Leqembi: The First Fully FDA-Approved Alzheimer’s Drug in Two Decades—Will the Market Embrace It?

Today, the new Alzheimer’s disease (AD) drug Leqembi (lecanemab), jointly developed by Eisai and Biogen, received full approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with mild cognitive impairment or mild Alzheimer’s disease.Leqembi becomes the first new AD drug to receive full FDA approval since 2003.

In June, further indications emerged that Leqembi was poised for full approval. On June 9, the FDA advisory committee unanimously voted (6-0) to confirm the clinical benefits of Leqembi in treating Alzheimer’s disease. Later that month, the U.S. Centers for Medicare & Medicaid Services released new details on coverage for Leqembi, and health systems had already made preparations for the drug’s imminent approval.

Currently, traditional medications for Alzheimer’s disease (AD) are predominantly small-molecule oral drugs, such as the cholinesterase inhibitors galantamine, rivastigmine, and donepezil, as well as the NMDA receptor antagonist memantine. Undoubtedly, Leqembi, an anti-β-amyloid (Aβ) monoclonal antibody, has introduced new possibilities for the pharmacological treatment of Alzheimer’s disease.

The industry’s attitude toward the full approval of this drug is one of optimism tempered by concern.

Optimism stems from the fact that, after a long journey of new drug development and the significant controversy surrounding Aduhelm in the past two years, Alzheimer’s disease has finally seen the good news of full approval for a new therapy. Concerns arise because many individuals and groups have pointed directly to the side effects of Leqembi, arguing that its safety issues outweigh its therapeutic benefits. Its commercial prospects remain unclear at present.

VCBeat promptly engaged with industry professionals and investors in China. Industry experts believe that the approval of Leqembi will undoubtedly accelerate the development of new drugs for Alzheimer’s disease (AD) within the industry, serving as a significant incentive.

Early this year, foreign media predicted that 2023 would be a pivotal year for Alzheimer’s disease research. The release of positive developments, including those related to Leqembi, has attracted significant investor interest in companies focused on Alzheimer’s disease. Although the drug’s efficacy is modest, it has reignited capital market enthusiasm because it demonstrates, to some extent, that a therapy for Alzheimer’s disease can receive full regulatory approval. Some industry insiders believe that both investors and large pharmaceutical companies will return to this field.

However, given the cautionary tale of Aduhelm’s commercial failure, whether Leqembi can achieve commercial success remains the true litmus test.

Leqembi is the second new Alzheimer’s disease (AD) drug jointly developed by Eisai and Biogen following Aduhelm. In comparison, Leqembi has experienced a smoother trajectory than Aduhelm in terms of both clinical development and regulatory approval progress:

• In September 2022, Eisai and Biogen announced that the Phase III clinical trial (Clarity AD) of Leqembi for the treatment of Alzheimer’s disease had met its primary endpoint and all secondary endpoints. The results showed that at 18 months, the Leqembi group experienced a 27% reduction in the primary endpoint measure, the CDR-SB score, compared with placebo;

• In January 2023, the FDA granted accelerated approval to Leqembi for the treatment of Alzheimer’s disease; this approval was based on its Phase II clinical data, which demonstrated that Leqembi reduced the accumulation of amyloid-beta (Aβ) plaques in the brain;

• In February 2023, the marketing application for Leqembi was included in the priority review by the Center for Drug Evaluation (CDE), with the proposed indication being early-stage Alzheimer’s disease;

• In June 2023, Eisai and Biogen jointly announced that experts at the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 6:0 in favor of granting full approval to Leqembi based on the positive results from the Phase III CLARITY AD study.

• In July 2023, Leqembi received full approval.

Compared with Leqembi, Aduhelm’s clinical trial phase was fraught with twists and turns. In the two pivotal Phase III trials of Aduhelm, EMERGE and ENGAGE, its potential benefits sparked significant controversy. The ENGAGE trial did not demonstrate any benefit, and the high-dose arm of the EMERGE trial initially showed no benefit either; significant positive results emerged only with longer follow-up.

One clinical trial failed to meet its primary or secondary endpoints, while another demonstrated statistically significant results across all four of its primary and secondary endpoints. These starkly contradictory clinical data have sparked debate over whether Aduhelm should have been approved and whether new clinical trials are necessary.

This has inevitably plunged the accelerated approval of Aduhelm into significant controversy, drawing united opposition from numerous physicians and scientists.

In contrast, the clinical trial data for Leqembi demonstrated significant statistical significance, supporting its subsequent FDA approval and making it the first fully approved new drug for Alzheimer’s disease in two decades.

However, its Phase III clinical data indicate that 13% of patients treated with Leqembi experienced brain swelling, and 14% experienced brain hemorrhage. Similar risks have been observed with Eli Lilly’s new Alzheimer’s disease (AD) drug, Donanemab, and these adverse events are comparable to the side effects associated with traditional AD therapies. The FDA has stated that brain swelling and brain hemorrhage caused by Leqembi are generally mild and asymptomatic; nevertheless, a segment of the population remains concerned that these side effects could be life-threatening.

