August 15, 2024
The Evolving Landscape of Alzheimer's Treatment
The journey to find effective treatments for Alzheimer's disease remains one of the most formidable challenges in healthcare. The emergence of monoclonal antibodies such as Leqembi (Lecanemab, Biogen and Eisai) and Kisunla (Donanemab, Eli Lilly), which both target amyloid plaques, represent a significant advancement in the treatment of Alzheimer’s. These drugs have brought new hope because they demonstrate modest impacts on slowing the progression of Alzheimer's. However, these treatments come with significant safety concerns, notably the risk of ARIA.
Leqembi: A Promising Yet Challenging Journey in Alzheimer's Treatment
Leqembi’s Phase 3 Clarity-AD trial, with results published in 2022, involved 1,795 participants aged 50-90 with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's). The primary endpoint was clinical decline assessed on the CDR-SB scale, which measures severity of cognitive and functional impairment.
After 18 months, participants treated with Leqembi exhibited a 27% slower clinical decline compared to those who received a placebo. This translates to an approximate six-month delay in the disease's progression, offering patients more time with better cognitive and functional abilities.
Secondary results showed that at 18 months, Leqembi slowed the decline of daily living activities by 37% as measured on the ADCS MCI-ADL scale, which measures the ability of patients to function independently.
However, the treatment posed significant safety risks. ARIA (-E or -H) was observed in 21% of patients receiving Leqembi versus 9% receiving placebo. This significant safety concern contributed to the EMA’s rejection of Leqembi, highlighting the delicate balance between therapeutic efficacy and potential risks.
Despite these promising outcomes on slowing Alzheimer’s disease progression, Biogen's Q1 '24 earnings reported a slower-than-expected start to Leqembi sales, reaching only $19 million. Even with a 2.5x increase in patients receiving the drug, Biogen encountered significant challenges during Leqembi's launch, particularly with providers struggling to initiate treatment for patients.
Kisunla: Promising Results amid Similar Safety Concerns
Kisunla was approved by the FDA in early July. Kisunla showed encouraging results in its 18-month Phase 3 TRAILBLAZER-ALZ 2 trial involving 1,736 participants aged 60-85 with early Alzheimer's. At 18 months, Kisunla delayed Alzheimer's progression by approximately 4.4 months on the iADRS scale, which measures cognition and activities of daily living, and by about 7.5 months on the CDR-SB scale. Remarkably, 47% of participants showed no disease progression at one year compared to 29% receiving placebo. These results indicate a significant slowing of cognitive and functional decline.
Like Leqembi, Kisunla carries a substantial risk of ARIA. ARIA occurred in 37% of patients treated with the drug, versus 15% in the placebo group. This similarity raises questions about the regulatory path forward for Kisunla, especially considering the EMA's recent rejection of Leqembi due to ARIA risks.
The Future of Alzheimer's Treatment
In addition to monoclonal antibodies such as Leqembi and Kisunla, other promising areas of development have emerged in the Alzheimer’s space.
GLP-1s, such as Novo Nordisk's semaglutide, are being explored as a potential Alzheimer's treatment. Semaglutide is currently under evaluation in two Phase 3 clinical trials due to its association with a lower dementia risk, with results expected in 2025. Additionally, preliminary results from a small Phase 2 trial assessing liraglutide, a predecessor to semaglutide, were recently announced at the Alzheimer’s Association International Conference, also showing potential as an Alzheimer’s treatment.
Eli Lilly's Remternetug is another drug in the spotlight, currently in Phase 3 clinical trials (TRAILRUNNER ALZ 1) with study completion anticipated in 2026. Early findings suggest it may remove amyloid plaques faster than Kisunla, though full results are pending.
As the medical community and regulatory authorities continue to evaluate the risk-benefit profiles of Alzheimer’s treatments, including their long-term impacts, the balance between therapeutic efficacy and safety will remain paramount in determining their success.
