Agenda/You Tube link: FDA Lecanemab Mtg June 9

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Agenda/You Tube link: FDA Lecanemab Mtg June 9

Post by NF52 »

For those wonky folks interested in how an FDA advisory committee works, here's a You Tube link to the ADCOMM meeting on lecanemab, which has gotten a fair amount of attention on this forum, available through out Search function. For context, per the FDA website:
Advisory committees provide independent expert advice to the FDA on broad scientific topics or on certain products to help the agency make sound decisions based on the available science. Advisory committees make non-binding recommendations to the FDA, which generally follows the recommendations but is not legally bound to do so. ... nformation

For the TL/DR (too long/ don't read) deep dive into the pre-meeting data on safety, here's more:

Here are the key questions the Committee seeks to answer: [Note the emphasis on ApoE 4/4 and CAA:
  • DISCUSSIONDiscuss the results from Study 301 (CLARITY AD) and whether they provide evidence of clinical benefit of lecanemab for the treatment of Alzheimer’s disease (AD).
  • VOTE: Do the results of Study 301 (CLARITY AD) verify the clinical benefit of lecanemab for the treatment of AD?
  • DISCUSSION: Discuss the overall benefit/risk assessment of lecanemab for the treatment of AD. Additionally, consider the following subgroups in your assessment:
    • Apolipoprotein E (ApoE) ε4 homozygotes
    • Patients requiring concomitant treatment with anticoagulant agents
    • Patients with cerebral amyloid angiopathy ... Questions

Here are agenda items and times from theDraft Agenda for Lecanemab (Lekembi™ FDA approval Advisory Committee Meeting June 9, 2023 to be held on Friday, June 9 from 10:00 AM-5:00 PM Eastern Time.

Presentations of data from the Phase 3 Lecanemab Study 301 CLARITY AD), which randomized 1795 patients across 2 treatment groups: placebo (n=897) and lecanemab (n=898), by Eisai scientists and Dr. Sharon Cohen, a behavioral neurologist, clinical trial principal investigator and Director of the Toronto Memory Program are scheduled for 10:30-11:45 AM Eastern. They will cover:
  • data on efficacy
  • "robustness of efficacy results"
  • safety
  • clinical perspective
Presentations from FDA Clinical Efficacy Reviewer, Clinical Safety Reviewer and Biostatistics Reviewer are scheduled for 12:30-1:45 PM Eastern and will cover
  • Clinical Overview of Efficacy
  • Statistical Overview
  • Clinical Overview of Safety
  • Concluding remarks
An open public hearing will begin at 2:00 PM Eastern and Committee Discussion will begin at 3:15 PM Eastern.

Here are previews from the Eisai Briefing Document, specifically looking at key ApoE4 and ARIA-H, both micro-and macro-hemorrhages. "Isolated ARIA-H" refers to micro-hemorrhages or macrohemorrhages that were seen on MRI with no evidence of ARIA-E (edema)

