Monoclonal Antibody Drugs Fail To Improve Alzheimer's Disease Symptoms

The investigational drugs gantenerumab and solanezumab – both monoclonal antibody (mAb) therapeutics – failed to slow cognitive decline in patients with dominantly inherited Alzheimer’s disease (DIAD), a new trial has found. The trial comes in the wake of the tentative US Food and Drug Administration's  approval of Biogen’s aducanumab (Aduhelm), the first new anti-Alzheimer’s drug to pass clinical testing in nearly two decades. Aducanumab is also a mAb.

The published results come a year after topline findings from the trial were reported. Both gantenerumab and solanezumab have previously been tested in trials for sporadic Alzheimer’s disease, but each failed Phase III testing. The two drugs target different forms of the amyloid protein that much of biomedical science believes is at the root of Alzheimer’s pathology. Gantenerumab targets amyloid fibrils, while solanezumab targets smaller chunks of soluble amyloid protein.

Sporadic vs DIAD Alzheimer's disease

DIAD is a rare form of Alzheimer’s that totals less than one percent of all cases. Unlike sporadic Alzheimer’s, which follows unpredictable symptom patterns and has a complex etiology, researchers know the origin and disease course of DIAD. DIAD is caused by autosomal dominant mutations in genes such as APP and PSEN1 that confer a huge risk of developing early-onset Alzheimer’s disease, with symptoms beginning between 30 and 50 years of age.

In DIAD, some biomarkers, including levels of proteins called amyloid and tau, increase in the brain decades before clinical changes to cognition become apparent. Researchers had hoped that targeting DIAD patients specifically would allow them to intervene at an earlier point in the course of disease to alleviate symptoms.

Cognitive decline

The trial has been ongoing since 2012, when it was set up by the Dominantly Inherited Alzheimer Network Testing Unit (DIAN-TU), based out of Washington University School of Medicine in St Louis. In 2015, the trial pivoted from assessing quantitative biomarkers of disease to monitoring the drugs’ ability to slow or prevent cognitive decline.

The trial enrolled 144 people with DIAD mutations, who were split into three groups, one receiving gantenerumab, another solanezumab and the third a placebo. In the results, neither of the two drugs were found to give a cognitive benefit above placebo. Patients taking solanezumab declined faster than those given placebo, when assessed via a battery of cognitive tests collectively termed the DIAN Multivariate Cognitive End Point (DIAN–MCE)  a finding that the authors were unable to fully explain.

The results of the trial were somewhat complicated by the inclusion of patients as subjects. These were individuals who were, genetically speaking, highly likely to experience DIAD cognitive decline but presented as cognitively healthy at time of study enrolment. These patients, contrary to expectations, did not show cognitive decline in their DIAN-MCE performance over the course of the study, even when treated with placebo.

During the study, poor results from other trials of the two drugs led to a change to study protocol, increasing the doses of gantenerumab and solanezumab from 225 mg to 1200 mg every four weeks and 400 mg to 1600 mg every four weeks respectively. The authors noted that, for symptomatic patients, cognitive decline had already set in by the time the dosing was increased, throwing some doubt on whether better results would have been seen with a higher dose administered at an earlier point in the trial. 

Amyloid analysis

The original biomarker study looked at molecular markers of DIAD, which continued to be analyzed through the follow-up study.  Amyloid levels were assessed by positive emission tomography (PET) brain imaging and through sampling of the patients' cerebrospinal fluid before and during treatment.

Gantenerumab was effective here, demonstrating a significant ability to cut levels of brain amyloid deposition. Solanezumab also engaged its molecular target, said the researchers. Interestingly, gantenerumab also had beneficial effects on levels of tau, a protein the authors say is downstream of amyloid in DIAD’s pathology. They take this as a hopeful sign that the pharmacological approach could ultimately prove clinically meaningful. But neither of these molecular effects were mirrored by cognitive benefit in study participants. The authors suggest that bigger, longer trials are the answer. In particular, the failure of patients that were administered with a  placebo to deteriorate may have hamstrung the ability of the trial to detect any benefits of the drugs.

Dr. Susan Kohlhaas, director of research at Alzheimer’s Research UK, who was not involved in the study, said, “While we have known for a while that gantenerumab and solanezumab weren’t able to slow down or reverse memory and thinking decline in this trial, the new data is further evidence that the drugs do target the biological processes in the brain they were designed to hit and have an impact on markers of neurodegeneration."

She added, “There are also signs that treating early in the disease process may be most beneficial. As this was a very small study one key aim will be to get more people with this rare form of dementia involved in the trial so that researchers can learn about more subtle cognitive changes that occur early in the disease."

Kohlhaas also focused on the sacrifices made by participants involved in the trial, for whom the wait for a DIAD cure goes on.

“We cannot thank the brave and committed volunteers who took part in this research enough, and we know as a field, we will have to redouble our efforts to help those with this particularly devastating form of Alzheimer’s.

Reference:

Salloway S, Farlow M, McDade E, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;0(0):1-10. doi: 10.1038/s41591-021-01369-8