The Alzheimer's treatment landscape is undergoing a transformation with the emergence of drugs like Leqembi and donanemab, which have demonstrated the ability to slow the progression of this devastating disease. Leqembi, developed by Eisai and Biogen, has already secured full FDA approval and expanded Medicare coverage, while Eli Lilly's donanemab is poised to potentially join it on the market, awaiting regulatory action by the end of the year. These developments offer a glimmer of hope for the over 6 million Americans living with Alzheimer's, particularly those in the early symptomatic stages. However, experts are urging caution, emphasizing the need for continued research to improve efficacy and address safety concerns.
Clinical Benefits and Limitations
Clinical trial results for donanemab, presented at the Alzheimer's Association International Conference, revealed a 35% slower progression of the disease compared to placebo over 18 months, as measured by the integrated Alzheimer's Disease Rating Scale (iADRS). This translated to a 6-point loss on the 144-point scale for those on donanemab, versus a 9-point loss for the placebo group. Notably, the benefits were more pronounced in patients with low to medium levels of tau protein, indicating that earlier intervention may yield better outcomes. Similarly, Leqembi demonstrated a 27% slowing of cognitive decline in an 18-month clinical trial.
Despite these encouraging results, experts have expressed reservations about the magnitude of the clinical benefits. Jennifer Manly, of Columbia University Irving Medical Center, and Kacie Deters, of the University of California, Los Angeles, noted that while donanemab effectively cleared cerebral amyloid, its clinical effect was "comparatively weak." Dr. Gil Rabinovici and Renaud La Joie from the University of California, San Francisco, emphasized that while the slowing of clinical decline is an important start, more impactful and safer treatments are still needed.
Safety and Accessibility Concerns
Both Leqembi and donanemab carry risks, most notably amyloid-related imaging abnormalities (ARIA), which manifest as swelling or bleeds in the brain. In the donanemab trial, the ARIA rate was 37% compared to 15% for placebo, with some cases being severe and resulting in treatment-related deaths. Leqembi's Phase 3 trial showed a 22% ARIA rate versus 10% on placebo. These safety concerns necessitate careful monitoring and patient selection.
Accessibility is another critical factor. Leqembi costs $26,500 per year before insurance, potentially creating a significant financial burden for patients despite Medicare coverage. The cost of donanemab is yet to be disclosed. Furthermore, logistical challenges such as the need for intravenous infusions every two weeks for Leqembi and every four weeks for donanemab, and the requirement for regular brain imaging, add complexity to treatment.
Future Directions and Ongoing Research
Eli Lilly is currently conducting a trial of donanemab in patients who are pre-symptomatic for Alzheimer's disease, with the hope of achieving even greater benefits through earlier intervention. Eisai is also studying Leqembi in individuals at elevated risk for Alzheimer's. These prevention studies could potentially revolutionize the management of Alzheimer's disease.
Dr. Daniel Skovronsky, Lilly's chief of research, highlighted that the donanemab trial showed that the drug's effect grows over time and that benefits continue even after patients stop taking the drug once amyloid plaques are cleared. This suggests that a finite course of treatment may be sufficient to alter the trajectory of the disease.
Addressing Health Equity
It is important to note that clinical trials for these drugs have predominantly included White participants, raising concerns about the generalizability of the findings to more diverse populations. Researchers emphasize the need to address structural inequalities that disproportionately affect historically marginalized communities, increasing their risk factors for cognitive impairment and reducing access to care. Efforts are underway to improve representation in clinical trials and ensure equitable access to these new treatments.
