Therapeutics

Donanemab

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Overview

Name: Donanemab
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.

Background

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).

In postmortem brain tissue from people with AD or Down's syndrome, donanemab bound to a subset of roughly one-third of amyloid plaques, and strongly reacted with the plaque core. It recognized vascular amyloid similarly to a pan-Aβ antibody. In brain tissue from AD mice, the antibody detected intraneuronal Aβ (Bouter et al., 2022).

Findings

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 newsIrizarry 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. Donanemab was dosed at 700 mg monthly for the first three months, then 1,400 mg for up to 18 months. The primary outcome was 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 included 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 offered rides to and from study sites via a partnership between the Global Alzheimer’s Platform Foundation and the ridesharing company Lyft. The study started up at 63 sites in North America and was set to run until December 2020.

In October 2018, Lilly discontinued the BACE inhibitor arm of this trial; evaluation of donanemab was completed in December 2020, with a final enrollment of 272 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 the 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). A post hoc analysis of the data was subsequently published, showing that people with high baseline amyloid had greater plaque reduction in the first six months, but less chance of reaching complete clearance compared to those with lower brain amyloid. Slowing of tau accumulation was more pronounced in people with complete amyloid clearance, and in brain regions affected later in disease. The extent of amyloid reduction correlated with change on the iADRS clinical endpoint only in ApoE4 carriers (Shcherbinin et al., 2022). In October, Lilly published additional fluid biomarker results from this trial, showing that plasma GFAP had fallen, but plasma NfL continued to rise (Pontecorvo et al., 2022).

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 2024.

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 United States, Canada, Japan, The Netherlands, and Poland.

Subsequently, Lilly enlarged TRAILBLAZER-ALZ 2 to become a Phase 3 registration study with 1,800 participants. The ongoing study had already enrolled some people with tau-PET above 1.46 SUVR, but primary efficacy will be determined in 1,000 people whose tau burden is below this cutoff. The primary outcome is iADRS, and effectiveness will be judged using a disease-progression model, rather than solely on change at the final time point. As of October 15, 2021, 1,625 participants had been randomized (Nov 2021 conference news). Results are expected in the fall of 2023.

In June 2021, the FDA granted donanemab Breakthrough Therapy designation, to speed development and review. Lilly submitted a licensing application in October 2021, under the same accelerated approval pathway used for aducanumab, with rolling submission of 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, age 50 to 55 and at high risk for AD based on elevated plasma ptau217. The primary outcome is time to clinical progression measured by the Clinical Dementia Rating–Global Score. After nine monthly infusions of donanemab or placebo, participants will be monitored every six months until 434 become cognitively impaired, defined as a score above zero on the CDR for two consecutive evaluations. Secondary outcomes include a battery of cognitive tests, steady-state donanemab concentration in plasma, and the incidence of anti-donanemab antibodies. This is a decentralized trial, where assessments and monitoring are done remotely using video calls and tablet computers; drug infusions, blood draws, and MRIs will be done at local facilities. Participants will report to study centers only for amyloid or tau-PET scans. The trial is running at more than 200 sites in the United States, Japan, and Puerto Rico until November 2027 (Jul 2021 news; Nov 2021 conference news).

In November 2021, Lilly began TRAILBLAZER-ALZ 4, a Phase 3, open-label, head-to-head comparison of plaque clearance by donanemab and Biogen’s Aduhelm. Two hundred participants with a positive amyloid PET scan and mild dementia were to be randomized to either aducanumab treatment per label or intravenous donanemab every four weeks for 18 months. The primary outcome is the number who reach complete plaque clearance after six months on each treatment, judged by florbetapir PET. Seventeen secondary outcomes all relate to amyloid PET measures out to 18 months. The trial, at 31 locations in the United States, reached primary completion with 140 participants in September 2022. According to results presented at the 2022 CTAD conference, donanemab removed four times more plaque than aducanumab in the first six months of treatment (Dec 2022 conference news). Thirty-eight percent of people on donanemab fell below the amyloid positivity threshold by six months, compared to 2 percent for aducanumab. Plasma p-tau217 fell 25 percent on donanemab, but not at all on aducanumab. ARIA-E was similar in both groups, occurring in 22 percent of participants. The trial is slated to end in mid-2024.

In August 2022, Lilly registered TRAILBLAZER-ALZ 5, another Phase 3 safety and efficacy trial in participants with early symptomatic Alzheimer’s. The trial began in October 2022 to enroll 1,500 participants with the same entry criteria as TRAILBLAZER-ALZ 2. They will receive monthly infusions of donanemab or placebo, against a primary outcome of change on the iADRS at 18 months. Planned for 148 sites in China, Korea, Taiwan, and Europe, the study will run until mid-2025. The company is concurrently running a Phase 1 safety trial involving 36 healthy Chinese people in Beijing, which will be complete in January 2023.

