The New Treatments For Ad
Alzheimers cure breakthrough studies and potential treatments have shown some promising results.
Dissolving the plaques: Most of the current focus on the management of AD has been targeting the protein plaques known as amyloid. These plaques are a classic feature of the disorder and often deposit early in the brain. Individuals who develop these plaques in the brain are more likely to develop symptoms of AD than those without plaques. Hence, several drugs have been developed that prevent the formation or clumping of these amyloid plaques. The monoclonal antibodies are very similar to the naturally occurring antibodies in the blood circulation, but they have only one target: amyloid beta. Unfortunately, amyloid is not found in all patients with AD and why this happens is not known. It is believed that close to 30%-35% of AD patients with mild to moderate disease may not have brain amyloid and, hence, cannot benefit from this treatment.
Currently, Aducanumab is only approved for use in select patients with mild cognitive impairment or early Alzheimers disease. Before the treatment can be administered, all individuals with AD must undergo a PET scan to determine if they have amyloid plaques.
Several other monoclonal antibodies have also been developed by different drug manufacturers and they also target amyloid in the brain. All these agents are currently being evaluated in clinical trials.
To be eligible for Aducanumab treatment, one has to meet the following criteria:
Drugs To Treat The Cognitive Symptoms Of Dementia
A number of drugs are currently available in Australia for use by people with dementia. These drugs fall into two categories, cholinergic treatments and Memantine.
Cholinergic
Cholinergic treatments offer some relief from the symptoms of Alzheimers disease for some people for a limited time. Drugs known as acetylcholinesterase inhibitors work by blocking the actions of an enzyme called acetylcholinesterase which destroys an important neurotransmitter for memory called acetylcholine.
Current cholinergic treatments are approved for use for people with mild to moderate Alzheimers disease. A number of the acetylcholinesterase inhibitors are available as subsidised medicines under the Australian Pharmaceutical Benefits Scheme.
People may receive these drugs at nominal cost if a physician or psychiatrist has found them to have a diagnosis of Alzheimers disease.
They must show improvement on a commonly used test of mental function in the first six months of treatment in order to receive further supplies of subsidised medication.
Memantine
Memantine targets a neurotransmitter called glutamate that is present in high levels when someone has Alzheimers disease. Memantine blocks glutamate and prevents too much calcium moving into the brain cells causing damage. It is the first in a new class of therapies and acts quite differently to the acetylcholinesterase inhibitors that are currently approved for treatment in Australia.
Am I Eligible To Receive Aducanumab
The clinical trials of aducanumab studied a limited, specific group of people. You may be eligible to receive the drug if you:
- Are younger than 85 years old
- Have confirmed mild cognitive impairment, defined as a mild decrease in memory and/or thinking that occurs daily but does not yet affect functioning
- Have amyloid present in the brain
- Do not have a history of microbleeds, transient ischemic attacks, or stroke due to bleeding
- Do not take blood-thinning medications
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Will The Fdas Decision Be Important
If aducanumab works, it would be the first drug that actually slows down the progression of Alzheimers. That means we could possibly turn Alzheimers from a fatal disease into one that people could live with for many years, in the same way that people are living with cancer, diabetes, and HIV/AIDS.
For researchers, it means that more than 20 years of scientific work, which suggests that removing amyloid from the brain can cure Alzheimers, may be correct. But many of us have begun to doubt this theory, because trial after trial has shown that amyloid could be cleared from the brain but clinical disease progression was not altered.
From Bench To Bedside
Drug discovery is a long process and involves many rounds of testing, ruling out and refining.
When researchers discover a promising protein or molecule that plays a part in a disease like Alzheimers, the next challenge is to develop ways to alter how that protein works to see whether it could slow or stop the disease. Researchers are developing many innovative ways to do this.
