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 2)
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 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 (see Aug 2016 conference news; Irizarry et al. 2016).
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).
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 memory had been worsening for at least six months, who met a cutoff on the CogState Brief Battery, and who had a positive flortaucipir PET scan between 1.15 and 1.36 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 (see press release). The study started up at 63 sites in North America and is set to run until October 2020 (Irizarry et al., 2018).
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 met its primary endpoint, with donanemab slowing decline on the iADRS by 32 percent compared to placebo at 18 months (news link TK). 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 six percent becoming symptomatic.
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, 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.
For all trials of this antibody, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Eli Lilly & Co.||NCT03367403||
Last Updated: 11 Jan 2021
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- 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.
- 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.