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The story so far: At the end of November, the news of the success of a drug in reducing cognitive decline in patients with Alzheimer’s Disease Explosion on the horizon with all the promise of being a silver bullet. The drug, lecanemab, co-developed by pharmaceutical companies Biogen and Eisai, was tested in patients with early Alzheimer’s. Results of the study presented in the Clinical Trials on Alzheimer disease conference in San Francisco, USA, and published in the New England Journal of Medicine (NEJM) showed moderate effects in arresting the decline of cognitive and functional aspects in patients with early disease. This has raised hope in a world where an estimated 55 million people live with the debilitating effects of Alzheimer disease.
What is lecanemab and how does it work?
Lecanemab is in a class of drugs called monoclonal antibodies. These antibody-mediated drugs target amyloid beta, the protein deposition seen in patients with Alzheimer’s disease, and alter the function of the cells.
Neuropsychiatrist Ennapadam. S. Krishnamoorthy, founder of Buddhi Clinic, Chennai, says: “For years, amyloid plaques were thought to be an important target for the treatment of Alzheimer’s. This class of drugs does just that.”
according to him NEJM article, the clinical trial, conducted over 18 months, a phase 3, double-blind, multicenter trial, involved people 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease ) with evidence of amyloid deposit. Participants were randomly assigned to intravenous lecanemab or placebo. Lecanemab was found to “strongly clear amyloid plaques”.
This was the primary endpoint of the trial, which showed a change in the baseline score when the trial began in the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Key secondary endpoints included a change in amyloid load on PET (positron emission topography). There were changes in both the lecanemab and placebo groups, the researchers concluded.
Will lecanemab be the silver bullet to treat Alzheimer’s?
the lancetIn an editorial, he argues that a Phase 3 trial showing efficacy in clinical outcomes, particularly after such a long and fruitless wait for successful Alzheimer’s disease therapy, is welcome news.
However, he points out that the difference noted on the CDR-SB scale may not be clinically significant, based on the metrics indicated in previous studies. In addition, the development of amyloid-related imaging abnormalities (ARIA) in one of five patients was a cause for concern.
the lancet editorial concludes that, given these concerns, “it remains to be seen whether lecanemab is the game changer that some have suggested.” He goes on to explain that ongoing trials are evaluating the efficacy of subcutaneous administration and whether lecanemab can prevent the onset of dementia in patients with amyloid pathology but no clinical symptoms. “However, the immediate impact of lecanemab should not be overstated.”
Dr. Krishnamoorthy said the first of the Alzheimer’s drugs, aducanumab, was fast-tracked, with much criticism. “Many experts were unhappy with the results of the trial that led to its approval. In addition to the questionably small differences between the test and placebo groups, concerns were also raised about serious side effects, such as bleeding in the brain and edema (swelling of the brain).”
Lecanemab, he adds, on the other hand, appears to have shown modest effects in early dementia both through clinical improvements (CDR and ADAS-Cog rating scale scores) and reduction in amyloid plaques. “The same problems of brain inflammation and bleeding may also exist with this drug, and may hold true for many antibody-mediated treatments,” he explains.
For practitioners like him, this is an opportunity to be ‘cautiously optimistic’. “This is definitely a step forward and offers hope with the following caveats, including eligibility criteria, intensity of treatment, need for imaging, and high costs.” Only those in the early course of the disease are likely to benefit. It must be administered via weekly intravenous injections that require hospital visits and close monitoring, and to identify amyloid deposits, an amyloid PET scan is required, which is not available in many countries in the developing world. The cost, like the lancet he speculates, it is likely to be prohibitively expensive for low- and middle-income countries where the majority of people with dementia live.
What is the future?
An initial decision on the drug’s approval is expected from the FDA on January 6, 2023, and from the European Medicines Agency later in 2023, according to the lancet. The lecanemab results, he argues, “could well pave the way for much-needed treatments for Alzheimer’s disease. But for now, the key public health message for Alzheimer’s disease remains the one set out in the 2020 Lancet Commission on Dementia Prevention, Intervention, and Care: Focus on modifiable risk factors for dementia, such as high blood pressure, smoking , diabetes and obesity, to maintain brain health throughout life.
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