We heard from Dr Zam Cadar at the University of Oxford and Dr Rick Livesey, who leads the Alzheimers Research UK Stem Cell Research Centre in Cambridge. Both are using cutting-edge stem cell techniques to understand the diseases that cause dementia and search for potential new drugs.
Nerve cells created from skin cells from a person with Alzheimers showing the build-up of hallmark Alzheimers protein, amyloid, in green .
Studies in mice are another important part of the drug discovery process, as they allow potential new treatments to be tested in a living organism. We also heard from several researchers whose research programmes use mice bred to develop particular features of diseases like Alzheimers.
Prof Giovanna Mallucci from the University of Cambridge used her time on the conference platform to highlight some common processes that go wrong in several different neurodegenerative diseases. Shes previously published promising findings in this area which raise the promise that one drug targeting such a common mechanism could hold benefits for multiple forms of dementia.
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Researchers Around The World Are Working To Develop Effective Treatments For Dementia And Eventually To Find A Cure
Much of this work is focussed on Alzheimers disease, the most common form of dementia.
There is currently no cure for Alzheimers disease. Available medications can reduce symptoms and improve quality of life in some people, but they do not stop the progress of the disease.
The potential treatments discussed below are in the early stages of research and are not currently available. However, they are all part of the research effort to find more effective treatments for Alzheimers disease and ultimately a cure.
Risks And Ripple Effects
While the benefits of Aduhelm remain murky, some risks are clear. The same Phase III trials showed that 41% of patients who received the high dose of Aduhelm the dose that may have led to cognitive benefits experienced cerebral swelling or hemorrhage. Although the majority of these were minor and asymptomatic, a 75-year-old woman in the trial died after experiencing brain swelling and seizures. The risk was considered high enough for the FDA to require the company to place a warning on Aduhelms label, advising physicians to monitor patients and obtain two MRI brain scans during the first year of treatment.
Patients selected for the Phase III studies were excluded if they had any of the many medical complications common for older people. This includes cardiac problems, the use of blood thinners or impaired liver or kidney function. These selected patients, who may be healthier than those in the general public who would receive the medication, underwent not two but seven MRIs for monitoring. MRIs are expensive procedures they raise the real cost of Aduhelm by about 20%.
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Clinical Trials And Fda Paving The Way
Now that we have better diagnostic tools and sensitive cognitive screening, like imaging and biomarkers, we can include trials for people in the earliest stages of the disease process who have no symptoms and we can measure even subtle changes in the progression of the disease, which maximizes our probability of finding better treatments, says Woodcock.
Whats more, earlier this year, the FDA announced revised guidelines for neurological disorders that for the first time will green-light clinical drug trials for preclinical Alzheimers, the stage before dementia symptoms become apparent.
This represents a major policy shift that the administration hopes will lead to better treatment at the earliest stages of the disease, where medical intervention is most promising, and open the door to treatments that stop the disease process before it progresses.
What You Need To Know About Aducanumab
The recent FDA approval of aducanumab for the treatment of Alzheimers disease has left people with a lot of questions. As the first drug authorized to treat Alzheimers since 2003, it has given hope to people who have had few treatment options for this devastating disease. However, aducanumab is not a cure for Alzheimers disease and it is not for all people with memory loss or Alzheimers disease. Here, Duke geriatric psychiatrist Kim Johnson, MD, answers some frequently asked questions about the new drug and how to find out if it might be an option for you.
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‘cure’ Could Take Many Forms
As varied as the research pipeline is, most experts agree on one thing: When it comes to finding a way to stop, slow or prevent dementia, it wont boil down to one drug treatment or even one drug target. Rather, it will be a combination approach, perhaps involving drugs that clear the amyloid plaques, knock out the tau tangles, target problem proteins and improve the synaptic health of the nerve cells in the brain.
