How close are we to a disease-modifying treatment for Alzheimer’s?

Figures from 2015 suggest there are an estimated 46.9 million people living with dementia worldwide, the majority of these will have Alzheimer’s; the annual incidence is estimated at 9.9 million, almost 30% higher than the comparable estimate for 2010 of 7.7 million. The prevalence is expected to continue to escalate dramatically, an anticipated 74.7 million people will have dementia in 2030, rising further to 131.5 million in 2050. The treatments currently available are predominantly cholinesterase inhibitors – drugs designed to increase the amount of acetylcholine available in synapses, making transmission of neuronal impulses more likely. In practice, this has only provided a symptomatic benefit for some patients. However, it is anticipated that we are on the cusp of a revolution in the management of Alzheimer’s disease, with a selection of potentially disease-modifying drugs nearing launch.

There are several potential targets available, and numerous drugs that are currently in a late stage of investigation. These range from dietary supplements intended to encourage the brain to use ketone bodies instead of glucose as an energy source, to both active and passive immunotherapies that act against amyloid beta plaques. In this article, we take a look at the most promising new drug classes.

BACE inhibitors

Figure 1. Plaque formation.

Beta-secretase-1 (BACE1) is one of two enzymes responsible for cleaving the amyloid precursor protein (APP), allowing the formation of amyloid beta. The normal function of amyloid beta is not clear at present – animal models have demonstrated no discernible lack of physiological function in its absence. The formation of plaques may be initiated by an initial mal-folded molecule that acts as a seed. There are several drugs which aim to inhibit BACE1, preventing the build-up of amyloid and theoretically preventing further accumulation of plaques. This could be applicable in two potential settings – either initiated early in the disease process alongside detection/screening strategies, or in more advanced disease allied with a drug that has an action against the plaques that already exist. Trials to date have failed to show convincing evidence, but have typically been started in patients with established disease, and some controversy persists over whether amyloid plaques are a cause or an effect of AD.

Figure 2. Enzymatic pathway resulting in amyloid plaques.
APP, amyloid precursor protein; CTF, C-terminal fragment; AICD, APP intracellular domain.

There are several drugs in this class currently in development, the most advanced of which are lanabecestat, verubecestat, elenbecestat, JNJ-54861911 and CNP-520. These are all in at least phase 3 trials. There have been several failed attempts at BACE1 inhibition, largely due to toxicity, while lack of efficacy has suggested that they may need to be explored in earlier disease to be beneficial. 

• Lanabecestat (formerly AZD3293) has skipped phase 2 trials, and is currently undergoing a phase 2/3 and a phase 3 trial (AMARANTH and DAYBREAK-ALZ). There are no published data available yet – the trials are expected to produce their first results in August 2019, it has received fast track designation from the FDA.
• Verubecestat had a phase 2/3 trial (the EPOCH study) stopped in Feb 2017, as it became increasingly obvious that it would not meet its primary endpoint (change from baseline in cognitive score measured by the ADAS-Cog tool), although there were few adverse events. Verubecestat had shown a reduction in cerebro-spinal fluid (CSF) amyloid beta in phase I trials, and there is a phase 3 trial ongoing that started treatment in prodromal (early symptomatic) AD patients – this is due to complete in February 2019.
• Elenbecestat has also demonstrated a dose-related reduction in amyloid beta plasma levels, and a phase 3 study (MISSION AD) has been initiated. With enrolment starting in October 2016, it will be some time before results are available.
• CNP520 underwent a dose-ranging phase II trial that completed in early 2016, and has progressed to a phase II/III trial (Generation S1). The latter trial is testing a combination of CNP520 with CAD106 – an immunotherapeutic vaccine treatment aiming to prime the immune system to breaking up amyloid.
• JNJ-54861911 has completed a phase II trial, which demonstrated reduction in amyloid beta and action of the drug in both the blood and CSF. A phase II/III trial is recruiting and ongoing until 2023.

Immunotherapy

As with many other potential therapeutic areas, immunotherapy has proven to be a tempting tool to explore. There are two main mechanisms suggested – either passive or active approaches. The passive immunotherapeutic approach seeks to design monoclonal antibodies which are able to cross the blood-brain barrier and exert a direct action on amyloid plaques – breaking them up in the process. The active approach attempts to engender recognition of the amyloid protein by the host immune system leading to its degradation. In theory, these agents may form part of a dual therapy as mentioned above – able to clear plaques, while other agents prevent further accumulation.

There are currently five immunotherapy agents in late-stage trials: aducanumab, CAD106, crenezumab, gantenerumab and solanezumab.

