Aduhelm – The new ‘wonder drug’ for Alzheimer’s disease?
Aduhelm is the first new treatment for Alzheimer’s disease for some decades. This should be a reason to celebrate but the story of the development of Aduhelm is not straightforward and has led to quite some controversy. So, how does Aduhelm actually work and what is all the controversy about?
Let’s find out.
For decades scientists and pharmaceutical companies have tried to develop treatments for Alzheimer’s disease, the most common form of dementia. But despite early successes in laboratory and animal experiments little or no effects were shown for these new drugs when they were administered to humans in clinical trials. This seems always a puzzle to people why would one test any way a drug for humans in animals first? Aren’t animals quite different to humans?
Well, yes and no.
Of course, animals look different to humans but physiologically (how our body works) we are not so different from animals, in particular from animals that are evolutionary closely related to us, such as mammals. So, even if we look quite different to mice, the physiology of mice is highly similar to humans. This makes mice one of the most commonly used ‘animal model’ to develop new drugs for humans. The term ‘animal model’ is clearly euphemistic but indicates that scientists and pharmaceutical companies see the animals as ‘models’ for a disease and how a treatment can affect the disease. Practically, this seems all very straightforward but ethically it is clearly problematic that we use animals to test new drugs out. Not surprisingly, advocates against animal testing have been increasingly vocal since the 1980s that animal testing should be stopped for drug development and there is an ongoing discussion about this topic. But for now, we need to accept that virtually all human drugs are first tested in animals to see if they work.
It is not any different for Aduhelm, which was first tested in animals and showed spectacular results by reducing the levels a key protein responsible for Alzheimer’s disease (beta-amyloid) dramatically in the animals to whom the drug was given. Similar results were shown in the first human studies using Aduhelm, which was at that time referred to as Aducanumab, showing again that it reduces the levels of beta-amyloid in the brain of people with Alzheimer’s disease dramatically. These findings, published in 2016, made the Alzheimer community very excited as it indicated for the first time that a new Alzheimer’s disease drug might be at the horizon which would actually treat the disease and not only its symptoms. Previous drugs, such as Aricept or Memantine, which are still commonly prescribed to people with dementia, ‘only’ boost the brain’s functioning but do not affect the proteins thought to cause Alzheimer’s disease. Aduhelm was different, as it clearly showed that it reduced the levels of beta-amyloid in the brains of people with Alzheimer’s disease.
How does Aduhelm work?
The original name of Aduhelm, Aducanumab, gives a hint as to how the drug work. The extension -mab in Aducanumab tells us that Aduhelm is based on Monoclonal Antibodies (MAB). Monoclonal antibodies are used in many drugs these days, from cancer to asthma, indicating that monoclonal antibodies offer a generic mechanism for drugs to work across many diseases. So, how do monoclonal antibodies work?
It is beyond the scope of this article to go into the details of monoclonal antibodies, but in a nutshell, monoclonal antibodies for most drugs help our own immune system fight disease. Antibodies are themselves proteins which ‘flag’ to our immune system that there are foreign bodies (e.g. virus) or changes to our tissue (e.g. cancerous growth) that need to be fought. The antibodies attach themselves to foreign bodies or the problematic tissue and with that flag to the immune system to attack, neutralise and remove these bodies/tissues. Now, for most diseases, our body produces its own antibodies to fight disease but for some diseases, such as Alzheimer’s disease, there are no natural antibodies in our immune system.
Enter monoclonal antibodies, which are essentially lab-grown antibodies (monoclonal means that they are cloned from one initial antibody), which can be designed/engineered to attach to any bodies/tissues we want the immune system to deal with. It makes one realised how simple, elegant and powerful monoclonal antibodies are, as we can use them for many disease to activate our own immune system to deal with the disease.
It’s the same for Aduhelm, which was designed/engineered, specifically to target beta-amyloid – one key protein for Alzheimer’s disease. Aduhelm antibodies attach themselves to beta-amyloid, and hey presto, our own immune system jumps into action and starting attacking and removing beta-amyloid. Removing beta-amyloid should therefore slow down or even stop the development of Alzheimer’s disease, as it is known that the more beta-amyloid we have in our brain the more likely we develop Alzheimer’s disease.
Easy, isn’t it? But not quite.
After the initial findings of Aduhelm, the Alzheimer community became very excited about this new drug. Finally, a potential drug that could slow down or even stop the Alzheimer’s disease process by reducing the amount of beta-amyloid in the brain. To test whether this was really the case, very large clinical trials were organised, involving thousands of people. Clinical trials are still the gold standard to test whether a new treatment is safe and works. Nearly all trials involve one group getting the new treatment while another group gets a placebo (basically no treatment). Crucially, neither the people taking part in the trial nor the scientists/clinicians administering the treatment know whether each participant gets the treatment or placebo – so-called double-blind trials as the participant and the scientist/clinician are ‘blind’ as to who gets what. If there is a significant difference between the treatment and the placebo groups, the new treatment is considered to be working and once considered safe, recommended for clinical use.
