Clinicians treating patients with dementia are excited about the potential approval of lecanemab for Alzheimer’s disease. But they’d also like to see more data from clinical trials. I don’t know yet.
It didn’t take long for lecanemab to enter the conversation between Liana Apostolova, MS, MD, FAAN, and her patient.
In late September, Eisai and Biogen reported that lecanemab, an amyloid-targeting monoclonal antibody, was found to be more effective than placebo in early AD patients with confirmed mild cognitive decline and amyloid lesions due to Alzheimer’s disease (AD). announced that it slowed cognitive decline.
Within days, Dr. Apostolova, a distinguished professor of Alzheimer’s research at Indiana University, discovered she was working on a new kind of topic. No disease-modifying treatment ever has full regulatory approval. The conversation had to be conditional because the data hadn’t been peer-reviewed or fully clarified, but it was still evocative, Dr. Apostolova said.
“I am telling my patients that while we need to see all the data, there appears to be a new promising treatment in our clinic. , I would be happy to talk to you about how they will be able to access treatment if they qualify,” she said. “These are great conversations I have never had with a patient before.”
The field of neurology is understandably reeling from information shared by manufacturers, but clinicians treating people with dementia are also eyeing development. They said it was clear that the fight to conquer AD would move forward, but the extent of its impact remains to be seen. Neurology Today.
Aducanumab’s rugged journey
The evaluation of lecanemab will inevitably be colored by the rocky trajectory of aducanumab, another biogen-developed amyloid-targeting monoclonal antibody. The U.S. Food and Drug Administration (FDA) accelerated approval in the summer of 2021, but the approval was embroiled in controversy.
Two identical trials of the drug were terminated early due to ineffectiveness in March 2019, but Biogen filed for approval based on a post hoc analysis of the drug’s highest dose. In one, the highest dose of 10 mg/kg showed statistically significant benefits on several outcome measures, but the same analysis of data from other trials showed no benefit. Amyloid-related imaging abnormalities, including edema (ARIA-E) or microhemorrhage (ARIA-H), were seen in 41%, mostly asymptomatic or mildly symptomatic, but severe in 1.0% of these cases. I had side effects.
The FDA said the approval of aducanumab, along with the requirement for post-marketing outcome analysis to better confirm its benefits, was based on the drug’s ability to reduce amyloid and whether such effects would reduce cognitive and functional decline “reasonable.” It is based on the belief that there is a high possibility that
The drug had limited coverage under Medicare and was mostly available only at a personal expense.
Neurologists said they were reassured that the monoclonal antibody could provide clinical results without the burden or uncertainty associated with aducanumab.
Eisai and Biogen said in a release that lecanemab reduced clinical decline in the CDR Sum of Boxes (CDR-SB), a scale that measures cognition and function, by 18% compared with placebo in the Clarity AD trial. It said it decreased by 27% in the month. According to the manufacturer, the difference was statistically significant at all time points after 6 months of treatment initiation. They said it showed significant benefits in
The incidence of ARIA appears to be lower with lecanemab than with aducanumab. ARIA-E was 12.5% in the lecanemab group and symptomatic ARIA-E was 2.8% and 0%, respectively, compared to 1.7% in the placebo group. According to the manufacturer’s release, 17% of patients taking lecanemab had ARIA-H, compared with 8.7% of patients taking placebo. Symptomatic ARIA-H was seen in 0.7% of patients taking lecanemab and 0.2% of patients taking placebo.
“At least from what they report, it means that it was a unequivocally positive trial and, as far as they described it, clearly seemed to meet the primary and secondary endpoints.” Bachelor of Arts in Psychiatry and Behavioral Medicine from Wake Forest University School of Medicine. “And nothing seemed to overshadow the results, as was the case with aducanumab.”
The main concerns with aducanumab are that “the effect magnitude is very small compared to the very clear and known risks of these imaging abnormalities” and that “while many are asymptomatic, Not everyone is asymptomatic.”
He said it was too early to calculate the risk-benefit of lecanemab, but added that he hoped it would have meaningful effects for patients and their families. , indicating a slowdown in decline of about half a point in CDR-SB, he said. Thresholds for clinically meaningful change on the scale range from 0.5 points to he 1 point, he said.
“This is reaching its limits,” he said. “If it’s durable and it continues to diverge, the gains could grow over time, but I don’t think we’ve yet found that to be the case.”
He added that the nature of the CDR-SB, which accounts for both subjective and objective measurements, makes it “a little sticky.”
“By showing that you’re making an impact on this scale and that you’re asking about functional outcomes at least to some extent, it gives me a little hope that they were able to truly show this.” Dr Bateman said.
Charles Bernick, M.D., Ph.D., a staff neurologist at the Cleveland Clinic Loulevo Brain Health Center in Las Vegas, said it was “difficult to interpret” what the 27% reduction would actually mean. but said it appeared to have a greater impact. Perhaps over time.
“If the change in disease-modifying therapy continues over time, what you would expect is to see segregation in treated patients after 3, 5 years. Dr. Bernick, a researcher closely monitoring another trial of lecanemab in AD, said.
“The idea is to delay the time it takes to develop dementia.”
Apostolova said patients and their families welcome any impact on the disease. “Any slowing down of decline makes sense for patients. I know that’s a popular opinion from what I hear in my practice,” she said. “You don’t know what it’s going to be like at 24 months and she’s at 36, right? If you slow down the slope of the decline, it can make a much bigger difference because over time it makes a big difference.”
She added: This is no exception. Alzheimer’s disease is as deadly as most deadly cancers, and in many ways far more daunting to caregivers. “
Still, she said she will look at all the data, including effect curves, other biomarkers, and adverse event data.
“Right? Does it all make sense in a cohesive picture of drug effects?” Dr. Apostolova asked. “I and every other scientist and doctor vetted all the data. I can vouch for that.”
Whatever the clinical efficacy of lecanemab itself, this is a conceptual breakthrough and hints at what’s to come, Dr. Bateman said.
“This is the first unshaded trial to show that amyloid removal has no effect in humans. That in itself is a big problem,” he said. “Whether aducanumab is the answer is another question.”
Dr. Bernick said the full availability of the lecanemab discovery and the results of donanemab, another monoclonal antibody that targets amyloid in development, would show that the class effect is real. .
“It may not be that big, it may not have an overwhelming impact, but it’s probably a consistent impact,” he said.
If that turns out to be true, the field will need to pay more attention to diagnosing patients early.
“Without effective treatments to ameliorate the disease, it may not matter so much,” he said. I think there are more reasons to try to get
Dr. Bateman agreed with the need for early diagnosis, which he said poses challenges for the field.
“Many clinical memory services are not currently set up for high throughput because of this lack of this pressing impetus to consider treatments that have a meaningful impact on the course of disease,” he said. “I think a lot of clinical services, myself included, will need to figure out a way to meet that demand if that really seems like a place to settle.”
Assessing amyloid levels will likely be part of lecanemab treatment, he said, adding, “I don’t know if all locations will have the capacity and readiness to start amyloid scans tomorrow.” ‘s approval kicked off those logistics conversations, so at least the area didn’t start from scratch.
Dr. Apostolova said the real potential of disease-modifying drugs like lecanemab is reason to ponder other potential breakthroughs. This is a new era,” he said.
“If you compare it to the war in Alzheimer’s disease, it feels like the first battle is won, but there are many more battles ahead. “I believe there is no single drug that can treat such a complex disease, and many experts would agree with me. We believe strong advances in multimodal therapeutic approaches and precision medicine to attack several facets of these diseases will be needed to be able to make a decision.”