Early diagnosis key to future Alzheimer’s treatments

The approval of Biogen’s Alzheimer’s treatment could herald a new generation of therapies, but before that can happen, more investment and better diagnostics may be needed, explains Ben Hargreaves.

This year has been marked by one of the biggest developments in the search for new treatments for Alzheimer’s disease, after the US FDA approval of Biogen’s Aduhelm (aducanumab) in June. The monoclonal antibody was the first new drug to be approved for Alzheimer’s since 2003.

However, the accelerated approval was not passed without controversy, after an advisory committee to the FDA had recommended that the treatment should not receive approval. The advisory committee was comprised of 11 independent experts, with ten members voting against recommending the treatment for approval and one voting that they were ‘uncertain’.

The committee’s vote was only advisory and the FDA decided to approve the drug under the accelerated approval pathway. As part of an approval statement, the agency noted that the decision was taken on a surrogate endpoint, wherein the treatment managed to display a reduction in amyloid beta plaques in the brain of patients treated with Aduhelm.

In the same statement, the agency admitted that “there remains some uncertainty about the drug’s clinical benefit”, with a label update occurring shortly after approval that limited Aduhelm’s use to patients with early stages of the disease – the same group as tested in clinical trials for the drug.

The challenge of treating Alzheimer’s

Alzheimer’s disease and other forms of dementias are the leading cause of death in the UK, and the sixth leading cause of death in the US. Despite these statistics, Alzheimer’s disease is not fully understood, particularly in regard to exactly how amyloid plaques and tau tangles, another biomarker of the disease, contribute to the mental decline of individuals with Alzheimer’s.

Dr Sara Imarisio, head of research at Alzheimer’s Research UK, explained to pharmaphorum that diseases driving dementia are ‘complex’, with “age, genetics, and lifestyle factors all playing a role in the development and progression of the condition”.

In addition, the fact that the diseases causing dementia occur decades before any symptoms begin to show makes creating treatment to slow the progression of these diseases particularly difficult.

Regarding the US approval of Biogen’s treatment, Imarisio called it “a positive step forward for people with Alzheimer’s disease”, further explaining that the post-approval studies the company will conduct will provide more detail about “the potential real-world benefits of aducanumab”.

The follow up studies refer to the confirmatory trials that Biogen will need to conduct in a nine-year timeframe to retain the approval of the treatment in the US. The uncertain real-world benefits of the treatment is a part of the reason that there has so far been limited uptake of the treatment in the US.

Alongside the difficulty in creating a therapy for the disease is the other, inextricably linked, barrier to new treatments: the low chance of financial return on the development of potential treatments. According to research, Alzheimer’s drug candidates have one of the highest failure rates of any disease area, at 99.6%. Even after the approval of Aduhelm, the industry is still closely watching the financial developments – should an approved treatment prove a financial failure, this could discourage further R&D in the area.

This is why continued funding to research institutions is regarded as essential for finding potential new therapies. Regarding the funding situation in the UK, Imarisio stated, “With four times more funding going to cancer research, dementia research has not yet seen the necessary support needed to change the lives of people with dementia. To change this, Alzheimer’s Research UK is now calling on the government to speed up the search for dementia treatments by doubling funding for dementia research to over £160 million a year, in line with their manifesto pledge.”

The next treatment for Alzheimer’s

Despite the high rates of failure for Alzheimer’s disease therapies, the approval of Biogen’s therapy has resulted in spurred interest across the industry in bringing forward the development of treatments. One of the companies aiming to follow on from Biogen’s approval is Eli Lilly. The company is looking to file its potential Alzheimer’s treatment, donanemab, for the FDA’s accelerated approval later this year.

Donanemab has already been provided a breakthrough designation by the FDA, with a spokesperson for Lilly telling pharmaphorum that it plans to submit the drug under accelerated ‘as soon as it can’.

According to Lilly, the reason the treatment holds such promise is that in a clinical trial the treatment showed “a significant reduction in the amount of amyloid deposition among patients treated with donanemab, but also the slowed clinical progression of the disease”, the spokesperson outlined.

The results were revealed earlier this year as part of a phase 2 study, with further trials currently enrolling to follow up on these findings. “Replication is important to overcome scepticism in the field,” the spokesperson noted.

Early testing

One differentiator within Lilly’s Alzheimer’s disease portfolio that thespokesperson chose to highlight was the company’s ‘diagnostic pipeline’. For Lilly, this includes an Alzheimer’s disease blood test “that could enable early diagnosis and advance understanding of how the disease impacts those living with it,” they said.

“While there is no cure for this devastating disease, a timely and accurate diagnosis can improve patients’ chances to benefit from current treatments and participate in clinical trials. We believe accelerating the diagnosis of Alzheimer’s can help accelerate the arrival of innovative treatments,” the spokesperson concluded.

Lilly is not the only organisation that has trained their focus on diagnosing Alzheimer’s disease earlier, when potential treatments could have a greater impact. Alzheimer’s Research UK is also working to develop technologies to identify the disease when it first starts, which “will transform research efforts today, helping scientists make faster breakthroughs in understanding the disease and testing potential new preventions and treatments,” Imarisio stated.

One organisation that has already developed such a potential technology is RetiSpec. The company is based in Toronto, Canada, and has developed medical imaging technology, utilising artificial intelligence, that is able to detect certain neurodegenerative diseases through the eye.

A spokesperson explained that, for the patient, this involves a simple eye exam, where images are taken of the eye through the use of a specialised, hyperspectral camera. The images use a broader range of the light spectrum than is visible to the human eye, and these retinal images allow the company’s algorithm to identify signatures associated with Alzheimer’s disease within the eye, such as amyloid beta.

According to the spokesperson, this is possible because “the back of the eye is a direct extension of the central nervous system and shares nervous tissue and vasculature with the brain”.

RetiSpec envisions the imaging becoming part of regular health checkups and eye care visits after a certain age, with longer-term plans to expand into other neurological conditions, such as Parkinson’s disease, among other areas.

Such a technology could also potentially be used by pharma companies developing Alzheimer’s treatments, the spokesperson outlined. With future use cases allowing for the screening of the patient population in the recruitment for a clinical trial, or as a companion diagnostic to monitor drug effectiveness during trials.

One of Alzheimer’s Research UK’s stated aims is to find ways to begin clinical trials in people decades earlier than is currently the case, technology such as RetiSpec’s could mark progress on the road to this goal. With the number of individuals developing Alzheimer’s disease and other dementias expected to triple by 2050, the need for better testing and therefore more effective treatments is only growing.