Article In Brief
The monoclonal antibody donanemab was effective in clearing amyloid-beta plaque in patients in the early stages of Alzheimer's disease; it was also associated with slower rates of cognitive decline.
Donanemab, a monoclonal antibody that targets a unique epitope on the amyloid-beta (Abeta) peptide, cleared the sticky plaque in the brains of people in the early stages of Alzheimer's disease (AD), according to a phase 2 clinical trial published online March 13 in The New England Journal of Medicine.
The study also met its primary endpoint—a change in a composite score on two cognitive/functional rating scales.
The patients taking the experimental drug had a significantly 32 percent slower rate of cognitive decline, compared with patients on a placebo dose, said Mark A. Mintun, MD, a senior scientist at Eli Lilly and Company, which sponsored the study. Dr. Mintun, the lead author of the paper, said that this is equivalent to slowing the course of the disease by about six months.
This study, called TRAILBLAZER-ALZ, was also the first to enroll people using two PET scans, one for Abeta and one for phosphorylated tau—to choose only those patients with a low level of tau tangle formation that they believed would give them a better chance of showing a positive effect from lowering Abeta levels.
The investigators used post-scan data to identify a marked reduction in the brain's amyloid burden. Almost 70 percent of the patients on the drug converted from amyloid-positive to amyloid-negative during the first 18-months of the study. The thinking is that amyloid is a trigger for tau to start misfolding and spreading from neuron to neuron. Based on the results from this phase 2 study, the company is already enrolling about 1000 patients for a phase 3 clinical trial; only 125 patients were enrolled in each arm of the phase 2 study. The investigators said that the numbers were too small to show an effect on several of its secondary measures.
“This monoclonal antibody approach to remove Abeta is looking more promising than it has ever,” said Liana G. Apostolova, MD, FAAN, Indiana University distinguished professor, the Barbara and Peer Baekgaard professor in Alzheimer's disease research, and professor in neurology, radiology, medical and molecular genetics at Indiana University. Dr. Apostolova was not involved in conducting the clinical trial but was asked to participate in the final data analysis and interpretation. She is a co-author on the study.
“This medication definitely reduced Abeta to an unparalleled extent,” she said. “This monoclonal antibody was designed to specifically target mature Abeta and it successfully reduced amyloid load. This led to successful slowing of cognitive decline.”
“If the drug can engage the target and reduce amyloid to undetectable levels, it might buy patients time, perhaps even a decade, before Abeta levels build up in the brain again. This gives us a path forward. We may even be able to safely discontinue this therapy when levels drop to undetectable levels as TRALBLAZER-ALZ shows it can.”
Study Design, Findings
The TRAILBLAZER-ALZ phase 2 trial, which was conducted across 56 sites in the United States and Canada, included 257 patients—131 were randomly assigned to receive 700 mg for the first three doses and 1400 mg thereafter every four weeks for up to 72 weeks; the other 126 received an intravenous placebo dose on the same schedule. Patients in the study were between 60 to 85 years old with either mild cognitive impairment or early symptomatic AD. The screening included a Mini–Mental State Examination (MMSE) score of 20 to 28 (the scoring is between zero and 30 with the highest cognitive score at 30), an amyloid-PET scan, a tau-PET scan, and an MRI.
This was the first study to use tau-PET to select patients in the earliest clinical stages of AD. The investigators enrolled patients with low to intermediate tau levels. Those with high tau levels were excluded from the study. The more phosphorylated tau buildup in the neurons, the greater the symptoms. The researchers wanted patients with early symptomatic AD, and some scientists said that using tau to screen for early stages of AD will probably be standard in future AD clinical trials.
The investigators conducted cognitive tests and had people fill out functional questionnaires at baseline and then again at 76 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS), where scores range from zero to 144. The lower scores suggest a greater cognitive and functional impairment.
The baseline iADRS score for both groups was 106. The change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo. The 3.20 difference was statistically significant (p=0.04).
The scientists conducted amyloid-PET scans at 24 and 52 weeks and once patients had a negative scan they were given a lower drug dose or placebo. By 24 weeks, a quarter of the patients who had received the active drug were amyloid-negative and switched to placebo; by 52 weeks, half the group was receiving placebo. By the 76th week, 68 percent of the group was amyloid-negative.
The researchers also compared the changes in amyloid and tau burden on PET from baseline to week 76. Global tau showed a non-significant reduction of 10 percent at the final PET scan. Frontal tau was most predictive of subsequent cognitive decline.
“Staging patients with tau pathology is our new standard,” said Dr. Mintun. “The longitudinal measurement of tau pathology will become important in assessing the extent of cognitive decline. The data suggest the drug had the most effect on patients with the lowest tau levels at baseline,” he explained.
The secondary outcomes did not differ between the two groups, although scientists said the phase 2 study was not powered with enough patients to see a change. The tests included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), which is a 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13). Other secondary analysis included comparisons on the Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL) and the MMSE.
“For most secondary outcomes, differences between the two groups did not provide clinical support for efficacy of donanemab in the MMRM [mixed model for repeated measures] analyses but showed support in a Bayesian disease progression model, in which credible intervals were not adjusted for multiple comparisons,” the study authors wrote. “There was a greater reduction in the amyloid plaque level in the donanemab group than in the placebo group, for which we were unable to show an association with clinical outcomes at the individual level.”
