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Second Alzheimer’s drug to slow disease’s progression may be approved in the US this year

<i>Mike Blake/Reuters</i><br/>Lilly said in a news release that it had completed its US Food and Drug Administration submission for the drug
Mike Blake/Reuters
Lilly said in a news release that it had completed its US Food and Drug Administration submission for the drug

By Meg Tirrell, CNN

(CNN) — The full approval this month of the Alzheimer’s drug Leqembi marked a historic shift in the treatment of the disease: For the first time, doctors have a medicine to prescribe that has been proven to slow the loss of memory and ability to do daily tasks that Alzheimer’s brings.

A second drug may join Leqembi — known as lecanemab before it got its brand name — on the market by the end of the year: Eli Lilly’s donanemab.

It was shown in May and in fuller Phase 3 clinical trial results released at the Alzheimer’s Association International Conference on Monday to delay the disease’s progression. Lilly said in a news release that it had completed its US Food and Drug Administration submission for the drug, and expects regulatory action by year’s end.

More than 6 million Americans are estimated to have Alzheimer’s disease, with about 1 million estimated to be in the early symptomatic stages where these drugs have shown benefit. But even though the medicines are the first to put a brake on the seemingly inexorable progression of Alzheimer’s, experts questioned the degree of their benefit in a series of editorials published Monday in the Journal of the American Medical Association, alongside the donanemab data.

Both Leqembi and donanemab work by clearing buildups of a protein in the brain called amyloid, a hallmark of Alzheimer’s.

“Donanemab was very effective at eliminating its target, cerebral amyloid, but the clinical effect was comparatively weak,” Jennifer Manly, of Columbia University Irving Medical Center, and Kacie Deters, of the University of California, Los Angeles, wrote in one editorial.

Patients taking the medicine in the more than 1,700-person trial had 35% slower progression of disease than those on placebo over a year and a half on a measure called the integrated Alzheimer’s Disease Rating Scale, or iADRS, the results showed. That equated to a loss of six points on a 144-point scale for those on the drug, compared with a loss of nine points for those on placebo.

In another editorial in JAMA, researchers sought to put that result and others from the trial into real-life terms: For patients taking donanemab, there’s a lower risk of progressing from having mild cognitive impairment, or being fully independent in daily activities, to mild dementia, requiring assistance with some daily activities; or of progressing from mild to moderate dementia, requiring some assistance with basic self-care.

Lilly assessed patients in groups based on their levels of another Alzheimer’s-associated protein, called tau, and the 35% slowing of disease progression was seen in those with low to medium levels, thought to be in less advanced stages of the disease than those with higher levels. When those with higher levels were included, the benefit was 22% versus placebo.

For patients in the low/medium tau category, the researchers pointed out the drug slowed decline by 4.4 months over the 18-month trial on the iADRS scale. On another scale, known as Clinical Dementia Rating-Sum of Boxes, or CDR-SB, it slowed decline by 7.5 months.

“While the slowing of clinical decline seen in this trial represents an important start, and may be deemed clinically meaningful for some patients, development of more impactful and safer treatments is still needed,” wrote the authors, the University of California, San Francisco’s Dr. Gil Rabinovici and Renaud La Joie.

Experts’ hesitation on the degree of benefit isn’t limited to donanemab; it also applies to Leqembi. On the CDR-SB measure of disease progression, donanemab showed a 36% slowing compared with placebo in the low/medium tau group, and a 29% slowing overall, while Leqembi, sold by the drugmakers Eisai and Biogen, showed a 27% benefit over placebo.

To Lilly’s chief of research, Dr. Daniel Skovronsky, the donanemab trial results answer some key questions, and hint toward ways to reach greater benefits for patients with Alzheimer’s.

“One of the questions we had was: Does the effect grow over time?” he said in an interview with CNN. “That’s important because Alzheimer’s disease is a chronic disease that can last a decade or more.”

He said at every time point researchers measured, the difference between patients on donanemab and placebo was growing.

The company also designed the trial so that patients could stop taking the drug if enough amyloid was cleared from their brain; about half the patients switched to placebo based on that metric at six or 12 months, Skovronsky said. Even for those patients, he noted, “the benefits continued to increase over time.”

“We were delighted to see that,” Skovronsky said. “Once you get rid of the plaques, you’ve fundamentally changed the trajectory of the disease in a positive way. You don’t need to continue to take therapy to get those benefits.”

Another question the trial sought to answer, Skovronsky said, was whether there was greater benefit for people earlier in the course of the disease. It’s been a hypothesis that treating Alzheimer’s earlier with amyloid-clearing drugs would yield better results; Skovronsky said the donanemab trial bore that out.

