Disease modifying therapies
On the 7th of June 2021, the United States Food and Drug Administration (FDA) approved the application to license a new drug - aducanumab – for the treatment of Alzheimer’s disease. Aducanumab also gets referred to by its brand name - Aduhelm.
This drug has received a lot of media attention for two main reasons. Firstly, despite lots and lots of clinical trials, there hasn’t been a new drug approved for Alzheimer’s disease since 2003. Secondly, all the drugs we currently have for Alzheimer’s disease are symptomatic treatments; they act to help ease symptoms, but they don’t do anything to stop or slow down the disease process that causes these symptoms. Aducanumab may be the first disease modifying therapy - a drug that acts to slow the progression of disease.
Imagine the damage caused by Alzheimer’s disease in the brain is equivalent to a boat springing a leak. The drugs we currently have act to bail water out of the boat, but they don’t do anything to plug the hole. Plugging the hole is the aim for disease modifying therapies.
The aducanumab journey has been a bit of a rollercoaster over recent years and its application for licensing approval has stirred a lot of debate.
Speaking in June 2021, Dr Terry Quinn explains the story of the initial decision to approve the drug 'aducanumab' in America.
Read our FAQs below to find out more. If you have suggestions for any more questions you would like to see answered get in touch.
UPDATE 17th December 2021: The European Medicines Agency (EMA) - the regulator who decides if a new drug gets approved for use in the European Union - have announced their decision to refuse a license for aducanumab for the treatment of Alzheimer's disease.
The EMA is the equivalent of the FDA in America - who decided to give accelerated approval to the drug back in June 2021 (see ‘What does accelerated approval and phase IV mean for aducanumab’ below).
So this latest announcement means that aducanumab will not be approved for clinical use in the EU at this moment in time but may well become available through future research programmes.
The decision on whether to approve aducanumab for use in the UK is not down to the EMA and instead sits with a separate UK-specific regulator – the MHRA. We haven’t heard the MHRA’s verdict on aducanumab yet but this decision not to license the drug in Europe makes it very likely the drug will also not be approved at this time in the UK.
The process of applying for a licence towards a new medication is dynamic. Decisions are re-visited as new evidence emerges from clinical trials and other research. The manufacturers of aducanumab are collecting new data all the time and these data may strengthen the case in support of the medication.
For more on the regulatory approval process see our section below ‘Who are the FDA, MHRA and EMA and what is their role?’
UPDATE 11th January 2022: The Centers for Medicare and Medicaid Services (the government health insurance provider in the US) have announced a draft decision to only cover the cost of aducanumab for people who are enrolled in approved clinical trials. This essentially means that the only people who will have access to aducanumab at this moment in time are those taking part in a research study designed to further investigate the safety and effectiveness of the drug.
This provisional decision by the US providers (to be finalised by 11th April) also extends to other potential new drugs in development that aim to work in a similar way to aducanumab – by breaking down the clumps of amyloid protein in the brain.
What is aducanumab?Aducanumab is a drug developed by the pharmaceutical company Biogen for the treatment of early stage Alzheimer’s dementia. Aducanumab has been tested in 2 large scale clinical trials. Following these, the Biogen company officially asked for approval to sell the drug in the US. The approval of aducanuab by the regulatory authority now opens the door for doctors in the US to prescribe the drug to slow the progression of Alzheimer’s disease in people who have either Mild Cognitive Impairment due to Alzheimer’s disease or mild Alzheimer’s dementia. Aducanumab is given by infusion into a vein on the arm.
