Wednesday, 19 June, 2024
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Concern over FDA's fast-track approval of Alzheimer's drugs

The US Food and Drug Administration (FDA) has approved a highly anticipated new drug – Leqembi, also known as lecanemab – designed to slow cognitive decline in patients in the early stages of Alzheimer’s disease. This comes days after the agency was slammed by Congress for green-lighting another Alzheimer’s drug, aducanumab (Aduhelm), despite trial results showing the monoclonal antibody treatment carries risks of brain swelling and bleeding.

Both drugs were approved by the FDA through an accelerated process allowing the regulatory agency to fast-track approval of drugs for serious conditions where there is an unmet medical need.

Leqembi and Aduhelm, both jointly developed by Japan’s Eisai and Biogen of the US, “represent an important advancement in the ongoing fight to effectively treat Alzheimer's disease”, said the FDA in a statement.

Leqembi is “the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease”, said Billy Dunn of the FDA’s Centre for Drug Evaluation and Research.

Preliminary data from a Leqembi trial was released in September and showed it slowed cognitive decline in Alzheimer’s patients by 27%, reports News24.

The phase three trial involved nearly 1 800 people, divided between those given the drug and given a placebo, and ran over 18 months.

The complete trial data, published in the New England Journal of Medicine, fleshed out the findings but also raised concern about the incidence of “adverse effects” including brain bleeds and swelling.

The results showed that 17.3% of patients given the drug experienced brain bleeds, compared with 9% of those receiving a placebo. And 12.6% of those taking the drug experienced brain swelling, compared with just 1.7% of those in the placebo group.

Deaths were reported at approximately the same rate in both arms of the trial of the drug.

In Alzheimer’s disease, two key proteins, tau and amyloid beta, build up into tangles and plaques, known together as aggregates, causing brain cells to die and leading to brain shrinkage.

Leqembi works by targeting amyloid.

Biogen and Eisai previously brought Aduhelm to market, but there was significant controversy over whether it worked, and its approval in 2021 led to three high-level resignations from the FDA.

An 18-month US congressional investigation said the approval process for Aduhelm was “rife with irregularities” and criticised both the agency and Biogen.

Additionally, said the congressional report, Biogen set an “unjustifiably high price” for Aduhelm of $56 000 a year. Eisai said Leqembi would be priced initially at $26 500 per year.

In the case of Aduhelm, by “inappropriately collaborating” with Biogen, the investigative report said the FDA broke with its own protocols in reviewing and then giving it the go-ahead, despite concerns about some of the clinical data.

It had also held unreported meetings and failed to gain internal consensus before engaging in the collaborations. Additionally, the company was admonished for its planned, aggressive marketing and sales campaign, the report uncovering that Biogen’s budget for this was double the cost of developing the medication.

In its long-term plans, Biogen estimated it would spend more than $3.3bn on sales and marketing for aducanumab from 2020 to 2024, more than double what the company spent on the drug’s development from 2007 to its approval in 2021.

The investigation by the House Committee on Oversight and Reform and the House Committee on Energy and Commerce, also questioned the agency’s decision to “abruptly” switch to the accelerated approval pathway from the traditional approval pathway and to grant approval of the drug’s label to a broad patient population.

MedPage Today reports that the probe involved multiple briefings with the FDA and review of more than 500 000 documents, including internal Biogen strategy documents, launch plans, materials from Biogen’s board of directors, communications between Biogen and FDA leaders, and internal FDA correspondence. The committees also examined the FDA’s internal review of its interactions with Biogen ahead of and during a key advisory meeting.

No support for data

The FDA granted aducanumab accelerated approval on 7 June 2021, an action clouded by Biogen's earlier decision to terminate trials of aducanumab in March 2019 after an interim analysis of trial data, the House Committees noted. Also muddying the waters was that no member of the FDA’s advisory committee voted in support of the data presented about aducanumab.

