Searching for new hope in Alzheimer’s

For the best part of two decades, it seemed as if pharma hit a brick wall as it tried to find new treatments for Alzheimer’s. But successive trial failures could pave the way for a radical new way to treat the disease, according to the CEO of a small Slovakian biotech that believes it could finally have a drug that could slow its progression. pharmaphorum’s Richard Staines met with Axon Neurosciences’ Michal Fresser to find out more.

This year saw yet another seemingly catastrophic Alzheimer’s trial failure, as results from Biogen’s phase 3 study of amyloid-targeting aducanumab drew a blank yet again.

This was followed shortly after by the failure of Biogen and Eisai’s BACE inhibitor elenbecestat, a class of drugs aimed at the mechanism that causes the rogue clumps of amyloid protein that have been linked with Alzheimer’s.

They were the latest in a long series of trial failures as pharma companies attempt to find drugs that can slow or stay disease progression.

To everyone’s surprise, Biogen later said that aducanumab did in fact show some benefit after a fresh look at the data – but this no guarantee of approval, and there still has not been a new drug approved for Alzheimer’s since memantine in 2003. The existing drugs can only help manage symptoms, instead of treating the underlying the cause of the disease.

Until recently pharma trials have focused on the theory that amyloid clumps were responsible for neural degeneration that causes Alzheimer’s.

This line of thinking suggests that amyloid protein seen in the brains of people with Alzheimer’s is a side-effect of the mechanism causing neurological destruction.

After so many failures, attention is switching to the other possible culprit, a protein called tau that has been seen to build up within neurons of people affected by Alzheimer’s.

Tau proteins are a naturally occurring part of neurons, helping to stabilise the microtubules that are an essential part of the cell’s structure.

But in Alzheimer’s these tau proteins seem to go rogue, and form into tangles – and the theory goes that these tangles are responsible for the destruction of the synapses that link nerve cells together in the brain.

Several biotechs are now looking into ways to stop the formation of these tangles, after the repeated failure to tackle the disease by targeting amyloid.

TauRx has a phase 3 trial under way to test the efficacy of its tau-targeting drug, while scientists based at Washington University School of Medicine think that the cause of the disease could be linked with malfunction microglia, the brain’s primary immune cells.

But a Slovakian biotech last month helped to make the case for tau as the main cause of the disease, after its AADvac1 drug showed promising results in a phase 2 trial.

AAdvac1 works in a different way than other approaches used so far: it is a vaccine that tells the body to make antibodies against pathological tau only.

According to Axon Neurosciences CEO Michal Fresser, the thinking behind this approach is to target pathological tau as it travels in between cells.

Axon is testing the theory is that destructive tau protein is capable of spreading between cells, and the way to stop the disease is to target the protein as it travels in between them.

Fresser, who has risen through the ranks at the biotech to become CEO this August, explained to pharmaphorum in an interview: “There is no benefit in saving disconnected neurons, you have to stop the spread and progression of the disease.”

He also cited clinical evidence that is building an increasingly convincing case that pathological tau is the culprit that causes Alzheimer’s.

“If (patients) have tau pathology in language parts of the brain, then patients suffer from speech difficulties.”

Cautious optimism

After so many years of trial disappointments, Fresser told pharmaphorum he is cautiously optimistic about the potential of AADvac1.

Aside from the success in the mid-stage trial, a vaccine-type approach has been made easier because of the increased knowledge about the disease and its progression – which has ironically been gained through the many unsuccessful trial failures over the last few years.

While the trials have not been able to say that amyloid is the root cause of the disease, they have given insight into how the disease develops and how it could be detected earlier.

Alzheimer’s can still only be definitively diagnosed after death, but there are a variety of tests and biomarkers that doctors can use to give increasingly accurate predictions about the presence or absence of the disease.

Fresser hopes that eventually this will develop into a more comprehensive screening programme that could be used widely in the population to help find people who have the disease but have not yet developed noticeable symptoms.

“I am confident we will move to broad-based testing, being used to diagnose patients prior to vaccination,” he said.

This new approach to diagnosis has been made possible because of the many thousands of people who took part in the trials of amyloid-targeting drugs over the last decade or so.

While companies like Biogen have not seen any financial reward, their efforts will help inform development of future therapies, Fresser said.

“It was a great effort. It has enabled us to better understand the disease,” said Fresser.

After the many disappointments in recent years, Fresser is hopeful that the neurological expertise within the company could create the breakthrough that pharma is looking for in Alzheimer’s.

His confidence stems from the expertise within Axon. Its co-founder is professor Michal Novak, who still serves as chairman of Axon’s scientific board and is one of the leading proponents of the theory that tau is the root cause of Alzheimer’s.

Novak spent 10 years working at the laboratory of molecular biology, MRC, at the University of Cambridge, before founding Axon in 1999.

Another neurologist, Norbert ZIlka has been helping develop Axon’s products since 1999, leading to his appointment as chief science officer in 2015.

With this expertise available in-house, Fresser said the company is now looking for a big pharma partner, with the financial muscle to fund larger trials, connections with regulators, and marketing expertise should trials go well.

He concluded: “There is such huge unmet medical need. We are looking for a partner to support us and bring this to patients.”