Drug Trials Snapshots: KISUNLA
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 KISUNLA Prescribing Information for all 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).
KISUNLA (donanemab-azbt)
Kih-SUHN-lah
Eli Lilly and Company
Original Approval date: July 2, 2024
DRUG TRIALS SNAPSHOT SUMMARY
What is the drug for?
KISUNLA is an amyloid beta-directed antibody 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 KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of the disease, the population in which treatment was initiated in the clinical trials.
How is this drug used?
KISUNLA is administered as an intravenous (IV) infusion over approximately 30 minutes every four weeks.
Who participated in the clinical trials?
The FDA approved KISUNLA based on evidence from a clinical trial of 1736 patients with Alzheimer’s disease (NCT04437511). The trial was conducted at 277 sites in eight countries in North America, Europe, Japan, and Australia. Seventy-two 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 KISUNLA were evaluated in a clinical trial of patients with Alzheimer’s disease. Patients received KISUNLA or placebo for up to 72 weeks. Treatment with KISUNLA was stopped based on brain amyloid levels measured during the study. Neither the patients nor the healthcare providers knew which treatment was being given until the trial was completed.
The benefit of KISUNLA was evaluated based on several clinical scales including the integrated Alzheimer’s Disease Rating Scale (iADRS), the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL), and the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB).
How were the trials designed?
The efficacy of KISUNLA was evaluated in a double-blind, placebo-controlled, parallel-group study in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease). Patients were enrolled with a Mini-Mental State Examination (MMSE) score of ≥20 and ≤28 and had a progressive change in memory function for at least six months. Patients were included in the study based on levels of tau pathology assessed by tau positron emission tomography (PET) imaging with flortaucipir. Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease. Patients could enroll in an optional long-term extension.
In the study, 1736 patients were randomized 1:1 to receive 700 mg of KISUNLA every four weeks for the first three doses and then 1400 mg every four weeks (N=860) or placebo (N=876) for a total of up to 72 weeks. Treatment with KISUNLA was stopped and patients were switched to placebo based on amyloid PET levels measured at Week 24, Week 52, and Week 76. Additionally, dose adjustments were allowed for treatment-emergent adverse events related to amyloid-related imaging abnormalities (ARIA).
The primary efficacy endpoint was change in the iADRS score from baseline to 76 weeks. The iADRS is a combination of two scores using the ADAS-Cog13 and ADCS-iADL scales. The total score ranges from 0 to 144, with lower scores reflecting worse cognitive and functional performance. Other efficacy endpoints included CDR-SB, ADAS-Cog13, and ADCS-iADL.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of KISUNLA.
Figure 1. Baseline Demographics by Sex Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by sex were enrolled in the trial used to evaluate the side effects of KISUNLA.
Figure 2. Baseline Demographics by Race Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by sex were enrolled in the trial used to evaluate the side effects of KISUNLA.
Figure 3. Baseline Demographics by Age Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by sex were enrolled in the trial used to evaluate the side effects of KISUNLA.
Figure 4. Baseline Demographics by Ethnicity Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics Efficacy Population
| Demographic | Placebo N=876 |
KISUNLA N=860 |
Total N=1736 |
|---|---|---|---|
| Sex, n (%) | |||
| Male | 373 (42.6) | 367 (42.7) | 740 (42.6) |
| Female | 503 (57.4) | 493 (57.3) | 996 (57.4) |
| Age, years | |||
| Mean (SD) | 73.0 (6.2) | 73.0 (6.2) | 73.0 (6.2) |
| Median (min, max) | 73.5 (59.0, 85.0) | 73.0 (59.0, 86.0) | 73.0 (59.0, 86.0) |
| Age group, years, n (%) | |||
| <65 | 88 (10.0) | 88 (10.2) | 176 (10.1) |
| ≥65 to <75 | 402 (45.9) | 414 (48.1) | 816 (47.0) |
| ≥75 | 386 (44.1) | 358 (41.6) | 744 (42.9) |
| Race, n (%) | |||
| White | 807 (92.1) | 781 (90.8) | 1588 (91.5) |
| Black or African American | 21 (2.4) | 19 (2.2) | 40 (2.3) |
| American Indian or Alaska Native | 0 | 2 (0.2) | 2 (0.1) |
| Asian | 47 (5.4) | 57 (6.6) | 104 (6.0) |
| Multiple | 1 (0.1) | 0 | 1 (0.1) |
| Missing | 0 | 1 (0.1) | 1 (0.1) |
Source: Adapted from FDA Review
Abbreviations: SD standard deviation
What are the benefits of this drug?
Patients treated with KISUNLA 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 endpoint was change in the iADRS score from baseline to 76 weeks. The iADRS is a combination of two scores using the ADAS-Cog13 and ADCS-iADL scales. The total score ranges from 0 to 144, with lower scores reflecting worse cognitive and functional performance. Other efficacy endpoints included CDR-SB, ADAS-Cog13, and ADCS-iADL.
