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 also have 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 October 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 enrolled 46 people between age 50 and 74 whose mild AD was confirmed by CSF biomarkers. The primary outcome was adverse events; secondary outcomes included 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 called for four dose administrations and seven lumbar punctures (Lane et al., ANA 2017).

In March 2019, Biogen/Ionis added a one-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 10, 30, or 60 mg every month for three months, or two doses of 115 mg 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). The study finished in May 2022, and the company published complete results of the placebo-controlled portion (Mummery et al., 2023). CSF total tau and p-181 tau were reduced by 60 percent in the higher-dose cohorts, and stayed low for six months. The reductions were consistently seen in most or all people in each dose group. Mild adverse events were more common on drug, and included nausea, vomiting, diarrhea, fatigue, confusion, and musculoskeletal pain. There were three cases of mild tinnitus in treated patients, and none on placebo. No serious adverse events were reported.

First results from the long-term extension were shown at the 2023 AD/PD conference. In a tau PET substudy in 12 patients, quarterly 60 mg doses reduced tau aggregates below baseline levels in all brain regions examined (Apr 2023 conference news). Full trial results, published after peer review, showed sustained reductions in ptau, p181 tau, and tau PET in the open-label period (Edwards et al., 2023).

At the October 2023 CTAD conference, a trend toward slower cognitive decline in the two higher-dose groups was reported for the placebo-controlled part of the trial, as was a trend toward slowing compared to historical controls during the open label extension (Nov 2023 conference news).

In August 2022, Biogen started a Phase 2 trial testing two doses and two injection regimens against placebo in what was to be 735 people with mild cognitive impairment or mild dementia due to Alzheimer’s. At 54 sites across North America, Japan, Australia, and Europe, participants are receiving high- or low-dose BIIB080 every 24 weeks, high dose every 12 weeks, or placebo, for 72 weeks. The primary outcome is the dose response in change of CDR-SB from baseline after 76 weeks. Secondary measures include ADCS-ADL-MCI, ADAS-Cog 13, MMSE, iADRS, ADCOMS, and adverse events. The trial offers a two-year open-label extension. The trial completed enrollment at 416 participants. The placebo-controlled phase is expected to finish in May 2026.

A Phase 1 study is expected to begin in May 2025 to determine the biodistribution of BIIB080 after an intrathecal microdose of radiolabeled drug in five healthy adults. After injection, a PET scan will visualize BIIB080 in the brain and spinal cord. The study is slated to finish by July 2025.

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

Clinical Trial Timeline