Can Biogen’s Alzheimer’s Relief Plan Succeed?

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Lecanemab is the latest in a long line of experimental drugs centered on a theory of Alzheimer’s disease: that the buildup of a sticky protein called amyloid in patients’ brains contributes to its debilitating conditions, including memory loss. and dementia. For years, neuroscientists hoped that removing large clumps of amyloid, called plaques, would stop the disease. So far, this hypothesis has not succeeded.

Although Aduhelm has reduced plaques, scientists and doctors have hotly debated whether it slows memory loss and cognitive decline in patients. The United States Food and Drug Administration sidestepped this issue entirely by granting Aduhelm so-called fast-track approval based on its ability to reduce amyloid.

Investors initially expected Biogen to profit from Aduhelm, but many hospitals refused to offer the drug and private insurers balked at its initial price of $56,000, which was later halved. The final blow came in April when Medicare said it would only pay for Aduhelm used by patients in clinical studies. Shortly thereafter, Biogen announced that it would be dismantling its Aduhelm business division.

Biogen declined interview requests for this story.

Neurologists are divided on whether lecanemab will be any different, but many are cautiously optimistic. “I put it in the bucket of promising drugs, but we need more data,” said Dr. Brian Silver, acting chair of the department of neurology at the University of Massachusetts Memorial Health.

Those data are coming soon, as Biogen and its Japanese partner, Eisai, conclude the phase 3 study, called Clarity AD. A patient with mild cognitive impairment who enrolled in the trial is 59 years old Hugh Courtney of Concord. Every two weeks he visits McLean Hospital in Belmont for an infusion – he won’t know if it’s lecanemab or a placebo until the tests are complete.

Alzheimer’s disease runs in Courtney’s family, so he always knew there was a chance of contracting the disease. As a former professor and dean of Northeastern University’s D’Amore-McKim School of Business, he understands the value of research. Joining the study was an easy decision for him.

“How could I not do this?” Courtney said during her 36th infusion at McClean last month. “Given my family’s history and mine, it made a lot of sense.” He still had several infusions to do before the end of the 18-month study.

Decades of failed attempts at a cure or better treat Alzheimer’s disease tempered expectations for new drugs. No one expects lecanemab to reverse the disease or even completely stop memory loss. In Eisai’s interim clinical trial of lecanemab, which was published last year, the highest dose slowed a measure of cognitive decline by about 33% over 18 months, compared with 22% in one. of Aduhelm’s two phase 3 trials.

“There may be a greater clinical effect with lecanemab,” but that might not be enough for clinicians or families to notice, said Dr. Brent P. Forester, chief of geriatric psychiatry. to McLean, who runs the hospital’s Clarity program. AD study and previously conducted studies on Aduhelm there. “It’s hard to imagine it will be significantly better, especially from what I’ve seen with people I’ve treated in these trials.”

That’s Courtney’s experience so far. “I suspect there is a bit of change, but not much,” he said. But since there’s nothing else available to slow memory loss, he added, even modestly effective therapy would “absolutely” make sense to him.

Aduhelm’s meager benefit in one trial was undermined by a second Biogen study which suggested the drug was no better than a placebo. And the potentially dangerous side effects made Aduhelm a tough sell. Now, many experts hope the Clarity AD trial will paint a clearer picture of the drug’s possible benefits.

In an earlier lecanemab study, about 80% of high-dose patients became “amyloid negative” on their brain scans after 18 months of treatment. “That’s pretty remarkable because it probably takes 10 to 15 years for amyloid to build up, and this drug can clear it up in a year and a half,” said Dr. Michael Irizarry, senior vice president of the Eisai Clinical Research and Deputy. clinic director.

In a decision that baffled doctors, Eisai and Biogen asked the FDA to grant expedited approval for lecanemab, based on its ability to lower amyloid — the same pathway that caused Medicare to reject Aduhelm.

“If canemab receives expedited approval” for this reason, Forester said, “nobody will pay for it.”

But if the Clarity AD trial proves lecanemab slows cognitive decline, Forester expects it to gain full FDA approval and Medicare coverage.

The questionable benefits of Aduhelm were further threatened by serious side effects, including brain swelling and bleeding in some patients, leading to at least a few deaths. In the previous lecanemab trial, regular MRI scans revealed that around 10% of participants developed brain swelling, compared with around 35% of those taking Aduhelm.

Irizarry said Aduhelm may be more likely to cause collateral damage to blood vessels in the brain because the amyloid plaques it targets build up there. Lecanemab, on the other hand, primarily targets a form of amyloid that is a precursor to plaques, which is not found as often in blood vessels.

Roche and Eli Lilly and Company are testing their own therapies to reduce amyloid, gantenerumab and donanemab, with results expected later this year and in the first half of 2023, respectively.

If all three have positive results, “that would really strengthen the amyloid hypothesis and make people more likely to believe that Aduhelm’s positive test was the right test,” rather than a fluke, said the Dr David Rind, Chief Medical Officer. for the Institute for Clinical and Economic Review, a drug price watchdog in Boston.

But even if the drugs fail, the amyloid hypothesis is unlikely to die. Companies can test the use of amyloid drugs earlier in life to prevent disease, or combine them with other therapies. For example, Biogen and Eisai are developing drugs to reduce a protein called tau, which forms toxic tangles inside the brain cells of people with Alzheimer’s disease.

Dr. Randall J. Bateman, a neurologist at Washington University School of Medicine in St. Louis, is leading a large study that will be the first to test anti-amyloid and anti-tau drugs simultaneously. “We think it’s going to be more effective,” he said.

This combined study, which is just beginning, will take years to get answers. But the most advanced studies testing amyloid-reducing therapies alone involve 18-month trials, which some doctors say may not be long enough to tell how well they’ll work in the long run.

“I want to see something that’s not just an improvement for six months; I want to see something over the years,” said Dr. Richard Dupee, chief of geriatric services at Tufts Medical Center.

Courtney learned that in August he is guaranteed to start receiving lecanemab, but he does not expect a miracle.

“It’s not the kind of thing where you take a picture and don’t have to worry about it anymore,” he said. “Hopefully what the drug can do is give me more clarity and more time.”


Ryan Cross can be contacted at [email protected] Follow him on Twitter @RLCscienceboss.

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