As 'harvest time' arrives for Alzheimer's, neuroscientist reflects on next steps for drug development

Howard Fillit, M.D., remembers a time when doctors didn’t have a name for the condition that robbed elderly patients of their memory.

“I can tell you when I went to medical school, back in the early 70s, Alzheimer’s disease was not in my textbooks,” Fillit said in a recent interview with Fierce Biotech.

In 1984, the Glenner and Wong paper was released describing the beta amyloid plaques that build up in the brain and cause the neurodegenerative disorder. While that was the start of the understanding of Alzheimer’s, it has taken nearly four decades to have a potentially disease-altering treatment available for patients.

Fillit is still a practicing physician—in fact, a patient of his called during the interview, underscoring his long history in the care of people with Alzheimer’s. He’s a geriatrician and neuroscientist, but also the co-founder and chief science officer for the Alzheimer’s Drug Discovery Foundation.

To listen to more from our interview with Howard Fillit, M.D., check out the latest edition of The Top Line podcast.

The new treatment, of course, is Eisai and Biogen’s Leqembi, while Eli Lilly is close behind with donanemab. There’s also been an explosion in advancements for biomarkers, imaging, diagnostics, clinical trial protocols and other aspects of Alzheimer’s care.

“I've seen us go from really nothing to a time when we have the first approval for a disease-modifying drug in the history of the world, and actually the first approval in our field in almost 20 years,” Fillit said. “This is the dawn of a new era.”

While the new drugs have been welcomed by patients and their caregivers, one key concern for this new class of monoclonal antibodies has been the side effects, which are referred to as ARIA-E for swelling in the brain and ARIA-H for bleeding in the brain. These are, of course, serious, but Fillit says they are highly manageable. The most common side effects, according to Fillit, are headaches, confusion and dizziness, which affect about 20% of patients.

Patients are given serial MRIs of the brain during the first three months of treatment for the more serious bleeding and swelling issues. If either is identified, treatment is paused to allow for healing and then restarted. Physicians are also receiving more education on the risk factors involved to ensure patients are treated safely.

For Fillit, it’s all about balancing benefit and risk.

“We know that Alzheimer's is the most feared disease and rightfully so. Having taken care of thousands of people over the last 40 years or so, this is a horrible nightmare for patients and their families in many cases,” he said.

The new Alzheimer’s drugs can lead to months of improved cognition, said Fillit, who likened the benefit-risk to oncology, where patients accept a certain level of risk in treatment.

"It's very clinically meaningful to be able to say to someone, 'If you take this drug, you'll get months of benefit in a disease that robs people of everything that makes them human, including being able to recognize their grandchildren,'" Fillit said.

What’s next

So the question begs to be asked: what now? Fillit is encouraged by the way Lilly’s donanemab trial stopped treatment once a certain level of amyloid clearance was reached. The amyloid did recur, but it took about four years to return to its prior levels. Fillit is hopeful that the future will see treated patients monitored using biomarkers and then re-treated once their plaques return, just as oncologists do with their patients.

He is also excited about emerging research into the biology of aging, particularly the role of inflammation in the brain. This could become a new pathway for developing even more treatments. Fillit said that researchers have learned through autopsies of elderly patients that beta amyloid can be present in the brain without progressing to Alzheimer’s. If there’s no strong immune reaction to the buildup, there’s no inflammation and no progression of disease.

Alector Therapeutics and Denali Therapeutics are two biotechs working on immunotherapies exploring this pathway. Both, however, have run into roadblocks with their programs. AbbVie walked away from a collaboration with Alector on AL003 in July 2022 after a phase 1 review. The biotech still has one candidate in the works with the Big Pharma called AL002, which aims to improve Triggering Receptor Expressed on Myeloid cells 2 (TREM2) signaling to enhance microglia activity. A phase 2 trial called INVOKE-2 is underway.

Denali similarly dropped a Takeda-partnered candidate in April after seeing phase 1 data. The partners are exploring back-up molecules, Denali said in August.

Combination treatments also represent a promising area of advancement. Fillit said there are plenty of existing therapies on the market now that could be used in a regimen to help modify the disease and address symptoms at the same time.

Reformulations of existing treatments are also needed to ease the treatment burden for patients. The future could mean at-home treatment for patients instead of traveling to an infusion center with a caregiver. That would lessen the burden and the cost.

All of this advancement is something that Fillit couldn’t have imagined in the earlier days of his career. When the ADDF began in 1998, he surveyed major American biopharmas and found that out of 1,600 companies, only three had Alzheimer’s programs—"and frankly, two of them weren't really respectable.”

Now there are hundreds working in the space, with 140 drugs in clinical development.

“That kind of portfolio for Alzheimer's didn't exist 15 to 20 years ago, there was so little going on,” Fillit said. “This is harvest time now. We're going to harvest all the basic research on neurodegeneration and Alzheimer's disease, neuro pathology and neuro chemistry and so on. We're starting to harvest all that information into new drugs.

“And because of Leqembi, and because of donanemab, and because of the new biomarkers that we have, there's confidence that we can actually test these drugs in clinical trials and get good answers,” he concluded.