Patients treated with KISUNLA demonstrated a statistically significant reduction in clinical decline on iADRS compared to placebo at Week 76 (2.92, p<0.001). There were also statistically significant differences (p<0.001) between treatment groups as measured on the two component scales ADAS-Cog13 and ADCS-iADL at Week 76.
Patients treated with KISUNLA demonstrated a statistically significant reduction in clinical decline on CDR-SB compared to placebo at Week 76 (-0.70, p<0.001) (Table 2).
Table 2. Efficacy Analysis Results at Week 76 Efficacy Population
| Clinical Endpoints | KISUNLA N=860 |
Placebo N=876 |
|---|---|---|
| CDR-SBa | ||
| Mean baseline | 3.92 | 3.89 |
| Adjusted mean change from baseline | 1.72 | 2.42 |
| Difference from placebo (%)c | -0.70 (29%) | |
| p-value | <0.001 | |
| ADAS-Cog13b | ||
| Mean baseline | 28.53 | 29.16 |
| Adjusted mean change from baseline | 5.46 | 6.79 |
| Difference from placebo (%)c | -1.33 (20%) | |
| p-value | <0.001 | |
| ADCS-iADLb | ||
| Mean baseline | 47.96 | 47.98 |
| Adjusted mean change from baseline | -4.42 | -6.13 |
| Difference from placebo (%)c | 1.70 (28%) | |
| p-value | <0.001 | |
Source: KISUNLA Prescribing Information
a Assessed using MMRM analysis.
b Assessed using NCS2 analysis.
c Percent slowing of decline relative to placebo: difference of adjusted mean change from baseline between treatment groups divided by adjusted mean change from baseline of placebo group at Week 76.
Abbreviations: ADAS-Cog13 Alzheimer’s Disease Assessment Scale – 13-item Cognitive Subscale; ADCS-iADL Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living subscale; CDR-SB Clinical Dementia Rating Scale – Sum of Boxes; MMRM mixed model for repeated measures; NCS2 natural cubic spline with 2 degrees of freedom
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: The effect of KISUNLA was similar in males and females.
- Race: The number of patients of races other than White was small; therefore differences in how KISUNLA worked among races could not be determined.
- Age: The effect of KISUNLA was similar in patients younger than 65 years, between 65 and 75 years, and older than 75 years of age.
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 Week 76 were generally consistent with the results of the overall population. Note that the number of Hispanic or Latino patients was small; therefore differences in how KISUNLA worked between ethnicities could not be determined.
Table 3. CDR-SB Change From Baseline at Week 76 Efficacy Population
| Demographic | KISUNLA N=860 Change From Baseline (SE) |
Placebo N=876 Change From Baseline (SE) |
Adjusted Mean Difference (95% CI) |
|---|---|---|---|
| Sex | |||
| Female | 1.7 (0.1) | 2.6 (0.1) | -0.9 (-1.2, -0.5) |
| Male | 1.7 (0.1) | 2.2 (0.1) | -0.5 (-0.9, -0.2) |
| Race | |||
| Asian | 1.5 (0.4) | 1.9 (0.4) | -0.4 (-1.4, 0.7) |
| Black or African American | 1.5 (1.0) | 2.5 (0.8) | -1.0 (-3.3, 1.2) |
| White | 1.8 (0.1) | 2.5 (0.1) | -0.7 (-1.0, -0.5) |
| Age, years | |||
| <65 | 2.1 (0.3) | 2.5 (0.3) | -0.5 (-1.3, 0.3) |
| ≥65 to <75 | 1.5 (0.1) | 2.5 (0.1) | -1.0 (-1.3, -0.6) |
| ≥75 | 1.9 (0.2) | 2.4 (0.1) | -0.5 (-0.9, -0.1) |
| Ethnicity | |||
| Hispanic or Latino | 1.9 (0.7) | 0.9 (0.7) | 1.0 (-0.8, 2.9) |
| Not Hispanic or Latino | 1.7 (0.1) | 2.5 (0.1) | -0.8 (-1.0, -0.5) |
Source: Adapted from FDA Review
Adjusted mean is from the MMRM that adjusted for visit, visit*treatment, baseline CDR-SB score, baseline score*visit, baseline age, baseline concomitant AChEI or memantine use, pooled investigator, and baseline tau PET category
Abbreviations: AChEI, acetylcholinesterase inhibitor; CDR-SB, Clinical Dementia Rating Scale – Sum of Boxes; CI, confidence interval; MMRM, mixed model for repeated measures; PET, positron emission tomography; SE, standard error
What are the possible side effects?
