I would not have guessed that a mere week after writing about FDA approval for leqembi for Alzheimer’s disease, I would feel compelled to write about another drug that also shows incredible promise for treating the disease. This makes three drugs that have either gained some form of FDA approval or shown clinical efficacy in a phase III trial. This has caused a flood of calls to my colleagues who specialize in treating dementia, so a review of where things stand could be helpful. It is also interesting to review how things have seemed to change so quickly after decades of disappointment.
To review, in June 2021 the FDA gave accelerated approval to Aduhelm (aducanumab) for the treatment of Alzheimer’s disease (AD), which is a progressive dementia caused by a neurodegenerative process. As I wrote at the time, this decision was somewhat controversial. First, it was one of the early tests for the FDA’s new accelerated pathway, which can approve a drug for an unmet need based entirely on improvement in a biomarker without evidence of actual clinical benefit. Further, there was good reason to be cautious about the amyloid hypothesis of AD on which the approval was based. The evidence itself also had some issues – an independent analysis questioned the statistical significance of the results.
All things considered, it was not looking good for Aduhelm or the FDA’s new accelerated pathway. Biogen, the manufacturer of Aduhelm, was given three years to provide clinical evidence that their drug actually works, and studies are still ongoing. Meanwhile, Aduhelm now appears to have been beaten to the finish line by two other similar drugs, answering many of the thorny questions about this entire approach to AD.
Early in 2023 leqembi (lecanemab) was given the same accelerated approval by the FDA based on the same kind of data, that the drug binds to and reduces amyloid. Last week, based on a large clinical trial, that approval was upgraded to full regular approval. Leqembi reduces the progression of clinical measures of AD by 27%. Now, a mere week later, a large clinical trial shows that a third drug, donanemab, reduces AD progression by 35%.
Before I discuss further what all this means, let’s review the new data. First, this was a very large trial:
Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021.
Of the 24 clinical outcomes measured in the trial, 23 were statistically significant. The effect size is also robust:
The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001)
Tau is another protein implicated in AD, and the group that did the best were the low-tau group. The mixed tau group also saw improvement, but not as much. Also, there was a correlation between early treatment and benefit. Like lecanemab, about 24% of subjects had changes on their MRI scan shows edema or effusion, 6% symptomatic. Three patients in the treatment group died of a treatment reaction, while one died in the placebo arm. The FDA is likely to have a decision by the end of the year, but given this data it is very likely that donanemab will gain full approval.
How is it that after three decades of failure, we now have three drugs in two years showing such promise? There are several factors. It is interesting to note that until these three drugs there was considerable controversy over the amyloid hypothesis of AD. It is clear that beta amyloid and other forms of amyloid and tau proteins build up in the brains of AD patients. These proteins become toxic when they form complexes, including plaque and fibrillary tangles. However, it was never fully clear if the plaque and tangles were the consequence of the disease or the cause of neurodegeneration. If the former, then targeting amyloid would cause cosmetic changes but not be disease-modifying. Many amyloid targeting drugs have been tested over the years, and none have worked, casting doubt on the notion that amyloid is the culprit.
Perhaps the most significant thing to come out of lecanemab and now donanemab showing clinical benefit is that these drugs are the first clinical confirmation of the amyloid hypothesis. Of note, lecanemab and donanemab target different forms of amyloid. Donanemab targets plaques directly, while lecanemab targets forms of amyloid before they form into plaques. Donanemab shows that clearing plaques themselves is beneficial. The data also show that the benefits last even after treatment stops, at least for 18 months.
So what was the breakthrough? Researchers give several reasons. First, these three drugs are all monoclonal antibodies (that is why they all end in “mab”). These are antibodies that bind to certain type of amyloid and target the immune system after them, which then breaks them down and clears them. This approach likely just works better than previous drugs.
Second, researchers have been more aggressive at dosing. It is almost a cliché that when a drug fails to show benefit in a clinical trial, proponents always argue that we simply need to give it in a higher dose, or perhaps there is a subgroup for whom the treatment works. It turns out, both are true when it comes to anti-amyloid treatments. You need to significantly reduce amyloid build up to see clinical benefit. Also, researchers started studying patients with early disease, and that seems to have made a big difference.
What, then, is the current state of treatment for AD and what can we expect in the future? First, studies of Aduhelm need to be completed to show clinical benefit. This is looking much more likely, given the results from lecanemab and donanemab. Assuming it works, and the FDA gives final approval to it and donanemab, we may soon have three FDA approved disease-modifying treatments for AD. It is a new world, and an exciting time for the field of AD research and treatment.
Patients now have interesting options. Of the three drugs, donanemab looks the most promising, both because it has the largest effect size, and because treatment does not necessarily need to be indefinite. Researchers think that a one year treatment phase followed by occasional maintenance treatments may be enough. Meanwhile, lecanemab requires treatments every other week indefinitely.
But it’s always good to have options. Not every patient may tolerate or respond to donanemab, and could cross over to one of the other drugs if necessary. Also, it is possible that combining lecanemab and donanemab (and eventually aducanumab) may have added benefit, since they target different versions of amyloid.
These treatment seem to work best, and may be only worth the risk and expense, in early disease. So it is important for patients with very mild or early symptoms to be evaluated by a specialist and start treatment as early as possible. Also, the availability of treatments tends to light a fire under diagnostic interventions. We generally don’t bother (outside clinical trials) with expensive, risky, or invasive diagnostic procedures for a disease that isn’t treatable anyway. But now that AD is treatable, early diagnosis becomes critical.
This will even cause a push for better diagnostic technology to identify AD earlier and earlier, perhaps even before clinical symptoms. The hope is that very early treatment will slow progression enough that people will not live long enough to ever develop severe dementia. This may lead to screening for AD in asymptomatic individuals, especially if there is a family history of AD.
Now that we know targeting amyloid can alter the disease, this will help focus future research. There are many subquestions about exactly which form of amyloid or tau to target, and in which combinations. The three approved drugs may be eventually considered to be just the crude beginning of this process – important proofs of concept, but not the mature treatments we will eventually have. The success of these drugs is likely to spawn and guide years of subsequent research.