Beyond the amyloid hypothesis – how small molecules are giving hope to Alzheimer’s research

Ever since it was discovered in 1906, scientists have been rushing to find a cure for Alzheimer’s disease – a form of dementia that affects 1 in 10 Australians aged over 65.

In recent years, the bulk of this research has been centred on the ‘amyloid hypothesis’, which highlights the role amyloid plaques and tau tangles play in the onset and progression of the disease.

Research has largely supported the idea that accumulation of both protein molecules in the brain is responsible for cognitive decline in Alzheimer’s, with amyloid acting as the gun and tau as the trigger.

With this knowledge, the pharmaceutical industry has so far invested billions of dollars on researching potential amyloid antibodies in its bid to strip the molecule from the brain.

The best of these, including Eisai’s Leqembi and Lilly’s donanemab drugs, have managed to remove amyloid quickly and profoundly, but have only made modest clinical improvements to individuals with Alzheimer’s. Such antibodies can slow the progression of Alzheimer’s by around 25-30 percent, according to phase 3 clinical trials.

Some argue that any improvement on cognitive decline among those living with dementia is positive; and support the FDA’s recent decision to grant accelerated approval for drugs like Leqembi.

Meanwhile, others claim the results are too modest to outweigh any risks, or even to validate further research on amyloid antibodies as a potential cure for Alzheimer’s.

Actinogen Managing Director Dr Steven Gourlay – a speaker at this year’s Cognitive Decline Emerging Treatments and Trends Forum – says it was once logical for pharmaceutical therapies to pursue amyloid antibodies, but the data demonstrates a clear need to move on to other mechanisms.

“A while ago, there was an expectation that we could just zap amyloid with an antibody and this would ‘cure’ the disease or stop the progression completely – and it certainly wasn’t a terrible idea. But it is pretty dramatic that after billions of dollars and three decades, the amyloid hypothesis has only recently produced two molecules with modest efficacy. Given that the new antibodies clear amyloid quickly and completely, other approaches to amyloid are unlikely to further improve efficacy. With antibody drugs also linked to brain swelling and rare cases of mortality, I think it is sensible to pursue alternative or additional hypotheses,” he said.

Small molecules are providing hope

As the amyloid hypothesis loses steam, a number of alternative solutions are gaining traction, particularly those involving small molecule targets.

Older small molecule therapies temporarily improve aceteylcholine nerve transmission in the brain and were first approved in the 90s. They improve cognition in the short term but do not appear to impact progression of the disease or be particularly durable in their effect. These drugs are anticholinesterase inhibitors such as donepezil, rivastigmine and galantamine and an NDMA inhibitor called memantine.

Numerous new small molecules are currently being developed to treat Alzheimer’s, with some already demonstrating positive effects on human cognition.

One group of these is targeting ‘amyloid adjacent’ mechanisms, which are designed to reduce or prevent amyloid formation and/or toxicity. Given the modest benefits of clearing amyloid with antibody therapy, the potential efficacy of this group is probably capped at the efficacy seen for the newer antibodies like Leqembi. There is not much logic in combining such molecules with an approved amyloid antibody either.

Other research on small molecules is targeting non-amyloid mechanisms. Actinogen’s lead molecule Xanamem, for example, reduces levels of the “stress hormone” cortisol in the brain.

“Non-amyloid approaches could help us treat the majority of the unmet medical need that amyloid antibodies can’t help with. Decreasing brain cortisol as a therapy is encouraging because it is known to be toxic, pro-inflammatory and strongly associated with cognitive decline” said Dr Gourlay.

Xanamem has already demonstrated promising results in several placebo-controlled trials. It reduced functional and cognitive decline in biomarker-positive patients with mild Alzheimer’s and was also found to improve attention and working memory in two Phase 1b trials in older volunteers.

If the findings in patients with biomarker-positive Alzheimer’s are replicated in future, larger and longer trials, Xanamem’s clinical effect could be eight times larger than that of the Leqembi amyloid antibody. To date, it is the only non-amyloid therapeutic that has demonstrated clinical efficacy in multiple controlled trials.

Xanamem will soon enter a global phase 2b trial using 330 patients similar to those in its prior trial, with biomarker-positive early-stage Alzheimer’s deemed likely to progress over the 9-month treatment period.
One existing diabetes and weight loss treatment is also giving hope.

