Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AstraZeneca, Eli Lilly & Co.
Developed originally at MedImmune, now part of AstraZeneca, this antibody is being developed jointly by AstraZeneca and Eli Lilly. MEDI1814 binds to monomeric Aβ42. According to researchers at Lilly, MEDI1814 is not being developed based on its peripheral binding and the peripheral sink hypothesis, as was solanezumab, a prior antibody targeting monomeric Aβ40 and 42. Rather, MEDI1814 development will focus on CNS compartments (personal communication).
MEDI1841 is an IgG1 specific for the C-terminus of Aβ42. A triple mutation in its Fc region weakens binding to microglia, a strategy to avoid ARIA (Nov 2015 news).
No peer-reviewed preclinical data on this antibody has been published. According to meeting abstracts, the antibody, delivered either into the brain or systemically, prevented synaptic toxicity induced by administration of Aβ42 aggregates in rats (Ondrejcak et al., 2017). MEDI1814 was also reported to increase total and decrease free CSF Aβ42 in mice, rats, and cynomolgus monkeys (Billinton et al., 2017).
In February 2014, AstraZeneca started a multicenter Phase 1 trial in the U.S., which was to enroll 242 people with mild to moderate Alzheimer's. The study evaluated single- and multiple-ascending doses of intravenously and subcutaneously delivered antibody and placebo. Outcomes included measures of safety, pharmacokinetics, and immunogenicity of the antibody, as well as pharmacodynamics of blood and CSF Aβ concentrations. This trial also planned to correlate results with ApoE genotype and test the usefulness of a new cognitive tool called MCI screen. In 2015, the enrollment target was reduced to 121. The trial was completed in September 2016, and data presented (May 2017 conference news; Aug 2017 conference news).
The study ultimately enrolled 77 people. In the single-dose phase, 45 participants received 25, 100, 300, 900, or 1,800 mg or placebo by IV infusion, or 100 mg subcutaneously. In the multiple-dose regimen, 32 participants received three infusions of 300, 900, or 1,800 mg or placebo, or 200 mg subcutaneously, at four-week intervals. In a 16-week follow-up, the investigators reported no serious adverse events. The most common complaints were dizziness, headache, and diarrhea, which appeared unrelated to dose. There were no injection or infusion reactions, or changes in vital signs. MRI scans found no evidence of ARIA-E or ARIA-H. Pharmacokinetics were similar to other antibodies, with a half-life in blood of 17 to 20 days, and brain levels of 0.1 to 0.6 percent of those in plasma. After dosing, plasma and CSF total Aβ42 rose. Free CSF Aβ42 fell to undetectable levels after multiple 900 mg doses. Aβ40 did not change. Data on exploratory fluid biomarkers, presented at the November 2020 CTAD conference, showed a statistically significant 20 percent decrease in plasma NfL in the 1,800 mg multiple dose cohort. Also seen was a trend to reduction in plasma pTau207, but no significant changes in plasma or CSF pTau181, total Tau, or neurogranin were observed.
Last Updated: 17 Dec 2020
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- Ondrejcak T, O'Malley TT, Perkinton M, Dudley A, Chessell I, Groves M, Walsh DM, Billinton A, Rowan MJ. [P3–036]: MEDI1814, a High-Affinity Antibody Directed to the C-Terminus of AβX‐42, Abrogates Synaptic Plasticity Disruption Caused by Synthetic or AD Brain-Derived Aβ Soluble Assemblies in Vivo. July 18, 2017: Alzheimer's Association International Conference: P3: Poster Presentations
- Ondrejcak T, O'Malley TT, Perkinton M, Dudley A, Chessell I, Groves M, Walsh DM, Billinton A, Rowan MJ. [P1–074]: Preclinical Discovery and Development of Medi1814, a Monoclonal Antibody Selectively Targeting Beta‐Amyloid 42 (Aβ42). July 18, 2017: Alzheimer's Association International Conference: P3: Poster Presentations
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