The Aduhelm clinical trials ran over several years with the first results emerging in 2018/2019. The results showed that Aduhelm indeed removes beta-amyloid from the brain in trial participants whereas the placebo group showed no change in their beta-amyloid levels. That was the good news. The bad news, however, was that Aduhelm did not seem to slow down the progression or affect the symptoms of Alzheimer’s disease. More specifically, the everyday function and cognition of people who took the drug still declined similar to the placebo group, which caused some head-scratching in the scientific community.
How come people still develop everyday function and cognitive symptoms even after the beta-amyloid is removed from the brain?
Several explanations were proposed to explain this surprising finding. For example, maybe treating beta-amyloid alone does not really stop the disease, since Alzheimer’s disease seems to be caused by the interaction of two proteins (beta-amyloid and phosphorylated tau)? But for now, this remains speculation and many studies are ongoing to investigate this further.
So, does this means that Aduhelm is ‘dead in the water’? Well, many people in the Alzheimer community thought so but then the pharmaceutical company who produces Aduhelm (Biogen) published data showing that in a smaller subgroup of trial participants, who received the highest dosage of Aduhelm, the everyday function and cognition problems seem to ‘slightly’ slow down. I put slightly in quotation marks, because there has been a lot of discussions whether the reduction in everyday function and cognition is really meaningful to see an effect in the real-world. Or to put it in other words, you might not notice or see a difference in people’s symptoms in everyday life as the effects of the drug on the symptoms is so small.
Based on these subgroup results, Biogen approached the US Federal Food and Drug Administration (FDA), to certify the new drug so that it can be used for clinical use. The FDA is a government body that reviews the evidence for new treatments and if satisfied issues a licence for the new drug so that it can be used in the clinical services in the US (Similar agencies exist in the UK – MHRA and the EU – EMA). The step by Biogen to approach the FDA for certification of Aduhlem raised quite a few eyebrows in the Alzheimer community. Didn’t the main trials show no everyday function, cognition benefit for Aduhlem, despite it successfully removing beta-amyloid? Why would Biogen approach therefore the FDA for a license for Aduhelm for which there was only a marginal clinical benefit in a subgroup of participants?
Most people in the Alzheimer community thought that further trials with the highest dosage of Aduhelm were needed to show that it truly affects symptoms in people with the disease before one can think about a license for the drug. Also, most people thought that the independent scientific review panel of the FDA would clearly raise this issue and recommend not to licence Aduhelm, until there is a clearer benefit established that the drug affects the symptoms and progression of the disease. And indeed, the independent scientific review panel recommended not to approve the licence Aduhelm until better evidence that it helps people with dementia is established.
Well, that’s that then. But hang on.
Despite the independent scientific review panel’s recommendation, the FDA took after several months the decision to issue Biogen an accelerated approval licence for Aduhelm in June 2021. There was an immediate uproar from the scientific and clinical community. What had happened? Didn’t the results show no clinical benefit AND the expert panel recommend for it not to be certified? The key is to understand that an ‘accelerated approval licence’ allows for a new drug to be used until its benefit is established. The FDA reserves the right to remove the license for Aduhelm if the benefit for people with dementia cannot be established. It was a highly controversial step, since it sidestepped the independent scientific panel (several panel members resigned in protest) and there have been rumours circulating that Biogen held ‘informal’ meetings with the FDA before the accelerated approval was given.
Where does this leave us now?
For now, Aduhem is a licenced drug for Alzheimer’s disease in the US only, with future MHRA (UK) and EMA (EU) decisions on whether Aduhelm will be available to people in the UK and EU upcoming. But the decision to approve Aduhelm has raised more questions than answers for the scientific and clinical community, in particular on a practical level.
What shall we tell people with dementia and their families as to what the real-world benefits are of taking the drug?
How shall we actually administer and use this new drug?
The last question, in particular, required some quick thinking, since after the approval people with dementia and their families rightly asked to be given the choice of taking the drug. However, and it is a big however, at that stage Biogen had not published extensive guidelines of how to prescribe Aduhelm, also known as appropriate-use recommendations (AUR). As we all know, even the common Paracetamol comes with a whole list of indications, contra-indications, dosage recommendations and so on. This information is critical so the drug can be used safely in most people but this information, until recently did not exist for Aduhelm.
Only in July/August 2021, an expert clinician group suggested a list of recommendations for the prescription of Aduhelm and these recommendations are by themselves quite a baffling read, as it becomes clear that many of the recommendations are simply based on estimating or even guessing ‘best practice’. This is highly unusual as commonly drugs at this stage should have clear prescription guidelines but again Aduhelm stands out. Still, the expert group should be commended for at least trying to come up with some recommendations. However, if we thought we could simply ‘pop into our GP/family doctor’s practice’ to get our prescription of Aduhelm then we would be mistaken. Instead, the recommendations suggest that people are required to undergo repeated hospital visits and MRI scans – at least for the first six months – when the prescription is started. And not at any hospital but ideally a dementia specialist centre (at the time of writing only 3 centres in the US offer Aduhelm to their patients).
What is the reason for that?
