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European Biopharmaceutical Review

Brain Power

Therapeutic development for Alzheimer’s disease (AD) is experiencing a much needed – albeit cautious – injection of optimism, with more pharmaceutical and biotechnology companies focusing their attention on disease-modifying and symptom-reducing agents. In particular, there is increased focus on combination regimens to tackle the disease’s multiple mechanisms.

Nonetheless, the number of high-profile treatment failures and obstacles to developing appropriate therapeutic combinations for this currently incurable disease make success a challenging prospect. There are only four approved treatments for AD in the US, based on generic memantine and acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine, and efficacy remains limited.

Attacking Multiple Mechanisms

“Combination therapy is certainly the way forward when it comes to diseasemodifying AD therapy, considering combinations are already part of the treatment paradigm for symptomatic medicines in AD,” says Dr Rachelle Doody, Director of the Alzheimer’s Disease and Memory Disorders Center, Houston, US. “The standard of care in the US is an acetylcholinesterase inhibitor, such as generic donepezil, combined with generic memantine.”

In March 2015, Phase 1b data for Biogen’s amyloid-beta targeting therapy – BIIB037 (aducanumab) – had experts optimistic for future AD potential, though caution remains over the preliminary data. If aducanumab does go on to demonstrate Phase 3 efficacy, there is no doubt this could be enhanced with combination therapy. However, following a recent 6mg/kg dosage trial, expectations have been somewhat dampened, with results revealing a high incidence of amyloid-related imaging abnormalities – a potential safety concern.

AD research has largely focused on reducing levels of amyloid-beta in order to reduce plaque formation and, thus far, has proved relatively fruitless, with high-profile Phase 3 trial failures including Pfizer and Johnson & Johnson’s bapineuzumab and Eli Lilly’s solanezumab.

“By the time patients display the cognitive symptoms of AD, there are multiple pathologies at work in the brain,” say Dr John Morris, Professor of Neurology, Washington University, US and Bojana Stefanovic, Associate Professor, Sunnybrook Health Sciences Centre, Canada. “Once the interaction between all the pathological processes is apparent, it becomes clear there is no such single target in AD,” adds Stefanovic.

Tau Burden

Despite the focus on amyloid-beta in drug trials, there is increasing evidence to suggest that Tau burden correlates better with cognitive decline. Tau could be more influential than amyloid-beta in AD-related cognitive decline (1). There are a number of neurodegenerative diseases that are caused by Tau aggregation – so called tauopathies – including progressive supranuclear palsy, Pick’s disease and chromosome 17 linked frontotemporal dementia and Parkinsonism, among others. This highlights the importance of Tau in neurodegeneration.

By the time patients reach advanced AD there are also a number of other pathologies involved, such as alphasynuclein protein aggregation. Research still needs to elucidate the relationship between amyloid-beta and Tau, because if one protein – such as amyloid beta – is targeted and reduced using a drug, it is unknown what will happen to the concentration of Tau. In addition, there are issues surrounding trial design: with no approved disease-modifying drugs, it becomes challenging to have a comparator arm.

Potential Combinations Combination trials of drugs targeting Tau and amyloid-beta are being planned by pharma companies. AC Immune has a diverse pipeline which contains drugs aimed at amyloid-beta and Tau, and it would make sense to test these drugs in combination once they have proof-of-concept data demonstrating target engagement.

Multiple drugs could be targeted to one protein, like amyloid-beta. For example, Merck’s BACE inhibitor, MK-893, could be combined with an immunotherapy that also targets amyloid-beta – such as Biogen’s aducanumab – to enhance efficacy. Furthermore, treatment duration and sequence may also play a major role in the therapeutic paradigm; for instance, antibodies for immunotherapy could be used for a certain period of time and then followed by a BACE inhibitor later.

“While many experts in the field talk about combination therapies and how they are likely to be the future in AD, optimal combinations still have yet to be determined,” says Dr Daniel Michaelson, Professor of Neurobiology, Tel Aviv University, Israel. The dose schedule of drugs will also require extensive work to elucidate optimal efficacy. However, commercial concerns may hinder and delay the industry’s progress; typically, companies do not wish to tie approval of one drug to a second drug, so they may wait for singular approval of the first product before launching combination studies.

Symptomatic Treatments

Psychiatric symptoms and cognitive deficits are all debilitating symptoms of AD, and a number of promising drug candidates are in development for these. Despite no new drugs for AD being approved in over 10 years, it is likely that new symptomatic treatments will reach the market before disease-modifying therapies, due to their aforementioned developmental challenges.

Companies actively involved in developing symptomatic treatments include Forum Pharmaceuticals, Lundbeck, Acadia Pharmaceuticals, Transition Therapeutics and Otsuka Pharmaceutical. The symptoms being targeted are cognitive deficits, psychosis, and agitation and aggression.

Cognitive Deficits

One of the primary features of AD is cognitive deficits, so any treatment that could improve cognition would be considered very important. Targeting the right neurotransmitter systems could be vital in achieving real benefits for patients with the disease.

Forum Pharmaceuticals’ EVP-6124 (encenicline) is currently undergoing a Phase 3 trial for the treatment of cognitive deficits associated with AD and has an estimated primary completion date of January 2017. Encenicline is a selective potentiator of the alpha-7 nicotinic receptor.

“The alpha-7 nicotinic receptor agonist approach holds promise given the loss of this receptor in the disease and its influence on the neurotransmitter acetylcholine,” says Dr Bengt Winblad, Professor of Geriatrics, Karolinska Institutet, Sweden. However, a number of high-profile failures from Roche, Targacept and AbbVie have dented confidence in this approach.

