In the Journals

Research continues for disease-modifying therapy in Alzheimer’s disease

Following the discontinuation of a phase 3 trial of aducanumab, an anti-amyloid compound that showed potential as a disease-modifying therapy, or DMT, no DMTs exist to combat the Alzheimer disease epidemic, researchers wrote in a viewpoint published in JAMA Psychiatry.

“Symptomatic treatments (eg, cholinesterase inhibitors) that temporarily slow decline are available, but these do not modify disease progression,” Brent P. Forester, MD, from the division of geriatric psychiatry at McLean Hospital, and colleagues wrote. “Earlier hope of addressing [Alzheimer’s disease] neuropathology by reducing buildup or enhancing removal of beta-amyloid plaques has been moderated by the failure of more than a dozen anti-amyloid compounds.”

In their viewpoint, Forester and colleagues investigated potential reasons for these failures as well as emphasized reasons for continued optimism in the Alzheimer’s disease (AD) community.

Two strategies to address the buildup of beta-amyloid — one that blocks the action of secretase enzymes on the amyloid precursor protein to wipe out the supply of beta-amyloid monomers and prevent plaque formation, and the other to remove beta-amyloid using antibodies that target beta-amyloid monomers, plaques or oligomers — have produced discouraging results, according to the researchers. However, these results triggered an important shift in later trials toward targeting earlier disease stages, like the prodromal to mild dementia range.

This shift yielded some methodological issues however, Forester and colleagues wrote. Many trials that have targeted earlier disease stages have used cognitive cutoff scores that may have biased study samples.

Another issue is the widespread use of the wrong outcome measurements as primary endpoints in prodromal or mild Alzheimer’s disease trials, such as the Clinical Dementia Rating–Sum of Boxes and Alzheimer Disease Assessment Scale–Cognitive. However, the investigators noted emerging alternatives, like the AD Composite Score and the Preclinical Alzheimer Cognitive Composite, which incorporate data from multiple sources to derive a composite score, that look promising.

“These developments demonstrate that the field can and should move beyond measures with ineffective end point measures,” Forester and colleagues wrote. “Creating more sensitive measures, however, should not come at the expense of developing treatments that produce clinically meaningful effects.”

Although often viewed as positive, targeting prodromal or mild Alzheimer’s disease may be too late for anti-amyloid therapies when there’s no optimal definition of amyloid positive at the preclinical stage, according to the researchers.

They also noted that nonamyloid strategies — such as therapies targeting glucose use, mitochondrial functioning, inflammation, and hyperphosphorylated tau — show promise. In addition, compelling evidence supports lifestyle modifications, like improving physical activity, cardiovascular disease management and socialization, as a central point of Alzheimer’s disease prevention, according to Forester and colleagues.

“Nonetheless, anti-amyloid agents continue to outpace all other phase 2 and 3 DMT trials,” they wrote. “Therefore, we argue that industry, government, and academia must take steps to ensure a more diverse portfolio of basic and intervention research, while continuing efforts to optimize anti-amyloid trials. Such continuation might involve targeting only patients with autosomal dominant AD, for whom evidence supporting the amyloid hypothesis is strongest.” – by Savannah Demko

Disclosures: Forester reports grant support from Biogen, Eli Lilly, the NIH/National Institute on Aging, the Rogers Family Foundation, and Spier Family Foundation, as well as consulting for Biogen. Please see the study for all other authors’ relevant financial disclosures.

Following the discontinuation of a phase 3 trial of aducanumab, an anti-amyloid compound that showed potential as a disease-modifying therapy, or DMT, no DMTs exist to combat the Alzheimer disease epidemic, researchers wrote in a viewpoint published in JAMA Psychiatry.

“Symptomatic treatments (eg, cholinesterase inhibitors) that temporarily slow decline are available, but these do not modify disease progression,” Brent P. Forester, MD, from the division of geriatric psychiatry at McLean Hospital, and colleagues wrote. “Earlier hope of addressing [Alzheimer’s disease] neuropathology by reducing buildup or enhancing removal of beta-amyloid plaques has been moderated by the failure of more than a dozen anti-amyloid compounds.”

In their viewpoint, Forester and colleagues investigated potential reasons for these failures as well as emphasized reasons for continued optimism in the Alzheimer’s disease (AD) community.

Two strategies to address the buildup of beta-amyloid — one that blocks the action of secretase enzymes on the amyloid precursor protein to wipe out the supply of beta-amyloid monomers and prevent plaque formation, and the other to remove beta-amyloid using antibodies that target beta-amyloid monomers, plaques or oligomers — have produced discouraging results, according to the researchers. However, these results triggered an important shift in later trials toward targeting earlier disease stages, like the prodromal to mild dementia range.

This shift yielded some methodological issues however, Forester and colleagues wrote. Many trials that have targeted earlier disease stages have used cognitive cutoff scores that may have biased study samples.

Another issue is the widespread use of the wrong outcome measurements as primary endpoints in prodromal or mild Alzheimer’s disease trials, such as the Clinical Dementia Rating–Sum of Boxes and Alzheimer Disease Assessment Scale–Cognitive. However, the investigators noted emerging alternatives, like the AD Composite Score and the Preclinical Alzheimer Cognitive Composite, which incorporate data from multiple sources to derive a composite score, that look promising.

“These developments demonstrate that the field can and should move beyond measures with ineffective end point measures,” Forester and colleagues wrote. “Creating more sensitive measures, however, should not come at the expense of developing treatments that produce clinically meaningful effects.”

Although often viewed as positive, targeting prodromal or mild Alzheimer’s disease may be too late for anti-amyloid therapies when there’s no optimal definition of amyloid positive at the preclinical stage, according to the researchers.

They also noted that nonamyloid strategies — such as therapies targeting glucose use, mitochondrial functioning, inflammation, and hyperphosphorylated tau — show promise. In addition, compelling evidence supports lifestyle modifications, like improving physical activity, cardiovascular disease management and socialization, as a central point of Alzheimer’s disease prevention, according to Forester and colleagues.

“Nonetheless, anti-amyloid agents continue to outpace all other phase 2 and 3 DMT trials,” they wrote. “Therefore, we argue that industry, government, and academia must take steps to ensure a more diverse portfolio of basic and intervention research, while continuing efforts to optimize anti-amyloid trials. Such continuation might involve targeting only patients with autosomal dominant AD, for whom evidence supporting the amyloid hypothesis is strongest.” – by Savannah Demko

Disclosures: Forester reports grant support from Biogen, Eli Lilly, the NIH/National Institute on Aging, the Rogers Family Foundation, and Spier Family Foundation, as well as consulting for Biogen. Please see the study for all other authors’ relevant financial disclosures.