SAN DIEGO—Solanezumab may not have slowed the clinical progression of Alzheimer’s disease, but it provided valuable evidence for the amyloid hypothesis, experts said during a wide-ranging discussion of Eli Lilly and Company’s recent EXPEDITION3 trial.
Lilly representatives and EXPEDITION investigators presented the study’s results at the Ninth Annual Clinical Trials for Alzheimer’s Disease meeting. While solanezumab failed to meet its primary end point, it did achieve significance on several secondary end points—findings that should be read as encouraging, rather than as a defeat, according to Paul Aisen, MD, Director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.
Paul Aisen, MD
“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, an EXPEDITION3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION3, but in its predecessors, EXPEDITION and EXPEDITION2.
“This is not a refutation of the amyloid hypothesis, but a confirmation of it.”
Nevertheless, the drug failed its trial, he said. There was no statistically significant separation between solanezumab and placebo on the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14), an assessment of cognitive function that was the study’s primary end point. The active treatment group experienced 11% less decline than did the placebo group, but the result was not significant.
If the result had been significant, “it would still be a small effect size,” which would have thrown into question the drug’s clinical utility, Dr. Aisen said. “We thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key [secondary end points]. Overall, the effect size looks to be about 12% to 13%, and that’s just too small.”
Three Phase III Trials
EXPEDITION3 was the last of a triad of solanezumab studies, all of which posted signals of cognitive and functional benefit in patients with mild Alzheimer’s disease. It was based on subgroup analyses of EXPEDITION and EXPEDITION2, both of which failed to meet their primary end points and included patients with mild and moderate disease. When researchers pooled the patients with mild disease from the first two studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. Lilly conducted EXPEDITION3 in an attempt to confirm those findings.
Lawrence S. Honig, MD, PhD, Professor of Neurology at Columbia University Medical Center in New York and principal investigator of the EXPEDITION3 study, detailed the study’s results, including biomarker data.
The study included about 2,000 patients with imaging-confirmed amyloid brain plaques and mild dementia due to Alzheimer’s disease. They were randomized to receive placebo or monthly injections of 400 mg of solanezumab for 80 weeks. The study was conducted at 210 sites in 11 countries.
While solanezumab’s effect on the ADAS-Cog was not significant, its effect on the Mini-Mental State Examination score was significant, with a 13% slowing of decline, compared with placebo. There was also a significant 5% difference in the Clinical Dementia Rating scale-Sum of Boxes score.
Outcomes were mixed in measures of function. On the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, patients who received solanezumab had significant 15% and 14% differences, respectively, relative to placebo.
But differences on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant.
Biomarkers trended the right way, Dr. Honig noted. Solanezumab resulted in a 500- to 800-fold increase in amyloid beta in plasma, relative to placebo. There were no changes in amyloid brain plaques, as measured by PET imaging. This finding was not surprising because the antibody does not recognize fibrillar amyloid, Dr. Aisen said.
“What we expect to see with biomarkers differs based on the epitope targeted,” he said. “Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble amyloid beta. Now, how that helps [treat Alzheimer’s disease] is something of a debate, but it is important to recognize that it does not attack plaques. Instead, by tying up monomeric amyloid beta, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma amyloid beta increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”
Solanezumab had no significant effect on tau in CSF or on imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.
The antibody was safe, with 17% of patients who received solanezumab reporting an adverse event, compared with 19% of patients who received placebo. There were nine deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.
In late November 2016, Eric Siemers, MD, Senior Medical Director of the Alzheimer’s Disease Global Development Team at Lilly, said the company would not seek regulatory approval for solanezumab based on the trial results. “We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress.... We are very disappointed,” Dr. Siemers said during the panel discussion.
Further Trials of Solanezumab
He and Dr. Aisen confirmed, however, that two other trials using solanezumab in different populations would go forward. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively healthy elderly people with Alzheimer’s disease risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study is investigating its effects in patients with autosomal dominant mutations in Alzheimer’s disease genes.
Dr. Aisen is excited about solanezumab’s potential to target the disease before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive,” he said. “Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of Alzheimer’s disease than even in the mild dementia stage.”
Maria Carrillo, PhD, Chief Science Officer of the Alzheimer’s Association, said that EXPEDITION3 was far from a path to nowhere and urged the research community, patients, and families to double down on their commitment to tackling the disease.
“These results stress the urgency for pushing forward harder,” Dr. Carrillo said. “This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway, and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach, and to broaden the armamentarium our clinicians will need to combat this disease.
“This is not a win, true. But it gets us a little closer to one.”
—Michele G. Sullivan