How does aducanumab work? And how could it help people with Alzheimer’s disease?Aducanumab breaks down the toxic build up of a protein called amyloid in the brain. There are two key proteins that are found clumped together in the brains of people with Alzheimer’s disease – amyloid and tau. In Alzheimer’s disease, the amyloid protein clumps together to form ‘plaques’ in between brain cells. Scientists think that the amyloid plaques interfere with the brain cells’ ability to talk to each other. The tau protein builds up inside brain cells and stops the cells working properly, causing them to die. We don’t fully understand how or why the toxic amyloid and tau proteins build up in the brains of people with Alzheimer’s disease. Amyloid plaques seem to appear early. Tau builds up later, and kills brain cells, causing the associated symptoms of problems with memory and thinking. Over recent years research has focused on developing drugs that break down amyloid plaques or stop them forming in the first place. We think that getting rid of amyloid plaques could break the chain of events that leads to tau building up and damaging brain cells. If this is correct, then the amyloid-targeting drugs would probably work most effectively if they were given early in the course of disease. However, right now we don’t know for sure if getting rid of amyloid plaques will stop Alzheimer’s disease getting worse.
What were the trial results?The Biogen company ran 2 big clinical trials of aducanumab. These were called ENGAGE and EMERGE. Over 1500 people took part in each trial. People in Scotland took part in the ENGAGE study. In March 2019 the Biogen company announced that it was stopping both trials early. They had looked at the data and said that it was very unlikely that aducanumab was going to work to significantly slow disease progression. What happened next was quite unusual. Biogen looked at all the final data (including some new results which weren’t available when they decided to stop the trials). When they analysed this data all together, they decided that aducanumab did have a helpful effect on memory and thinking, and on being able to carry out day to day tasks. People in the trials had been put on different doses of aducanumab. Only people who had been on the highest dose of aducanumab benefited from it. The analysis suggested that people in the EMERGE trial were helped by the aducanumab. In the ENGAGE trial, aducanumab made no difference. The trials did show that aducanumab definitely can get rid of some of the amyloid build up. But we’re still not sure if this definitely helped people with memory, thinking and everyday life.
Was aducanumab safe?The trials both showed that aducanumab was reasonably safe. The trials were stopped early because the Biogen company thought aducanumab didn’t work, not because they thought it wasn’t safe. Aducanumab can cause damage to small blood vessels in the brain. We can see this on brain scans. This is called ARIA: Amyloid Related Imaging Abnormalities. ARIA doesn’t always cause any symptoms but it can cause headaches and increased confusion. People taking aducanumab may need to have a number of brain scans, particularly when they first start the drug, to check for any signs of ARIA. About 1 in 3 people who took the highest dose of aducanumab developed ARIA.
Why is aducanumab controversial?There is understandably a huge interest in getting new drugs for people living with Alzheimer’s disease. People really need new treatments that slow down Alzheimer’s disease and some experts and organisations have come out publicly to say they think Aducanumab should be approved. Usually a drug company only asks for approval of a new drug if they have 2 clinical trials which both showed that the drug works. For Aducanumab, 1 of the trials said it worked, and 1 said it didn’t. The Biogen company first said that Aducanumab didn’t work, but then changed their minds. Lots of scientists think that it is not clear whether Aducanumab works or not. Many experts have said that we need another clinical trial to find out if Aducanumab works or not. In November 2020 the FDA said that there wasn’t enough evidence to know if Aducanumab works or not. Out of 11 FDA experts, 10 said there wasn’t enough evidence, 1 wasn’t sure. None of the experts thought there definitely was enough evidence. On the 7th June the FDA announced they have approved aducanumab. As part of this approval Biogen will be required to continue to monitor the effectiveness of the drug as it starts to be prescibed. There are three areas in particular which have generated the most heated debate about aducanumab: Is clearing amyloid from the brain helpful? There is no doubt that there is a build-up of an abnormal protein called amyloid in the brains of people with Alzheimer’s disease. It is less clear if removing the protein will slow down or halt the disease. People who believe that amyloid is the driver of brain changes in dementia, compare the protein to a fire - slowly spreading through a building and causing damage. Others think that amyloid is an after effect of other damaging processes within the brain, but it is not the main cause of the damage. People who believe this argument, compare amyloid to the smoke from a fire – it is dangerous, but clearing the smoke will not stop the underlying problem. Finally, others feel that Amyloid may be a trigger or a spark that starts the fire BUT that this occurs very early in mid-life and once the fire is established then removing amyloid or ‘the spark’ is of little benefit. As you can