Final results of the failed phase 3 EXPEDITION3 trial of solanezumab (Eli Lilly) in patients with mild Alzheimer’s disease (AD) were formally published this week in the New England Journal of Medicine.
In the trial, solanezumab did not meet its primary outcome of a statistically significant slowing of cognitive decline, as measured on the AD Assessment Scale-Cognitive subscale (ADAS-Cog), compared with placebo.
Results of the trial were discussed and dissected during a packed oral presentation at the 2016 Clinical Trials on Alzheimer’s Disease (CTAD) meeting and reported by Medscape Medical News at that time.
Still Optimistic
In an interview with Medscape Medical News, EXPEDITION3 principal investigator, Lawrence Honig, MD, PhD, said he remains optimistic about antiamyloid therapies.
“There is a spectrum of opinions between those who believe that every time a trial fails it means we are barking up the wrong tree to those that believe we are getting closer and each failure we can build on and do better. As it happens, I’m of the latter persuasion,” said Dr Honig, professor of neurology at Columbia University Medical Center, New York City.
“It’s widely appreciated now that the drug was significantly underdosed in this study, and the recognition of that has caused both studies that are still going on with this drug to quadruple the dose,” Dr Honig noted.
Those studies are the Anti-amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial and the Dominantly Inherited AD (DIAN-TU) trial, which are testing solanezumab in cognitively healthy people at risk for AD because of genetic mutations or brain amyloid deposition.
“The hope is that perhaps giving enough of a drug of this sort might be effective,” Dr Honig said.
In EXPEDITION3, 2129 patients (mean age, 73 years) were enrolled and randomly assigned to intravenous infusions of 400 mg of solanezumab (n = 1057) or matching placebo (n = 1072) every 4 weeks for 80 weeks total. All participants were amyloid positive, as shown by F18 florbetapir positron emission tomography or cerebrospinal fluid Aβ1-42.
Although change in cognition on the ADAS-Cog14 was significantly slower with solanezumab than placebo at weeks 28 (P < .05), 40 (P < .01), and 52 and 64 (P ≤ .05 for both), it was no longer significantly different at week 80 (P = .095).
Patients receiving solanezumab had an 11% reduction in decline on the ADAS-Cog at 80 weeks relative to those receiving placebo. The investigators had hoped for about a 30% effect size, given results of the EXPEDITION1 and EXPEDITION2 trials, Dr Honig said.
“EXPEDITION3 did not show as much of an effect as we might have expected from EXPEDITION1 and EXPEDITION2, which suggested a roughly 30% change. And we hoped to do better because EXPEDITION3 had a milder population and all amyloid proven, but in fact we did not do as well. There was a pretty consistent 11% effect that did not reach statistical significance in the primary outcome,” he explained.
However, the direction of the effects on most secondary outcomes in EXPEDITION3 favored treatment with solanezumab. These included greater slowing of cognitive decline on the Mini-Mental State Examination and a slowing in decline on the Clinical Dementia Rating-Sum of Boxes scale and the AD Cooperative Study-Instrumental Activities of Daily Living scale.
The secondary outcomes with solanezumab suggest a “small effect in the right direction,” said Dr Honig. However, because the primary outcome did not meet statistical significance, the secondary outcomes were considered to be “descriptive” and are reported in the NEJM paper without significance testing.
Time to Let Go?
In an accompanying editorial, M. Paul Murphy, MD, from University of Kentucky, Lexington, notes that solanezumab is a humanized monoclonal antibody designed to clear soluble Aβ from the brain and in this trial it was “highly effective” at targeting soluble Aβ.
Unfortunately, the EXPEDITION3 trial did not replicate the earlier finding of a modest effect in slowing cognitive with solanezumab “and instead becomes another disappointment for amyloid immunotherapy,” writes Dr Murphy.
Although it’s possible that the magnitude of reduction in soluble Aβ was “simply insufficient to create a measurable clinical benefit, recent results from an early trial of aducanumab (Biogen Inc) could indicate that the ability of an antiamyloid therapy to clear insoluble Aβ is an important factor in the success of treatment,” he writes.
“Although it may not be quite the time to give up on Aβ immunotherapy for treating Alzheimer’s disease, it would be foolish to ignore the continued failures of anti-amyloid approaches. We may very well be nearing the end of the amyloid hypothesis rope, at which point one or two more failures will cause us to loosen our grip and let go,” he notes.
Dr Murphy also highlights the need for innovative ideas for new treatments.
“Even if there is some future success in a primary prevention trial, there is still little headway being made in improving the treatment of Alzheimer’s disease. There is some hope that a combination of therapeutic approaches might help, since there is evidence that the different pathologic aspects of Alzheimer’s disease are interactive. Whether a multifaceted strategy or something entirely unforeseen is the answer, the field is clearly in need of innovative ideas,” he notes.
N Engl J Med. 2018;378:321-330, 391-392. Abstract, Editorial
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