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Kisunla ^™ (donanemab-azbt) injection, for intravenous infusion

350 mg/20 mL (17.5 mg/mL)

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What is the efficacy of Kisunla™ (donanemab-azbt) in the treatment of early symptomatic Alzheimer’s disease?

At week 76 in the TRAILBLAZER-ALZ 2 study, donanemab-treated participants had a 22.3% slowing of clinical progression as measured by the iADRS, and 76% reached amyloid reduction to minimal levels (ie, <24.1 CL) in the combined population.

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See important safety information, including boxed warning, in the attached prescribing information.

TRAILBLAZER-ALZ 2 Trial of Donanemab in Patients With Early Symptomatic Alzheimer's Disease

The safety and efficacy of donanemab were evaluated in TRAILBLAZER-ALZ 2, a phase 3, placebo-controlled 72-week study. This study enrolled adults aged 60 to 85 years with early symptomatic Alzheimer's disease (AD), defined as

prodromal AD, the symptomatic phase of AD in which mild cognitive impairment is apparent, or
AD with mild dementia, in which symptoms are sufficiently severe to meet diagnostic criteria for dementia.1

Eligible participants had

a Mini-Mental State Examination (MMSE) score of 20 to 28 (scores range from 0 to 30, with higher scores indicating better mental performance), and
presence of amyloid pathology assessed by amyloid positron emission tomography (PET) imaging (≥37 centiloids [CL]) with either florbetapir F 18 or florbetaben F 18, and tau pathology assessed by flortaucipir F 18 PET imaging.1

Tau PET scans were interpreted by visual and quantitative reads and categorized as

low/medium or
high tau.1

The Appendix provides a description of the study populations by tau PET level at baseline.

Participants were randomized at the beginning of double-blind treatment in a 1:1 ratio to receive intravenous infusions every 4 weeks of either

donanemab 700 mg for the first 3 doses and 1400 mg thereafter (n=860), or
placebo (n=876; administered as saline).1,2

Completion of active treatment in the clinical trial was guided by amyloid PET levels measured at week 24 and week 52. Participants were eligible to be switched to placebo if the amyloid plaque level was

<11 CL on a single PET scan, or
11 to <25 CL on 2 consecutive PET scans.1

Efficacy Results in Donanemab-Treated Participants With Early Symptomatic Alzheimer's Disease

The efficacy results summarized include

Clinical Outcomes
Key Biomarker Outcomes, and
Time Prolonged in Current Disease State.

Clinical Outcomes

The primary outcome of TRAILBLAZER-ALZ 2 was a change in the Integrated Alzheimer's Disease Rating Scale (iADRS) from baseline through week 76 in either the

combined low/medium tau pathology and high tau population, or
low/medium tau population.1,3

Worsening scores on the iADRS have been significantly associated with decreased patient quality of life, as well as increased burden on caregivers and society.4 The iADRS is an integrated score ranging from 0 to 144, and includes the

Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13-item version (ADAS-Cog₁₃), range 0-85, with higher scores correlating to greater global cognition deficit, and
Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL), range 0 to 59, with lower scores correlating to greater deficit in daily function.5

To align the scales, the ADAS-Cog₁₃ score is multiplied by -1, so that lower iADRS overall score correlates to greater impairment.5

The baseline iADRS score was similar between donanemab and placebo (approximately 104 in the combined population and approximately 106 in the low/medium tau population, on scale of 0 to 144). TRAILBLAZER-ALZ 2 Clinical Outcomes at Week 76 shows that compared with placebo, the donanemab cohort had a slowing of clinical progression at week 76 as evidenced by iADRS scores in the

combined population (22.3%, p<.001), and
low/medium tau population (35.1%, p<.001).1

Secondary clinical outcome measures included change from baseline through week 76 in either the combined or low/medium tau population as measured by the

Clinical Dementia Rating scale sum of boxes (CDR-SB)
ADAS-Cog₁₃ score
ADCS-iADL score, and
MMSE score.1

Participants in the donanemab cohort experienced statistically significantly less decline on these measures at week 76 compared with placebo, in both the combined and low/medium tau populations (TRAILBLAZER-ALZ 2 Clinical Outcomes at Week 76 ).1

