Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Donanemab · 14 trials · 18 indications
Percentage of participants with occurrence of ARIA-E at Week 24 is reported here.
Change from Baseline on the iADRS in at least one of the low-medium tau pathology population or no-very low and low-medium tau pathology population.
Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease (AD). Amyloid PET scan assesses cerebral amyloid load using florbetapir tracer which is standardized into Centiloids for evaluation of AD. Florbetapir exhibits high affinity specific binding to amyloid plaques. Centiloid values on Centiloid scale is based on mean composite Standardized Uptake Value Ratio (SUVR) in cingulate, frontal, parietal and temporal cortexes using whole cerebellum as reference region. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. Complete brain amyloid plaque clearance is a binary outcome and is defined as a Centiloid value \<24.1 from the florbetapir F18 PET scan.
Complete brain amyloid plaque clearance is a binary outcome and is defined as a Centiloid value \<24.1 from the florbetapir F18 PET scan.
Time to clinical progression as measured by CDR. CDR is a clinician-rated scale that provides an overall assessment of the participant's stage on the spectrum of Alzheimer's Disease (AD) dementia
Integrated Alzheimer's Disease Rating Scale is used to assess whether donanemab slows down the clinical decline associated with AD compared with placebo. iADRS is an integrated assessment of cognition and daily function comprised of items from the ADAS-Cog13 and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). The scale ranges from 0 to 144, where lower scores indicate worse performance and higher score indicates better performance. Least Squares (LS) Mean value was adjusted for basis expansion terms (two terms), basis expansion term-by-treatment interaction, and covariates for age at baseline, pooled investigator, baseline tau level, and baseline acetylcholinesterase inhibitor (AchI)/Memantine use.
Integrated Alzheimer's Disease Rating Scale is used to assess whether donanemab slows down the clinical decline associated with AD compared with placebo. iADRS is an integrated assessment of cognition and daily function comprised of items from the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). The scale ranges from 0 to 144, where lower scores indicate worse performance and higher score indicates better performance. LS Mean value was adjusted for basis expansion terms (two terms), basis expansion term-by-treatment interaction, and covariates for age at baseline, pooled investigator, and baseline AchI/Memantine use.
Part A didn't involve any drug and drug related efficacy analyses. Participants in Part A were divided into 2 groups, and they completed the same set of clinical assessments. Participants in Part A Group 1 completed the clinical assessments at a clinic site first (on-site) followed by at home assessments (VTC). Participants in Part A Group 2 completed the assessments at home first, followed by on-site assessment. The goal of Part A was to evaluate the comparability of remote and on-site clinical assessments. The intra-class correlation coefficient (ICC), a measure of agreement for continuous outcome measures, was used to determine agreement between remote and onsite assessments for each outcome measure. Outcome measure tested were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Mini Mental State Examination (MMSE), and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).
Percentage of participants with TEAEs and SAEs were reported here. A summary of SAEs and other non-serious AEs, regardless of causality is located in the Reported Adverse Events section of this record.
Number of Participants with Suicidality Based on C-SSRS was reported.
Integrated Alzheimer's Disease Rating Scale is used to assess whether donanemab slows down the cognitive and functional decline associated with AD compared with placebo. iADRS is a simple linear combination of 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). The scale ranges from 0 to 144, where lower scores indicate worse performance and higher score indicates better performance. Least Squares (LS) Mean value was controlled for fixed, categorical effects of treatment, visit and treatment-by-visit interaction, pooled investigator, acetylcholinesterase inhibitor (AChEI) and/or memantine use at baseline, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.
As per the prespecified analysis, AUC\[0-4 weeks\] will be calculated as the sum of AUC0-2weeks for: * treatment period 1 and 2 (dosing days 1, 15 respectively) represented as period 2 * treatment period 3 and 4 (dosing days 29, 43 respectively) represented as period 4 * treatment period 5 and 6 (dosing days 57, 71 respectively) represented as period 6.
PK: Cmax, ss of Donanemab
PK: AUCτ,ss of Donanemab
A summary of SAEs and other non-serious adverse events (AEs), regardless of causality is located in the Reported Adverse Event module. Drug related TEAEs are any untoward medical occurrences that either occurs postdose or presents prior to dosing yet becomes more severe postdose, and in the opinion of the investigator is possibly related to study drug.
