Lilly's Alzheimer’s Drug Donanemab Receives Unanimous FDA Advisory Committee Support After 30-Year Quest

On June 10, the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) of the U.S. FDA announced the results of the meeting regarding the Biologics License Application (BLA) for Donanemab in the treatment of early symptomatic Alzheimer's disease (AD). The committee unanimously agreed on the efficacy of Eli Lilly and Company’s Alzheimer’s treatment drug Donanemab with a vote of 11:0, and unanimously concluded that its benefits outweigh the risks.

Although the FDA is not obligated to follow the advisory committee's recommendations, its suggestions are typically adopted by the FDA. The FDA usually makes a regulatory decision 1-2 months after the advisory committee meeting. If approved, donanemab will become the second Alzheimer's treatment on the U.S. market after Leqembi.

Donanemab is a next-generation Aβ monoclonal antibody developed by Eli Lilly and Company. It can bind to the N3pG subtype of β-amyloid protein, thereby promoting the clearance of amyloid plaques in patients' brains to delay the progression of AD.

The marketing application of Donanemab is primarily based on the results of the Phase 3 study TRAILBLAZER-ALZ 2. This trial is a double-blind, placebo-controlled study designed to evaluate the safety and efficacy of Donanemab in patients aged 60-85 with early symptomatic Alzheimer's disease (AD) confirmed by AD neuropathology, who have mild cognitive impairment or mild dementia due to AD. Participants were divided into low-to-moderate tau groups or high tau groups (a later pathological stage of disease progression) according to their tau levels as shown by positron emission tomography (PET) imaging. All participants were then assessed over 18 months using scales that measure cognition and function, including the Integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating – Sum of Boxes (CDR-SB, with higher scores indicating lower clinical function). The trial recruited 1,736 participants from 8 countries.

Trial results showed that in patients with low-to-moderate tau levels (n=1182), donanemab treatment significantly improved iADRS and CDR-SB scores by 35% and 36%, respectively. In all amyloid-positive early symptomatic AD patients (n=1736), donanemab significantly improved iADRS and CDR-SB scores by 22% and 29%, respectively. Among patients with mild cognitive impairment (n=214), donanemab treatment led to a 60% improvement in iADRS scores and a 46% improvement in CDR-SB scores. Additionally, donanemab reduced the risk of disease progression to the next stage by 37% (HR=0.626; p<0.0001).

In terms of safety, 24% of patients in the Donanemab group experienced MRI-confirmed amyloid-related imaging abnormalities-edema (ARIA-E), with 6% experiencing symptomatic ARIA-E; 31.4% of patients in the Donanemab group experienced cerebral microhemorrhages and superficial siderosis (ARIA-H), compared to 13.6% in the placebo group. The majority of ARIA cases were mild to moderate in severity, with a serious ARIA rate of 1.6%, including two patients who died from ARIA and severe ARIA; 8.7% of patients experienced infusion-related reactions, most of which were mild to moderate.

ARIA is an adverse reaction associated with amyloid plaque-clearing antibody therapies, typically asymptomatic and detectable only through magnetic resonance imaging (MRI), presenting as temporary swelling (ARIA-E) or microhemorrhages (ARIA-H) in one or more regions of the brain. Therefore, although ARIA has no clinical symptoms, it can potentially be fatal.

Eli Lilly's executives stated that in the later stages of the trial, high-frequency MRI detection was used to identify ARIA, and Donanemab administration was delayed in patients who developed ARIA until the swelling subsided to prevent it from becoming more severe. For high-risk populations of ARIA, such as those with the APOE4 genetic marker, closer monitoring is recommended. However, for general AD patients, the advisory committee believes that the benefits of receiving Donanemab treatment outweigh the risks.

In addition, for the use of Donanemab, Eli Lilly and Company has proposed a new option: if a patient's amyloid protein levels fall below the threshold, the use of Donanemab can be discontinued. This innovative approach sets Donanemab apart from other AD drugs, which typically require lifelong administration, making Donanemab more cost-effective.

But this also brings new questions: What happens after patients stop taking the drug, do they need regular testing, and how to handle if amyloid starts accumulating again, etc.

It is estimated that approximately 6 to 7 million people in the United States are living with Alzheimer’s disease. This condition, a leading cause of death, inflicts significant physical, mental, and emotional harm on patients and their caregivers. Research published in The American Journal of Managed Care indicated that the estimated medical costs associated with Alzheimer’s treatment reached $321 billion in 2022.

Currently, the only Alzheimer's drugs approved by the U.S. FDA are Biogen's Aduhelm and Lecanemab. However, Biogen has terminated the development and commercialization of Aduhelm. As a result, only Lecanemab remains on the market. According to Biogen's 2023 financial report, the 2023 sales of Lecanemab were only $10 million. The sales figures reflect the market's hesitation towards Lecanemab.