Targeting the alpha-7 nicotinic receptors makes sense, given the expression of these receptors on cholinergic neurons. Up-regulating cholinergic systems through this receptor could also play an important role in other indications – such as schizophrenia – as this mechanism is not specific to AD patients. Since alpha-7 nicotinic receptors are lost during the course of disease progression, it makes sense to target and compensate for the damage to the system.

“One of the ways that encenicline is different from other alpha-7 nicotinic receptor agonists is that it can be considered a partial agonist”, says Dr Gehrard Koenig, Chief Scientific Officer at Forum Pharmaceuticals. “The drug binds to one site at the receptor rather than the full complement of five, which prevents desensitisation,” he explains. This is an advantage as it means the drug will remain effective in the long-term.

“Still, tachyphylaxis (drug desensitisation) remains a concern for all cognitiveenhancement drugs as it appears to feature over time,” suggest Dr Jasmeer Chhatwal, Neurologist at Massachusetts General Hospital and Amy Arnsten, Professor of Neurobiology, Yale University School of Medicine, US. The worry is that if a drug targets a very specific mechanism, the brain can compensate very quickly.

Lundbeck’s Lu AE58054 (idalopirdine), meanwhile, is under investigation in a Phase 3 trial to improve the cognition of patients with mild-to-moderate AD. Idalopirdine is a selective 5-HT6 receptor antagonist. These antagonists bind to serotonin and are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex (2).

The 5-HT6 receptor is expressed largely on GABA interneurons, which inhibit other neurons. Therefore, inhibiting the 5-HT6 receptor on these inhibitory neurons is like ‘taking the brakes off’ other excitatory neurons, which boosts cognition. The drug also appears to have a synergistic effect with approved acetylcholinesterase inhibitors.

Alzheimer’s Psychosis

“Psychosis in AD is a huge unmet need, with approximately a quarter of patients going on to develop symptoms at some stage of the disease,” says Dr Clive Ballard, Professor of Age-related Diseases, Kings College London, UK. Psychosis becomes particularly prevalent in moderate-to-severe patients and is especially common in nursing homes.

“There are no approved treatments for AD-related psychosis, and classic antipsychotics cannot be used off-label because of black box warnings for their use in elderly patients due to increased risks of mortality”, says Dr Herbert Meltzer, Professor in Psychiatry and Behavioural Sciences, Feinberg School of Medicine, US.

Acadia Pharmaceuticals’ Nuplazid (pimavanserin) is under investigation in a Phase 2 trial for AD psychosis, with the trial set to finish in November 2015. Pimavanserin is a small molecule that acts selectively as an antagonist/ inverse agonist on serotonin-2A (5- HT2A) receptors. Patients with AD who experience delusions and hallucinations often have a polymorphism in the 5-HT2A receptor, which leads to its increased activity. As a result, the inference from genetic studies is that, in order to reduce psychosis, a drug targeting 5-HT2A receptors is required – something like pimavanserin. Tests show that serotonin plays an important role in psychosis, and drugs controlling this system could be a strong strategy for managing this symptom.

Agitation and Aggression

“Irritability, agitation and aggression is seen throughout all stages of AD, though is more common in moderate and early-severe AD patients,” says Dr Anton Porsteinsson, Professor of Psychiatry, University of Rochester Medical Centre, US. “Agitation and aggression can be a debilitating problem and up to 70% of AD patients will experience bouts of this symptom, indicating a great unmet need for treatments,” he explains.

Earlier this year, it was reported that Acadia was investigating pimavanserin for signs of efficacy in patients experiencing agitation and aggression with AD. Meanwhile, Otsuka’s AVP-923 (dextromethorphan/quinidine sulphate) recently completed a positive Phase 2 trial in agitation associated with AD.

“Agitation appears to be a matter of frontal-lobe limbic system interaction and, when patients react to emotional triggers, the frontal lobes supress anger and agitation, so that patients behave in a socially acceptable manner,” says Dr Deborah Gelinas, Associate Professor of Neurology, Michigan State University, US. In AD, patients lose large portions of the frontal lobes due to neuronal loss and lose this inhibition. Therefore, the drug AVP-923 tries to modulate N-methyl-Daspartate receptors in nerve cells, allowing patients to regain some of their inhibition. There is little doubt this is an effective mechanism to treat agitation, and there has been cautious optimism among experts regarding its potential in the treatment of AD.

Despite widespread drug development for AD and its related symptoms, the disease still remains one of today’s major unmet medical needs. There remains expert debate on the appropriate drug combinations and mechanisms to target, and how best to approach a reduction in related symptoms, such as cognitive deficits, psychosis, and agitation and aggression.


1. Murray ME et al, Clinicopathologic and 11C-Pittsburgh compound B implications of thalamyloid phase across the Alzheimer’s disease spectrum, Brain 138(5): pp1,370-1,381, 2015
2. Wilkinson D, Windfeld K and Colding-Jorgensen E, Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): A randomised, double-blind, placebocontrolled phase 2 trial, Lancet Neurology 13(11): pp1,092-1,099, 2015

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Hamish McDougall has a BSc in Neuroscience from the University of Sussex, UK and is primarily covering the neuroscience indications for BioPharm Insight where he is a reporter. Previously, he was Assistant Commissioning Editor for a well-known collection of biomedical journals at Expert Reviews, including Expert Review of Gastroenterology & Hepatology, Expert Review of Clinical Pharmacology and Expert Review of Respiratory Medicine.

Peter Murphy has a first-class honours BSc degree in Chemistry with Medicinal Chemistry from Newcastle University, UK, from where he was also awarded the Wynne-Jones Book Prize for outstanding performance. Peter undertook three years of medical school training before joining the BioPharm Insight team as an editorial analyst.

Hamish McDougall
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