Synonyms: N3pG-Aβ Monoclonal Antibody, LY3002813
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Eli Lilly & Co.
Donanemab, aka N3pG, is a humanized IgG1 monoclonal antibody developed from mouse mE8-IgG2a. This biologic drug recognizes Aβ(p3-42), a pyroglutamate form of Aβ that is aggregated in amyloid plaques. Most Aβ antibodies in therapeutic development bind various soluble or insoluble species but have low affinity to deposited amyloid plaques. The rationale behind donanemab is that targeting deposited plaque itself is necessary to clear existing amyloid burden from the brain, rather than merely prevent deposition of new plaques or growth of existing plaques. Some previous plaque-binding antibodies have been abandoned because they caused microhemorrhages in the brain. The mE8 antibody was reported to clear plaques in mice without causing microhemorrhages (Demattos et al., 2012).
At the 2014 AAIC conference, Lilly reported that a randomized preclinical study of combination therapy with N3pG and the BACE inhibitor LY2811376 cleared more than 80 percent of amyloid from the brains of PDAPP-transgenic mice, compared to about 50 percent clearance each for the respective monotherapies. Neuropathology studies showed that donanemab removed both cored and diffuse plaques (see Jul 2014 conference news).
From May 2013 to August 2016, Lilly ran a Phase 1 study in 100 people with mild cognitive impairment due to Alzheimer's disease, or mild Alzheimer's disease, in the United States and Japan. Participants had to have a positive amyloid PET scan. This seven-arm study evaluated five intravenous doses from 0.1 mg/kg to 10 mg/kg, infused monthly up to four times, and a single subcutaneous injection against placebo for safety, pharmacokinetics, and pharmacodynamics. At the 2016 AAIC conference in Toronto, Lilly presented results from 49 patients, average age 74, who had completed the trial. Thirty-seven volunteers received a single initial dose, 12 placebo. After adverse-event monitoring, they received up to four additional monthly infusions of the same dose; people in the 0.1mg/kg cohort subsequently received 0.3mg/kg. The highest dose was reported to reduce plaque load in the brain, though that group had but six participants. Overall, their mean florbetapir SUVR fell from 1.65 at baseline by 0.26 over seven months, corresponding to a 40 percent reduction. No cases of ARIA-E were seen in this small trial, but there were two asymptomatic cases of ARIA-H. The antibody was reported to be strongly immunogenic. In the multiple-dose phase, six of the 37 patients had an infusion reaction with chills, flushing, dizziness, rash, and fever, and anti-drug antibodies in plasma (Aug 2016 conference news; Irizarry et al. 2016). Full trial results are published (Lowe et al., 2021). Only the 10 mg/kg dose reduced amyloid deposits, and the drug had a shorter than expected half-life of 10 days. Most people developed anti-drug antibodies within three months of dosing.
In December 2015, Lilly started a second Phase 1 study in 150 people with prodromal to moderate AD, again in the United States and Japan. This trial had three dosing regimens, the first consisting of a single dose of 10, 20, or 40 mg/kg, the second of 10 mg/kg every other week for 24 weeks, and the third of 10 or 20 mg/kg every month for 16 months. Participants were randomized 3:1 to drug or placebo. The study measured primarily donanemab's effect on brain amyloid load with florbetapir PET; secondary outcomes were blood pharmacokinetics of donanemab and auto-antibodies directed against this biologic drug. At the 2018 AAIC, Lilly reported that a six-month course of 20 mg/kg shrank amyloid load by an average of 70 centiloids, with three of the six people who had reached that timepoint falling below the threshold for amyloid positivity. About one in four participants developed ARIA-E, mostly asymptomatic. Nearly all patients made anti-drug antibodies, and one had an infusion reaction (Aug 2018 conference news).
This trial ended in August 2019, having enrolled 61 people. According to a presentation at the 2019 CTAD conference, monthly doses of 10 or 20 mg/kg for 16 months reduced amyloid by an average of 90 to 100 centiloids. All five people on the higher dose fell below the amyloid-positivity threshold. As observed at the earlier timepoint, one-quarter of patients developed ARIA-E; two cases were symptomatic and resolved after dosing stopped (Dec 2019 conference news). Trial results were peer-reviewed and published (Lowe et al., 2021).