Donanemab May Become a Potential "Blockbuster" After Approval for Marketing. According to an analysis by investment firm Jefferies in early March, Donanemab's peak annual sales are estimated to be close to $3 billion.

Eli Lilly has invested thirty years of effort into Alzheimer's disease. Donanemab is not the company’s only project on Alzheimer’s, but it is the most important and promising pipeline. Donanemab is an Aβ monoclonal antibody that binds to the N3pG subtype of beta-amyloid, thereby promoting the clearance of amyloid plaques in patients' brains.

As early as October 2021, based on data from the Phase II TRAILBLAZER-ALZ study, Eli Lilly submitted a BLA application to the FDA, seeking approval through the expedited pathway. However, the application was rejected by the FDA in January 2023 due to an insufficient sample size in the TRAILBLAZER-ALZ clinical study supporting the BLA.

Four months later, Eli Lilly and Company submitted the BLA for Donanemab to the FDA again, based on the TRAILBLAZER-ALZ 2 study. However, the originally scheduled PDUFA date at the end of 2023 was first postponed to the first quarter of 2024, and then further delayed to March 2024 due to the FDA's decision to convene an advisory committee meeting to discuss several key issues regarding Donanemab.

Against the backdrop of the initial BLA rejection and repeated delays of the second BLA, Donanemab's path to market has been fraught with challenges, even sparking some skepticism. However, the unanimous 11-0 vote by the advisory committee has increased the likelihood of Donanemab's approval.

Once Donanemab is approved and launched in the future, it will become a direct competitor to Leqembi. According to an analysis report by Jefferies, if Donanemab receives approval, the long-term presence of two companies in the market will benefit both Eli Lilly and Biogen. This is because both companies will intensify their efforts, strongly advocate for increased investment in various centers, develop infrastructure, allocate more resources, and simultaneously promote greater education for patients and doctors.

There is no doubt that the approval of Leqembi has played an incentivizing role in the industry. Eli Lilly's Donanemab unanimously passing expert review will further accelerate the development process of new Alzheimer's disease (AD) drugs. Moreover, with the FDA granting full approval for Leqembi to treat AD, the demand in the testing field is also becoming extremely hot.

Traditional AD diagnosis mainly relies on memory tests to evaluate patient symptoms, but this increases the risk of misdiagnosis for AD and is considered one of the reasons for the failure of early amyloid-clearing drug treatments. Diagnosis based on biomarkers will significantly improve diagnostic accuracy.

In 2018, brain PET scans and cerebrospinal fluid tests were included in the guidelines for detecting amyloid plaques in the brain, becoming the primary method for diagnosing AD. However, these techniques can only be performed through lumbar puncture, have low accessibility, and are expensive, typically not used in standard clinical practice. Therefore, the 2018 guideline revisions were intended for research purposes.

The approval and market launch of Leqembi have driven changes in AD diagnostic methods, with research-oriented diagnostic approaches needing to align more closely with large-scale clinical practices. Since Leqembi requires evidence of amyloid plaque accumulation in the brain, Medicare will expand its coverage of brain PET scans. However, this does not address large-scale public health issues.

Studies show that blood tests can work synergistically with new AD therapies and are expected to become the gold standard for measuring amyloid proteins. In the Alzheimer's disease clinical guidelines released at last year's AAIC conference, doctors were guided for the first time to use blood tests to assess signs of Alzheimer's disease in the brain. Blood testing will reduce diagnostic costs for patients. Moreover, since Alzheimer's disease biomarkers appear in the blood before evidence of the disease shows up on brain scans, this test will also help doctors better stage the disease and determine the phase of the disease a patient is in.

The emergence and popularization of new diagnostic methods will benefit the industry. Previously, due to the uncertainty in diagnosing AD patients, enrolling suitable participants for clinical trials of AD drugs often faced challenges. Under stringent requirements, finding qualified subjects was extremely difficult. With the inclusion of blood tests in guidelines, pharmaceutical companies will be provided with a more precise approach to identify AD patients for future clinical trials. It can be anticipated that one obstacle in the development of new AD drugs will be reduced, marking a new starting point for the Alzheimer's disease industry.

At the same time, we also see that the share price of Quanterix, a single-molecule detection technology company, has risen for three consecutive days. Some industry insiders believe that this linkage effect confirms that the "biological definition era" of Alzheimer's disease has officially arrived.

References:

"2023 AAIC: A New Era for AD Has Truly Begun" — VCBeat

Lilly Alzheimer’s drug gets unanimous backing of FDA panel——BioPharma Dive