Patients may also receive nonpharmacological prescriptions from their doctors. Some of the most recent research has shown that cardiovascular health and cerebral vascular health play a critical role in overall brain health throughout ones lifetime. Exercise, diet and sleep have all been shown to reduce risk of cognitive decline in adults. Whats more, a landmark study in 2018 showed that intensive blood pressure control significantly lowered the chances that participants developed mild cognitive impairment.
The mishmash of therapies likely wont cure dementia, but as Rafii explains, we have very few cures in medicine. He and others in the field, including the DDFs Grant, are optimistic, however, that the ongoing advancements will lead to treatments that can delay the disease and improve the lives of millions.
What Im seeing is great progress in the building blocks, the foundation of new future therapeutic approaches, Grant says.
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The Devastation Of Alzheimers Disease
With all this said, we are extremely aware of the gradual and cumulative devastation that Alzheimers disease causes, as patients lose their memory and cognitive functioning over time. In late-stage disease, people can no longer hold a conversation or respond to their environment. On average, a person with Alzheimers disease lives four to eight years after diagnosis, but some patients can live up to 20 years with the disease.
The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimers disease and this number is expected to grow as the population ages. Alzheimer’s is the sixth leading cause of death in the United States.
Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients. As a result of FDAs approval of Aduhelm, patients with Alzheimers disease have an important and critical new treatment to help combat this disease.
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Next In The Dementia Drug Pipeline
For the handful of other developmental Alzheimer’s drugs hoping to clear those same regulatory hurdles and prove their efficacy Eli Lilly‘s donanemab, Roche’s gantenerumab and Eisei’s lecanemab among them there may be a silver lining to ceding first-mover advantage to Aduhelm.
After decades of expensive but thus far largely fruitless research trials, the CEO of pharma giant Eli Lilly, David Ricks, said his firm was “getting closer and closer to the goal” after a positive set of Phase Two results for its offering, donanemab.
Speaking at CNBC’s Healthy Returns Summit in May, a month before the FDA’s approval for rival Biogen’s Aduhelm, he said his team felt “good about the probability of success,” and said he wanted to explore an “accelerated” route too, using what he called “adaptative pathways at the FDA to consider looking at data sooner” that “should be applied in a serious and widespread condition like Alzheimer’s.”
However, he acknowledged that recruitment for the next phase of trials required a significantly larger cohort of participants, and given that it would last 18 months, he did not expect a new approved product before late 2023 at the earliest.
Several experts told CNBC the Biogen drug’s unique threshold for regulatory approval, with treatment potential seeming to trump uncertain real-world benefits, could reinvigorate efforts by competitors like Lilly, who are focused on developing drugs that rely on relatively similar techniques.
Who Is A Candidate For Aducanumab
Based upon the clinical trials in which it was studied, the drug can be potentially considered for use in individuals with early-stage Alzheimers disease. This means individuals who have Alzheimers in its mild cognitive impairment or mild dementia stage. Individuals in this early stage of Alzheimers may be able to function normally, or they may require a little bit of help with complicated activities like paying bills, grocery shopping, preparing meals, or balancing their checkbook. Individuals who need help with dressing, bathing, or other basic activities would be beyond the early stage and the drug would not be indicated for them.
Note that not everyone with mild cognitive impairment or mild dementia has Alzheimers disease. There are other causes of these problems as well. To determine if Alzheimers is present, you need to get either an amyloid PET scan or a lumbar puncture to be sure you have the amyloid plaques of Alzheimers. Currently, a lumbar puncture is generally covered by insurance, but an amyloid PET scan is not.
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So Does The Drug Work
I attended the day-long FDA hearing on November 6, 2020, and also independently reviewed all the publicly available data for aducanumab. There was one small clinical trial to assess efficacy and side effects, and two large clinical trials to assess effectiveness, side effects, safety, and how the drug might be used in clinical practice. The small phase 2 study and one of the large phase 3 studies were positive, meaning that the drug worked to slow down the decline of thinking, memory, and function that is usually impossible to stop in Alzheimers. The other large study was negative. Hmm Is two out of three positive studies good enough? Biogens scientific team had many plausible explanations for why that one study was negative.
