According to the authors of a new Cochrane systemic review which examined data from 17 clinical trials with a total of 20,342 participants, the effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD) was trivial, while on functional ability, it was small at best.”
The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants’ cognitive impairment ranged from 17 to 52 months.
The 17 studies assessed seven different amyloid‐beta‐targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months.
“Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients,” said lead author Francesco Nonino, neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna, Italy, in a statement. “There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect. While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance. It is common for trials to find statistically significant results that do not translate into a meaningful clinical difference for patients.”
According to the Cochrane report, in addition to the absence of clinically meaningful effects, the review found that “anti-amyloid drugs likely increase the risk of swelling and bleeding in the brain. This was observed in brain scans without any apparent symptoms for most patients, although any long-term effects remain unclear since reporting of symptoms was inconsistent across trials.”
While striking, these findings likely don’t come as a surprise to closely held Casp-Aid, a company that BioTuesdays featured in early March.
In that piece, Andréa LeBlanc, founder, president, and interim CEO of Casp-Aid, noted that while anti-amyloid therapies have demonstrated plaque reduction, their clinical impact on cognition remains modest. “These therapies modestly slow cognitive decline by six months, but they do not restore memory. Acetylcholinesterase inhibitors provide a short-term—three- to six-month—improvement in memory, after which they only slightly slow cognitive decline.” She also indicated that safety concerns have limited adoption. “Cholinesterase inhibitors have been known to cause gastrointestinal issues, leading to about 50% of patients discontinuing use. Anti-amyloid antibodies carry risks of brain bleeding and swelling, which in rare cases have been associated with deaths in clinical trials.”
As the BioTuesdays feature examined, Casp-Aid is pursuing a fundamentally different hypothesis. Rather than targeting amyloid or tau—proteins known to be primary biomarkers of AD—or inflammation individually, the company is focused further upstream on repairing neuronal structure itself, regardless of the initiating stressor. Casp-Aid is now preparing a Phase 2b clinical trial evaluating approximately 180 patients across the U.S. and Canada.
