Aisen: Negative Anti-Amyloid Trial Confirms Amyloid Hypothesis

SAN DIEGO -- Although the amyloid-scavenging drug solanezumab failed to slow Alzheimer's disease progression significantly in the phase III EXPEDITION3 trial, investigator Paul Aisen, MD, of the University of Southern California, insisted that the amyloid hypothesis remains alive and well.

"We have a negative study that confirms a beneficial effect," Aisen said during the presentation of the results at the Clinical Trials in Alzheimer's Disease (CTAD) meeting here Thursday night. "Two other studies [EXPEDITION and EXPEDITION2] have shown a small benefit. They all show a very consistent story that treatment with solanezumab slows disease progression."

"This is not a refutation of the amyloid hypothesis," he continued. "I think this is a confirmation of the amyloid hypothesis. I think it is the strongest confirmation to date."

At least one audience member reminded Aisen that "not everyone on Twitter agrees with your interpretation" -- not least because both the drug and placebo groups continued to worsen, and questions have long been raised as to whether the benefit would be detectable clinically.

Anton Porsteinsson, MD, of the University of Rochester School of Medicine, told MedPage Today that he's staking out a middle ground regarding the study findings and the hypothesis: "I don't think they dispute it, and I don't think they necessarily affirm it either," he said.

He acknowledged the small effect size is fairly consistent across measurements, and that it only looks at patients who've already developed plaques, raising the question about whether the drug could have an effect earlier in the amyloid build-up process. That possibility is currently being tested in an ongoing trial called A4.

David Knopman, MD, of the Mayo Clinic in Rochester, Minn., had a similar perspective. He told MedPage Today that the study added "a great deal more negative" to the debate over the hypothesis, but noted that "this was not a failure of amyloid beta but of this particular drug."

Indeed, one of the big questions was whether the solanezumab results would spell the end for another anti-amyloid drug under investigation -- Biogen's aducanumab. Since solanezumab targets monomeric forms of soluble amyloid beta, most researchers agreed that the findings shouldn't have an effect on aducanumab because that drug targets an insoluble form that's already gunked up in the brain as plaques.

"Not all monoclonal antibodies are created equal," Alzheimer's Association chief science officer Maria Carillo, PhD, said during a panel discussion following the presentation of the findings. "This is not the time for companies to sit back and say, we need to drop this [amyloid] pathway."

Solanezumab drugmaker Eli Lilly reported the top-line results of the highly anticipated EXPEDITION3 trial in a press release last month. There was an 11% slower decline in disease progression for those on the drug, but the difference on the ADAS-Cog₁₄ wasn't significant at 80 weeks (P=0.095).

At the meeting, researchers released additional details from the study, which randomized 2,129 patients to either 400 mg of solanezumab infusion every 4 weeks for 80 weeks, or to matching placebo. All patients had to be amyloid-positive on either a PET scan or on cerebrospinal fluid (CSF) analysis.

About 85% of patients in each group completed the trial, which was conducted at 210 sites in 11 countries.

Although the ADAS-Cog14 wasn't significant, another measure of cognition -- the Mini-Mental State Examination (MMSE) -- did show a significant difference of 13% less decline with the drug, they reported (P=0.014).

The researchers also saw better results on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale: a significant 15% smaller decline for those on the drug (P=0.004).

There were similar significant reductions in decline in function, with 14% less decline on the ADCS-iADL (P=0.019) and 15% less decline on the ADCS-ADL (P=0.009) -- although there was no difference in function as measured by the FAQ (7% less decline, P=0.14).

It did appear that the drug does what it's supposed to do, clearing soluble, monomeric forms of beta amyloid as confirmed by a rise in plasma concentrations of the protein, the researchers said.

But there were no differences between groups in terms of amyloid plaque burden in PET scans or in CSF total tau or p-tau levels or on tau PET scans. Nor were there any differences in MRI whole brain atrophy between groups.

There were similar rates of adverse events, with serious AEs occurring in about 17% of the solanezumab group and 19% of the placebo group.

Larry Honig, MD, PhD, of Columbia University, who delivered the main findings, concluded that solanezumab missed its primary endpoint in mild Alzheimer's disease, and that while several secondary endpoints favored the monoclonal antibody, the magnitude of treatment differences were small.

He noted that factors "possibly relevant to interpretation of study results include drug target, disease stage studied, and dosage of drug delivered" -- and several commenters said that since the drug has shown such good safety, perhaps a larger dose would provide different results.

Although Eli Lilly said it won't pursue an indication for solanezumab in mild Alzheimer's, it hasn't ruled out continued development for other indications. The A4 trial, which is looking at solanezumab in early stages of disease -- asymptomatic patients who have amyloid deposits in the brain confirmed on PET scans -- is still enrolling patients.

"Obviously we're very disappointed that we didn't reach our primary outcome," said Eric Siemers, MD, of Eli Lilly. "We didn't expect solanezumab to be the cure for this disease, but we hoped it would be the first to slow down the progression."

"It's been a rough time," Siemers said.

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