Promising Alzheimer’s Antibody Passes First Key Trial, But Long Road Remains

The next part of the story will be answered by a pair of large phase 3 studies of aducanumab that are already under way. These two international studies (which are identical except for the participating institutions) aim to enroll 2,700 people with early Alzheimer’s and compare aducanumab and placebo over 78 weeks, with CDR-SB now being the primary outcome measure. In consideration of the safety issues raised in this current study, ApoE4 carriers participating in the phase 3 will be capped at 6 mg/kg aducanumab.

Even if the trial finds aducanumab can improve cognition, there will still be patients who have dementia due to factors other than amyloid buildup and who may not benefit from the drug, including some who receive a clinical diagnosis of Alzheimer’s.

Eric Reiman, M.D., executive director at Banner Alzhemier’s Institute Phoenix, noted that about a quarter of people who receive a clinical diagnosis of mild to moderate dementia, including more than a third of those without the ApoE4 risk gene, do not have biomarker or autopsy evidence of appreciable amyloid plaque deposition.

“If aducanumab is ultimately confirmed to have a clinical benefit and approved for use in patients in the early stages of Alzheimer’s disease, PET scans or other biomarkers would likely be needed to confirm the presence of amyloid plaques at which the anti-amyloid antibody is aimed,” said Reiman, who wrote an editorial regarding the recent Nature paper.

To date, the Centers for Medicare and Medicaid Services has been reluctant to pay for these expensive tests without additional evidence to support their value in the diagnosis or management of the disease. One large national study known as IDEAS is aiming to change this designation by assessing whether PET scans can influence clinicians’ decision making (Psychiatric News, March 18).

“I personally believe that amyloid PET scans already have some value in the diagnosis and nonmedication management of certain patients with mild cognitive impairment or dementia,” said Reiman. “But if anti-amyloid-like treatments like aducanumab are confirmed to have a clinical benefit, PET or other measurements of amyloid plaque deposits are likely to play major roles in the clinical diagnosis, treatment, and prevention of Alzheimer’s disease.”

Reiman is particularly interested in the implications for prevention, since amyloid plaques begin to accumulate more than two decades before the onset of dementia, and about 30 percent of healthy people over the age of 70 have appreciable plaques.

These anti-amyloid treatments may therefore have the most profound benefit if started before the disease is already extensive. If that proves to be the case, it would help to find amyloid screening tests that are less expensive than a PET scan and less invasive than a lumbar puncture to monitor response to the therapy in older adults, Reiman said.

Even as researchers continue to evaluate the effectiveness of anti-amyloid treatments, Reiman emphasized the importance of building a diversified portfolio of treatments for Alzheimer’s disease. Combining anti-amyloid treatments with others that target other elements of the disease will likely prove even more effective than the individual treatments alone, particularly in the later stages of the disease, he suggested.

“For instance, imagine the chance to simultaneously target earlier stages and later stages of the disease in clinically affected patients, such that we could extinguish both the kindling and the fire in the fight against Alzheimer’s disease,” Reiman told Psychiatric News. “There is no guarantee that any of these treatment strategies will work, but now is the time to find out.” ■