CTAD honoree Lars Lannfelt’s work on a Swedish family’s Alzheimer’s-causing mutation in the late 1990s spurred the decades-long development of Alzheimer’s drug Leqembi.
In just a single year of studying a rare genetic mutation in a single family in the Arctic reaches of remote northern Sweden, a neurologist uncovered a biochemical pathway that would go on to reshape Alzheimer’s research. Swedish neurologist Lars Lannfelt’s discovery, a quarter century ago, of the approach of clearing toxic forms of beta-amyloid from the brains of people with Alzheimer’s as a means of slowing down the disease has since ignited a multi-billion-dollar drug research industry and transformed the pursuit of Alzheimer’s therapeutics.
In 2023, Eisai’s Alzheimer’s drug Leqembi became the first anti-amyloid to receive full FDA approval in the U.S., showing that clearing toxic forms of beta-amyloid from the brain led to a small slowing of cognitive decline in people with early Alzheimer’s. And today, Lannfelt received a lifetime achievement award at the Clinical Trials of Alzheimer’s Disease conference for developing Leqembi.
Before he took the stage at CTAD to present the conference’s keynote speech, Being Patient caught up with Lannfelt about how drugs get made, why Leqembi succeeded while anti-amyloid other drugs failed, and what’s in store for the future of Alzheimer’s treatment.
Chasing Alzheimer’s to a remote Swedish village
Lannfelt started his research career in the 1980s studying a rare metabolic disorder called acute intermittent porphyria. In 1992, Lannfelt switched his focus to Alzheimer’s — he appreciated the opportunity to focus on a more widespread disease.
In Sweden, there are family records going back to the 1700s allowing researchers to track hereditary diseases like Alzheimer’s. This, Lannfelt says, is a unique cultural feature: “The Swedish state has always been very good at taxing the population,” Lannfelt said during his keynote, “and the other reason [they kept food records] was to conscript the young men to the army.”
In 1998, his search took him to a remote village in Northern Sweden, where several generations of people were developing an early-onset, quickly progressing form of Alzheimer’s disease. By 1999, he found the family had a mutation in the gene that makes the beta-amyloid protein — which Lannfelt called the Arctic mutation. Intriguingly, people with the Arctic mutation didn’t develop as many plaques as other people with Alzheimer’s.
“It had interesting biochemical propensities,” Lannfelt told Being Patient.
The beta-amyloid formed into aggregates called protofibrils. “I thought these soluble aggregates of amyloid [protofibrils] are probably a very good target for treatment.”
The protofibrils, even in the absence of beta-amyloid plaques, was enough to cause the disease.
Could targeting the toxic protofibrils be the key to treating Alzheimer’s disease?
Turning a genetic discovery into a drug
The possibility that he’d cracked the code to familial Alzheimer’s in protofibrils captured his full attention. In 2001, Lannfelt and team published the scientific resutls and in 2003, Lannfelt co-founded BioArctic, a biotech company that would develop a treatment that targets protofibrils.
When immune cells encounter something new or potentially harmful, they release many different antibodies in the hopes that one of them will stick to the intruder.
Lannfelt exploited this property of the immune system, and injected toxic protofibrils into mice. The mouse immune system generated antibodies to try and get rid of the protofibrils. Lannfelt and his team eventually isolated an antibody that sticks to protofibrils in 2005; the antibody also stuck to amyloid plaques.
BioArctic began working with Eisai and eventually licensed the antibody for further development in 2007. Lannfelt chose to work with Eisai because they developed Aricept (donepezil), one of the most effective cholinesterase drugs for treating symptoms of Alzheimer’s.
After more than a decade of clinical trials, Leqembi was fully approved by the FDA in July 2023.
It has been rejected by regulators in the EU and Australia, and the UK’s state insurer has refused to cover its cost for patients, as neurologists disagree on whether the risks of Leqembi outweigh the clinical benefits.
Lannfelt wants patients to know that drug development is a long, expensive process.
“I have been working on this project for more than 20 years, and without the collaboration with Eisai, it would not have been possible,” he said.
Lannfelt said he has seen data that supports the idea that protofibrils do play a significant role in the disease — and, potentially, in treating it if Leqembi is administered early enough, though more research is needed.
Researchers are testing a subcutaneous formulation that could be injected under the skin like GLP-1 diabetes drugs or insulin pens. Lannfelt emphasized that treatment with drugs like Leqembi will need to be ongoing.
“Alzheimer’s disease is a chronic disease, and I’m sure it needs a chronic treatment,” he said during the keynote.
What’s next for Alzheimer’s anti-amyloids?
Drugmakers and researchers are still struggling to develop anti-amyloid Alzheimer’s treatments that can make it from the bloodstream and into the brain to do their work. They must pass through the blood-brain barrier, a gatekeeper that stops pathogens and toxic molecules from getting to the brain.
Right now, patients need high doses of these (so far) infusion-based anti-amyloid drugs to ensure that enough gets into the brain, making treatment more expensive. The pitfall of this approach: Higher doses raise the risk of side effects like brain swelling or bleeding in ARIA.
This, Lannfelt says, is a focus for the future generations of Alzheimer’s anti-amyloids.
“The most important development is to increase penetration into the brain,” he said. And some companies are on to a new approach.
Along these lines, drugmaker Roche is developing an anti-amyloid drug called trontinemab, which tricks the blood-brain barrier into letting it in.
The company has presented study findings at recent conferences that indicate patients only need a small dose of the drug to clear beta-amyloid.
And following Lannfelt’s prediction, in a very small group of trial participants taking trontinemab, the rates of ARIA are far lower than they were among patients taking Leqembi and Kinsula.
Under Lannfelt’s supervision and research direction, drugmaker BioArctic is working on a similar approach to getting past the blood-brain barrier for Alzheimer’s, as well as experimental treatments for Parkinson’s disease and amyotrophic lateral sclerosis.
By searching far and wide for the mechanism behind a genetic form of Alzheimer’s and uncovering the impact of amyloid protofibrils, Lannfelt changed the way scientists understand and treat the disease and opened up a new pathway for treatments — one the industry is still charting.