On December 18, Eli Lilly announced that the application for the listing of Donanemab injection (Donanemab) has been approved by the China National Medical Products Administration for the treatment of mild cognitive impairment and mild dementia caused by Alzheimer's disease in adults. This is another blockbuster new drug in the field of Alzheimer's disease (AD) treatment after Lencanerizumab, which was approved by Eisai in January this year. In the past, drugs for the treatment of AD were mainly symptomatic treatments, including memantine, donepezil, etc., which symptomatically treated mild, moderate and severe AD. Lencanerizumab and Donanemab, which were launched this year, are targeted treatments for causes.

▍Crossing the Death Valley of Drug Development
The research on new drugs for Alzheimer's disease has always been called the "Death Valley" of drug development. According to a study published by Scientific American magazine, the development of new AD drugs has a high failure rate of 99.6% recognized by the industry, which is higher than the 81% of cancer. Even pharmaceutical giants have had numerous pipelines fail. This year alone, Roche has repeatedly interrupted its cooperation on Alzheimer's disease projects, including Johnson & Johnson/Pfizer and Merck, which have announced failures.

The most fundamental reason for this result is that the cause of AD is still unknown. The most mainstream theories now are the Aβ protein pathogenicity theory and the Tau protein pathogenicity theory. Among the disease-modifying therapies (DMT) drugs currently centered around the "pathogenic mechanism" in the world, anti-Aβ monoclonal antibodies are a very important direction. Lencanerizumab and Donezumab, which were launched in China after a failure rate of up to 99.6%, are both drugs that have been successfully approved for marketing based on the "Aβ theory".

With the approval of Donezumab, AD treatment has also entered the "Double Hero Era" just like the weight loss market. But it is worth noting that although both rely on the "Aβ theory", Lencanerizumab and Donezumab actually take two different paths.

▍Benefits > Risks
Lencanezumab targets Aβ oligomers and fibrils. Aβ oligomers/fibrils are the intermediate hubs of the AD pathological process. Further, Aβ fibrils will form insoluble and relatively inert Aβ plaques. Donenan is targeting N3pG-Aβ. Since N3pG-Aβ does not appear until the plaque stage, Donenan is actually a drug targeting Aβ plaques.

This has caused the problem of Donenan: because the deposited Aβ plaques are too large and entangled with neurons, direct range attacks will affect many normal tissues. This is why Donenan has frequent clinical amyloid-related imaging abnormalities (ARIA). Donenan's Phase III clinical trial data showed that its amyloid-related imaging abnormalities (ARIA) incidence was as high as 31.4%, while the previous Phase III clinical trial of Lencanezumab was 17.3%.

For the review of Donenan, the FDA Independent Scientific Advisory Committee finally voted in June this year. The committee voted unanimously with a vote of 11:0, believing that the current evidence is sufficient to show that the drug is effective and that the benefits of the drug outweigh the risks.

▍Long window period for new AD drugs
This result is actually expected and reasonable. The treatment effect of Donezumab Phase III clinical data can be said to be very impressive. Regardless of the baseline pathological stage, Donezumab treatment can significantly reduce the level of amyloid plaques. Among all participants, after 18 months of treatment with Donezumab, amyloid plaques were reduced by an average of 84%, while participants using placebo only reduced by 1%. Moreover, the drug does not require lifelong medication.

Participants can stop taking the drug if they meet the predetermined criteria for amyloid plaque clearance during the fixed phase of the clinical trial. About half of the participants have reached the standard in 12 months. More importantly, there has been a long window period for new AD drugs. Previously, Lencanermab received accelerated approval (AA) from the FDA based on its therapeutic effect of reducing amyloid deposition in the patient's brain, even though its safety and effectiveness had not been fully confirmed. It became the world's first new AD drug fully approved by the FDA in nearly 20 years.

Accelerated approval is a regulatory pathway to speed up the launch of drugs, designed to make drugs that treat serious diseases, have advantages over existing therapies, and are used for unmet medical needs available to patients more quickly. In the "Accelerated Procedure Guidelines for Serious Diseases" issued by the FDA in 2014, the importance of addressing serious diseases and unmet medical needs was emphasized.

▍Alzheimer's disease market, open book
According to Biogen's financial report, in 2024Q1, Lencanermab had global sales of US$19 million. Since the end of 2023, the number of AD patients receiving treatment has increased by nearly 2.5 times, and new patients have increased significantly in March, accounting for more than 20% of the current cumulative patients. However, just as sales were moving forward in strides, Lencanermab was also questioned for its safety. In July, the European Medicines Agency (EMA) rejected the marketing application of Lencanezumab after evaluating its efficacy and safety.

EMA believes that although most ARIA cases in the main study were not serious and asymptomatic, some patients had serious events, and the severity of this side effect should be considered in conjunction with the mild effects of the drug. But just one week after the European Medicines Agency rejected the marketing application, Eisai expressed its firm optimism about Lencanezumab, a new drug for Alzheimer's disease, in its financial report. Eisai expects global sales of Lencanezumab to reach US$370 million throughout fiscal 2024.

In the 2024Q3 results released by Biogen in October, global sales of Lencanezumab for Alzheimer's disease in the third quarter were approximately US$67 million, an increase of 66% from the previous quarter, of which sales in the US market were approximately US$39 million. The good news is that after re-examining Lencanezumab, the EMA Committee for Medicinal Products for Human Use (CHMP) still recognized the effectiveness of Lencanezumab and finally recommended the approval of Lencanezumab. This information fully demonstrates the urgent need of patients for AD drugs. After the approval of Donezumab, it is bound to become a strong competitor in this market.

According to the website of the International Alzheimer's Association, there were 55.2 million AD patients in the world in 2019. According to the United Nations population forecast, the number of AD patients is expected to rise to 78 million by 2030 and 139 million by 2050. In 2015, the global annual total cost of AD was US$818 billion, equivalent to 1.09% of the global GDP. It has reached US$1.3 trillion in 2019, and according to estimates, it is expected to reach US$2.8 trillion in 2030. There is no doubt that the AD market will become a battleground for major pharmaceutical companies.

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