It erodes cherished relationships, leaving loved ones grappling with the heart-wrenching realities of a gradual decline of cognitive function. The emotional toll is immeasurable, leaving a lasting imprint on those affected. Under such conditions, the boundaries of what the efficacy of a treatment actually means may be blurred. Whilst therapies resulting in the slowing of cognitive impairment in numerical terms makes for positive reports in medical journals and mainstream media, what do such results mean for the patient and their families? What are the tangible effects patients can see and feel?
How to define Efficacy within the context of Alzheimer’s Disease (and for whom)?
Noun FORMAL
“The ability to produce a desired or intended result.”
As I seek to understand the diseases I investigate more fully, I make a conscious effort to look beyond the superficial concept of the clinical efficacy of the therapies that treat them. The word "efficacy" is often associated with images of clinical endpoints and statistical measures. However, it is vitally important that we grasp the profound impact that treatments have on individuals grappling with conditions in the real world – the patients who must bravely navigate their daily lives while bearing the weight of disease. The true essence of efficacy reveals itself when treatments have the ability to uplift, empower, and offer a glimmer of hope amidst the trials of living with a life-changing affliction. This discussion is not new. In fact, I was inspired by a recent article on efficacy, positing the statement, “But, really, I ask – what is efficacy in human terms?” You can read the article here.
The burning question is, can we expect to find cures for diseases as complex as Alzheimer’s – and if not, then what should the definition of “efficacy” be? A cure is a very different proposition from merely slowing the parameters of advancing disease. And yet, mainstream media, clinicians and charities often discuss the hope for a cure for Alzheimer's. When decisions to accept treatment are signed off by patients and relatives who are likely in a state of upheaval and even denial about the reality of their situation, the onus for transparency falls squarely on the clinicians and the companies that produce treatments.
What is the current landscape with Alzheimer’s Disease?
Alzheimer's Disease (AD) is widely considered to be the “The Great Morbidity of the 21st Century” and has been described as a plague of epidemic proportions. Yet, despite the increasing prevalence of the disease, there have been very few significant drug approvals over the last twenty years until recently.
Until the approval of aducanumab, the therapies available to treat AD were known as ‘symptomatic treatments’, which treat the symptoms of the disease but not the underlying cause. Aducanumab was the first ‘disease-modifying therapy’ approved for AD, meaning that aducanumab claims not just to treat symptoms but also aspects of the pathology of Alzheimer's Disease that lead to cognitive decline.
In the case of aducanumab and lecanemab, these monoclonal antibodies aim to target the amyloid-beta plaques in the brain of AD patients. These plaques have long been considered a key hallmark of the disease. However, it is essential to note that while they are indeed a hallmark of the disease, whether these plaques are a cause or a consequence of Alzheimer’s Disease remains to be established. This is not to say that these treatments are targeting the wrong aspect of the disease, but rather that this is an incredibly complex disease where so many unknowns still remain.
As a result, while aducanumab and lecanemab have been shown to clear amyloid in the brain effectively, progression is not halted, and patients continue to decline. It is clear that while aducanumab and lecanemab have been a significant step towards effectively treating Alzheimer’s Disease, we are nowhere near the finish line.
Aducanumab (Approved July 2021)
Aducanumab is a prime example of a drug that has shone a beacon of hope in the murky darkness that envelops many patients and their families. When its unexpected approval was announced, reactions were mixed. Searching New York Times will result in pages of articles analysing its controversy. The internet is awash with people on both sides of the camp, from doctors who immediately contacted friends to those who claimed that aducanumab’s approval was a disgraceful decision. Neurologists shunned the drug at the clinical trial stage, and three members of the FDA panel overseeing the approval process had resigned at the time of writing.
There is no doubt that aducanumab’s approval was controversial. However, it has sparked some hope that we could have therapies for Alzheimer's Disease that benefit patients. Is this hope overly optimistic? Time will reveal the success of the product. However, it is wise to remember that it is unfair to expect this one treatment type to be able to provide a ‘cure’ or miraculous improvement to a disease with this level of complexity.
Lecanemab and Donanemab
These two products emerged post-aducanumab’s approval. Early claims cite the ability to reduce the progression of Alzheimer’s Disease by 27% and 36%, respectively, over an 18-month period of use. (Based on CDR-SB or the Clinical Dementia Rating-Sum of Boxes).
It is too early to say whether or not lecanemab and donanemab will yield better results than aducanumab. However, the interesting fact is that we have gone from not having any disease-modifying treatment options for Alzheimer's Disease to having three possible options within a two-year period. While this is a significant turn for the better in the provision treatment of Alzheimer’s Disease, the conversation as to what this means to patients has never been more pertinent.
“People should be really encouraged by this news, which is yet more proof that research can take us ever closer towards a cure.”
The Guardian (UK)
With powerful quotes such as this, it would be easy to assume that the answer for your AD diagnosed loved one is just around the corner. As we have seen with aducanumab, that may not be the case. Aducanumab, lecanemab, and donanemab are the first emerging therapies that claim promising ‘efficacy’ profiles for treating Alzheimer's Disease. While there is a clear improvement in the slowing of advancement with lecanemab and donanemab, what does this 27% or 36% reduction in cognitive decline mean to a patient? Will the slowing equate to years of cognitive function that would otherwise not have been possible? Are we talking about a few months of a reprieve? Worse still, could we be looking at situations where the net suffering of a patient is increased in exchange for minimal real-world benefits?
In Part 2, I will guide you through a real-life example as well as discuss finding a "cure".