In October 2022, Lilly started a Phase 1 study assessing single-dose blood exposure and degradation in 30 healthy volunteers. 

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
Sponsor Clinical Trial 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033
Eli Lilly & Co. NCT03367403
N=266
Eli Lilly & Co. NCT04437511
N=1500
Eli Lilly & Co. NCT04640077
N=100

Last Updated: 02 Jan 2023

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References

News Citations

  1. New Ways to Target Aβ and BACE Show Promising Phase 1 Data
  2. Four Immunotherapies Now Banish Amyloid From the Brain
  3. Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
  4. In Phase 2, Donanemab Curbs Cognitive Decline in Early Alzheimer’s
  5. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
  6. On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
  7. Donanemab Phase 3 Puts Plasma p-Tau, Remote Assessments to the Test
  8. Can Donanemab Prevent AD? Phase 3 TRAILBLAZER-ALZ3 Aims to Find Out
  9. Donanemab Mops Up Plaque Faster Than Aduhelm
  10. Anti-Amyloid Therapies Combine Forces to Knock Out Plaques

Therapeutics Citations

  1. Aduhelm

Paper Citations

  1. . 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
  2. . Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. Alzheimers Dement (N Y). 2021;7(1):e12112. Epub 2021 Feb 14 PubMed.
  3. . 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.
  4. . 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.
  5. . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.
  6. . Brain volume loss due to donanemab. Eur J Neurol. 2021 Sep;28(9):e67-e68. Epub 2021 Jul 16 PubMed.
  7. . Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol. 2022 Oct 1;79(10):1015-1024. PubMed.
  8. . Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol. 2022 Dec 1;79(12):1250-1259. PubMed.
  9. . A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron. 2012 Dec 6;76(5):908-20. PubMed.
  10. . Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome. Acta Neuropathol. 2022 May;143(5):601-603. Epub 2022 Apr 16 PubMed.

Other Citations

  1. LY3202626

External Citations

  1. press release
  2. clinicaltrials.gov

Further Reading

Papers

  1. . Stealth attack: plaque-specific antibody allows for efficient Aβ removal without side effects. Neuron. 2012 Dec 6;76(5):859-61. PubMed.
  2. . 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.
  3. . 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.
  4. . Still grasping at straws: donanemab in Alzheimer's disease. Expert Opin Investig Drugs. 2021 Aug;30(8):797-801. Epub 2021 Jul 8 PubMed.
  5. . Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39. PubMed.
  6. . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 Aug 12;385(7):666-667. PubMed.
  7. . Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice. Int J Mol Sci. 2021 Oct 30;22(21) PubMed.
  8. . Still grasping at straws: donanemab in Alzheimer's disease. Expert Opin Investig Drugs. 2021 Aug;30(8):797-801. Epub 2021 Jul 8 PubMed.
  9. . Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39. PubMed.
  10. . Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease. Front Neurol. 2022;13:862369. Epub 2022 Mar 23 PubMed.
  11. . Optimal anti-amyloid-beta therapy for Alzheimer's disease via a personalized mathematical model. PLoS Comput Biol. 2022 Sep;18(9):e1010481. Epub 2022 Sep 2 PubMed.
  12. . Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome. Acta Neuropathol. 2022 May;143(5):601-603. Epub 2022 Apr 16 PubMed.
  13. . Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease-Estimating the True Value. JAMA Neurol. 2022 Oct 3; PubMed.
  14. . Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Mol Psychiatry. 2022 Apr;27(4):1880-1885. Epub 2021 Dec 8 PubMed.
  15. . Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US. JAMA Neurol. 2022 May 1;79(5):478-487. PubMed.
  16. . [Causal treatment of Alzheimer's disease: amyloid antibodies]. Inn Med (Heidelb). 2022 Sep;63(9):1000-1008. Epub 2022 Mar 15 PubMed.
  17. . Therapeutic news in Alzheimer’s disease: soon a disease-modifying therapy?. Geriatr Psychol Neuropsychiatr Vieil. 2022 Jun 1;20(2):256-260. PubMed.
  18. . Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease. Ther Innov Regul Sci. 2022 May;56(3):501-516. Epub 2022 Mar 23 PubMed.
  19. . Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease-Estimating the True Value. JAMA Neurol. 2022 Oct 3; PubMed.
  20. . High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects. Rev Neurol (Paris). 2022 Dec;178(10):1011-1030. Epub 2022 Sep 29 PubMed.
  21. . High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 2: putative scenarios and timeline in case of approval, recommendations for use, implementation, and ethical considerations in France. Rev Neurol (Paris). 2022 Dec;178(10):999-1010. Epub 2022 Nov 3 PubMed.
  22. . Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China. Front Neurol. 2022;13:1034243. Epub 2022 Nov 15 PubMed.
  23. . Donanemab for Alzheimer's Disease: A Systematic Review of Clinical Trials. Healthcare (Basel). 2022 Dec 22;11(1) PubMed.