Synonyms: N3pG-Aβ Monoclonal Antibody
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.
LY3002813 is a humanized IgG1 monoclonal antibody developed from mouse mE8-IgG2a. This antibody 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 LY3002813 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 LY3002813 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 LY3002813 removed both cored and diffuse plaques (see Jul 2014 conference news).
In 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 U.S. 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 the same diagnosis, again in the U.S. and Japan. This trial also starts with a single dose and safety monitoring, but it then proceeds to repeated dosing for up to 18 months. The study measures primarily LY3002813's effect on brain amyloid load with florbetapir PET; secondary outcomes include blood pharmacokinetics of LY3002813 and auto-antibodies directed against this biologic drug. The trial is expected to run until 2019.
In December 2017, Lilly began TRAILBLAZER, a combination trial of two investigational drugs targeting different points in the amyloid cascade. This phase 2 study was to evaluatee safety, tolerability and efficacy of an 18-month course of LY3002813 alone and in combination with Lilly's BACE inhibitor LY3202626. It aims to enroll 375 participants whose memory has been worsening for at least 6 months, and who meet a cutoff on the CogState Brief Battery and have a positive tau PET scan. 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 to be as follows: One group to receive intravenous LY3002813 plus placebo administered orally, the second group to receive intravenous LY3002813 plus LY3202626 orally, the third group to receive 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 takes place at 69 sites in North America and is set to run until March 2020.
In October 2018, Lilly discontinued the BACE inhibitor arm of this trial; evaluation of the antibody remains ongoing, with a revised enrollment estimate of 266 participants.
For all trials of this antibody, see clinicaltrials.gov.
- New Ways to Target Aβ and BACE Show Promising Phase 1 Data
- Anti-Amyloid Therapies Combine Forces to Knock Out Plaques
- 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.