September 05, 2016

How is this Monoclonal Antibody Different from all Other Monoclonal Antibodies?

A new study published in Nature offers some potentially good news. The researchers report that a monoclonal antibody given intravenously to patients with mild cognitive impairment (referred to as “prodromal Alzheimer’s) or mild Alzheimer’s disease was generally well-tolerated and effective in reducing amyloid plaques in the brain. The drug also seemed to have beneficial clinical effects, although the study was not designed to address clinical outcomes. The results were impressive and the prospect of an effective treatment tantalizing. But the response to the paper was at best guardedly enthusiastic.  Why so tepid—given the hype that usually surrounds promising studies of this and other dread diseases?

The answer is that similar efforts in the past have repeatedly fizzled. The New England Journal of Medicine published back-to-back articles in January, 2014 of two drugs, both monoclonal antibodies, both tested in patients with mild to moderate Alzheimer’s disease. Both drugs flopped. Bapineuzumab failed to improve the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog11) or the Disability Assessment for Dementia (DAD) when given to patients with mild to moderate Alzheimer’s Disease who were positive for the strongly predictive apolipoprotein E4. And it failed to improve the scores of patients without that apolipoprotein E variant. Solanezumab did nothing for patients with mild to moderate Alzheimer’s disease whether the outcome was the ADAS-Cog11, the ADAS-Cog14, or the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL). A different approach to immunotherapy, use of a “vaccine” to stimulate the production of antibodies against amyloid (rather than passive administration of those antibodies, as with Bapineuzumab and Solanezumab) only led to the desired antibodies in 25 percent of patients and it had an intolerably high likelihood of causing meningoencephalitis, a potentially lethal inflammation of the brain.

In light of these earlier disappointments, CNN asks if the new drug, Aducanumab is a game-changer (rather than simply asserting that it is). Fox News says it “shows promise.” The editorial accompanying the scientific report in Nature says that if the early findings are confirmed in larger studies, it “might help to accelerate the evaluation and regulatory approval of promising Alzheimer’s prevention therapies.”

Just what did the researchers, who were from Biogen (Cambridge, MA), Neurimmune (Zurich, Switzerland), Butler Hospital (Providence, RI), and the Institute for Regenerative Medicine (Zurich, Switzerland) do? They took as their starting point what scientists have known for over 100 years: in Alzheimer’s disease, there is an abnormal accumulation of amyloid plaques in the brain; next they acknowledged what scientists have known for 25 years: the abnormal amyloid peptide, Aβ a 42-amino acid fragment cleaved from amyloid precursor protein, is toxic to neurons (unlike, say, the 40-amino acid fragment more commonly formed from amyloid precursor protein). They then generated a human monoclonal antibody that selectively reacts with particular aggregates of Aβ. Previously, they demonstrated that this antibody, which they named Aducanumab, could cross the blood-brain barrier and clear amyloid plaque from transgenic mice. In the current work, they tested 165 patients with the very earliest stages of Alzheimer’s disease and evidence of amyloid plaques on PET scans. These patients received monthly infusions for one year, of either one of 4 different dosage levels of the drug or placebo.

Only 125 patients completed the trial, with 40 dropping out either because of adverse events they attributed to the study (20 patients), or because they no longer gave consent. Of note, “adverse events” were just as likely in the patients receiving placebo as in the patients receiving any of the three lower doses of the drug. Patients receiving the highest dose of the drug, however, were more likely to report an adverse event.

In terms of the primary outcomes of this small trial, the researchers found that active treatment reduced brain Aβ plaques as measured by PET scan in all the groups. The effects were similar in both the prodromal and mild Alzheimer’s patients.

As to the secondary outcomes—the clinical measures that the study was not designed to examine—the researchers found a dose-dependent slowing of the progress of disease on a variety of measures, including performance on the Mini Mental Status Exam, but no effect on a composite neuropsychological battery.

Finally, with respect to actual adverse events, the researchers did detect a dose-dependent risk of “amyloid-related vasogenic abnormalities,” in particular of edema surrounding blood vessels. This effect usually subsided within 4-6 months and it wasn’t associated with any symptoms, but it did occur in as many as 41 percent of those receiving the highest dose of the drug.

Why did the new drug seem to perform better, at least to the extent that even tentative conclusions can be drawn from this very small pilot study, than its predecessors? The scientists clearly learned something from the earlier failures. They opted not to use a vaccine: the vaccine had caused both meningo-encephalitis and accelerated brain atrophy. Instead, they used a monoclonal antibody. But they created an entirely human antibody, rather than the “humanized” mouse monoclonal antibodies that formed Bapineuzumab and Solaneuzumab. And finally, they made an antibody that targeted a different part of the abnormal Aβ peptide, hoping that this would be less toxic than earlier antibodies.

So will it work? An op ed in Scientific American gave the best response: “A new drug trial that some researchers are calling the most promising yet in the fight against Alzheimer’s suggests it may be possible to clear the brain of the amyloid protein that is characteristic of the disease. The study was small and researchers caution that it is far too soon to declare victory against a fatal disease that robs people of their memories and ability to function in daily life. But despite repeated failures of Alzheimer’s drugs in the past, there was room for enthusiasm about the trial…” (Italics added.) Like everyone else, I am cautiously optimistic. Given my usual level of skepticism, that’s actually pretty positive.

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