In December 2017, Lilly began TRAILBLAZER-ALZ, a combination trial of two investigational drugs targeting different points in the amyloid cascade. This Phase 2 study was to evaluate safety, tolerability, and efficacy of an 18-month course of donanemab alone and in combination with Lilly's BACE inhibitor LY3202626. It aimed to enroll 375 participants whose memories had been worsening for at least six months, who met a cutoff on the CogState Brief Battery, and who had positive flortaucipir PET scans between 1.15 and 1.46 SUVR. Within this range, people have detectable cognitive decline over one to two years, but are not yet at advanced disease stages. Because the antibody requires an infusion and the BACE inhibitor comes as a capsule, the three treatment arms in this blinded, placebo-controlled trial were as follows: One group received intravenous donanemab plus placebo administered orally, the second group received intravenous donanemab plus LY3202626 orally, the third group received both intravenous and oral placebo. Hence the trial was to evaluate the antibody alone and in combination with the BACE inhibitor, but not the BACE inhibitor alone. The primary outcome is change on the Integrated Alzheimer's Disease Rating Scale (iADRS), a combined cognitive/functional measure for early stage AD developed by Lilly (Wessels et al., 2015). Secondary measures include the ADAS-Cog13, CDR-Sum of Boxes, MMSE, ADCS-iADL, as well as amyloid and tau PET and volumetric MRI. To ease the logistical burden of trial participation, this study offers rides to and from study sites via a partnership between GAP and the ridesharing company Lyft. The study started up at 63 sites in North America and was set to run until October 2020 (Irizarry et al., 2006).
In October 2018, Lilly discontinued the BACE inhibitor arm of this trial; evaluation of donanemab remains ongoing, with a revised enrollment estimate of 266 participants.
In January 2021, Lilly announced by press release that TRAILBLAZER-ALZ had met its primary endpoint, with donanemab slowing decline on the iADRS by 32 percent compared to placebo at 18 months (Jan 2021 news). The company claimed improvement on all secondary endpoints of cognition and function, although not all were statistically significant. Treatment resulted in an average reduction in amyloid plaque by 84 centiloids, from 108 at baseline. Safety was similar to earlier trials. ARIA-E developed in 27 percent of treated patients, with 6 percent becoming symptomatic. According to data presented at AD/PD and simultaneously published, two-thirds of treated participants were amyloid-negative by the end of the trial. Donanemab slowed the rate of accumulation of tau neurofibrillary tangles in the frontal cortex and other regions (Mar 2021 conference news; Mintun et al., 2021). All secondary clinical measures trended in favor of treatment, but only the ADAS-Cog13 slowed significantly, by 39 percent. In addition to ARIA-E, treated participants also had more ARIA-H, superficial siderosis due to small brain bleeds, and nausea. The groups did not differ in serious adverse events or death. Ninety percent of patients developed anti-drug antibodies. Like other anti-amyloid treatments, donanemab treatment accelerated brain shrinkage assessed by MRI. Loss of brain volume is sometimes attributed to amyloid removal; however, the extent of this effect and timing relative to donanemab administration may point to other causes, possibly inflammation (Ayton, 2021).
At the July 2021 AAIC, the company showed additional data from TRAILBLAZER-ALZ. Donanemab led to rapid amyloid reduction in the first six months of treatment, which was sustained to the end of the trial. Participants who cleared amyloid below a brain-wide threshold, and were switched to placebo, did not reaccumulate amyloid after one year. People with amyloid clearance also showed a reduction in tau burden in the temporal, parietal, and frontal lobes, and a significant decline in the biomarker plasma ptau217. At end of the trial, ptau217 concentrations fell by 24 percent in the treated group, while rising 6 percent in placebo (see Aug 2021 conference news).
In November 2020, an open-label extension began to enroll 100 participants for a one-month validation of at-home assessments, followed by 18 months of donanemab. The primary endpoints are correlation between video teleconference and in-clinic scores on ADAS-Cog, ADCS-ADL, MMSE, CDR-SB in the first month, and safety over the entire dosing period. Secondary outcomes are changes in cognitive and functional measures, amyloid PET, and MRI from baseline to 18 months, as well as pharmacokinetics, and development of anti-donanemab antibodies. The extension will run through early 2023.
In October 2020, Lilly began recruiting for TRAILBLAZER-ALZ 2, initially as a Phase 2 safety and efficacy trial in 500 people with early Alzheimer’s. Inclusion criteria are similar to TRAILBLAZER-ALZ, i.e., participants must have had a progressive and gradual memory decline for at least six months, MMSE scores between 20 and 28, and meet criteria on amyloid and tau PET scans. Participants will receive donanemab or placebo, with the primary outcome being change in CDR-Sum of Boxes after 18 months. Secondary measures include the MMSE, ADAS-Cog13, iADRS, and ADCS-iADL, amyloid and tau PET, and volumetric MRI, plus pharmacokinetics and measures of anti-donanemab antibodies. The trial is set to run through early 2024 at 87 sites in the U.S., Canada, Japan, The Netherlands, and Poland.
Since then, Lilly has enlarged TRAILBLAZER-ALZ 2 to become a Phase 3 registration study with 1,500 participants. The ongoing study has already enrolled some people with tau-PET above 1.46 SUVR, but primary efficacy will be determined in 1,000 people who are below this cut-off. The primary outcome will be iADRS, and effectiveness will be judged using a disease-progression model, rather than solely on change at the final time point. Results are expected in the first half of 2023.
