Synonyms: IONIS-MAPTRx, ISIS 814907
Therapy Type: RNA-based (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Biogen, IONIS Pharmaceuticals
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 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.
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 randomize portion.
For all trials on this drug, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 1/2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 31 Oct 2019
- Devos SL, Goncharoff DK, Chen G, Kebodeaux CS, Yamada K, Stewart FR, Schuler DR, Maloney SE, Wozniak DF, Rigo F, Bennett CF, Cirrito JR, Holtzman DM, Miller TM. Antisense Reduction of Tau in Adult Mice Protects against Seizures. J Neurosci. 2013 Jul 31;33(31):12887-97. PubMed.
- DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017 Jan 25;9(374) PubMed.