Drug Trials Snapshots: LEQEMBI
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the LEQEMBI Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
LEQEMBI (lecanemab-irmb)
Leh kem’ bee
Eisai Inc.
Original Approval date: January 6, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
LEQEMBI is a prescription medicine used to treat people with Alzheimer’s disease. Alzheimer’s disease is a common degenerative disease of the brain that starts with mild thinking, judging, and memory problems and progresses to dementia and death. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials.
How is this drug used?
LEQEMBI is administered as an intravenous (IV) infusion over approximately one hour every two weeks.
Who participated in the clinical trials?
The FDA approved LEQEMBI based on evidence from one main clinical trial of 1,795 patients with Alzheimer’s disease. The trial was conducted at 253 sites in 13 countries in North America, Europe, Asia, and Australia. Fifty-three percent of patients were enrolled in the United States. The trial assessed both efficacy and safety.
How were the trials designed?
The benefits and side effects of LEQEMBI were evaluated in one main clinical trial of patients with Alzheimer’s disease. Patients received LEQEMBI or placebo for 76 weeks. Neither the patients nor the health care providers knew which treatment was being given until the trial was completed.
The benefit of LEQEMBI was evaluated on several clinical scales including the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale - Cognitive subscale (ADAS-Cog 14), and the Alzheimer’s Disease Cooperative Study - Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).
How were the trials designed?
The efficacy and safety of LEQEMBI were evaluated in a double-blind, placebo-controlled, parallel-group, randomized study in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease). Patients were enrolled with a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater. All patients had a Mini-Mental State Examination (MMSE) score of ≥22 and ≤30 and had objective impairment in episodic memory as indicated by at least one standard deviation below age-adjusted mean in the Wechsler-Memory Scale-IV Logical Memory II (subscale) (WMS-IV LMII). Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease.
The study included a 60-day screening period, an 18-month (78-week) placebo-controlled period, and a safety follow-up period of 3 months after the final dose. Patients were randomized to placebo or 10 mg/kg LEQEMBI once every two weeks in a 1:1 ratio in the placebo-controlled period. Patients who completed the placebo-controlled period and met the inclusion or exclusion criteria had the option to directly enter the open-label extension phase of the study.
The primary efficacy endpoint was change from baseline at 18 months in the CDR-SB. Key secondary endpoints included change from baseline at 18 months for the following measures: amyloid Positron Emission Tomography (PET) using Centiloids, ADAS-Cog14, and ADCS MCI-ADL.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of LEQEMBI.
Figure 1. Baseline Demographics by Sex
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the clinical trial used to evaluate the efficacy of LEQEMBI.
Figure 2. Baseline Demographics by Race
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were enrolled in the clinical trial used to evaluate the efficacy of LEQEMBI.
Figure 3. Baseline Demographics by Age
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the clinical trial used to evaluate the efficacy of LEQEMBI.
Figure 4. Baseline Demographics by Ethnicity
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics, Randomized Population
| Demographic | Placebo | LEQEMBI | Total |
|---|---|---|---|
| Sex, n (%) | |||
| Age | |||
| Age group, years, n (%) | |||
| Race, n (%) | |||
| Ethnicity, n (%) | |||
| Male | 421 (46.9) | 436 (48.6) | 857 (47.7) |
| Female | 476 (53.1) | 462 (51.4) | 938 (52.3) |
| Mean (SD) | 71.1 (7.8) | 71.4 (7.9) | 71.3 (7.8) |
| Median (min, max) | 72.0 (50.0, 90.0) | 72.0 (50.0, 90.0) | 72.0 (50.0, 90.0) |
| <65 | 178 (19.8) | 175 (19.5) | 353 (19.7) |
| 65 to 74 | 391 (43.6) | 383 (42.7) | 774 (43.1) |
| ≥75 | 328 (36.6) | 340 (37.9) | 668 (37.2) |
| White | 696 (77.6) | 685 (76.3) | 1381 (76.9) |
| Black or African American | 25 (2.8) | 22 (2.4) | 47 (2.6) |
| Asian | 150 (16.7) | 153 (17.0) | 303 (16.9) |
| American Indian or Alaskan Native | 2 (0.2) | 0 | 2 (0.1) |
| Native Hawaiian or other Pacific Islander | 0 | 1 (0.1) | 1 (0.1) |
| Missing | 12 (1.3) | 16 (1.8) | 28 (1.6) |
| Other | 12 (1.3) | 21 (2.3) | 33 (1.8) |
| Not Hispanic or Latino | 759 (84.6) | 744 (82.9) | 1503 (83.7) |
| Hispanic or Latino | 114 (12.7) | 117 (13.0) | 231 (12.9) |
| Missing | 24 (2.7) | 37 (4.1) | 61 (3.4) |
Source: Adapted from FDA Review
Abbreviations: SD, standard deviation
What are the benefits of this drug?
Patients treated with LEQEMBI demonstrated a reduction in cognitive and functional decline as measured by several clinical scales.
What are the benefits of this drug (results of trials used to assess efficacy)?
The primary efficacy outcome was change from baseline at 18 months in the CDR-SB. Other endpoints included change from baseline at 18 months for the ADAS-Cog14 and ADCS MCI-ADL.
