J. Falatko
If you follow financial markets and biotech you may have seen this week a big “pop” in the company Biogen. Biogen is a biotech firm focused mainly on neurodegenerative disorders. The stock rose 40% in one day when the FDA issued a statement of confidence in its investigational drug Aducanumab.
Optimism around Aducanumab has been growing since 2016. The medication is a mono-clonal antibody that targets Beta-amyloid plaques in the brain. When the antibody is bound the amyloid plaques can no longer aggregate inside neurons. Beta-amyloid aggregation is one of the leading theories for the mechanism of Alzheimer’s disease. The thought is, if the aggregation is stopped or slowed, the disease will be halted or substantially hindered.
Many of us know someone that suffers from Alzheimer’s disease. It is a slow, progressive, terminal disease. Caregiving for these patients is very difficult. There is no effective treatment for it.
The disease sets up perfectly for a blockbuster medicine. Its large market size and slow nature of the disease could ring the cash register for big pharma. There is currently no significant competitor on the market. The cost of Aducanumab is estimated to be $40,000 annually. There are 4.5 million people over the age of 65 living with some form of cognitive impairment. If you estimate just 10% of those eligible patients are treated with the drug, that’s 18 billion in revenue per year. Most analysts following the company stated it is worth at least 7 billion in revenue per year. Biogen’s current annual revenue for its entire portfolio is 14 billion.
Given the implications of this drug’s success and the amount of money being bet on its approval I thought I would look into the clinical trials to see what all the fuss is about. I was surprised to find that when I searched for the published data there was none. I found out the trial was stopped early due to futility. The only published data I could find was a slide-deck on the company’s website.
So, why would the FDA consider approving a drug based on a trial stopped early for futility? How effective could this medicine be against a disease that has eluded treatment for so long?
Let’s dive in.
The trials executed by the company are the EMERGE and ENGAGE trials. They were randomized, double blind, placebo controlled trials. Their design was identical. They enrolled 3300 patients in the two trials. Patients with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease with confirmed amyloid plaques were eligible.
The two trials divided groups up into a placebo group, low dose Aducanumab and high dose Aducanumab. The treatment protocol was 14 doses 1 month apart. The medication is infused through an IV. The primary endpoint was a dementia score known as the CDR-SB. This score is derived from a survey of 6 primary mental domains: memory, problem solving and judgement, orientation, community affairs, home and hobbies, and personal care.
The observation period was 18 months.
The randomization strategy was successful since they did not find any significant differences between the two groups. They had a significant amount of attrition (drop-outs) due to adverse effects from the medication and withdrawals from the treatment protocol. Roughly 40% in each trial either discontinued treatment or withdrew from the study.
Here is a summary of the results.
The results of the trial were not impressive. To start, they targeted patients with mild symptoms. It was not inclusive for all patients that suffer from dementia. The mean baseline mini mental status score (MMSE) was 26 in both trials. This is the equivalent of a patient that may have some issues with word finding, remembering the day or the week from time to time, or have difficulty with complex reasoning, but overall pretty functional. These were not patients dependent on others for their daily needs.
Since I do not understand the CDR score well I am going to present the mini-mental status (MMSE). This is a common tool we use in the office to assess cognitive impairment.
One of the trials (ENGAGE) showed no statistical difference. There were roughly 540 patients in each group. The decline in MMSE at the end of 18 months was about 3 points in all participants.
The EMERGE trial did show a statistically significant difference in the MMSE. In the high dose group, the mean change from baseline was 2.5 points vs. 3.3 points in the placebo group. A difference of 0.8 points after 18 months.
The CDR data showed similar small improvements. The difference between high dose Aducanumab and placebo was only 0.5 points on this scale.
In a subgroup and imaging analysis, the drug was shown to do what it is marketed to do. All of the imaging and CSF studies showed a significant reduction in beta-amyloid plaque.
As mentioned above there was a significant amount of attrition. Only 60% of enrollees completed the protocol. Serious adverse events occurred in 12-13% of the patients assigned to Aducanumab regardless of dose. Participants cited adverse events as the reason for permanent discontinuation 8-11% of the time. Small hemorrhages in the brain occurred in 18% of patients assigned to Aducanumab. In the Aducanumab group, 20% of the participants complained of headache and dizziness related to brain swelling or small cerebral hemorrhages.
