A recent review article in the Journal of Alzheimer Disease identified 9 compounds targeting amyloid that had failed in phase 3 trials since 2018.
In January 2019, Roche, Genentech’s parent company, announced it was discontinuing 2 phase 3 trials of crenezumab in patients with mild, sporadic Alzheimer disease because preplanned interim analyses concluded that the treatment was unlikely to meet its primary end point of slowing cognitive decline.
And a year before the findings of the Colombia crenezumab trial were reported, the US Food and Drug Administration (FDA) approved aducanumab (Aduhelm), another antiamyloid monoclonal antibody, even though none of the agency’s panel of outside experts had voted “yes” when asked whether clinical trials had shown it to be effective in treating Alzheimer disease.
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Todo sobre Aduhelm en PHARMACOSERÍAS
The agency granted aducanumab “accelerated approval,” which is based on a surrogate end point—in this case, a reduction in amyloid-β plaque in the brain—that, according to the FDA, “is reasonably likely to predict a clinical benefit to patients.” Aducanumab, the only antiamyloid drug that has ever received FDA approval, is the first Alzheimer therapy designed to modify the underlying disease process and not just treat symptoms.
After the FDA approved aducanumab, the Centers for Medicare & Medicaid Services (CMS) released a national coverage policy for the therapy as well as future antiamyloid antibodies to spur the collection of more information about their safety and effectiveness.
Medicare will cover aducanumab and other such therapies granted accelerated approval based on a surrogate end point, such as amyloid reduction, only for beneficiaries participating in FDA-sanctioned randomized clinical trials to determine clinical effectiveness. Aducanumab isn’t cheap. In January, Biogen cut the drug’s wholesale acquisition cost in half, to $28 200 per year for an average-size patient (dosing is based on patients’ weight).
For monoclonal antibodies that receive FDA approval via the conventional pathway, which involves demonstrating clinical benefit, Medicare will still only cover the cost for patients in CMS-approved or NIH-supported studies.
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No matter their opinion about the usefulness of targeting amyloid, dementia experts seem to agree that the complexity of Alzheimer disease calls for a multipronged treatment approach tailored to the particular patient, depending on such factors as the stage of their disease.
“I have a hard time imagining how targeting any single molecule or any single pathology is likely to yield a meaningful clinical benefit,” Gandy said.
(Sam Gandy, MD, PhD, director of the Mount Sinai Center for Cognitive Health in New York)
Although the final answer on amyloid may not yet be in, researchers are branching out in their search for tools—both drugs and lifestyle changes—that could at least slow the development or progression of Alzheimer disease.
“A decade ago, there wasn’t much in terms of alternative targets” to amyloid, Hodes said. To illustrate his point, he noted that 5 of the 8 late-stage Alzheimer trials funded by the NIA involve antiamyloid therapies. However, Hodes said, only 13 of the 61 phase 1 or phase 2 trials receiving NIA funding target amyloid.
(Richard Hodes, MD, director of the National Institute on Aging (NIA))
Nonamyloid therapeutic targets include other proteins, such as tau—tau neurofibrillary tangles are a hallmark of Alzheimer disease that haven’t received as much attention as amyloid plaques—TDP-43 (transactive response DNA-binding protein 43), the accumulation of which in the central nervous system is also a feature of other neurodegenerative diseases; and α-synuclein, which appears to interact with tau in neurodegenerative diseases, Hodes said. Besides proteins, other Alzheimer therapeutic targets for which the NIA is funding trials include inflammation, genetics, and vascular system changes, he said.
The NIA is also supporting 131 studies of nonpharmacological interventions focused on cognitive training, sleep, and exercise, among others, Hodes said. One NIA-funded phase 3 trial presented at the Alzheimer’s Association conference evaluated whether regular exercise could benefit people with amnesic mild cognitive impairment (MCI), which primarily affects memory and increases the risk of Alzheimer disease or related dementias.
The trial randomized 296 adults to either moderate-intensity aerobic training or low-intensity stretching, balance, and range-of-motion exercises for 18 months.
Exercise sessions took place at a YMCA 4 times a week for a total of 120 minutes to 150 minutes per week. In the first 12 months, a trainer supervised 2 sessions a week, while the other 2 were unsupervised. All exercise was unsupervised in the last 6 months. Neither group showed significant declines from baseline in the primary measure of cognitive function over 12 months, suggesting that both the moderate- and low-intensity exercise, and, possibly, the socialization participants received with it, stalled cognitive decline, researchers reported at the meeting. In contrast, cognitive function did decline over a year in similar adults with MCI who participated in a large “usual care” observational study.
Approximately 6.5 million people aged 65 years or older in the US are living with Alzheimer disease, and that number is expected to nearly double by 2050, according to the Alzheimer’s Association.
”The stakes are too high just to focus on amyloid,” Reiman said.
(Eric Reiman, executive director of the Banner Alzheimer Institute in Phoenix)
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