According to Novo Nordisk, their oral semaglutide treatment is associated with a 50 percent reduction in dementia risk, adding weight to the theory that insulin resistance, obesity and metabolic disease are relevant to Alzheimer’s.

This finding is also encouraging in that it overlaps with the findings from Actinogen’s research.

“By reducing tissue cortisol you reduce insulin resistance as well as impacting inflammation” Dr Gourlay explained.

Anavex also produced positive phase 2 data for its oral blacarmasine drug – a SIGMAR1 agonist. However, a side-effect of the drug was confusion, raising concerns about its suitability as an Alzheimer’s drug. Additionally, there were complexities around the presentation of data.

“In the presentations released so far, the dose groups were pooled making it unclear whether a lower dose is viable,” Dr Gourlay said.

Singapore company, TauRx has been studying an oral tau inhibitor based on the chemical Methylene Blue but, after many years, has failed to produce positive data in controlled studies. Tau antibodies are also being tested but published trial results have been negative for a number of anti-tau antibodies so far.

Meanwhile, Biovie is progressing its NE3107 molecule through a phase 3 trial but, as yet, doesn’t have strong cognitive data behind it.

Green Valley from China already has its non-amyloid Alzheimer’s drug on the market in China after a single positive phase 3 trial. A second, global phase 3 trial was suspended during the COVID-19 pandemic and the status of ex China developments is unclear.

Where does this leave us?

Being the only non-amyloid approach to have demonstrated clinical efficacy over multiple trials, Dr Gourlay believes his molecule has a “serious chance” of gaining TGA and FDA approval within the next few years for Alzheimer’s.

“Big pharma has viewed cortisol as a ‘hot target’ for decades, but until now we haven’t had a molecule that truly penetrated the brain adequately to inhibit brain cortisol synthesis and truly test the ’cortisol hypothesis’. It is exciting that we are getting close to major phase 2 clinical readouts on this.

“Xanamem is a highly active molecule and we know the right dosage to give after testing the drug in a PET brain scan study in Melbourne. That study proved that the drug gets into the brain and binds to is target. We are moving quickly into a phase 2b in 330 people – a global study that we expect to report results in 2025.”

At present the molecule is being explored as a way to both provide symptomatic benefit and to halt progression of Alzheimer’s disease, but Dr Gourlay says using it as a way to prevent the disease may also make sense once it is proven to work.

“Increasing cortisol in the brain is potentially part of programmed aging, presumably exaggerated in patients with Alzheimer’s. There is certainly theoretical scope for this to become a preventative line of therapy not only for AD but for other conditions with cognitive impairment,” he said.

If successful, Dr Gourlay anticipates his drug being prescribed alone or in combination with anti-amyloid antibodies or existing therapies such as an acetylcholinesterase inhibitor like oral donepezil. Novel non-amyloid therapies, like that by Nova Nordisk, would likely compete if successful in trials, he says.

“Nova is spending some serious money to see whether it can prevent Alzheimer’s and if successful it is likely to be an early treatment. Combination of multiple therapies may well be the future in Alzheimer’s as it is in most chronic diseases.”

That said, Dr Gourlay cautions against over-optimism when it comes to Alzheimer’s therapeutics.

“Most drugs in Alzheimer’s disease have failed. People don’t understand the biology fully – amyloid being a case in point. Who would have thought you could completely strip out amyloid from the brain but only slow disease progression by a 25-30%? It is certainly a more complex condition than we previously thought and not a space in which we can get complacent.”

Dr Gourlay has more than thirty years of experience in the development of novel therapeutics and brings considerable skills and experience to the clinical program for Xanamem. Formerly the founding Chief Medical Officer (CMO) at successful US-based Principia Biopharma Inc., Dr Gourlay was responsible for the supervision of multiple pre-clinical, first-in-human, Phase 2 and 3 clinical trial programs in orphan immunological diseases, multiple sclerosis and cancer. Dr Gourlay has significant small molecule regulatory experience with the US Food and Drug Administration (FDA), European Medicines Agency (EMA) at many levels.

Hear more from him at the upcoming Cognitive Decline Emerging Treatments and Trends Forum, as part of the National Dementia Conference.

This year’s event will be held 21 – 22 June at the Crowne Promenade Melbourne.

Learn more and register your place here.