ApoE2 gene therapy. In a different approach, Dr Anastasia Khvorova et al. of the University of Massachusetts Medical School are developing RNAi constructs, which are called anti-sense oligonucleotides, to reduce APOE gene expression, according to the ADDF, which funds the studies.

Ageless Regenerative Institute is studying adipose-derived stromal cells as a cell therapy approach to protect neurons. The investigations have reached Phase 2 stage.

AstroStem by Nature Cell Co. Ltd is another stem cell therapy being explored in Phase 1/2. Some of the leading pharmaceutical companies, including Novartis, Eli Lilly, Janssen, Biogen, AbbVie, AC Immune, AB Science, AstraZeneca, Genentech, Sanofi, MSD as well as universities and Alzheimer’s organisations are also working on the Alzheimer’s drug pipeline, which is broadening by the day.