Patients treated with LEQEMBI demonstrated a statistically significant reduction in clinical decline on CDR-SB compared to placebo at Month 18 (-0.45, [-27%] p<0.0001). Statistically significant differences (p<0.01) between treatment groups were also seen in the results for ADAS-Cog14 and ADCS MCI-ADL at 18 months.
Table 2. Efficacy Results, Efficacy Population
| Clinical Endpoint | LEQEMBI | Placebo |
|---|---|---|
| CDR-SB | N=859 | N=875 |
| Mean baseline | 3.17 | 3.22 |
| Adjusted mean change from baseline at 18 months (%) | 1.21 | 1.66 |
| Difference from placebo | -0.45 (-27%) | |
| p-value | p<0.0001 | |
| ADAS-Cog14 | N=854 | N=872 |
| Mean baseline | 24.45 | 24.37 |
| Adjusted mean change from baseline at 18 months (%) | 4.140 | 5.581 |
| Difference from placebo | -1.442 (-26%) | |
| p-value | p=0.00065 | |
| ADCS MCI-ADL | N=783 | N=796 |
| Mean baseline | 41.2 | 40.9 |
| Adjusted mean change from baseline at 18 months | -3.5 | -5.5 |
| Difference from placebo | 2.0 (-37%) | |
| p-value | p<0.0001 | |
Source: Adapted from LEQEMBI Prescribing Information
Abbreviations: ADAS-Cog14, Alzheimer’s Disease Assessment Scale - Cognitive subscale; ADCS MCI-ADL, Alzheimer’s Disease Cooperative Study - Activities of Daily Living Scale for Mild Cognitive Impairment; CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: The observed effect was larger in males compared to females. Because of limited data, this difference may be due to chance.
- Race: The number of patients of races other than White was small; therefore, differences in how LEQEMBI worked among races could not be determined.
- Age: The observed effect was largest in patients older than 75 years of age. Because of limited data, this difference may be due to chance.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
The subgroup results of CDR-SB change from baseline at 18 months were generally consistent with the results of the overall population. The number of patients of races other than White was small; therefore, differences in how LEQEMBI worked among races have considerable uncertainty.
Table 3. CDR-SB Change From Baseline at 18 Months by Subgroup, Efficacy Population
| Subgroup | LEQEMBI | Placebo | Adjusted Mean |
|---|---|---|---|
| Sex | |||
| Race | |||
| Age, years | |||
| Ethnicity | |||
| Female | 1.5 (0.1) | 1.7 (0.1) | -0.2 (-0.5, 0.1) |
| Male | 0.9 (0.1) | 1.7 (0.1) | -0.7 (-1.0, -0.4) |
| Asian | 1.7 (0.3) | 2.0 (0.3) | -0.3 (-0.9, 0.2) |
| Black or African American | -0.1 (0.5) | 0.7 (0.5) | -0.8 (-2.2, 0.6) |
| White | 1.0 (0.2) | 1.5 (0.2) | -0.5 (-0.7, -0.2) |
| <65 | 1.4 (0.2) | 1.5 (0.2) | -0.1 (-0.6, 0.4) |
| ≥65 to <75 | 1.2 (0.1) | 1.6 (0.1) | -0.4 (-0.7, 0.0) |
| ≥75 | 1.1 (0.1) | 1.8 (0.1) | -0.7 (-1.1, -0.4) |
| Hispanic or Latino | 0.0 (0.2) | 0.5 (0.2) | -0.5 (-1.1, 0.1) |
| Not Hispanic or Latino | 1.4 (0.1) | 1.8 (0.1) | -0.5 (-0.7, -0.2) |
Source: Adapted from FDA Review
The MMRM used to estimate adjusted means included baseline CDR-SB as a covariate, with treatment group, visit, stratification variables (i.e., clinical subgroup, use of AD symptomatic medication at baseline [yes, no], APOE4 carrier status [carriers, noncarriers], and geographical region [North America, Europe, and Asia Pacific]), baseline CDR-SB-by-visit, and treatment group-by-visit interaction as fixed effects. Subgroup effects were estimated by adding fixed interaction effects between the subgroup variable and treatment and visit variables to the primary MMRM model. An increase from baseline indicates worsening of symptoms.
Abbreviations: AD, Alzheimer’s Disease; CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes; CI, confidence interval; MMRM, mixed model for repeated measures; SE, standard error
What are the possible side effects?
LEQEMBI can cause serious side effects.
The most common side effects of LEQEMBI include amyloid-related imaging abnormalities (ARIA) and infusion-related reactions.
ARIA refers to temporary swelling in areas of the brain (ARIA-E), or small spots of bleeding in or on the surface of the brain (ARIA-H). The swelling in areas of the brain usually resolves over time, while the small spots of bleeding in or on the surface of the brain may not resolve. Most people with ARIA do not get symptoms; however, some people, especially those with swelling in the brain may have symptoms, such as headache, nausea, confusion, difficulty walking, dizziness, seizures, and vision changes. Some of these symptoms may be serious and life-threatening. While ARIA may occur any time during treatment with LEQEMBI, it has most frequently been observed during the first 14 weeks of treatment.