“We could look at people who had mild cognitive impairment, MCI, which is the earliest stage, versus mild Alzheimer’s versus moderate Alzheimer’s,” Skovronsky explained. “And the drug worked in all three groups, but the effect was strongest in the earliest, in the MCI patients.”

They saw a similar effect when patients were separated by age: those under 75, in the low/medium tau group, had greater disease slowing than those 75 or older: 48% on the iADRS scale for the younger patients compared with 25% for the older ones.

Lilly is running a trial in patients who don’t yet have symptoms of Alzheimer’s disease to see if the results are stronger, and Skovronsky said these results give them more confidence that study will succeed.

“If this trial could slow disease progression by 40 or 50% in the early stages of the disease, now we go even earlier in our prevention study, and maybe we can stop it entirely,” Skovronsky said. “So we’re really excited about that.”

Leqembi is also in a prevention study in people at elevated risk for Alzheimer’s.

For the current use of the medicines, in people with early stages of the disease, the editorials emphasized the need to continue study over longer periods, which the companies will continue to do. They also noted that how well they work isn’t the only concern.

“The modest benefits would likely not be questioned by patients, clinicians, or payers, if amyloid antibodies were low risk, inexpensive and simple to administer,” wrote UCSF’s Dr. Eric Widera, SUNY Upstate Medical University’s Dr. Sharon Brangman and the University of Wisconsin’s Dr. Nathaniel Chin. “However, they are none of these.”

The drugs are administered by intravenous infusion – Leqembi, every two weeks, and donanemab, every four.

The biggest safety concerns are swelling or bleeds in the brain typically seen on MRI, known as amyloid-related imaging abnormalities, or ARIA. Donanemab had an ARIA rate of either type of 37%, compared with 15% for patients on placebo. While Lilly said most of the cases were mild to moderate, a few were severe, and there were three patient deaths in the donanemab group, and one on placebo, considered treatment-related.

In Leqembi’s Phase 3 trial, 22% of patients experienced ARIA of either type, compared with 10% on placebo. Some patient deaths have been reported in extension studies of Leqembi as well.

Patients can also experience infusion reactions.

And the medicines aren’t inexpensive: Leqembi costs $26,500 per year before insurance. Its full approval by the FDA unlocked broader Medicare coverage, but researchers noted in the editorials Monday that some patients could still be on the hook for large out-of-pocket costs for portions of treatment or accompanying testing that insurance doesn’t cover. Lilly hasn’t disclosed where it will price donanemab once approved, as drugmakers typically don’t comment on pricing before approval.

The fact that donanemab is designed to be stopped once patients reach a certain level of amyloid clearance differentiates it from Leqembi. Dr. Lawrence Honig, a professor of neurology at Columbia University Irving Medical Center who had not yet seen the full donanemab results, argued that it’s scientifically and medically “unrealistic to think that the Alzheimer process will be stopped by six to 18 months of antibody treatment.”

“Alzheimer’s is a chronic disease involving slow, gradual accumulation of amyloid beta forms in the brain,” he wrote to CNN in an email. “It is not likely that removing plaques over some months will prevent the disease process from progressing.”

Further, Honig, who said he consults for companies including Eisai, Biogen and Lilly and does clinical research on Alzheimer’s medicines, said it may be difficult to use donanemab longer-term, because many patients develop an immune response against it in the form of antidrug antibodies. This immune response happens with Leqembi as well, Honig said, but noted they “occur in a much more prominent fashion” with donanemab.

One limitation to the donanemab trial, researchers argued in the editorials, was that a majority of patients were White – about 90%.

“Dementia-related burdens are disproportionately felt within historically marginalized communities because structural inequalities rooted in racism, xenophobia and sexism increase risk factors for cognitive impairment, increase barriers to diagnosis, and reduce access to care,” Manly and Deters wrote. “It has been discouraging that recent clinical trials of amyloid-clearing monoclonal antibodies have not been able to meet goals of inclusion of minoritized groups.”

Lilly said that more than a quarter of the people it screened for the trial were members of minority groups, but that fewer people who were Black or Hispanic had positive scans confirming they had both amyloid and tau proteins required to join the study. The company said in a statement there’s a need for more study to understand why, and pledged that it’s “committed to identifying and implementing solutions that will result in diverse representation, improve health equity, and generate evidence to support better patient outcomes.”

Even with the many questions about the magnitude of the new medicines’ benefit, their cost, safety and complexity of administration, for some patients, they represent one of the most important things there is: hope.

“When we get our diagnosis, there are many things that go through our minds — and it’s not just how this disease is going to impact my family and myself, but that there’s really no hope for our future,” said Joe Montminy, who at 59 is living with younger-onset Alzheimer’s. “And with these treatments, we now have hope, the hope that one of these treatments might help us.”

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