More than a year after the release of EXPEDITION 3’s negative data, a new report is reminding the world once more that antiamyloid antibodies have yet to live up to their promise.

Solanezumab, an antibody that targets soluble amyloid-beta (AB) did nothing to improve cognition in the phase 3, placebo-controlled trial of 2,129 patients with mild Alzheimer’s disease, Lawrence Honig, MD , and his colleagues reported in the Jan. 24 issue of the New England Journal of Medicine. Eli Lilly initially released the disappointing topline data in November 2016. The next month, Lilly detailed the numbers at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting in San Diego.

Dr. Honig of Columbia University Medical Center, New York, presented the data at the San Diego meeting, as well as being primary author of the journal paper. In a nutshell, solanezumab was no better than placebo on any of the primary or secondary endpoints of cognition or function, he and his coinvestigators wrote.

Patients received monthly infusions of either 400 mg solanezumab or placebo for 76 weeks. Those who completed the double-blind phase had the chance to enter into a 24-month open-label study.

At 80 weeks, scores on the Alzheimer’s Disease Assessment Scale-Cognitive subscale were similar in both treatment arms, with a change of 6.6 points in the solanezumab group and 7.4 in the placebo group. The secondary endpoints were considered descriptive only, but treated patients worsened on all of them: the Mini Mental State Exam, Clinical Dementia Rating Scale Sum of Boxes, Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, Functional Activities Questionnaire, and the Integrated Alzheimer’s Disease Rating Scale.

Adverse events were common among both groups, occurring in 84.5% of the active group and 83.4% of the placebo group. However, four categories of events occurred significantly more often among those taking solanezumab: vitamin D deficiency, nasal congestion, spinal osteoarthritis, and dysuria. The placebo group was more likely to experience gait disturbance and somnolence.

Adverse events led to study discontinuation in 4.5% of the solanezumab group and 3.6% of the placebo group. One patient taking solanezumab and two taking placebo developed amyloid-related imaging abnormalities of edema/effusions. These were asymptomatic.

The authors provided several explanations for the negative results. Solanezumab does not attack consolidated amyloid plaques but rather binds to soluble AB. Biomarker studies did indicate that the antibody was hitting this target, but, the team said, “the observed peripheral reductions in soluble-free AB concentrations may not have been sufficient to reduce deposited cerebral amyloid, neuronal atrophy, or the pathobiologic events that lead to clinical decline.”

This observation renders null the peripheral sink hypothesis, which proposes that reducing free AB in plasma should lead to AB clearance from the brain. Despite reducing plasma concentrations of AB by about 90%, there was no obvious clinical impact on cognition, and no evidence of change in existing brain plaques. “Thus, a reduction in peripheral-free AB alone is unlikely to lead to clinically meaningful cognitive benefits,” they noted.

The investigators also suggested that the 400-mg monthly dose was probably much too small. Only about 3% of the antibody crossed the blood-brain barrier – too little to have a clinically meaningful effect, they posited.

Indeed, this idea of ineffective dosing has saved solanezumab from the ever-growing scrap heap of a decade’s worth of failed antiamyloid drugs. Solanezumab is also being investigated in the ongoing Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) prevention study and the Dominantly Inherited Alzheimer Network Trial (DIAN-TU).

Based on a rethinking of the failed EXPEDITION 3 and its likewise negative predecessors (EXPEDITION and EXPEDITION 2), researchers announced at CTAD 2017 that they will quadruple the dose of solanezumab in A4. Patients already enrolled will be titrated up from 400-mg to 1,600-mg infusions every month, principal investigator Reisa A. Sperling, MD, said at the meeting. DIAN-TU follows a dose-escalation pattern with no stated upward limit.

Timing – every AD researcher’s nightmare – also may have been a factor in EXPEDITION 3’s failure, Dr. Honig and his coauthors said. Even though it enrolled only patients with mild AD, they already may have been beyond the critical tipping point of potentially successful cognitive rescue.

“Some data from mouse models suggest that neurodegeneration in Alzheimer’s disease may reach a point at which it becomes self-propagating and not susceptible to intervention,” the team wrote.

At CTAD 2017, Dr. Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, Boston, echoed this comment, saying the fear of treating too late “keeps me up at night.” But recent advances in imaging confirm that amyloid pathology begins years, or even decades, before any cognitive changes occur. This gives researchers hope that backing up the treatment timeline even further may interrupt, or at least slow, the pathology that leads to memory loss.

“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment and prodromal Alzheimer’s,” Dr. Sperling said at the meeting. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”

Studies of cognitively healthy elderly who are amyloid positive, like A4, and of healthy younger subjects with high genetic risk factors, like DIAN-TU and the Colombian study of those with presenilin-1 mutations, should answer this question.

Finally, Dr. Honig and his colleagues wrote, the amyloid cascade hypothesis – the foundation of all antiamyloid therapies – may itself be flawed.

“Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression. A single study ought not to be viewed as disproving a hypothesis; nevertheless, the amyloid hypothesis will need to be considered in the context of accruing results from this trial and other clinical trials of antiamyloid therapies.”

Eli Lilly sponsored EXPEDITION 3. Dr. Honig reported receiving financial remuneration from the company and financial ties with numerous other pharmaceutical manufacturers.

SOURCE: Honig LS et al. N Engl J Med. 2018;378:321-30 .