TRAILBLAZER-ALZ 2 Clinical Outcomes at Week 761,3
Clinical Endpointsa	Combined Population		Low/Medium Tau
Clinical Endpointsa	Donanemab (N=860)	Placebo (N=876)	Donanemab (N=588)	Placebo (N=594)
iADRSb^,c
Mean baseline	104.55	103.82	105.92	105.95
Change from baseline	-10.19	-13.11	-6.02	-9.27
Difference from placebo (%)	2.92 (22)d	NA	3.25 (35)d	NA
CDR-SBe^,c
Mean baseline	3.92	3.89	3.72	3.64
Change from baseline	1.72	2.42	1.20	1.88
Difference from placebo (%)	-0.70 (29)d	NA	-0.67 (36)d	NA
ADAS-Cog₁₃b^,c
Mean baseline	28.53	29.16	27.41	27.60
Change from baseline	5.46	6.79	3.17	4.69
Difference from placebo (%)	-1.33 (20)d	NA	-1.52 (32)d	NA
ADCS-iADLb^,c
Mean baseline	47.96	47.98	48.20	48.56
Change from baseline	-4.42	-6.13	-2.76	-4.59
Difference from placebo (%)	1.70 (28)d	NA	1.83 (40)d	NA
MMSEb
Mean baseline	22.52	22.20	23.11	22.88
Change from baseline	-2.47	-2.94	-1.61	-2.09
Difference from placebo (%)	0.47 (16)f	NA	0.48 (23)g	NA

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; iADRS = integrated Alzheimer’s Disease Rating Scale; NCS2 = natural cubic spline with 2 degrees of freedom; MMRM = mixed model for repeated measures; MMSE = Mini-Mental State Examination; NA = not applicable.

aClinical outcomes were scored as follows: iADRS range from 0 to 144, with lower scores indicating greater impairment; CDR-SB scores range from 0 to 18, with higher scores indicating greater impairment; ADAS-Cog₁₃ scores range from 0 to 85, with higher scores indicating a greater deficit; ADCS-iADL scores range from 0 to 59, with lower scores indicating greater impairment; MMSE scores range from 0 to 30, with lower scores indicating greater impairment.

bAssessed using NCS2 analysis.

cGated outcome.

dp<.001 vs placebo.

eAssessed using MMRM analysis.

fp=.01 vs placebo.

gp=.02 vs placebo.

Key Biomarker Outcomes

Secondary biomarker outcome measures included

percentage of participants with amyloid reduction to minimal levels (ie, <24.1 CL on amyloid PET) at 24 and 76 weeks, and
change from baseline in amyloid plaque levels at 76 weeks.1

Donanemab-treated participants met eligibility to switch to placebo1,6 and had amyloid reduction to minimal levels1 as early as week 24, and at all time points with scheduled amyloid PET scan in both the combined and low/medium tau populations (Percentage of Donanemab-Treated Participants With Amyloid Plaque Reduction in TRAILBLAZER-ALZ 2). In contrast, ≤0.3% of participants receiving placebo had amyloid reduction to minimal levels at any time point (p<.0001 vs donanemab).1

Percentage of Donanemab-Treated Participants With Amyloid Plaque Reduction in TRAILBLAZER-ALZ 21,6
	Combined Population, % (n/N)			Low/Medium Tau Population, % (n/N)
	Week 24	Week 52	Week 76	Week 24	Week 52	Week 76
Eligible for switch to placeboa^,b	17 (130/761)	47 (313/672)	69 (429/620)	20 (106/521)	52 (241/464)	74 (321/437)
Amyloid plaque reduction to minimal levelsc	30 (226/761)	66 (443/670)	76 (469/614)	34 (178/521)	71 (330/463)	80 (347/433)

Abbreviations: CL = centiloids; PET = positron emission tomography.

aEligibility criteria: amyloid plaque level of <11 CL on any single amyloid PET scan or 11 to <25 CL on 2 consecutive scans.

bIncluded participants from unscheduled visits at each time point.

cDefined as <24.1 CL on amyloid PET scan, consistent with a negative visual read.