KISUNLA can cause serious side effects. The most common side effects of KISUNLA include ARIA, headache, 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 who develop ARIA do not get symptoms; however, some people, especially those with swelling in the brain, may have symptoms such as headache, confusion, dizziness, vision changes, nausea, seizures, and difficulty walking. Some of these symptoms may be serious and life-threatening. ARIA can be fatal. While ARIA may occur any time during treatment with KISUNLA, it has most frequently been observed during the first 24 weeks of treatment.
Some people may also develop larger areas of bleeding in the brain while taking KISUNLA which may also 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 (antithrombotic medicines) while receiving KISUNLA.
Some people have a genetic risk factor (homozygous apolipoprotein E [ApoE] ε4 gene carriers) that may cause an increased risk for ARIA. Patients should discuss the risk of ARIA with different ApoE genotypes and the implications of genetic testing results with their health care providers.
Allergic reactions associated with KISUNLA include swelling of the face, lips, mouth, or eyelids, difficulty breathing, and hives. Infusion-related reactions may also occur. Symptoms of infusion-related reactions include chills, irritation of skin, nausea, vomiting, sweating, headache, chest pain, and problems breathing.
What are the possible side effects (results of trials used to assess safety)?
Table 4. Adverse Reactions Reported in at Least 5% of Patients Treated With KISUNLA and at Least 2% Higher Than Placebo Safety Population
| Adverse Reaction | KISUNLA N=853 % |
Placebo N=874 % |
|---|---|---|
| ARIA-Hemorrhage microhemorrhagea | 25 | 11 |
| ARIA-Edema | 24 | 2 |
| ARIA-Hemorrhage superficial siderosisa | 15 | 3 |
| Headache | 13 | 10 |
| Infusion-related reaction | 9 | 0.5 |
Source: KISUNLA Prescribing Information
aAs assessed by MRI. A patient could have both microhemorrhage and superficial siderosis.
Abbreviations: ARIA amyloid-related imaging abnormalities; MRI magnetic resonance imaging
Were there any differences in side effects among sex, race, and age?
- Sex: The occurrence of side effects was similar in males and females.
- Race: The number of patients of races other than White was small; therefore, differences in the occurrence of side effects could not be determined.
- Age: The occurrence of side effects was similar in different age groups.
Were there any differences in side effects in the clinical trials among sex, race, and age groups?
Table 5. Incidence of Common Treatment-Emergent Adverse Events by Sex Safety Population
| Preferred Term | KISUNLA | Placebo | ||
|---|---|---|---|---|
| Male N=365 n (%) |
Female N=488 n (%) |
Male N=373 n (%) |
Female N=501 n (%) |
|
| ARIA – edema or effusion | 84 (23.0) | 120 (24.6) | 10 (2.7) | 7 (1.4) |
| ARIA – microhemorrhages and hemosiderin deposits | 74 (20.3) | 96 (19.7) | 23 (6.2) | 41 (8.2) |
| Infusion related reaction | 32 (8.8) | 42 (8.6) | 2 (0.5) | 2 (0.4) |
| Superficial siderosis of central nervous system | 28 (7.7) | 26 (5.3) | 6 (1.6) | 4 (0.8) |
| Headache | 45 (12.3) | 70 (14.3) | 27 (7.2) | 59 (11.8) |
Source: Adapted from FDA Review
Abbreviations: ARIA amyloid-related imaging abnormalities
Table 6. Incidence of Common Treatment-Emergent Adverse Events by Age Group (Years) Safety Population
| Preferred Term | KISUNLA | Placebo | ||||
|---|---|---|---|---|---|---|
| <65 N=88 n (%) |
≥65 to <75 N=414 n (%) |
≥75 N=351 n (%) |
<65 N=86 n (%) |
≥65 to <75 N=402 n (%) |
≥75 N=386 n (%) |
|
| ARIA – edema or effusion | 20 (22.7) | 107 (25.8) | 77 (21.9) | 2 (2.3) | 9 (2.2) | 6 (1.6) |
| ARIA – microhemorrhages and hemosiderin deposits | 15 (17.0) | 86 (20.8) | 69 (19.7) | 4 (4.7) | 29 (7.2) | 31 (8.0) |
| Infusion related reaction | 10 (11.4) | 37 (8.9) | 27 (7.7) | 0 | 1 (0.2) | 3 (0.8) |
| Superficial siderosis of central nervous system | 4 (4.5) | 30 (7.2) | 20 (5.7) | 0 | 6 (1.5) | 4 (1.0) |
| Headache | 12 (13.6) | 63 (15.2) | 40 (11.4) | 14 (16.3) | 43 (10.7) | 29 (7.5) |
Source: Adapted from FDA Review
Abbreviations: ARIA amyloid-related imaging abnormalities
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 used in clinical trials 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.