Florbetapir PET imaging was used to confirm the presence of amyloid pathology consistent with AD. Change from baseline was done to test the hypothesis that amyloid burden was reduced in participants in the treatment group. The change from baseline to the postbaseline visit of the composite summary standard uptake value ratio of florbetapir F18 was calculated. Least square (LS) mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. The composite summary measure is an unweighted average of the 6 smaller regions (anterior cingulate, frontal medial orbital, parietal, posterior cingulate, precuneus, and temporal) normalized to whole cerebellum or subject-specific white matter.
Data presented are the number of participants who experienced SAEs which were considered to be related to study treatment by the investigator while on treatment and during the follow-up. Summaries of SAEs and other non-serious adverse events (AEs), regardless of causality, are located in the Reported Adverse Events module.
| Arm | Type | Description |
|---|---|---|
| Donanemab | EXPERIMENTAL | Donanemab administered intravenously (IV) |
| Placebo | PLACEBO_COMPARATOR | Placebo IV |
| 1400 mg Donanemab - Standard Regimen | EXPERIMENTAL | Participants received: * 700 milligrams (mg) donanemab administered intravenously (IV) at baseline, week 4, and 8. * placebo administered IV at week 2, 6, 10, and 14. * 1400 mg of donanemab administered IV at week 12, 16, 20, and 24. Participants enrolled to addendum 3 will receive a single dose at least 12 months after their last dose |
| 1400 mg Donanemab - Dose Skipping | EXPERIMENTAL | Participants received: * 700 mg donanemab administered IV at baseline. * placebo administered IV at week 2, 4, 6, 10, and 14. * 1400 mg of donanemab administered IV at week 8, 12, 16, 20, and 24. Participants enrolled to addendum 3 will receive a single dose at least 12 months after their last dose |
| 1400 mg Donanemab - Titration | EXPERIMENTAL | Participants received: * 350 mg donanemab administered IV at baseline. * placebo administered IV at week 2, 6, 10, and 14. * 700 mg donanemab administered IV at week 4. * 1050 mg of donanemab administered IV at week 8. * 1400 mg of donanemab administered IV at week 12, 16, 20, and 24. Participants enrolled to addendum 3 will receive a single dose at least 12 months after their last dose |
| 1400 mg Donanemab - Maximum Concentration (Cmax) | EXPERIMENTAL | Participants received: * 350 mg donanemab administered IV at baseline, weeks 2, 4, 6, 8, and 10. * 700 mg donanemab administered IV at weeks 12 and 14. * 1400 mg of donanemab administered IV at weeks 16, 20, and 24. Participants enrolled to addendum 3 will receive a single dose at least 12 months after their last dose |
| Donanemab Addendum 2 Arm 1 | EXPERIMENTAL | Participants will receive donanemab by IV infusion. Participants will receive placebo pretreatment to preserve the blind prior to donanemab infusion. |
| Donanemab Addendum 2 Arm 2 | EXPERIMENTAL | Participants will receive donanemab by IV infusion. Participants will receive dexamethasone pretreatment prior to donanemab infusion |
| Aducanumab | ACTIVE_COMPARATOR | Aducanumab administered IV per US label. |
| Donanemab (LY3002813) | EXPERIMENTAL | Donanemab (LY3002813) administered as an intravenous (IV) infusion |
| Part A: Validation of Remote Scale Assessments | OTHER | Participants from the originating trials did not receive any drug in Part A. Participants were randomized 1:1 into two groups to have their cognitive and functional scales assessed. Group 1: Cognitive/functional scale assessment at the study site (on-site), followed by an at-home assessment (VTC; video teleconference), or Group 2: Cognitive/functional scale assessment at home (VTC), followed by assessment on-site. Total time in Part A was up to 24 weeks. |
| Part B: Donanemab | EXPERIMENTAL | Participants who had received placebo in the originating trials received 700 milligrams (mg) donanemab administered intravenously (IV) every 4 weeks (Q4W) for 3 doses, then 1400 mg donanemab administered IV Q4W for up to 48 weeks. |