In June 2021, the FDA granted donanemab Breakthrough Therapy designation, to speed development and review. Lilly announced it will submit a licensing application in 2021, under the same accelerated approval pathway used for aducanumab, and based on the TRAILBLAZER-ALZ trial data (press release).
In August 2021, Lilly and the Banner Alzheimer’s Institute began a placebo-controlled Phase 3 prevention trial. Called TRAILBLAZER-ALZ3, it aims to enroll 3,300 cognitively normal people at high risk for AD based on elevated plasma ptau217. The study will run for three years, though the donanemab treatment period is intended to be brief. The primary outcome is time to clinical progression measured by the Clinical Dementia Rating–Global Score. Secondary outcomes include a battery of cognitive tests, steady-state donanemab concentration in plasma, and the incidence of anti-donanemab antibodies. Assessments and monitoring will be done remotely using video calls and tablets. The trial will run at 82 sites in the U.S. until September 2027 (see Jul 2021 news).
For all trials of this antibody, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 13 Oct 2021
- New Ways to Target Aβ and BACE Show Promising Phase 1 Data
- Four Immunotherapies Now Banish Amyloid From the Brain
- Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
- In Phase 2, Donanemab Curbs Cognitive Decline in Early Alzheimer’s
- Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
- On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
- Can Donanemab Prevent AD? Phase 3 TRAILBLAZER-ALZ3 Aims to Find Out
- Anti-Amyloid Therapies Combine Forces to Knock Out Plaques
- Irizarry MC, Sims JR, Lowe SL, Nakano M, Hawdon A, Willis BA, Gonzales C, Liu P, Fujimoto S, Dean RA, Konrad RJ, Shcherbinin Se, Schwarz AJ, Mintun MA, Devous MD, DeMattos RB, A.A.C.C. Investigators. O4‐08‐06: Safety, Pharmacokinetics (PK), and Florbetapir F-18 Positron Emission Tomography (PET) After Multiple Dose Administration of LY3002813, a β‐Amyloid Plaque-Specific Antibody, in Alzheimer's Disease (AD). Alzheimer's & Dementia, July 2016
- Lowe SL, Willis BA, Hawdon A, Natanegara F, Chua L, Foster J, Shcherbinin S, Ardayfio P, Sims JR. Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. Alzheimers Dement (N Y). 2021;7(1):e12112. Epub 2021 Feb 14 PubMed.
- Lowe SL, Duggan Evans C, Shcherbinin S, Cheng YJ, Willis BA, Gueorguieva I, Lo AC, Fleisher AS, Dage JL, Ardayfio P, Aguiar G, Ishibai M, Takaichi G, Chua L, Mullins G, Sims JR. Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging. J Prev Alzheimers Dis. 2021;8(4):414-424. PubMed.
- Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims JR, Sundell K, Stern Y, Rentz DM, Dubois B, Jones RW, Cummings J, Aisen PS. A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS). J Prev Alzheimers Dis. 2015 Dec 1;2(4):227-241. PubMed.
- Irizarry MC, Fleisher AS, Hake AM, Liu P, Shcherbinin S, DeMattos RB, Mintun MA, I5T‐MC‐AACG investigators. P4‐388: Trailblazer‐Alz (Nct03367403): A Phase 2 Disease‐Modification Combination Therapy Trial Targeting Multiple Mechanisms of Action Along the Amyloid Pathway. Alzheimer's & Dementia, July 2006
- Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, Shcherbinin S, Sparks J, Sims JR, Brys M, Apostolova LG, Salloway SP, Skovronsky DM. Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.
- Ayton S. Brain volume loss due to donanemab. Eur J Neurol. 2021 Sep;28(9):e67-e68. Epub 2021 Jul 16 PubMed.
- Demattos RB, Lu J, Tang Y, Racke MM, DeLong CA, Tzaferis JA, Hole JT, Forster BM, McDonnell PC, Liu F, Kinley RD, Jordan WH, Hutton ML. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron. 2012 Dec 6;76(5):908-20. PubMed.
- Roh JH, Holtzman DM. Stealth attack: plaque-specific antibody allows for efficient Aβ removal without side effects. Neuron. 2012 Dec 6;76(5):859-61. PubMed.
- Hettmann T, Gillies SD, Kleinschmidt M, Piechotta A, Makioka K, Lemere CA, Schilling S, Rahfeld JU, Lues I. Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer's disease with reduced complement activation. Sci Rep. 2020 Feb 24;10(1):3294. PubMed.
- Bayer TA. N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease. Front Aging Neurosci. 2021;13:710579. Epub 2021 Aug 20 PubMed.
- Doggrell SA. Still grasping at straws: donanemab in Alzheimer's disease. Expert Opin Investig Drugs. 2021 Aug;30(8):797-801. Epub 2021 Jul 8 PubMed.
- Decourt B, Boumelhem F, Pope ED 3rd, Shi J, Mari Z, Sabbagh MN. Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39. PubMed.