Fierce Next Gen: Despite another key trial failure, Alzheimer's therapy developers find reason for optimism

As Genentech’s Greg Rippon, M.D., detailed his company’s failed Alzheimer’s disease study for a drug called crenezumab, his fellow panelists nodded solemnly. They’d all been there before.

Rippon, who serves as vice president and chief medical partner of neurology, ophthalmology and internal medicine at Roche’s Genentech unit, was describing the disappointing news that had dropped a few days earlier that crenezumab had failed to impact the cognitive abilities or episodic memory function in a group of patients with an inherited form of Alzheimer’s during a phase 2 trial.

“We're very proud of the contributions that this study has made, particularly to the emerging science of how to conduct a prevention study in the Alzheimer's space,” Rippon said. “Although we're disappointed in the results of that trial, like many of the trials that we've all been involved with here in this space, we anticipate that this will contribute quite a bit of information to the field as we all learn and grow in our approach to Alzheimer's disease clinical development.”

A number of amyloid-targeting therapies are expected to read out over the next year or so, including phase 3 assets from Eli Lilly and Genentech, donanemab and gantenerumab, respectively. Brandy Matthews, M.D., who serves as associate vice president, global & U.S. medical affairs for Alzheimer’s disease at Lilly, acknowledged that of the many studies to come “we might not expect all of those will be positive,” especially given the “complicated history in Alzheimer's disease.”

And yet, as the conversation at Fierce Biotech’s Next Gen event shifted to what’s to come in R&D and how to ensure patients get involved in clinical studies, all had a sense of hopefulness, not despair.

“I am hoping we're very close to getting a therapy with at least some sort of modest benefit because I think that's going to change the whole paradigm for patients and for clinicians because there’ll be a point of making a diagnosis,” said Roger Lane, M.D., senior vice president and head of clinical development, neurology at Ionis Pharmaceuticals. “It will rid the sort of nihilism that's pervading some areas, that there's nothing that can be done, this is just old age or whatever.”

So what is coming down the pike? Both Rippon and Matthews argue that there’s still more to interrogate on the amyloid theory, despite the recent clinical failure and the many that came before it.

“The course is not altogether too different from the one we have been charting,” Rippon said, noting the pharmaceutical industry’s combined efforts, different modalities and targets under investigation. “It takes time in this space, as we all know, to get there.”

The idea behind the pervading theory in Alzheimer’s is that clearing or preventing the buildup of amyloid plaques in the brain can impact cognitive decline in patients. But the clinic has not been kind as company after company has tried to move therapies through testing.

“It's not unusual in neurology for that progress to be incremental. It doesn't move on as fast a timeframe as maybe some other therapeutic areas and it's complex,” Rippon said. “But I really do take a lot of encouragement from the steady progress that's been made and I really do feel like we're on the cusp of a new era here in Alzheimer's therapeutics.”

The fact is, “there's quite a bit we still don't know,” he said. But Rippon sees a field that continues to learn and progress, despite the struggles, to refine how clinical trials are conducted, how patients are identified, how therapies are dosed and more. Like Lane, he says we need a better understanding of the fundamental disease process that drives Alzheimer’s.

Lane said drug development in Alzheimer’s has improved greatly, with better tests and imaging techniques that previous researchers “can only dream about.”

“It's never been easier to index what's going on in the brain than it is now,” he said.

Lane’s company Ionis is partnered with Biogen on an antisense therapy tackling a protein in the brain called tau. He said that target holds promise because it shows up fairly late in the amyloid cascade—the term for the buildup of plaques that is believed to cause Alzheimer's. The theory is that if a drugmaker can find a therapy that can help sort out the tangles of tau in the brain, they can intervene in the disease even at a late stage. Whereas amyloid, which Lane referred to as “the fundamental causative mechanism of Alzheimer's,” should be addressed earlier, because it can begin to build up as much as 20 years prior to the onset of symptomatic disease.

Waiting until the brain has essentially failed is not the right approach for an amyloid mechanism, he said. Lane likened it to “giving a statin to a patient with heart failure and expecting good results. It’s too late.”

One major challenge that has faced Alzheimer’s researchers is that the disease works slowly.

“This is what's plagued the field, that this is a chronically progressive disease that evolves over a long period of time, and so it's very challenging to demonstrate the therapeutic impact in the short window of a clinical trial,” Lilly's Matthews said.

The many failures are certainly indicative of that. Matthews appreciates the data sharing that has gone on across the industry to fine-tune the trials that come next and hopes that collaborative spirit will continue. This has helped companies like Lilly narrow down the trial population to patients who may benefit and figure out new clinical endpoints that can tell a story in the standard trial timeframe.

Matthews would like to see more research on treatment combinations and interventions at different points in the amyloid cascade. Her company has a few early prospects in the pipeline looking at these ideas. She also believes there’s lots to learn about the speed and depth of plaque clearance, the stage of tau and the best clinical endpoints to interrogate in studies.

“It will be important not just to shift our focus from amyloid to these other exciting potential interventions, but to acknowledge the long history of learning from clinical trials in the Alzheimer's disease space and just to stick to it … and continue to pursue these therapies on behalf of the patients,” Matthews said.