As with other monoclonal antibody drugs that have gone through clinical trials for AD, a high number of patients in the donanemab group–27 percent– experienced amyloid-related imaging abnormalities with edema or effusions (ARIA-E). Most were asymptomatic, according to the study results. If ARIA-E was identified during the first three doses, the scientists did not increase the study dose. They reported infusion-related reactions in 7.6 percent of study participants on the active drug.
The final safety and efficacy assessments were done a month after the final infusion, at 76 weeks.
The study authors acknowledged a number of vexing problems that need further study. For one thing, there was no significant change in hippocampal volume. Trials of BACE1 inhibitors reported significant volume changes, and they said that the “implications of this finding of retained hippocampal volume are unclear.”
They also found a greater decrease in whole-brain volume and a greater increase in ventricular volume with donanemab than with placebo. This is counter to the thinking that global changes on volumetric MRI represent atrophy in studies of the natural history of AD. The scientists said that the atrophy could represent the rapid removal of the aggregated protein, but more work is needed to figure out why.
The phase 3 Trailblazer2-ALZ began enrolling last summer. The researchers hope to focus on patients with intermediate tau levels at baseline.
“It is a unique and interesting clinical trial design,” said Howard Fillit, MD, founder, director and chief science officer of the Alzheimer's Drug Discovery Foundation and clinical professor of geriatric medicine and palliative care, medicine and neuroscience at Mount Sinai School of Medicine.
“They used amyloid-PET to confirm AD and enroll people with plaques, and tau-PET to confirm tangles, and eliminate people with either no tau pathology or end-stage tangle pathology,” Dr. Fillit noted.
“The drug worked to remove the plaques. This monoclonal antibody approach to remove amyloid-beta is looking more promising than it's ever been. This is the first phase 2 trial in AD that met its primary outcomes on cognitive testing and function.”
However, he added, “the secondary outcome measures were not strong. We need additional studies to confirm these results. I don't think anyone has the expectation that this will be the cure for AD, or a sole treatment. The future of AD treatments will be a combination of drugs such as anti-neuroinflammatory drugs, medications that clear away aggregating amyloid-beta and phosphorylated tau, and other approaches to create a precision medicine approach with combination therapies.”
“The donanemab story is big news,” added Paul Aisen, MD, director of the Alzheimer's Therapeutic Research Institute at the University of Southern California. “This was an innovative (dual PET inclusion criteria) phase 2 trial that hit its primary cognitive/functional endpoint while confirming the robust amyloid-normalizing effect of this interesting antibody. The secondary outcomes all moved in the right direction (they could not be expected to hit significance with the small sample size). These results show two things: Donanemab is a promising therapeutic and the amyloid hypothesis continues to strengthen.”
Dr. Aisen collaborates with Lilly on the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) study.
Samuel E. Gandy, MD, PhD, the Mount Sinai professor of Alzheimer's disease research, professor of neurology and psychiatry, and associate director of the Mount Sinai Alzheimer's Disease Research Center said that the most dramatic effect of donanemab was the conversion of nearly 70 percent of subjects from amyloid PET-positive to amyloid PET-negative by the 18th month of treatment.
“While we have seen amyloid burden reduced by passive immunotherapy since bapineuzumab was tested in 2010, donanemab appears to be more consistent in rapidly purging the brains of most subjects of essentially all fibrillar amyloid detectable by PET scan. What we still cannot tell is how much oligomer amyloid peptide persists because amyloid PET only detects fibrillar deposits (basically, plaques).”
He added that “this could still be an important limitation to try to overcome. There is evidence that at the very first stages of amyloid accumulation, it is toxicity from oligomers that is key. Both BAN2401 and donanemab are potentially capable of depleting the brain of oligomers; we just have no PET ligand that will ‘light up’ oligomers.”
Dr. Gandy added that there is at least one more potentially key novel feature of donanemab. In 2012, George S. Bloom, PhD, a professor of biology, cell biology and neuroscience at the University of Virginia reported in Nature that the “N3 truncated, pyroglutamylated” amyloid species is an especially poisonous cause of tauopathy and prion-like spreading or “seeding” of amyloid pathology even though its abundance is low.
Donanemab is an immunoglobulin aimed specifically at “N3 truncated, pyroglutamylated” Abeta. If removal of this especially poisonous and prion-like “N3-truncated, pyroglutamylated” form of amyloid is one key to clinical benefit, then there will be redoubled efforts at purging the brain of this “baddest of bad guys,” explained Dr. Gandy.
“Perhaps there are even more [toxic agents] yet to be discovered among other modified amyloid peptides that may also be minor in relative quantity compared with the abundant but relatively innocuous Abeta 40, for example,” he said, adding “but still if left behind, trace amounts of particularly poisonous Abeta prions might sustain neuronal and synaptic dysfunction.”
Dr. Mintun is an employee and shareholder of Eli Lilly and Company. He reported personal fees and others from Eli Lilly and Company, as well as personal fees from Avid Radiopharmaceuticals, Inc., outside the submitted work. In addition, patent applications (Title: Anti-N3pGlu Amyloid Beta Antibodies and Uses Thereof) are planned. Dr. Apostolova reported non-financial support from Avid Pharmaceuticals outside the submitted work. Dr. Gandy has a grant from Constellation Wines for investigator initiated research using Constellation grapeseed extract to treat dementia. He is one of several founders of Recuerdo Inc., a company intended to offer concurrent access to multiple anti-amyloid and anti-cytokine interventions. Drs. Fillit and Aisen had no disclosures.