The advisory panel, however, was not convinced. They pointed out that phase 2 studies are always positive, because otherwise you wouldnt move on to phase 3, so that study doesnt count. They also pointed out that, although you can think of the positive phase 3 study as the true one, and try to understand why the negative one failed , you could equally think of the negative study as the true one, and try to understand why the other one showed positive results.
Medicines To Treat Related Conditions
There are some conditions, such as heart problems, that can affect symptoms of dementia, particularly vascular dementia. It’s important that these are diagnosed and treated.
These conditions include:
- delusions
- hallucinations
These changes in behaviour can be very distressing, both for the person with dementia and for the person caring for them. However, there are coping strategies that can help.
If coping strategies do not work, antipsychotic medicines such as risperidone or haloperidol may be prescribed for those showing persistent aggression or extreme distress.
These are the only medicines licensed for people with moderate to severe Alzheimer’s disease and vascular dementia where there’s a risk of harm to themselves or others.
Risperidone should be used at the lowest dose and for the shortest time possible as it has serious side effects. Haloperidol can be used only if other treatments have not helped.
The decision to prescribe a medicine should be taken by a consultant psychiatrist.
Antidepressants may sometimes be given if depression is suspected as an underlying cause of anxiety.
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Questions To Ask The Doctor If Drugs Are Prescribed
- What are the potential benefits of taking this drug?
- How long before improvement may be noticed?
- What action should be taken if a dose is missed?
- What are the known side effects?
- If there are side effects, should the drug be stopped?
- If the drug is stopped suddenly, what happens?
- What drugs might interact with the medication?
- How might this drug affect other medical conditions?
- Are there any changes that should be reported immediately?
- How often will a visit to the doctor who prescribed the drug be needed?
- Is the drug available at a subsidised rate?
Large And Longer Trials
These findings allowed Biogen to conduct larger clinical trials of Aducanumab. Two trials, called ENGAGE and EMERGE, collectively enrolled over 2,500 people with MCI or early-stage dementia caused by Alzheimers disease.
The changes in the brain caused by Alzheimers disease tend to start many years before symptoms show. This means that earlier treatment is likely to have a better chance of being effective. The main aim of the ENGAGE and EMERGE trials was to see if Aducanumab could reduce signs of cognitive decline in the people with MCI and mild dementia. Participants received different doses of the drug and were compared to people receiving a placebo treatment. The placebo contained no active ingredient.
The two large Aducanumab trials began in 2015 but were cut short in March 2019. Although the EMERGE trial was said to be trending positive in terms of potential outcomes, early results indicated the ENGAGE study was not going to be successful. In order to progress, Biogen had specified that both trials needed to be heading in the right direction. The results meant that both trials were terminated.
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What Does This Mean For People Living With Dementia In The Uk
In light of this decision, Aducanumab remains unavailable for people living with Alzheimers disease in Europe and in the UK.
The UK has a medicines regulation body called the Medicines and Healthcare products Regulatory Agency . Although the EMA have made their decision for Europe, we await the decision by the MHRA, on whether or not Aducanumab will be approved as a treatment for Alzheimers disease in the UK.
However, in Government guidance published in January 2021 it is stated that the MHRA may rely on decisions taken by European Commission for the next two years. This suggests that Aducanumab may not be approved for use in the UK, however we will need to wait for the MHRA to announce their official decision.
Its disappointing that there are still no treatments that can slow down the progression of Alzheimers disease available in the UK. However, it is crucial that any new treatment is safe and provides clinical benefit for people living with Alzheimers disease before it is made available. It is essential that regulatory authorities are confident that Aducanumab is both effective and safe before it can be made available as a treatment.
Aducanumab is likely to continue to split opinion. However, the results of additional clinical trials will help to bring clarity to the effectiveness and benefits of Aducanumab.