This is another baffling fact from the approval of Aduhelm. Remember that only the participants with the highest dosage of Aduhlem showed ‘some’ clinical benefit. Unfortunately, for some people in this highest dosage group, Aduhelm caused some severe side effects in the brain, called ARIA (Amyloid Related Imaging Abnormalities). It is beyond the scope of the article to go into the details of what ARIAs are but in essence they either cause fluid or blood to enter the brain, with some leading to more significant bleeding into the brain, which requires treatment and can lead to further symptoms.
We can see that the highest dosage of Aduhelm is not ideal as there is a risk of severe side effects (ARIAs) but we also know that it is this dosage which showed some benefit to the symptoms of participants. Again, it is unusual for such a drug to be approved. Often, drugs with potentially significant side effects are only approved when they show a clear benefit for the treatment of the disease, so that the side effect can be justified – it is a straightforward risk-benefit analysis. That does not seem to be the case with Aduhelm.
Because of these side effects, Aduhelm, which is given as an injection or transfusion, will need to be carefully monitored when the drug is started. Hence, the regular hospital visits and MRIs which are to check for ARIAs in people’s brains when they start taking Aduhelm. So, one better gets used to the inside of an MRI scanner if we want to take Aduhelm. It makes it also very clear that if we live more remotely taking the drug might not be straightforward, since we need to travel to a specialist centre for it to be prescribed and monitored. This might not be a problem for most people in the developed world but clearly not feasible in the developing world, where MRI scanners are not common – not to forget the costs for all those MRIs which need to be covered by our insurance, national health service or ourselves.
Speaking of costs, the actual costs of Aduhlem has raised further eyebrows – how many eyebrows can one raise? – and has even led to an investigation by the US senate, since they seem very high. A one year course of Aduhlem will set us back by $56,000, not taking into account the hospital visits, procedures and MRIs that go with its prescription. That is quite some serious money. Now, it would be easy to simply blame Biogen for racking up the price but that would be too simplistic, as we have to understand that the pharmaceutical industry is a ‘boom and bust’ industry. With that, I mean that they invest very large amounts of money in the development of new drugs with a low chance of success but if they succeed, they hit the jackpot. Pharmaceutical companies need to make therefore their money back with a new drug until its patent runs out and generic drugs emerge on the market. It is simply their business model but still the question is whether Aduhelm is overpriced. The current price tag makes it clearly unaffordable for many people to pay for it privately, not to speak of people in the developing world, but even health insurances and national health systems are scoffing at the price for Aduhelm.
The other caveat is that there is still no recommendation as to when the drug should be stopped. For example, when during the course of Alzheimer’s disease might Aduhelm not anymore helpful and should be stopped? This is at the moment not clear and it is up to the discretion of the clinician. Unfortunately, this is not only a treatment but also an economic question since the high price means that there will be pressure to continue the drug not for too long – whatever that means. And just remember this is a drug which only showed marginal every day benefits, so likely will only slightly affect the progression of the disease.
So, is there anything truly positive about Aduhelm?
Yes, there is. People with dementia and their families have waited for decades for a drug that treats the actual disease. Aduhelm does that, albeit with limited effects on the symptoms and progression of the disease. Aduhelm clearly reduces the amyloid in the brain, which is undoubtedly a very good thing. Further, due to the ‘boom or bust’ nature of the pharmaceutical industry, many pharmaceutical companies have pulled out over the years from Alzheimer disease drug development, since their drug development were unsuccessful. That is terrible and has caused for only very few new drugs to be developed for Alzheimer’s disease. The success of Aduhelm has caused, therefore, not only a stir in the scientific/clinical community but also in the pharmaceutical community, albeit in a positive way with many companies seeing the success of Aduhelm and start developing again Alzheimer’s drugs. Some people compare it, therefore, to the development of HIV drugs in the 1980s. When the first HIV drugs came out they were not very effective but it lead then to a plethora of new drugs being developed which in the end led to current drugs which do not cure HIV but people can live with the disease a full life. Maybe it will be a similar story for Alzheimer’s disease and Aduhelm is only the start? Let’s hope so.
In summary, it is exciting to see finally a new drug (Aduhelm) being available to people with dementia. However, the approval process of Aduhelm has been far from perfect if not controversial. There are still uncertainties as to whether it will affect the symptoms and progression of the disease, although it clearly removes beta-amyloid from the brain. It is still a puzzle that despite removing beta-amyloid people will still develop more symptoms and progress in the disease. On top of that the clinical management of Aduhelm is still little known but looks like to require multiple hospital visits and MRI scans, since the recommended dosage for Aduhlem can cause some severe side effects (ARIA) in a proportion of people. On top of that, the costs of $56,000 just for Aduhelm, not taking into account hospital visits and MRI scans, makes one wonder whether taking this drug, which has little real-world effects is worth taking? It is clearly an individual decision for each person but likely many people will want to take it, even though of the potential side effects, costs and little benefit. Who knows it might work for them and hence is worth the risk. But I know that many clinicians feel very uneasy to prescribe Aduhelm, as it shows little effect on the symptoms while having potentially significant side effects. On the positive side, that there is a new drug for Alzheimer’s disease is a true breakthrough and will hopefully open the floodgates for further and better Alzheimer’s disease drugs to be developed in the near future. In that sense, Aduhelm is truly a wonder.