Background

Zagotenemab is a humanized anti-tau antibody derived from MCI-1, Peter Davies' mouse monoclonal antibody against an early pathological conformation of tau. Zagotenemab binds and neutralizes soluble tau aggregates.

Preclinical studies in tau transgenic mice showed that immunotherapy with MCI-1 reduced levels of hyperphosphorylated insoluble tau levels and neurofibrillary pathology (Chai et al., 2011).

At the 2017 AAIC meeting, Lilly presented data from surface plasmon resonance binding and ELISA assays to assess LY3303560's selectivity to aggregates over monomer and characterize its epitope. LY3303560 reportedly had high affinity to soluble tau aggregate in vitro, at a KD of below 220 picomolar, compared to monomer, KD of 235 nanomolar. The antibody reportedly recognizes a conformational epitope whose primary epitope is in tau's N-terminal region. Intravenous administration to monkeys indicated clearance of 0.15 ml/h/kg and a half-life of 13 days. SC administration indicated a bioavailability of 79 percent, and rat CSF concentration was 0.1 percent of plasma at 24 hours after IV administration (Alam et al., 2017).

Findings

From April 2016 to July 2018, Lilly ran a first-in-human trial of LY3303560 in 110 people, both healthy volunteers and people whose MCI due to AD or mild to moderate AD was ascertained with a positive amyloid PET scan. This study evaluated a single, escalating intravenous infusion or subcutaneous injection of LY3303560 or placebo. It measured adverse effects up to 85 days after this dose, as well as exposure and maximal achieved drug concentration in both serum and CSF. This study required a four-day stay in a clinical research unit and 10 follow-up visits. It was conducted in California and Maryland. Results are posted on clinicaltrials.gov.

From January 2017 to June 2019, a second Phase 1 study intravenously delivered multiple escalating doses of LY3303560 or placebo to 24 people with the same diagnosis. Over a planned treatment period of six months plus four months of follow-up, the trial measured adverse events and pharmacokinetic parameters. Notably, this trial infused LY3303560 or placebo, and amyloid and tau PET tracers, in the same session. The study initially was going to measure change in tau PET as a secondary outcome, but dropped this measure in February 2018. This trial ran at 12 sites in the U.S., the U.K., and Japan. According to published results, 22 patients were randomized to 70 or 210 mg antibody, or placebo, for up to 49 weeks. The study was stopped before running two planned higher dose cohorts of 700 and 1,400 mg, because the investigators realized they would likely not reach an effective dose. No dose-limiting adverse events occurred. Pharmacokinetics were linear, and typical for a monoclonal antibody. Treatment caused a dose-dependent increase in plasma tau; tau-PET was not changed (Willis et al., 2023).

In April 2018, Phase 2 began with a first efficacy trial enrolled 360 people who had a gradual and progressive decline in memory for at least six months. The study compared 1,400 mg or 5,600 mg monthly intravenous doses to placebo. Change from baseline on Lilly's integrated Alzheimer's Disease Rating Scale (iADRS) after two years was the primary outcome; secondary measures included ADAS-Cog13, ADCS-iADL, CDR-SB, MMSE, the CogState Brief Battery (CBB), as well as tau PET, volumetric MRI, the Columbia Suicide Severity Rating Scale (C-SSRS), and antigenicity of LY3303560, also out to two years. This trial ran at 60 sites in North America and Japan. It finished enrolling in August 2019 and ran until August 2021. In an October 2021 investor call, Lilly disclosed that the trial had missed its primary endpoint, and the company was ending development of zagotenemab (slides 5, 17 in presentation). Full trial results were published after peer review (Fleisher et al., 2024).

For all trials, see clinicaltrials.gov.

Clinical Trial Timeline