see there is much uncertainty and debate on the role of amyloid – is it the spark, the fire or the smoke? How much improvement will aducanumab offer? For a condition like Alzheimer’s, that can have an impact on every part of a person’s life, it is difficult to measure in numbers the harm caused by the disease. However, we do need a way to measure change in the disease. This allows us to compare what happened to those people receiving the new drug compared to those who did not. In one of the aducanumab studies, there was a numerical difference between the study groups, with the participants receiving aducanumab showing less severe disease. Some have argued that the difference was so small it would be unlikely to be important to an individual living with Alzheimer’s disease. Others have argued that for a condition with so few treatments, any benefit to slow the progression of disease is a worthwhile benefit. There is no consensus on how much of a difference constitutes an ‘important’ difference. What was the role of lobbying and endorsement? The American regulator that makes decisions on new medications (the FDA) was presented with lots of information on aducanumab. As well as results from scientific studies, the FDA received petitions from patient groups most notably the American Alzheimer’s Association. As well as appealing to the FDA, these groups have been running campaigns to support the use of aducanumab, they argued that they were giving a voice to people living with Alzheimer’s disease. Biogen (the company that has developed aducanumab) has been public in giving support to the American Alzheimer’s Association. In Brain Health Scotland and the Scottish Dementia Research Consortium, we think it is important to be transparent about any research activity that could potentially influence our thinking. As mentioned in the declarations section below, Brain Health Scotland has received grant funding from Biogen to support our activities.
How does aducanumab compare with existing treatments for Alzheimer’s disease?The main tool that was used to measure the effectiveness of the drug in both trials was the Clinical Dementia Rating (CDR) Scale. This an interview based assessment of memory and thinking skills and of ability to carry out day to day tasks as reported by both the patient and their caregiver. Over 18 months, when compared to placebo (a dummy drug used to compare against the effects of taking the real version of the drug), there seemed to be about a 20% slowing down of changes to the CDR score. The scores still got worse, just not as fast as for those patients taking placebo. When compared to currently available drugs for Alzheimer’s disease, such as donepezil, this rate of slowing is not as good BUT the argument that this slowing is maintained over a longer period AND is related to clearing a disease process (the amyloid in the brain) is why some argue that this change is more meaningful than for the existing symptomatic drug treatments like donepezil.
Has any of the aducanumab research been done in Scotland?Yes. One of the clinical trials testing aducanumab was called the ENGAGE trial. People took part in this trial in Edinburgh, Glasgow and Dundee.
Who are the FDA, MHRA and EMA and what is their role?"The Food and Drug Administration (FDA) is the regulator in the United States that decides whether or not a new drug can be licensed for use as a medicine. The FDA looks carefully at all the data collected during clinical trials to reach their decision. In Scotland and the rest of the UK we have the MHRA (Medicines and Healthcare products Regulatory Agency) which does the same job. The EU has the EMA (European Medicines Agency). The chart below shows the steps a drug must go through to be successfully approved by the FDA. Figure adapted from U.S. Government Accountability Office review of the FDA approval process
Will the NHS be able to offer aducanumab to people with Alzheimer's disease?The MHRA (the UK equivalent of the FDA) decide if a drug can be prescribed in the UK. The FDA and the MHRA approval processes are separate, so a drug could be approved by one authority and not by the other. The MHRA may give full licensing approval or conditional approval. Given the uncertainties about the existing results, the most likely outcome from the MHRA may well be for conditional approval. The conditions being that more research is carried out to really understand how well the drug works in a ‘real world’ setting, over a longer time period and taking into account whether some people taking the drug do better than others or have more side effects. These trials are called Phase IV trials. Even when MHRA gives approval, the NHS then has to decide if the drug is cost-effective and organisations like NICE or SIGN will play a role in this. Many experts are advising that Phase IV testing is the best, safest and most appropriate way forward. This would make sure that patients can be very closely monitored on the treatment by experts in the field before widespread use. This is quite common with new treatments where the results of earlier trials have been somewhat inconclusive. Within Brain Health Scotland and working with Scottish Government, Alzheimer Scotland and the NHS, we have been developing pathways for as many people as possible in Scotland to get access to new treatments. Both in Phase IV testing or if they are given full approval. This will be through new Brain Health Clinics that will compliment Memory Clinics but have a specific focus on people at very early stages of Alzheimer’s disease.
