Background

This investigational therapeutic is the first antisense oligonucleotide (ASO) targeting tau expression to enter clinical trials. Developed by IONIS in collaboration with Timothy Miller at Washington University, St. Louis, ASOs that inhibit the translation of tau mRNAs into protein have been shown to reduce toxin-induced seizures, neuronal loss, and neurofibrillary pathology in adult tau-transgenic mouse models. They have also been shown to normalize behavioral phenotypes and lengthen survival in such mice. Infusion of tau ASO into the CSF of cynomolgus monkeys was shown to reduce tau mRNA across different brain regions, and CSF tau levels following ASO exposure have been correlated to hippocampal tau levels (Devos et al., 2013; DeVos et al., 2017).

Previous ASO therapies—developed by IONIS against mutant SMA, SOD1, and huntingtin proteins—are delivered intrathecally to patients. The SMA, SOD1, and this tau-targeted ASO are partnered with Biogen; the ASO targeting huntingtin is partnered with Roche.

Findings

In June 2017, Ionis started a 13-week, multiple-ascending-dose study of monthly intrathecal BIIB080 injections. Conducted at 13 sites in Canada and Europe, this trial enrolls 44 people between age 50 and 74 whose mild AD is confirmed by CSF biomarkers. The primary outcome is adverse events; secondary outcomes include pharmacokinetic parameters such as trough and maximum concentrations reached in the CSF, time to maximal concentration and plasma elimination half-life, and concentration-time curves. The trial uses a sentinel design, whereby the first two participants in each dose group are randomized 1:1 to placebo and at least one week must pass between dosing in these patients and any other patients. The design calls for four dose administrations and seven lumbar punctures (Lane et al., ANA 2017).

The randomized portion of the trial is set to run until February 2020. In March 2019, Biogen/Ionis added a 4-year open-label extension of quarterly injections for people who completed the randomized portion. At AAIC 2021, Ionis reported first data from this trial. There were no serious adverse events from intrathecal injection of either three different doses every month for three months, or two high doses injected three months apart. The ASO produced a dose-dependent reduction in total tau and phosphoTau-181 in CSF by 30 to 50 percent (Aug 2021 conference news).

For all trials on this drug, see clinicaltrials.gov.

Clinical Trial Timeline