I am going to do my best to sum up this experience. Patients with early stage Alzheimer’s eligible for the drug will need to go to an infusion center once per month. Either the patient or medicare will pay between $3500-4000 per infusion. Roughly 40% of them will not be able to tolerate the medication. At the end of 18 months they will be fortunate to be 0.5 points better on a convoluted dementia scale designed to assess cognitive function in a medical research setting. Sound like a good deal?
There are several critical pieces of information missing. First, the study was never published, so it was not subjected to peer review. Second, the study was stopped early for futility, there could be more harm than anticipated had the trial continued. Third, we have no idea how the patients that dropped out of the study were analyzed or accounted for in the final analysis. Fourth, the protocol was changed half way through one of the trials to create synergy between the two, which impacted the final reported results.
When the FDA agreed to have an independent panel review the trial data, Biogen’s stock surged 40% in one day. I can see why the FDA would agree to review this trial. Treatment for dementia is a significant unmet need. However, after reviewing the data myself I thought this was a big stinker, and the independent panel agreed. They voted 8-1 against approval. The official review is due in March. The stock appropriately plummeted 50% when it opened the following Monday.
Most internists and Neurologists are aware of the beta-amyloid theory. The theory was developed over 2 decades ago when brain imaging and biopsies discovered an association between beta-amyloid plaques and dementia. Since that time there has been significant time and resources into solving the beta-amyloid plaque problem. Despite these efforts there have been no breakthroughs. This medication delivered as advertised. Per their imaging data it cleared a significant amount of amyloid plaque, yet patients did not experience any tangible improvement after a year on the medication.
It's possible patients were not far along enough in the disease to notice a difference in this study. Or it was already too late since the plaque was there. A longer protocol may have shown a desirable plateauing of impairment. Who knows? The investigators will need to run another study to see if this is the case. Maybe beta-amyloid plaques don’t matter like we think they do. How does one decide when a theory may be wrong? Beta-amyloid may be the end result of some other process and not the cause. This was a concept discussed in N.N. Taleb’s book Fooled by Randomness. You can really screw up following a casual relationship identified from a data set. There's a possibility your data set is flawed. Or worse the relationship doesn't actually exist. You were fooled by bad data, or a random variable.
My personal view on the treatment of dementia some may find controversial. When we treat dementia, we are treating the family members and caregivers. Being a caregiver for a patient suffering from dementia is a terrible burden. The patients are not cooperative. They don’t realize they are being helped. The work is long, arduous, hopeless, and thankless. They require assistance with all of their tasks. The caregiver just wants the mind of their loved one back. They are desperate.
Getting old isn’t a battle, it’s a massacre. The body breaks down slowly for most of us. One ailment at a time. Most of us don’t think about death on a regular basis. We’re too busy. Our jobs, children, hobbies, favorite movies and games keep us distracted from our eventual fate. Thank goodness. One would go mad if they had to contemplate their death regularly.
When you’re old most of these things are gone. Your children are grown and often far away. You can’t work. You have difficulty seeing and hearing, so movies and TV shows and reading books are out. Every joint you move hurts. Your hands are arthritic, you can barely write or clean yourself properly. What are you left with? Your thoughts. What are you thinking about? Probably your death and the life you had, fading away.
Some of us are prepared to die, but this is probably a minority. It’s going to be scary, I don’t care who you are. Even Jesus Christ during the crucifixion yelled , “Why have you forsaken me.” According to the story, that’s God incarnate, in the flesh, at the moment His time was up, calling out for help.
Dementia, in an odd way, is a natural cure for this. It’s a release from the existential pain and anxiety that comes when your time draws to a close. You don’t even realize it. You're oblivious. The disease protects you from this anguish. Is reversing it the best solution? Maybe not. I don’t want to be insensitive. The experience of the parties involved is very different. If you are a caregiver for someone with dementia your experience has likely been horrific. How was the experience for your loved one? Was it the disease that ruins their life, or what we do to them as it draws to a close?
My grandmother eventually passed from Alzheimer’s dementia. The disease progressed over the course of 5-6 years. She lost her mental capacity about three years in. I recommended several times for her to be placed in hospice, but my grandfather wasn’t interested. She spent the last 2 years in and out of nursing homes. Two weeks before her death she fell and broke her neck. She was placed in a collar and sent to the nursing home. It was very difficult to feed and hydrate her in the collar. She became confused, dehydrated and died of kidney failure. Does this make sense to anyone?
An alternative would be to devote resources towards preparation at the end of life. We could spend more time setting expectations, education about this disease, what the end might look like, and streamlining respite opportunities instead of constantly pushing the goal post further down the field.