What does Accelerated Approval and Phase IV Trial mean for aducanumab?The FDA granted ‘Accelerated Approval’ and insisted that Biogen undertake a 'Phase IV trial'. With aducanumab, this means that the FDA were happy that the drug cleared amyloid from the brain and they expect that this should lead to clinical benefit BUT the trials that have been done so far did not prove this. Therefore, Biogen are being asked to do more clinical trials to confirm the benefit to clinical symptoms that was only seen in a small number of patients in the original studies. What this means is that there will need to be more research with aducanumab, at least in the USA. How long and how large these new trials will be will be up to Biogen in discussions with the FDA. It is likely though that they will still need to be placebo controlled - which means that up to half the people in the trial will be randomised to receive an infusion that does not contain the active drug.
Are there any other drugs like aducanumab being trialled?There are lots of different drugs currently going through trials for Alzheimer’s disease (over 100). Many are aiming to target the same amyloid protein as aducanumab, but in slightly different ways. One of the main challenges for drug trials is finding enough people to take part. In fact, just to complete all the trials planned currently will require nearly 40,000 research volunteers! The research effort needs far more people living with, and at risk of, Alzheimer’s disease to volunteer for studies. You can register your interest in hearing about research studies and be given the opportunity to take part by signing up to Join Dementia Research.
Where can I get more information about aducanumab?This FAQ section will be updated regularly as and when new information becomes available and when new questions are submitted via the form below. Please continue to check back for the latest updates. We will also announce on our social media channels when any major updates to this page are made. For more general information on aducanumab and the current state of Alzheimer’s disease clinical trials, see the further information section below.
Brain Health Scotland works closely with Biogen to advance the brain health environment in Scotland and has received funding from Biogen to carry out research projects.
These FAQs were written by Dr Catherine Pennington, Dr Terry Quinn, Prof Craig Ritchie and Dr Jenny Waymont.
Dr Catherine Pennington is currently funded by the Clinician Scientist Office in Scotland. She previously worked on the EPAD study, and received grant funding from the BRACE charity, and training funded by Merz Pharmaceuticals. She is also an NHS consultant neurologist working for NHS Forth Valley and NHS Lothian.
Dr Terry Quinn has received honoraria, to his University, for his participation as a member of an advisory board for Novartis and as chair of a Data Monitoring Committee for Novo-Nordisk. Terry’s University has received speaker fees for non-promotional educational symposia organised by Bayer, BMS and Pfizer. Terry’s University has received investigator initiated research funding for studies supported by BMS-Pfizer Alliance where he is the Principal Investigator.
Prof Craig Ritchie has been a paid consultant for several companies developing treatments for Alzheimer’s disease over the last 5 years including Biogen, Eli Lilly, Merck, Roche, Janssen, Abbvie, Kyowa Kirin, Actinogen and Eisai. He was the UK Chief Investigator for the ENGAGE Trial and Academic Lead on the EPAD (European Prevention of Alzheimer’s Dementia) Programme which was a public:private partnership between the EU and several companies with an interest in developing treatments for AD www.ep-ad.org His unit at the University of Edinburgh (Edinburgh Dementia Prevention) has received grant funding from Biogen, Janssen, AC Immune and Actinogen. He is the unpaid chairperson of the Brain Health Clinic Consortium established in the UK by Biogen.
Dr Jenny Waymont is currently funded through an educational grant provided by Biogen (who developed aducanumab), and has previously received funding from TauRx Pharmaceuticals (who develop drugs targeting Tau). Jenny holds a PhD in Medical Imaging, but is not a medical doctor.