Within the FDA itself, biostatisticians had raised concerns regarding “the inconsistency of the drug’s clinical data”, according to the Committees’ report.

In January 2022, Medicare announced that aducanumab and other monoclonal antibodies targeting amyloid beta in Alzheimer’s disease would only be covered if patients were enrolled in qualifying clinical trials.

Summary of findings

The FDA and Biogen developed a collaborative “working group” to examine the company’s clinical trials, leading to at least 40 working group meetings and more than 115 other meetings, calls, and “substantive” email exchanges from July 2019 to July 2020, according to the Committees’ report. However, at least 66 calls and email exchanges among the FDA and Biogen working group were not properly documented, it was found.

The agency also opted to collaborate on a joint FDA-Biogen briefing document, later presented at an advisory committee meeting, although such collaboration had been used in the past mainly for oncological drugs and “under circumstances of broad consensus”.

Both the Committees’ investigation and a separate FDA internal review concluded that decision was “not an appropriate approach”, given clashing views of the drug within the agency.

Documents reviewed by the Committees also suggested the agency “abruptly changed course” in granting approval under that accelerated approval pathway rather than the traditional approval pathway, after “unfavourable feedback” for the traditional pathway during an expert council meeting.

The Committees’ investigation also exposed numerous concerns related to Biogen’s “aggressive launch and marketing plans”. Documents showed the company estimated a peak revenue of $18bn per year. The company set an initial price of $56 000 for treatment per year, despite what the Committees described as “a lack of demonstrated clinical benefit in a broad population”.

Company documents suggested Biogen knew the high price would trigger “pushback” from payers and providers. “Biogen developed an external narrative about the drug’s value to sell to the patients and the public,” the report stated.

Internal company documents showed Biogen knew its high price would weigh heavily on Medicare and Medicare patients. A November 2020 presentation included an estimate of aducanumab costing the Medicare programme $12bn over the span of one year. A Biogen analysis also found Medicare patients could incur out-of-pocket costs for aducanumab that could account for as much as 20% of their income.


In response to the findings, the Committees urged the FDA to commit to taking certain measures in the future “to help restore the American people’s trust in the agency’s processes and assurances of drug safety and efficacy”.

This included properly documenting “all substantive FDA interactions with drug sponsors”, developing a protocol to address joint briefing documents between FDA and drug sponsors for advisory committees, and updating the agency’s industry guidance for developing new Alzheimer’s drugs.

The Committees noted the agency’s internal review included similar recommendations about meeting documentation and joint briefing documents. The FDA reported such changes were “still in process” as of August 2022.

The Committees also called on Biogen and other drug companies to “communicate safety and efficacy concerns clearly” to the FDA in the future and to “consider the value assessment made by outside experts including patient access, when setting drug prices”.

Study details

Lecanemab in Early Alzheimer’s Disease

Christopher van Dyck, Chad Swanson, Paul Aisen, Randall Bateman, Christopher Chen, Michelle Gee, Michio Kanekiyo, David Li, Larisa Reyderman, Sharon Cohen, Lutz Froelich, Sadao Katayama, et al.

Published in New England Journal of Medicine on 5 January 2023


The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanised IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.

We conducted an 18-month, multicentre, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favouring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.


NEJM article – Lecanemab in Early Alzheimer’s Disease (Open access)


News24 article – US approves new drug to treat Alzheimer's (Open access)


MedPage Today article – Congressional Probe of Alzheimer's Drug Approval Finds Fault With FDA Actions (Open access)



See more from MedicalBrief archives:


Scientists hail Alzheimer’s breakthrough despite two trial candidates’ deaths


Patient’s death in Alzheimer’s trial raises concern about risk


Alzheimer’s drug slows cognitive decline in trial – breakthrough or another false dawn?


FDA’s approval of aducanumab will bring enormous pressure on doctors


Leading Alzheimer’s study under investigation over possible manipulation



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