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April 2, 2023:
There is something strange going on with the brain MRI results from the lecanemab Alzheimer’s disease (AD) clinical trials.
What is strange? Lecanemab, in addition to many other drugs that target a brain protein called beta-amyloid, is causing the brain to shrink in AD.
The medical term for shrinkage is atrophy. Brain atrophy reflects neurodegeneration, which is the progressive death of brain cells, and also reflects the worsening of symptoms in AD. As a result, brain atrophy is a well-established “biomarker” of AD. The fact that lecanemab is causing accelerated brain atrophy raises the possibility that use of drugs like lecanemab may accelerate the rate of brain cell death and symptom decline in AD and worsen AD patients’ long-term prognosis.
And yet, lecanemab received “accelerated FDA-approval” on 1/6/23 for treating AD (see my below post on 1/29/23). This accelerated approval was based on the fact the lecanemab clears beta-amyloid from the brain. However, it is not at all clear whether clearing brain beta-amyloid provides benefit to AD patients. On 7/6/23, the FDA will be rending a decision on granting “full FDA-approval” to lecanemab based on the results of a single, 18-month study showing lecanemab to slow cognitive decline in AD by 27%. If lecanemab receives full FDA-approval on 7/6/23, it is highly likely that Medicare and most private insurances will then cover its $26,500/year cost and lecanemab will be widely prescribed and used by AD patients.
How can this be? How can the FDA be ignoring the well-established AD biomarker of brain atrophy and instead focus on brain beta-amyloid levels when considering approval of drugs like lecanemab?
This question and others were raised in an excellent review article published on 3/27/23 by Alves et al. titled, “Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis”:
Although several anti-beta-amyloid drugs, including lecanemab, accelerate brain atrophy among the group of AD patients receiving these drugs, it is possible that only a subset of AD patients experience these brain MRI changes and others do not. However, the pharmaceutical company that holds these patient-specific data for lecanemab, Eisai, has so far not released them publicly or provided them to Alves et al. despite several direct requests. Those who are paying attention are voicing alarm:
“These data are extremely concerning, and it’s likely these changes are detrimental” says Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital.
“We’re talking about the possibility of brain damage” from treatment, says Scott Ayton, who was an author on the paper published on 3/27/23. “I find it very peculiar that these data, which are very important, have been completely ignored by the field.”
Alves et al. state that “it is conceivable that lowering [beta-amyloid] levels damages the brain by the restriction of a vital function of [beta-amyloid]. The sequence of [beta-amyloid] is highly conserved among vertebrates, and all healthy brains contain [beta-amyloid]. Indeed, the production of [beta-amyloid] requires complex mechanisms that suggest an important reason for its presence.”
As an alternate explanation, Eisai and others have postulated that the reduced brain volume seen in patients receiving lecanemab may be from reduced inflammation resulting in a process called “pseudo-atrophy”. But this is just a theory. Another possibility is that lecanemab is providing short-term, 18-month benefit to cognition at the cost of long-term acceleration in neurodegeneration and symptom progression leading to a worsened overall prognosis. Based on the MRI data Eisai has released to date, this question cannot be answered.
The FDA plans to assemble an advisory committee to review lecanemab’s data. This advisory committee will then issue a recommendation to the FDA on whether to approve lecanemab. Usually, the FDA follows the advice of its advisory committees. However, in a shocking rebuke of this precedent, the FDA approved an AD drug very similar to lecanemab called aducanumab on 6/7/21 despite a near unanimous recommendation against approval from its advisory committee.
Due to this unprecedented event and reports of questionable interactions between the FDA and the pharmaceutical company, Biogen, leading up to FDA approval of aducanumab, a US congressional investigation was launched. The conclusion of this investigation was that the FDA approval of aducanumab was “rife with irregularities” and that there were “serious concerns about FDA’s lapses in protocol”.
In order to avoid another fiasco like what happened with aducanumab, Alves et al. and others are strongly recommending that Eisai voluntarily provide the patient-specific MRI data from their lecanemab trials to researchers, to the FDA and to the FDA’s pending advisory committee. This will allow for a sober and balanced assessment of the brain MRI volume data in the FDA’s overall evaluation of lecanemab.
AD is a grueling and devastating disease for patients and their caregivers and we desperately need treatments that can improve patients’ lives. Nevertheless, we must remember the words of Hippocrates from the 17th century: “first, do no harm”. How horrible it would be if in our haste to offer treatments to AD patients, we end up making them worse than they already are.