4.2.4 APOE4 Carrier Status p. 58
The majority of patients in Study 301 were APOE4 carriers (1231 [68.6%]; 957 [53.3%] heterozygous APOE4 carriers, 274 [15.3%] homozygous APOE4 carriers) with the remainder APOE4 noncarriers (564 [31.4%]). The APOE4 carrier status was similar for placebo and lecanemab (Table 10), per the randomization strata....
Isolated ARIA-H pp. 34-35
In Study 301, the incidences of isolated ARIA-H were similar in placebo (70/897 [7.8%]) and lecanemab (80/898 [8.9%]). For placebo, the incidence of isolated ARIA-H ...[in] homozygous APOE4 carriers [was] (24/133 [18.0%]). Lecanemab showed a similar pattern of increasing frequency based on increasing number of E4 alleles. Isolated ARIA-H events occur throughout the course of treatment with similar rates in placebo and lecanemab. Rates for symptomatic isolated ARIA-H were similar between placebo (2/897 [0.2%] and lecanemab (4/898 [0.4%]). Therefore, isolated ARIA-H has similar incidence, timing, and risk factors (APOE4) for lecanemab and placebo, without a lecanemab-related increase in incidence. The overall incidence of ARIA-H was lower in placebo (81/897 [9.0%]) than lecanemab (155/898 [17.3%]).
For lecanemab patients experiencing ARIA-H, 33/278 (11.9%) patients were APOE4 noncarriers, 67/479 (14.0%) were heterozygous APOE4 carriers, and 55/141 (39.0%) were homozygous APOE4 carriers....The incidence of ARIA-H leading to discontinuation of study drug in lecanemab was higher in APOE4 carriers (lecanemab 16 [2.6%]) than in APOE4 noncarriers (lecanemab 2 [0.7%]).
Overall ARIA-H p. 35
The overall incidence of serious AEs [serious adverse events] due to ARIA-H were 1/897 (0.1%) in placebo and 5/898 (0.6%) in lecanemab...[and]lower in the heterozygous APOE4 carriers (placebo 0/478; lecanemab 1/479 [0.2%]) and APOE4 noncarriers (placebo 1/286 [0.3%]; lecanemab 2/278 [0.7%]) than in homozygous APOE4 carriers (placebo 0/133 [0%]; lecanemab 2/141 [1.4%]).
Most ARIA-H events were radiographically mild (placebo 73/897 [8.1%]; lecanemab 97/898 [10.8%]) to moderate (placebo 5/897 [0.6%]; lecanemab 26/898 [2.9%]) in severity; with 3 (0.3%) patients in placebo and 32 (3.6%) in lecanemab reporting severe ARIA-H, mostly driven by any microhemorrhage event that resulted in a cumulative number greater than 10 microhemorrhages (27/898 [3.0%]). Similar trends were observed in all ARIA-H subcategories.[/b]...Most symptomatic cases were concurrent ARIA-E and ARIA-H. Preferred terms for symptoms occurring in more than 1 patient in lecanemab were headache (4 patients), dizziness (3 patients), and confusional state (2 patients). ARIA-E, ARIA-H (Microhemorrhage and Superficial Siderosis), and Intracerebral Hemorrhage, and Antithrombotic Use p.88.
There was no increase in ARIA-E or ARIA-H in patients who were on lecanemab and ]antithrombotics relative to those that were on lecanemab alone The number of intracerebral hemorrhage cases was small, limiting risk assessment of concomitant use of antithrombotics
CAA p.54
Amyloid deposition in blood vessels, called CAA, is ubiquitous in AD. It can cause common asymptomatic microhemorrhage and asymptomatic superficial siderosis, and rare lobar macrohemorrhage or inflammatory CAA spontaneously in AD. APOE4 is a risk factor for CAA and intracerebral hemorrhage due to CAA. Mobilization of amyloid from blood vessels in CAA is the likely mechanism of ARIA observed with anti-amyloid antibodies.
Deaths [see pp 102=104 of for detailed info
  • Eight placebo trial participants died during the 18-month CLARITY study, ages 72-90, including one from COVID, two from cancer; one from cardiac arrest, one from heart attack and one from intracerebral hemorrhage
  • Seven Lecanemab patients died during the 18-month CLARITY study, ages 70-88, including one from COVID, one from diabetic ketoacidosis, one age 85 from an unknown cause. Only two occurred earlier than 400 days into their treatment:
    • (Study Day 230) Suspected myocardial infarction: A 70 year old patient, significant medical history included diabetes, hypertension, coronary artery disease, prior myocardial infarction, and cardiac arrythmia and conduction defects. Experienced dyspnea, collapsed, and died suddenly.
    • (Study Day 282) Stroke, acute, symptomatic: A 79 year old patient, no other relevant details.
    Open Label Extension (all lecanemab): Nine total to date, ages 63 to 85, including a 64 year old killed in a car accident and two deaths from COVID. Possible drug interactions include:
    • A 85 year old patient who received placebo in the double-blind Study. Death considered possibly related to study drug by Investigator. Myocardial infarction was considered the proximal cause of death in a setting of atrial fibrillation, anticoagulant therapy with apixaban, falls, macrohemorrhage, and pneumonia. The autopsy confirmed CAA and concluded a terminal cardiopulmonary event was the likely cause of death.
    • Day 33 at acute stroke; 9 days since last of 3 infusions) A 63 year old patient who received placebo in the double-blind Study. Death considered possibly related to study drug ( by Investigator. tPA treatment was administered in the setting of an acute stroke, which was considered the proximal cause of macrohemorrhage and death.
    • Symptomatic suspected cerebral vascular accident.A 72 year old patient who received lecanemab in the double-blind Study. Death considered possibly related to study drug by Investigator.
4/4 and still an optimist!
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