Alzheimer’s disease, the most common cause of dementia, is a progressive, neurodegenerative condition that slowly destroys memory and the ability to carry out simple tasks.
In order to raise awareness of the disease and challenge the related stigma, September has been designated as World Alzheimer’s Month, this year marks the seventh year this has been observed. Also, World Alzheimer’s Day was established in 2012 and is marked on 21 September every year.
Alzheimer’s Research UK estimates approximately 50 million people worldwide live with Dementia, and this is expected to increase 204% to 152 million by 2050. The region with the most people living with dementia is East Asia with 9.8 million, followed by Western Europe with 7.5 million, South Asia with 6.1 million and North America with 4.8 million.
In the UK, 850,000 people are living with dementia and this expected to rise to one million by 2025, and then double to two million by 2050. According to the UK National Health Service (NHS), Alzheimer’s disease affects approximately one in 14 people aged over 65 and one in six people over the age of 80.
Alzheimer’s Research UK notes that Alzheimer’s disease and dementia were the leading cause of death of women and the second leading cause of men in the UK in 2016. The numbers of people expected to die from dementia, of which Alzheimer’s is one type, are expected to quadruple by 2040, according to the British Medical Council.
Despite the global prevalence of dementia, no new treatments have been approved for the disease in over 15 years. This is in spite of billions of dollars being spent on research and development by both pharmaceutical companies and research organisations.
Challenges to finding treatments for Alzheimer’s
One major challenge to the successful treatment of the disease is nobody understands precisely how the disease causes neurodegeneration and cognitive decline, making it difficult to know what to target when developing drugs.
Alzheimer’s Society Research Officer Hannah Churchill mentions other issues, such as learning from the pharmaceutical approach to cancer, which has three times the number of researchers of Alzheimer’s and dementia, that research really can help with sufficient funding and commitment in the field. She notes: “With cancer, we have come such a long way in twenty years and that is the result purely of research.”
However, the most important in her opinion is the fact that: “with Alzheimer’s there can be changes within the brain that happen 15 years before people present with the clinical symptoms. So people going into clinical trials often have progression within the disease for a number of years before they even take part in the study, so the changes in their brain are at a quite a high level, and perhaps their symptoms are quite severe.”
She continues: “Bringing people into clinical trial at that stage seeing a positive result is quite difficult because they are a step further down the line that we would like them to be.
“So one of the main challenges in Alzheimer’s research is finding a way that we can diagnose people at an early stage. If we can find a way to identify the really early changes that people experience in dementia earlier on, then we can recruit them into clinical trials quicker and have more positive results.”
Linked to this is the issue of finding and persuading people to take part in clinical trials, with Churchill saying ‘some of them do close as a result of lack of recruitment’. An innovative approach created by the National Institute of Health Research and supported by organisations such as Alzheimer’s Society is Join Dementia Research, an online database that matches people to research buddies.
These challenges and lack of progress in drug success and approvals has not deterred R&D from seeking to find new treatments and hopefully a cure for Alzheimer’s and Dementia. On top of trial participation-related initiatives, the field is beginning to see positive results for a range of treatment options for these extremely prevalent disorders.
GlobalData expects new drug approvals to drive growth in the Alzheimer’s disease market over the next decade to 2026.
World Alzheimer’s Day: two examples of innovative new treatments in the pipeline
BAN2041: potentially validating the amyloid beta theory
US-based Biogen and Japanese Eisai announced positive top-line results from its phase IIb study of BAN2401, an anti-amyloid beta protofibril antibody at the Alzheimer’s Association International Conference in Chicago in July this year.
This makes BAN2401 ‘the first late-stage anti-amyloid antibody study to successfully achieve statistically-significant results at 18 months’, according to Eisai’s neurology business group chief clinical officer and chief medical officer Lynn Kramer.