As shown in Change From Baseline in Amyloid Plaque Levels at Week 76 in TRAILBLAZER-ALZ 2, donanemab-treated participants had statistically significantly greater amyloid plaque reduction from baseline compared with placebo-treated participants as assessed by amyloid PET measurement in the

combined population (-87 CL), and
low/medium tau population (-88 CL).1

Placebo-treated participants had a change of -0.7 CL in the combined population and 0.2 CL at week 76 in the low/medium tau population.1

Change From Baselinea in Amyloid Plaque Levels at Week 76 in TRAILBLAZER-ALZ 21,3,6
	Combined Population		Low/Medium Tau
	Donanemab (N=765)	Placebo (N=812)	Donanemab (N=525)	Placebo (N=556)
Amyloid beta PET centiloid
Mean baseline	104.0	101.8	103.0	100.9
Change from baseline (%)	-87.0 (-83.7)	-0.7	-88.0 (-85.5)	0.2
Difference from placebo	-86.4b	NA	-88.2b	NA

Abbreviations: MMRM = mixed model for repeated measures; NA = not applicable; PET = positron emission tomography.

aChange from baseline derived using MMRM methodology with fixed factors for treatment, visit, treatment-by-visit interaction, and covariates for baseline score, baseline score-by-visit interaction, baseline tau category, and age at baseline.

bp<.0001 vs placebo.

The treatment effect of donanemab on changes in plasma phosphorylated-tau 217 (P-tau217) at week 76 was also evaluated as an exploratory outcome.1

A reduction in plasma P-tau217 was observed with donanemab compared to placebo in the combined and low/medium tau populations (Change From Baseline in Plasma P-tau217 at Week 76 in TRAILBLAZER-ALZ 2).1,3

Change From Baselinea in Plasma P-tau217 at Week 76 in TRAILBLAZER-ALZ 21,3,6
	Combined Population		Low/Medium Tau
	Donanemab (N=758)	Placebo (N=786)	Donanemab (N=522)	Placebo (N=537)
Mean baseline	0.67	0.66	0.62	0.59
Change from baseline (% of original value)	-0.19 (-35.0)	0.03	-0.22 (-39.0)	0.04
Difference from placebo	-0.22b	NA	-0.25b	NA

Abbreviations: MMRM = mixed model for repeated measures; NA = not applicable; P-tau217 = tau phosphorylated at threonine 217.

aChange from baseline and p-value are derived using MMRM methodology with fixed factors for treatment, visit, treatment-by-visit interaction, and covariates for baseline score, baseline score-by-visit interaction, and age at baseline.

bp<.0001 vs placebo.

Time Prolonged in Current Disease State

The TRAILBLAZER-ALZ 2 study evaluated the efficacy of donanemab to prolong time in the current disease state for participants as exploratory outcomes by assessing the

delay in clinical progression on the iADRS and CDR-SB (ie, months saved with treatment)
risk of progression to a later stage using CDR-Global (CDR-G), and
probability of remaining stable at 1 year on the CDR-SB (ie, nonprogressing).1

Donanemab-treated participants experienced statistically significantly less disease progression compared with placebo in all the time-based efficacy analyses.1

Delay in Clinical Progression

The delay in clinical progression due to donanemab treatment as assessed by the iADRS and CDR-SB was estimated using a time-progression model for repeated measures (PMRM).1,6

As summarized in Delayed Disease Progression at 76 Weeks in TRAILBLAZER-ALZ 2, donanemab treatment statistically significantly delayed disease progression at week 76 compared with placebo as measured by the iADRS and CDR-SB in the

combined population, and
low/medium tau population.1

Delayed Disease Progression at 76 Weeks in TRAILBLAZER-ALZ 21,6
	iADRSa b	CDR-SBa c
Combined populationd
Months saved vs placebo	2.5	5.4
Percent time savings	14.1	31
P value vs placebo	<.001	<.001
Low/medium tau population
Months saved vs placebo	4.4b	7.5
Percent time savings	24.9	42.9
P value vs placebo	<.001	<.001

Abbreviations: CDR-SB = Clinical Dementia Scale - Sum of Boxes; iADRS = Integrated Alzheimer's Disease Rating Scale.

aiADRS scores range from 0 to 144, with lower scores indicating greater impairment, and CDR-SB scores range from 0 to 18, with higher sores indicating greater clinical impairment.

bThe model did not assume proportional time slowing. Results from the prespecified test of proportional time slowing assumption at 76 weeks was 2.6 months saved, p=.002, but the proportional time slowing assumption was not met for the iADRS (p=.001 from a likelihood ratio test).

cThe model assumed proportional time slowing.

dNot prespecified as gated in the statistical analysis plan.

