Science magazine writes on donanemab: “It’s not a miracle drug”
Antibody slows progression of Alzheimer’s disease, but concerns remain
The antibody donanemab is expected to give Alzheimer’s patient:in new hope for more effective treatment. But opportunities and risks, as with lecanemab, remain controversial in the world of science.
Although an initial review of clinical trial data suggests that donanemab may be more effective than its similarly acting competitor, lecanemab, the Eli Lilly company admits that deaths and serious brain side effects have occurred.
Study results: Donanemab may slightly slow disease progression
Clinical trial results on the antibody donanemab presented by Eli Lilly on May 03, 2023, show that the drug may marginally slow the progression of Alzheimer’s disease. These data reinforce the controversial theory that reducing beta-amyloid accumulation in the brain could help treat the neurodegenerative disease.
Daniel Skovronsky, chief scientific officer of Eli Lilly, commented that donanemab improved cognitive and functional abilities in early-stage Alzheimer’s patients by 35 percent compared with a placebo. Alzheimer’s researcher Donna Wilcock pointed out that the benefits of donanemab were similar to, and possibly exceeded, those of the similar antibody lecanemab.
However, massive risks associated with donanemab were also noted, including brain swelling and bleeding, which were linked to several deaths in the study, the Eli Lilly company acknowledged. Similar risks were also observed with lecanemab. Both drugs are marketed by Eisai and Biogen.
With the U.S. Food and Drug Administration (FDA) deciding whether to approve lecanemab and Eli Lilly planning to submit donanemab for review, there could now be many difficult conversations ahead about the risks of taking these drugs.
Neurologist Nicolas Villain of Sorbonne University in Paris, for example, who is doing his own research on donanemab, warns that donanemab is “not a miracle drug” and may carry high risks. Both antibodies, donanemab and lecanemab, bind to beta-amyloid in the brain and promote its removal. Brain scans showed that donanemab effectively degrades the protein, leading to a reduction in amyloid plaque in more than half of the study participants:in.
Preliminary results of the study also showed that cognitive and physical function deteriorated more slowly in those treated with donanemab than in the placebo groups. Thus, donanemab showed similar results to the study on lecanemab published a year earlier.
Manufacturer to release further study details in July 2023
Eli Lilly has so far presented only the topline numbers from the study and plans to release more data at an Alzheimer’s conference in July 2023. The company reports that based on their own scale, the drug slowed disease progression by 35 percent. 36 percent according to the broader Clinical Dementia Rating-Sum of Boxes scale. Forty-seven percent of treated study participants:had no worsening of disease severity, according to the CDR-SB, compared with 29 percent in the placebo group. Treated subjects were also better able to perform activities of daily living, according to Eli Lilly.
Role of tau protein also studied
The Eli Lilly study also examined the tau protein, which plays a role in Alzheimer’s disease. Unlike beta-amyloid, tau forms clumps within neurons. Because it was suspected that people with high levels of tau might respond less to antibody treatment, they were assigned to a special study group.
According to Eli Lilly, those with high tau levels also benefited from donanemab, suggesting that the drug may be useful in later stages of the disease. The question of whether regulators can be convinced by this new patient selection method remains open, however.
In debate: clinical benefit versus serious side effects
In any case, external researchers will critically examine Eli Lilly’s analysis to assess the drug’s actual clinical benefit relative to the risks of serious side effects. In particular, Eli Lilly’s own Alzheimer’s scale is less validated than the CDR-SB scale, and the absolute difference between the treatment and placebo groups according to CDR-SB was small. Debate about which scale score represents a significant difference in disease severity is ongoing.
In any case, the Eli Lilly results may heighten concerns about the risks of antibodies targeting amyloid. Lecanemab has been linked to deaths and severe brain damage. Scientists:inside are therefore eager for additional data to assess the risks of donanemab. In addition, sufferers who take certain medications or have the APOE4 gene variant may be particularly susceptible to the antibodies’ side effects, experts say.
According to Eli Lilly, 24 percent of people who received the antibody experienced a form of brain swelling called ARIA-E, while 31.4 percent of those treated with antibodies developed a more severe form called ARIA-H. The company noted in this regard that most ARIA cases were mild to moderate in severity and stabilized after appropriate treatment. However, there were also severe cases of ARIA, and details of the deaths of three study participants were not disclosed.
Despite all these risks, those scientists who support the amyloid hypothesis for the development of Alzheimer’s disease see the current results as confirmation that beta-amyloid is a major factor in the disease. Even if the overall risk-benefit ratio of the antibodies is not positive, their partial success could lead to better and safer methods of removing or reducing amyloid formation.
Clinical significance, safety, and also costs still remain open
Many other questions, such as whether donanemab or just lecanemab offers the greater advantage and how much the treatment will cost, remain to be answered. Although some scientists say that the “new era of Alzheimer’s treatment” is finally beginning, others urge great caution. Ultimately, “the clinical meaningfulness, safety, and accessibility of donanemab have yet to be determined and can only be assessed through full, transparent, and timely disclosure of all data, particularly those related to adverse events and safety concerns,” tweeted Madhav Thambisetty of the U.S. National Institute on Aging on the morning of May 03, 2023, accordingly.