• Aducanumab is an IgG monoclonal antibody that binds to parenchymal amyloid and has been noted to clear plaques in both animal models and humans. There are two phase III trials exploring whether these findings have a clinical impact, ENGAGE and EMERGE, both due to complete in early 2022.
• CAD106 is an active vaccination therapy that has shown itself to be relatively well tolerated; sustained anti-amyloid beta antibodies were noted in patients with mild Alzheimer’s disease. It is under investigation in combination with the BACE inhibitor CNP520 as discussed above.
• Crenezumab is another passive immunotherapy under investigation. Early investigations revealed a decrease in CSF amyloid beta, but no difference in plaques was seen on imaging. A large-scale phase II trial is ongoing, studying cognitive decline in patients with preclinical disease; while a phase 3 trial has also commenced, due to complete in mid-2021.
• Gantenerumab is a human IgG antibody – as with other passive immunotherapies it is designed to bind to a target on amyloid beta molecules and cause degradation. A previous phase III trial had the dosing arm halted (although follow-up continues) due to futility, while two further phase III trials are in their early stages. A parallel phase II/III trial is due to complete in 2023.
• Solanezumab is also an IgG monoclonal antibody, but is somewhat different in that its molecular target is soluble monomeric amyloid beta – theoretically removing the small soluble variants that are toxic to synaptic function. A completed phase 3 trial failed to meet its clinical endpoint of slowing cognitive decline with significance, however there was benefit demonstrated for many secondary endpoints – leading to two trials being initiated for exploration of secondary prevention in ‘at-risk’ individuals.

Figure 3. Model of amyloid beta molecule.

Inflammation theory

Another avenue of research is into the potential role that inflammation may play in the pathogenesis of Alzheimer’s disease. Pathological evidence has long demonstrated activation of pro-inflammatory pathways – while observational studies have suggested that people on long-term anti-inflammatories have less risk of developing the disease. The exact nature of this link has not been firmly established or explored, however there is ongoing research into the role inflammation suppression may play in the prevention or management of Alzheimer’s disease. There are three agents in late stage investigation that are linked to the inflammation hypothesis: ALZT-OP1, azeliragon and masitinib.

• ALZT-OP1 is a combination regimen of two-pre-existing drugs: ibuprofen and cromolyn. Ibuprofen is a well-established non-steroidal anti-inflammatory, while cromolyn is a mast-cell stabiliser. There is a 600-person trial ongoing into this regime with four treatment arms – variations of active treatment and placebo.
• Azeliragon inhibits the action of RAGE – a receptor found on numerous cell-types. RAGE binds with modified lipids that can become glycalated and play a role in inflammation. RAGE also binds to amyloid beta – it has been noted to be upregulated in patients with Alzheimer’s and may be involved with the transport of precursors into the brain. A phase II trial started in 2007 and was terminated due to safety signals and faster deterioration at high doses, while later analyses suggested a potential benefit for those on lower dose. This resulted in a new trial being initiated due to complete in early 2019.
• Masitinib influences the survival, migration and activity of mast cells, having a theoretical role in treating neuroinflammation. Tolerability has been an issue, although there was an apparent slow in cognitive decline noted in the phase II trial. A phase II trial is ongoing, with an interim analysis expected in 2017 at some point.

Neurovascular theory

Although Alzheimer’s has a separate pathogenesis compared to vascular dementia, there has nonetheless been research into whether drugs which improve the reliability of cerebral bloodflow can counter Alzheimer’s disease. Carvedilol, nilvadipine and prazosin are all under examination to determine whether they may have an impact.

• Carvedilol is a widely available adrenoreceptor antagonist and vasodilator used primarily in hypertension. Theoretically, mitigating neurovascular dysfunction may slow cognitive decline, while some epidemiological evidence has supported mid-life hypertension as a risk factor for Alzheimer’s. At present, a pilot study has completed but is yet to report.
• Nilvadipine is a calcium channel blocker used for treatment of hypertension. A few small-scale studies have demonstrated improvement in cerebral blood flow and some cognitive measures. These have served as the basis for a larger trial – although this completed in early 2017, these data have yet to be reported.
• Prazosin is an alpha-1 adrenoceptor blocker, primarily prescribed for hypertension as an anti-vasoconstrictive agent but also used in prostatic hypertrophy. It has been reported to decrease amyloid plaques in mice models, and is part of a growing theory linking amyloid deposition with neuroinflammation and hypertension. It was shown to outperform placebo in a small-scale study, while a further trial was reportedly planned there is little further detail available.

There are other drugs in development which are less straightforward to categorise:

• Currently designated LMTM or TRx0237, this drug is a second-generation tau protein aggregation inhibitor, and a successor to Rember. The compound consists of a small molecule based on methylene blue with the aim of preventing aberrant tau protein formation and dissolving existing aggregates. Although phase III results have been disappointing thus far, the suggestion that it may produce benefit as a monotherapy is under investigation, and a trial was due to complete in September 2017 – although results have yet to be published.
• AC-1204 is a successor to a medical food product named Axona. The rationale is to provide an alternative energy source to glucose, boosting cellular metabolism. There are several trials ongoing, the first of which reported failure to meet its endpoint – potentially due to poor bioavailability.

Alzheimer’s is clearly a therapeutic area in much need of meaningful, disease-modifying treatments. It is reassuring that there is much research into this area, however, to date the trials which appear positive have largely displayed a small effect. This may indicate that the pathogenesis is more complex than previously thought and the role played by amyloid beta may require further elucidation. It is clearly a problem which is growing and will continue to grow; as the scale becomes increasingly apparent, the relative investment towards developing an effective treatment or combination treatment will hopefully grow.

Further reading

ALZFORUM – Networking for a cure. Available at http://www.alzforum.org/

Alzheimer’s association. Alz.org Research Center – treatment horizons. Available at http://www.alz.org/research/science/alzheimers_treatment_horizon.asp

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimer's Research & Therapy 2016 8:39