Risk of Disease Progression

A clinical worsening event was defined as meeting a CDR-G score increase from baseline at 2 consecutive visits. A Cox proportional hazard model was fit to estimate the hazard ratio of progressing to clinical worsening between treatment groups.6

Donanemab-treated participants had a lower risk of disease progression to the next stage through week 76 compared with placebo as measured by the CDR-G scale in the

combined population (-37%, p<.0001 vs placebo), and
low/medium tau population (-39%, p<.001 vs placebo).1,3

Probability of Remaining Stable at 1 Year (Nonprogressing)

To evaluate the probability of remaining stable, participants' status was classified as "nonprogressing" if their CDR-SB change from baseline was ≤0 at each of the scheduled visits.6

At Week 52, a statistically significantly greater proportion of donanemab-treated participants were non-progressing compared with placebo, in the

combined population, and
low/medium tau population (No Progression at 52 Weeks as Measured by CDR-SB in TRAILBLAZER-ALZ 2 ).1

No Progressiona at 52 Weeks as Measured by CDR-SBb in TRAILBLAZER-ALZ 21
	Donanemab	Placebo
Combined populationc
Estimated percent with no progression	36%	23%
P value vs placebo	<.001	NA
Low/medium tau population
Estimated percent with no progression	47%	29%
P value vs placebo	<.00001	NA

Abbreviations: CDR-SB = Clinical Dementia Rating Scale - Sum of Boxes; NA = not applicable.

aNo progression was defined as a CDR-SB score change from baseline of ≤0.

bCDR-SB scores range from 0 to 18, with higher scores indicating greater clinical impairment.

cNot specified as gated in the statistical analysis plan.

Enclosed Prescribing Information

KISUNLA™ (donanemab-azbt) injection, for intravenous use, Lilly

References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1Sims JR, Zimmer JA, Evans CD, et al; TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527. https://doi.org/10.1001/jama.2023.13239

2Solomon PR. TRAILBLAZER-ALZ 2: clinical background and study design. Abstract presented at: Alzheimer's Association International Conference (AAIC); July 16-20, 2023; Amsterdam, Netherlands.

3Kisunla [package insert]. Indianapolis, IN: Eli Lilly and Company; 2024.

4Wessels AM, Belger M, Johnston JA, et al. Demonstration of clinical meaningfulness of the Integrated Alzheimer’s Disease Rating Scale (iADRS): association between change in iADRS scores and patient and caregiver health outcomes. Alzheimers Dis. 2022;88(2):577-588. https://doi.org/10.3233/JAD-220303

5Wessels AM, Rentz DM, Case M, et al. Integrated Alzheimer's Disease Rating Scale: clinically meaningful change estimates. Alzheimer's Dement. 2022;8(1):e12312. https://doi.org/10.1002/trc2.12312

6Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Appendix

Definitions of Populations by Baseline Tau PET Levels

Populations by Baseline Flortaucipir F 18 Tau PET Levels1
Population Analyzed	Description
Low/medium tau	Population including participants with baseline SUVr ≤1.46 and a topographic deposition pattern consistent with advanced AD neuropathology, or 1.10 ≤ SUVr ≤1.46 and a topographic deposition pattern consistent with moderate AD neuropathology.
High tau	Population including participants with baseline SUVr >1.46 and a topographic deposition pattern consistent with either moderate or advanced AD neuropathology.
Combined population	Population including participants with both low/medium tau and high tau levels.

Abbreviations: AD = Alzheimer's disease; PET = positron emission tomography; SUVr = standard value uptake ratio.

Date of Last Review: August 23, 2023

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Kisunla ™ (donanemab-azbt) injection, for intravenous infusion