Two investigational Alzheimer’s immunotherapies failed to show any benefit in a series of phase III trials comprising more than 4,000 patients.

Neither bapineuzumab, which targets soluble and aggregated amyloid-beta (Abeta), nor solanezumab, which targets soluble Abeta, achieved the primary endpoints in their overall cohorts, investigators wrote Jan. 23 in the New England Journal of Medicine.

No clinical gains were detected with either drug on the primary endpoints of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale, as well as the Disability Assessment for Dementia and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

The two failed bapineuzumab studies were each 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all the final data, including several a priori subanalyses that were designed to tease out any possible treatment effect (N. Engl. J. Med. 2014;370:322-33). Although bapineuzumab didn’t show any clinical benefits, it did apparently engage its main target: brain plaques composed of aggregated Abeta.

In one trial involving patients who carried the high-risk apolipoprotein E epsilon-4 allele (APOE-epsilon-4), positron emission tomography (PET) brain scans with Pittsburgh compound B (PiB) showed no increase in Abeta plaque burden in bapineuzumab-treated patients, compared with increases seen among those who had placebo infusions.

APOE-epsilon-4 carriers also showed significant changes in two biomarkers of plaque dissolution. Phosphorylated tau, a marker of neuronal damage, decreased in serum and cerebrospinal fluid (CSF). Abeta in CSF increased, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers didn’t show these changes.

Amyloid-related imaging abnormalities with edema (an adverse event associated with immune response directed toward plaques) occurred in up to 27% of APOE-epsilon-4 carriers, depending on their zygosity. It also appeared in up to 14% of noncarriers; the relationship was dose dependent.

The picture was similarly bleak in the two solanezumab studies sponsored by Eli Lilly (N. Engl. J. Med. 2014;370:311-21). EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and comprised about 2,000 patients. They were initially reported at the 2013 Alzheimer’s Association International Conference.

The newly published data are more detailed, and include numerous biomarker findings. Solanezumab increased Abeta in plasma and CSF, a sign that the protein had stopped clumping in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab didn’t have any significant effect on plaque burden or brain pathophysiology. Because it’s designed to prevent plaques from forming, investigators didn’t expect that it would attack existing plaques.

The drug was a bust in terms of cognitive and functional gains. Unlike with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted Eli Lilly to launch EXPEDITION 3. The study is now recruiting patients who have both cognitive changes consistent with Alzheimer’s and brain plaques detected with 18F-florbetapir Abeta imaging.

These more stringent entry requirements should ensure a purer cohort. Investigators on prior EXPEDITION studies said that up to 25% of the mild participants didn’t actually have Alzheimer’s, which they said could have diluted or negated any treatment effect.

If EXPEDITION 3 can reconcile its potentially positive biomarker data with solidly positive clinical benefit, it might have some future as a preventive agent, Dr. Samuel E. Gandy said in an interview.

"Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit," said Dr. Gandy, professor of Alzheimer’s disease research at the Icahn School of Medicine at Mount Sinai, New York. He was not involved in the four studies.

"There are currently two pathways to FDA [Food and Drug Administration] registration of a new Alzheimer’s drug," he said. The first is proof of cognitive and functional benefit. "Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely."

That leaves the potential for approval as a preventive agent, which means providing both biomarker and neuropsychological benefit.

"This seems the most attractive pathway, until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the Food and Drug Administration would be supportive."

Pfizer and Janssen Alzheimer Immunotherapy sponsored the bapineuzumab studies. Eli Lilly sponsored the solanezumab studies. Dr. Gandy has been an adviser to or received research support from several pharmaceutical companies, including Pfizer and Lilly.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

Two Alzheimer’s immunotherapy drugs flunk in four studies