The Alzheimer’s community cheered in early July when the FDA approved donanemab (Kisunla) for the treatment of early Alzheimer’s disease. This is the third FDA-approved monoclonal antibody therapy for the disease (though, notably one of three is no longer on the market). As a disease-modifying treatment, donanemab is approved for those with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Patients must have confirmed elevated beta-amyloid in the brain to receive this anti-amyloid IV infusion therapy.
Clinical trial data show that those receiving donanemab experienced a 35% slower decline reflected on the integrated Alzheimer’s Disease Rating Scale compared to those on placebo. For context, it’s crucial to consider these two factors: first, some clinicians and researchers aren’t convinced that the 35% difference in the iADRS measurement will be noticeable to patients and loved ones (Source). Second, the drug comes with serious side effects.
These risks to those taking donanemab include amyloid-related imaging abnormalities (ARIA). One in four receiving donanemab experienced brain swelling (ARIA-E), at least three in 10 had documented brain bleeding (ARIA-H), and 13% in the donenmab arm left the study due to side effects (Source). These are serious risks for a disease progression delay that may or may not be noticeable.
I do not mean to bash donanemab–it represents hope and potential improved/prolonged quality of life for some of the 6.7 million Americans over 65 with Alzheimer’s disease, and potentially for those with early-onset AD as well. Of course, it’s not just the patients who suffer. It’s a burden and heartache as well for 11 million loved ones, who provide 18 billion hours of unpaid care to those with Alzheimer’s and other dementias. If donanemab and other treatments can help avoid some of this, that’s a boon for everyone.
New Research Targets
Researchers were hopeful that the anti-amyloid approach was the ultimate solution. However, this solution does not seem to be satisfactory. The three approved disease-modifying beta-amyloid drugs are less effective than we’d like, with many questioning whether the risks outweigh the benefits. Aducanumab (Aduhelm) was controversially given conditional approval and later taken off the market. Lecanemab (Leqembi) is picking up some steam, with the number of patients currently taking it up almost 2.5 times compared to the end of 2023.
One option when staying with the anti-amyloids is the prevention route. Targeting those with a high risk for the disease was the subject of at least one study using anti-amyloids, and the currently approved drugs could certainly be tested in that population as well. The caveat is that it would be a long study–at least a decade or two–to see whether patients develop Alzheimer’s disease symptoms. Subjects must be willing to accept the risks of brain bleeds and inflammation. And to receive regular infusions. That’s a lot to ask.
There are multiple directions those of us in pharma development can go in trying to treat (and someday cure) Alzheimer’s disease. While anti-amyloids are definitely a step forward, we need to ask if this is a direction we want to continue pursuing. We may have reached the limit of what we can do with this angle. Much research is still needed, as studies have shown that decreasing the amount of amyloid proteins doesn’t necessarily resolve symptoms. Alzheimer’s is a complicated disease and we need to try additional approaches.
Source: Alzheimer's Association
Fortunately, there are plenty of other clinical trials. As of January 2024, there are 164 trials studying 127 drugs. This includes 48 Phase 3 trials focusing on 32 drugs. One-third (34%) target disease-modifying biological agents, 41% focus on disease-modifying biological agents, 10% study cognitive enhancing agents, and lastly, 14% are testing treatments for neuropsychiatric symptoms.
In this 2024 pipeline, 22% of the Phase 3 trials target amyloid, a similar percentage as all the drugs in development. Other targets include the tau protein, neurotransmitters, and inflammation. GLP-1s, the therapeutic making a splash in treating diabetes and obesity, is also being studied for early Alzheimer’s.
Pharmaceutical manufacturers continue to make significant R&D investments for Alzheimer’s medications, yet more than 95% of clinical trials for treatments have failed, so far. I know that pain and frustration well from my time at Wyeth Pharma, one of bapineuzumab’s codevelopers. We hoped that bapineuzumab, which lowered key Alzheimer’s disease biomarkers, would make a significant disease impact. Unfortunately, it was part of that 95%, and ultimately it did not have clinical efficacy.
In the true spirit of Pharma for Good, we need to redouble our commitment to Alzheimer’s research, to develop effective treatments, regardless of the success rate. It’s that important.
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