Solanezumab Finally Failed in Phase III Trial

Monoclonal antibody shows no effect in preclinical Alzheimer’s disease

The search for an effective drug to treat or prevent Alzheimer’s disease is one of the most pressing medical challenges of our time. Many experts believe that Alzheimer’s treatment with anti-amyloid antibodies is useful and should be initiated as early as possible in affected individuals.

While there are already several drugs on the market aimed at alleviating the symptoms of this degenerative brain disease, none has yet proven effective in actually preventing or reversing the disease.

Solanezumab: Safe but lacking efficacy even in preclinical Alzheimer’s

Another candidate, the monoclonal antibody solanezumab, has now finally failed in a phase III trial. Solanezumab had already failed to delay the course of the disease in symptomatic Alzheimer’s patients in previous studies, and in the so-called A4 study (“Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease”) it also showed no effectiveness in patients in the preclinical stage of the disease over an observation period of 4.5 years.

Solanezumab was selected for the study because it had been shown to be safe in previous studies. In addition, it initially appeared to show positive effects in patient:in with mild cognitive impairment, although these results could not be confirmed in subsequent phase 3 trials.

Solanezumab should stop new amyloid deposits from forming in the brain

Another reason for using solanezumab was its ability to bind to the monomers of beta-amyloids and prevent their aggregation. According to the “sink” hypothesis preferred at the time of study design, solanezumab should prevent the formation of new deposits in the brain. In contrast, the drugs donanemab and lecanemab, already approved in the U.S., aim to break down pre-existing amyloid accumulations.

In the study, a total of 4,485 people aged 65 to 85 years from 67 centers in North America, Australia and Japan were examined by PET. All showed unremarkable scores on both the Clinical Dementia Rating scale and the Mini-Mental State Examination. Only people with particularly high scores in the “Logical Memory Delayed Recall” of the Wechsler Intelligence Test were excluded from the study.

The participants received an intravenous injection every four weeks. Initially, the dose of solanezumab was 400 mg, but it was increased to 1,600 mg in 2017 after the unconvincing results of phase 3 trials in symptomatic patients were published.

The therapy extended over a period of 240 weeks, or about 4.5 years. According to the research team led by Paul Aisen of the Alzheimer’s Therapeutic Research Institute at the University of California in San Diego, the PACC (“Preclinical Alzheimer’s Cognitive Composite”) showed little difference in the two groups during the first two years of the study.

As the study progressed, the scores showed a decline. This decline tended to be greater in the group treated with solanezumab. After 240 weeks, they recorded an average drop of 1.43 points, compared with a drop of 1.13 points in the placebo group. The resulting difference of 0.30 points proved nonsignificant, with a 95% confidence interval between -0.22 and 0.82 points.

One-third of the subjects developed cognitive impairment during the course of the study

Most disappointingly, amyloid deposition increased by 11.6 centiloids less in the solanezumab-treated group, compared with an increase of 19.3 centiloids in the placebo group. This difference of 7.7 centiloids was significant with a 95% confidence interval of 5.1 to 10.4 centiloids. However, even this did not prevent cognitive impairment from developing in the first patients in both groups during the course of the study. According to the Clinical Dementia Rating Scale, this was the case in 36% of the subjects.

Although treatment with solanezumab proved to be safe and amyloid-related imaging abnormalities (ARIA) did not occur more often than in the placebo group, there is no proven benefit, making the use of solanezumab obsolete. Aisen interprets the results to mean that merely slowing amyloid accumulation without breaking down preexisting amyloids is apparently insufficient to halt the creeping cognitive decline in patient:s in the early, asymptomatic stages of AD.