| Donanemab Monotherapy (Donanemab-M) | EXPERIMENTAL | Participants received 700 milligram (mg) donanemab intravenously (IV) every 4 weeks (Q4W) x 3 doses, then 1400 mg donanemab IV Q4W for up to 72 weeks. |
| Donanemab in Combination With LY3202626 (Donanemab-C) | EXPERIMENTAL | Participants received 700 mg donanemab IV Q4W x 3 doses, then 1400 mg donanemab IV Q4W in combination with 12 mg of LY3202626 orally for up to 72 weeks. As per protocol amendment (d) approved on Oct 9, 2018, donanemab in combination with LY3202626 (donanemab-C) arm discontinued as there was a low probability of identifying a statistically significant effect of 12mg of LY3202626 slowing cognitive decline. |
| 350 milligram (mg) Donanemab | EXPERIMENTAL | Single 350 mg Donanemab dose administered intravenously (IV) on Day 1. |
| 700 mg Donanemab | EXPERIMENTAL | Single 700 mg Donanemab dose administered IV on Day 1. |
| 1400 mg Donanemab | EXPERIMENTAL | Single 1400 mg Donanemab dose administered IV on Day 1. |
| Part A: Placebo Single Dose (SD) | PLACEBO_COMPARATOR | Participants received single intravenous (IV) dose of placebo. |
| Part A: 10 Milligram Per Kilogram (mg/kg) LY3002813 SD | EXPERIMENTAL | Participants received single IV dose of 10 mg/kg LY3002813. |
| Part A: 20 mg/kg LY3002813 SD | EXPERIMENTAL | Participants received single IV dose of 20 mg/kg LY3002813. |
| Part A: 40 mg/kg LY3002813 SD | EXPERIMENTAL | Participants received single IV dose of 40 mg/kg LY3002813. |
| Part B: Placebo Q2W | PLACEBO_COMPARATOR | Participants received multiple IV dose of placebo every 2 weeks (Q2W) for 24 weeks. |
| Part B: 10 mg/kg LY3002813 Q2W | EXPERIMENTAL | Participants received multiple IV dose of 10 mg/kg LY3002813 Q2W for 24 weeks. |
| Part C: Placebo Q4W | PLACEBO_COMPARATOR | Participants received multiple IV dose of placebo every 4 weeks (Q4W) for 72 weeks. |
| Part C:10 mg/kg LY3002813 Q4W | EXPERIMENTAL | Participants received multiple IV dose of 10 mg/kg LY3002813 Q4W for 72 weeks. |
| Part C:20 mg/kg LY3002813 Q4W | EXPERIMENTAL | Participants received multiple IV dose of 20 mg/kg LY3002813 Q4W for 72 weeks. |
| LY3002813-Single 0.1 mg/kg then multiple 0.3 mg/kg | EXPERIMENTAL | 0.1 milligram per kilogram (mg/kg) single dose then 0.3 mg/kg LY3002813 given every 4 weeks for up to 16 weeks intravenously (IV) |
| LY3002813-Single then multiple 0.3 mg/kg | EXPERIMENTAL | 0.3 mg/kg single dose then 0.3 mg/kg LY3002813 given every 4 weeks for up to 16 weeks IV |
| LY3002813-Single 1 mg/kg in Healthy Participants | EXPERIMENTAL | 1 mg/kg single dose LY3002813 given once by IV infusion. |
| LY3002813-Single then multiple 1 mg/kg | EXPERIMENTAL | 1 mg/kg single dose then 1 mg/kg LY3002813 given every 4 weeks for up to 16 weeks IV |
| LY3002813-Single then multiple 3 mg/kg | EXPERIMENTAL | 3 mg/kg single dose then 3 mg/kg LY3002813 given every 4 weeks for up to 16 weeks IV |
| LY3002813-Single then multiple 10 mg/kg | EXPERIMENTAL | 10 mg/kg single dose then 10 mg/kg LY3002813 given every 4 weeks for up to 16 weeks IV |
| Placebo-Single then multiple | PLACEBO_COMPARATOR | Placebo given once, then every 4 weeks for up to 16 weeks IV |
| LY3002813-SC | EXPERIMENTAL | Up to 3 mg/kg LY3002813 given once subcutaneously (SC) |
| LY3002813-IV | EXPERIMENTAL | Up to 3mg/kg LY3002813 given once intravenously (IV) |
| Name | Type | Description |
|---|---|---|
| Donanemab | DRUG | Administered IV |
| Placebo | DRUG | Administered IV |
| Dexamethasone | DRUG | Administered IV |
| Aducanumab | DRUG | Participants received aducanumab administered by IV infusion per US label (prescribing information/routine clinical practice). |
| No Intervention | OTHER | No intervention |
| LY3202626 | DRUG | Administered orally |
| LY3002813 | BIOLOGICAL | Administered IV |
| LY3002813-IV | BIOLOGICAL | Administered IV |
| LY3002813-SC | BIOLOGICAL | Administered SC |
| Placebo-IV | DRUG | Administered IV |
Inclusion Criteria: * Have completed study AACM Addendum 7. * Have a reliable study partner and backup study partner familiar with overall function and behavior, such as day-to-day activities and cognitive abilities. * Are individuals assigned female at birth who are not of childbearing potential, ...
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