Ever since Biogen and Eisai’s Aduhelm (aducanemab) was approved in 2021 as the first antibody to treat Alzheimer’s disease by clearing amyloid plaques from the brain, the modality has been dogged by a serious side effect: brain bleeding called amyloid-related imaging abnormalities, or ARIA.
Now, researchers from Denali Therapeutics have debuted an antibody that can cross the blood-brain barrier and attack amyloid, but without triggering this potentially life-threatening complication.
When given to mice, the molecule was able to spread broadly throughout their brains and dismantle amyloid plaques, with MRIs showing this didn’t result in any ARIA-like leakage from blood vessels. The results were published in Science on Aug. 7.
The Bay Area biotech plans to bring an optimized form of the antibody, which targets beta amyloid (Abeta), into the clinic next year, Chief Scientific Officer Joe Lewcock, Ph.D., told Fierce Biotech.
“The molecule is currently undergoing the standard IND-enabling studies,” Lewcock said. “Once we get to the clinic, there's potential to learn from the lessons that the Abetas that have come before us have provided in terms of how to efficiently get towards a proof of concept.”
First-generation Abeta drugs, like the now-discontinued aducanemab, Eli Lilly’s Kisunla (donanemab) and Biogen and Eisai’s Leqembi (lecanemab), have proven controversial due to ARIA safety concerns that may not outweigh the approach’s benefits. These drugs don’t target the brain but are instead given systemically through the blood, so only a small fraction of the given antibody actually reaches the brain.
One hypothesis for ARIA’s cause is that the antibodies bunch up around amyloid within blood vessels, rather than reaching the plaques that occur within the actual brain tissue, triggering an immune response that damages the vessel and causes bleeding.
To circumvent this, Denali designed its antibody to bind to transferrin receptors (TfR) on the outside of the blood-brain barrier. TfRs are meant to ship iron, a vital nutrient, into the brain, a process that can be hijacked to smuggle other payloads across the barrier as well.
“This is a superb innovation,” said Matthew Schrag, M.D., Ph.D., a neuroscientist at Vanderbilt University Medical Center who was not involved with the research. “Controlling the delivery of drugs of any sort to the brain, getting them effectively into the compartment that you want to get them into, is a major accomplishment.”
Not content to stop there, Denali also tried to tamp down a potential immune reaction by removing one of the antibody’s effector sites. This is the part of the antibody that, once the molecule has bound to Abeta, actually recruits the brain’s waste disposal system to clear the plaques.
“What we've shown in the paper is that if you remove effector function entirely, you lose the ability to clear plaques as effectively,” Lewcock explained. “We essentially removed effector function from one side of the molecule,” which made the antibody safer but still as effective, he said.
Whether Denali’s antibody is truly safer remains unanswered for Schrag, who said the small number of mice used in the study may have made it tricky to detect ARIA, which typically occurs at single-digit percentages of human patients.
“When you're looking at a relatively low frequency event, you need to have significant numbers to detect the difference,” Schrag said.
Lewcock agreed that the sample size was small but is confident in the findings.
“Putting animals into the MRI on a regular basis is a little bit of a challenging task,” he said. “But we're excited because the differentiation we saw between the first-generation molecules and our molecules was just huge.”
Differentiation also matters when it comes to the second generation of Abeta antibodies. Roche already has a transferrin-binding candidate, trontinemab, poised to enter phase 3 trials. And AbbVie bought Aliada Therapeutics last fall to gain access to an in-licensed Johnson & Johnson asset that is also designed to cross the blood-brain barrier. Against both of these rivals, Lewcock thinks Denali’s candidate stands out.
Aliada removed effector function entirely from its molecule, he said, which could make it less able to clear amyloid plaques. And, as for Roche, “instead of building TfR binding into the molecule itself, it has an appended TfR binding sequence,” Lewcock said. “We think, and it's shown already in the clinic, there's potential for immunogenicity there.”
One benefit of Denali’s approach is that it isn’t limited to targeting Abeta, or even to just antibodies. The biotech also uses TfR to get enzymes, like lead asset tividenofusp alfa, and antisense oligonucleotides into the brain.
“We have a tau program using our oligo delivery system that is also very close to clinical studies,” Lewcock said. And, if the approach really is safer for Alzheimer’s patients, could that open the door for a combined therapy to tackle both amyloid and tau?
“It's an exciting idea ripe with potential and complexities,” Lewcock said. “But I think where the field overall is heading is in terms of combinations, whether they're individual molecules or being able to combine modalities.”