Regarding the side effects of Leqembi, Dr. Ma Weiwei, CEO of Zhuokai Biopharma, also expressed concerns. “Previous clinical data showed that after 18 months of treatment, patients receiving Leqembi experienced a reduction in brain volume, suggesting that the drug may accelerate brain atrophy. Since this side effect is common to multiple Aβ antibody drugs—for example, with Donanemab, another drug demonstrating superior efficacy, a reduction in brain volume can be observed after just six months of treatment—this adverse effect is more likely attributable to target specificity rather than drug specificity, and it would be difficult to overcome with new Aβ antibodies.”

The significant controversy and commercial failure following Aduhelm’s approval demonstrate that, for Alzheimer’s disease (AD) therapeutics, regulatory approval is merely the first step, while commercialization represents the critical challenge.

Reviewing the commercialization journey of Aduhelm, after receiving accelerated approval, this drug suffered a series of setbacks in the market, and its commercialization has essentially been declared a failure:

• In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency rejected the marketing authorization of Aduhelm in Europe;

• In December 2021, due to Aduhelm’s dismal performance, Biogen planned to lay off up to 1,000 employees, and Alfred Sandrock, Biogen’s Chief Research and Development Officer, resigned;

• In March 2022, Biogen announced the dissolution of its Aduhelm commercialization team and laid off some employees in the United States;

• In April 2022, the U.S. Centers for Medicare & Medicaid Services (CMS) announced that it would restrict coverage of Aduhelm under Medicare to patients participating in clinical trials, following a review of trial data and patient feedback. Meanwhile, Biogen decided to withdraw its marketing authorization application in Europe.

• In early May 2022, Biogen CEO Michel Vounatsos announced his departure. The company reported that Aduhelm’s sales revenue for the first quarter of 2022 amounted to only $2.8 million, following full-year sales of just $3 million in 2021.

Biogen has largely discontinued the commercialization of Aduhelm.

Thus, Leqembi’s approval marks only the first hurdle; the next focal point is whether it will gain market acceptance and recognition.

Following its full market approval, Leqembi will gain a first-mover advantage; however, its commercialization trajectory may not progress as rapidly.

“Leqembi has a relatively slow onset of action, requiring approximately 18 months to achieve optimal therapeutic efficacy. Therefore, its sales performance may not be particularly strong during the first one to two years after launch, as it will take some additional time for market adoption to mature."Ma Weiwei analyzed for VCBeat,"Therefore, its market explosion may not arrive so quickly. It will take time for the initial group of patients to use the drug and build word-of-mouth reputation before it can gain momentum in the later stages.”

Therefore, whether Leqembi can drive a surge in R&D and investment for Alzheimer’s disease may become increasingly clear over the next 18 months as its commercialization deepens.

While the market may not see a large-scale surge in the short term, the full approval of Leqembi has already impacted patients and the industry.

“The impact on patients is the most direct. Leqembi provides a new therapeutic option for Alzheimer’s disease (AD) and will also alleviate the caregiving burden on patients’ families. After all, this is a therapy costing $26,500 per year. Previously, Aduhelm had mixed clinical data—one positive and one negative—making its efficacy and price difficult for both patients and physicians to accept. Although the magnitude of Leqembi’s clinical benefits is modest, the results are consistently positive. For patients, it finally marks the arrival of a new AD medication with long-term efficacy,” Ma Weiwei told VCBeat New Medicine.

The approval of Leqembi will also incentivize the pharmaceutical industry’s R&D of new drugs for Alzheimer’s disease (AD).“For the industry, what everyone fears most is not knowing how to successfully develop a new drug for Alzheimer’s disease.”Ma Weiwei believes that the significance of Leqembi’s approval lies in its potential to pave a viable path toward successful commercialization for follow-on therapies, thereby offering clearer prospects for domestic companies focused on Alzheimer’s disease (AD) drug development.

“Once the development of new Alzheimer’s disease (AD) drugs reaches maturity in China, companies will be able to leverage economies of scale to achieve cost-effectiveness, potentially even bringing the annual price of new AD medications down to RMB 26,500,” said Ma Weiwei. This means that not only will foreign companies with candidates in Phase II and Phase III clinical trials accelerate their research efforts, but many domestic firms will also expedite project initiation and R&D, further advancing the development of new AD therapies.

Currently, Leqembi has been submitted for marketing approval in China, and Eli Lilly has also launched the international multicenter Phase III clinical trial of Donanemab in China. For the Chinese new-drug pipeline for Alzheimer’s disease (AD), which is still in its early stages of development, this will provide valuable experience for domestic R&D and clinical trial design of new AD therapies. It serves as a strong starting point for aspects such as patient recruitment speed, patient enrollment, and the identification of experienced hospitals and principal investigators (PIs).

An investor who has long followed the Alzheimer’s disease (AD) field also told VCBeat New Medicine that, while he believes the approval of Leqembi is undoubtedly a positive development for the industry, a breakout in the AD sector still awaits.The root cause of Alzheimer’s disease remains unidentified, pharmaceutical companies continue to face frequent setbacks in the AD field, and truly breakthrough therapies have yet to emerge.

This is also why most investors remain on the sidelines in this field. According to Ma Weiwei’s observations, domestic investors still hope that the R&D of new Alzheimer’s disease (AD) drugs in China can proceed more steadily. “Compared with previous years, the number of investors interested in new AD drugs has indeed increased in the past two years, but many investors are still more willing to invest only after seeing safety and efficacy data from patients.”

Furthermore,“The Alzheimer’s disease field also needs the emergence of blockbuster new drugs similar to semaglutide or DS-8201.”An investor said.