February 8, 2023:
Well, that was fast. "The Promise of Lithium" book was released on 1/31/23 and already there's been a new development in terms of a recently approved treatment for Alzheimer's disease (AD). So, here it is:
On January 6, 2023, the Food and Drug Administration (FDA) approved the drug lecanemab for treating patients with very early AD. This was based on a study showing this drug to slow cognitive decline in AD by 27% compared to patients receiving placebo in addition to its ability to clear a sticky protein called beta-amyloid from the brain. The drug was approved through a special "accelerated approval" pathway that the FDA established to allow patients quick access to new therapies that addressed diseases with an unmet need such as AD. It remains to be determined if the FDA will grant "full approval" to lecanemab and if major insurance companies including Medicare will cover the $26,500 annual price tag.
In "The Promise of Lithium", there are a few sections that review the highly controversial FDA approval of the drug aducanumab for treating AD, which was granted on June 7, 2021. Like lecanemab, aducanumab also cleared beta-amyloid from the brain; however, only one of the two aducanumab studies showed that it slowed cognitive decline in AD. Because of the inconsistencies in the aducanumab studies' results, most experts do not believe that the evidence sufficiently supports FDA-approval of aducanumab and several private insurance companies as well as Medicare have refused to cover the cost of aducanumab.
In addition, both lecanumab and aducanumab can cause brain swelling and brain bleeding. These side effects are usually mild and don't cause any new symptoms in patients; however, potential long term effects of these brain changes caused by lecanemab and aducanumab are still unknown.
In summary, there are now two FDA-approved "disease-modifying" treatments for patients in the very early stages of AD that may slow down the progression of AD symptoms; however, neither has received full FDA approval and neither has received Medicare coverage. Because the vast majority of AD patients are over 65 years old, Medicare coverage will be essential for the wide-spread use of these very expensive therapies. If Medicare does eventually approve coverage for one or both of these drugs, it likely will be restricted to patients recently diagnosed with AD who are still in the earliest stages of the disease.
Although it is exciting for AD patients to finally see some positive news after years of failed clinical trials, there clearly is much more that needs to be done to improve AD patients' lives. First of all, the 27% reduced rate of cognitive decline in early AD shown for lecanemab in a single study is a fairly small treatment effect size. Because of this small magnitude of benefit, it is unclear if lecanemab can provide long-term, meaningful benefit for AD patients. Also, it is unclear how problematic the brain swelling and brain bleeding side effects from both lecanemab and aducanumab will be with long-term treatment. Finally, these findings only apply to early AD patients. It sure would be nice to have something to offer AD patients who are not in the earliest stages to help slow down their disease progression, too.
Fortunately, the LATTICE trial, that is discussed in detail in "The Promise of Lithium", is underway at the University of Pittsburgh with results expected in late 2024. The LATTICE trial seeks to determine if low-dose lithium therapy can slow cognitive decline and brain changes in early AD patients. Previous studies with low-dose lithium in both early and more mid-stage AD have shown positive results with much larger treatment effect sizes than that seen with lecanemab. These studies were also reviewed in great detail in "The Promise of Lithium". Of course, further research is needed but it is very encouraging to see a major lithium study like LATTICE underway.
TABLE OF CONTENTS
Introduction: Every Day that Passes is a Day Brain Cells Vanish:
What Causes Alzheimer’s and Parkinson’s Disease?
The Brain’s Bermuda Triangle: Sticky Proteins, Inflammation and Oxidative Stress
Alzheimer’s Disease (AD)
Parkinson’s Disease (PD)
What’s Going on With Smoking?
The Connection Between Smoking, Lithium and PD
How Could Smoking Cause AD but Prevent PD?
Lithium’s Multitude of Neuroprotective Actions
Lithium is Effective in AD and PD Animal Models
Chapter 3: The Human Evidence
Lithium in Drinking Water
Prescription Lithium Use
Lithium, Melanoma and PD Connected by Beta-Catenin and Nurr1
Clinical Trials with Lithium: The “Gold-Standard” Level of Evidence
It’s too good to be true
Once a failure always a failure
The Patent Paradox
What are biomarkers and why are they so important?
Lithium’s Effects on AD Biomarkers
PD Clinical Trial Biomarker Results
Follow Your Nose, It Always Knows
Lithium is Not FDA-Approved for Treating AD or PD
Lithium’s Safety Depends on the Dose
Lithium Orotate or Lithium Aspartate?
What Dose Should I Take?