Some people may also develop larger areas of bleeding in the brain while taking LEQEMBI which also may be serious and life-threatening. Some people may be at a higher risk of developing bleeding in the brain if they are taking medicines to reduce blood clots from forming (i.e., antithrombotic medications) while receiving LEQEMBI.
Some people have a genetic risk factor (homozygous apolipoprotein E [ApoE] gene carriers) that may cause an increased risk for serious ARIA. Patients should discuss the risk of ARIA with different ApoE genotypes and the implications of genetic testing results with their health care providers.
Some patients taking LEQEMBI may experience infusion-related reactions. An infusion-related reaction is a side effect that may occur during or shortly after the infusion of LEQEMBI. The symptoms of an infusion-related reaction may include fever, flu-like symptoms (chills, body aches, feeling shaky and joint pain), nausea, vomiting, dizziness and lightheadedness, changes in heart rate, difficulty breathing.
LEQEMBI can cause allergic reactions that may be serious.
What are the possible side effects (results of trials used to assess safety)?
The most common side effects that were seen in patients taking LEQEMBI in the pivotal study conducted with LEQEMBI are shown below in Table 4.
Table 4. Side Effects Reported in at Least 5% of Patients Treated With LEQEMBI and at Least 2% Higher Than Placebo
| Adverse Reactions | LEQEMBI | Placebo |
|---|---|---|
| Infusion-related reactions | 26 | 7 |
| ARIA-H | 14 | 8 |
| ARIA-E | 13 | 2 |
| Headache | 11 | 8 |
| Superficial siderosis of central nervous system | 6 | 3 |
| Rash1 | 6 | 4 |
| Nausea or vomiting | 6 | 4 |
Source: Adapted from LEQEMBI Prescribing Information
1 Rash includes acne, erythema, infusion site rash, injection site rash, rash, rash erythematous, rash pruritic, skin reactions, and urticaria.
Abbreviations: ARIA-E, amyloid-related imaging abnormalities with edema; ARIA-H, amyloid-related imaging abnormalities with hemosiderin deposition
Less common side effects seen during LEQEMBI treatment include atrial fibrillation, an abnormal rhythm of the heart, which occurred in 3% of patients treated with LEQEMBI compared to 2% in patients on placebo.
Were there any differences in side effects of the clinical trials among sex, race, and age?
The small number in most of these subgroup analyses limit conclusions about the significance of these differences.
- Sex: While ARIA-E and ARIA-H rates were comparable between males and females, infusion-related reactions were slightly lower, and headache was slightly higher in females compared to males.
- Race: The number of patients of races other than White was small; therefore, the interpretation of the occurrence of side effects by race was limited.
- Age: The overall occurrence of side effects was similar in patients younger and older than 65 years of age. Those over 80 years old appeared to have lower rates of ARIA-E and headache; however, the conclusions about the differences are limited by the small numbers of patients over 80 years old.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5. Side Effects by Subgroup, Safety Population
| Subgroup | LEQEMBI, N=898 | ||||
|---|---|---|---|---|---|
ARIA-E | ARIA-H | Headache | Infusion Related | Overall TEAEs | |
| Sex | |||||
| Age, years | |||||
| Race | |||||
| Disposition | |||||
| Region | |||||
| BMI | |||||
| Males (n=436) | 12 | 15 | 9 | 28 | 90 |
| Females (n=462) | 13 | 13 | 13 | 24 | 80 |
| <65 (n=175) | 14 | 9 | 14 | 24 | 87 |
| 65 to 80 (n=593) | 14 | 16 | 12 | 27 | 90 |
| >80 (n=130) | 5 | 13 | 5 | 27 | 88.5 |
| White (n=685) | 14 | 15 | 13 | 28 | 90 |
| African American (n=22) | 9 | 14 | 9 | 9 | 86 |
| Asian (n=153) | 6.5 | 10.5 | 5 | 12 | 84 |
| Other (including missing) (n=38) | 21 | 18 | 16 | 67 | 97 |
| MCI (n=552) | 13 | 14 | 12 | 26 | 88 |
| AD (n=346) | 12 | 14.5 | 10 | 27 | 90 |
| North America (n=537) | 13 | 14.5 | 11 | 29 | 89 |
| Europe (n=215) | 15 | 15 | 17 | 29 | 94 |
| Asia Pacific (n=146) | 6 |
| 4 | 12 | 84 |
| <22.5 (n=212) | 9 | 9 | 8 | 18 | 86 |
| 22.5 to 24.9 (n=194) | 13 | 13 | 12 | 39 | 90 |
| 24.9 to 27.9 (n=222) | 11 | 17 | 11 | 28 | 88 |
| >27.9 (n=268) | 15 | 16 | 13 | 36 | 91 |
Source: Adapted from FDA Review
Abbreviations: AD, Alzheimer’s Disease; ARIA-E, amyloid-related imaging abnormalities with edema; ARIA-H, amyloid-related imaging abnormalities with hemosiderin deposition; BMI, body mass index; MCI, mild cognitive impairment; TEAE, treatment-emergent adverse event
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.