In 856 patients, the drug demonstrated statistically significant slowing in clinical decline and a reduction in amyloid beta deposits that had accumulated in the brain after 18 months. In the highest dose arm, cognitive decline reduced 30% on a new measure for early cognitive decline, the Alzheimer’s Disease Composite Score (ADCOMS), and 47% on Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
Biogen executive vice-president and chief medical officer Alfred Sandrock said: “This BAN2401 18-month data offer important insights in the investigation of potential treatment options for patients with Alzheimer’s disease and underscores that neurodegenerative diseases may not be as intractable as they once seemed.”
The companies see these results as validating the amyloid beta hypothesis: accumulation of beta-amyloid in the brain disrupt cell-to-cell communication, destroy neurons and synapses, and are, therefore, the main cause of the cognitive effects of Alzheimer’s.
This drug’s success lies in the context of numerous BACE inhibitor drugs, which were designed to prevent the production of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), the enzyme required to produce amyloid beta deposits, failing in clinical trials.
In February 2017, Merck announced it would discontinue its EPOCH study of verubecestat after an external monitory committee concluded there was ‘virtually no chance of finding a positive clinical effect’.
The next stage for BNA2401 will be to discuss these phase II results with regulatory authorities regarding a larger phase III trial and the possibility of acceleration of the drug’s approval process.
At the end of the companies’ presentation at the conference, Kramer said: “We view this as robust enough to approach regulatory authorities to discuss next steps in terms of additional trials or even breakthrough status.”
However, pharmaceutical industry experts remain cautiously optimistic at most about these results.
This is primarily linked to the European Medicines Agency restricting the patients who could participate in the highest and most efficacious dose group of the trial mid-way through due to safety concerns. Apolipoprotein-E e4 (APOE4) carriers who have a higher risk of Alzheimers and faster progression were excluded because of worries about ARIA-E, an inflammatory reaction often seen in the first three months of amyloid beta therapy.
There were suggestions that leaving APOe4 patients in the placebo groups and lower doses arms raised the possibility that this exclusion helped researchers reach high statistical significance in the highest dose group.
Biogen CMO Al Sandrock responded to these concerns, telling analysts: One of the first things we’re going to look at, is the subgroup analysis of APOE4 carriers versus non-carriers.”
In addition, questions still remain about whether reducing amyloid deposits causes cognitive benefit.
Repurposing diabetes drug liraglutide for Alzheimer’s
One of the Alzheimer’s Society programmes to overcome challenges facing the development of treatment for Alzheimer’s is linked to repurposing drugs.
An example is liraglutide, a novel GLP-1 analogue, which has already been approved for type 2 diabetes. There is a clearly established connection between type 2 diabetes and Alzheimer’s; patients with this type of diabetes have an increased risk of developing Alzheimer’s and dementia.
Churchill noted: “I think the most important thing about that trial is that if you take a completely novel drug it could take 20 years and millions of pounds to bring to patients. Whereas if you take a drug that is completely licensed in people, we already know a lot about it. If we can see the benefits of repurposed drugs for Alzheimer’s through trials like this, then we can bring the product to patients faster.
“There hasn’t been a new treatment approved for dementia in 15 years, so speed is really important. The drug repurposing programme is key to bringing drugs to people faster.”
Following success in laboratory studies, the Alzheimer’s Society is helping to fund a phase II study being conducted by Dr Paul Edison and his team at Imperial College London’s Memory Research Centre on patients with mild-to-moderate Alzheimer’s. It tests patient benefits and side effects of the study’s participants.
Churchill said: “We have funded a number of studies looking at this particular drug, which lead up to this larger trial with Imperial College London.
“The results from a 12 month period were fairly positive, so we are at the stage now of moving into another 12 months to looking at whether the effect continues over time. The trial hasn’t come to an end yet.”
Edison’s team has also been supported by other funding sources, including the pharmaceutical company that makes liraglutide, Imperial College London and the NHS. The researchers are hopeful that if the next phase of the trial is successful, then the drug could be available to patients within the next five to ten years.