Paper Alert: Tau Antisense Oligonucleotide BIIB080 Hits Its Target

One strategy for targeting tau pathology—suppressing expression with an antisense oligonucleotide—has recently made strides. At AD/PD 2023, Biogen and partner Ionis Pharmaceuticals had reported that their tau antisense oligonucleotide BIIB080 lowered tangles throughout the brain in a six-month Phase 1 trial of people with early Alzheimer’s disease, with greater effects during a one-year extension (Apr 2023 conference news). Now, in the April 24 Nature Medicine, researchers led by Catherine Mummery at University College London formally published data from the six-month, placebo-controlled portion of the trial, showing strong suppression of tau in the cerebrospinal fluid.

Lasting Effect BIIB080 reduces CSF total tau (left) and p-tau181 (right) dose-dependently, with higher doses (purple, blue) squelching tau for more than six months after the last injection (arrows). [Courtesy of Mummery et al., Nature Medicine.]

As previously reported, CSF total tau and p-tau181 dropped dose-dependently, with the lowest dose cutting levels by 30 percent, the highest by 50 percent (Aug 2021 conference news). The paper describes how these markers changed during a six-month gap period following treatment. In the lowest-dose group, of 10 mg monthly, t-tau and p-tau181 fully rebounded to the levels seen in the placebo group. In the 30 mg dose group, these markers partially rebounded, whereas in the 60 mg monthly and 115 mg quarterly groups they dropped further, to 60 percent below baseline, and then remained low (see image above).

Mummery and colleagues reported the CSF t-tau/Aβ42 ratio as well, with similar results to the other markers at each dose. Also new in the paper are spaghetti plot data of individual patients, showing consistent effects within dose groups (see image below).

Consistent Response. Spaghetti plots show tau ASO has similar effects on CSF t-tau in nearly all members of a given dose group. [Courtesy of Mummery et al., Nature Medicine.]

The paper contains more detail on side effects. Most were due to the method of administration, that is, injection into the spinal column. Post-LP headaches were more common in the treatment than placebo group, at 44 versus 33 percent. Adverse events judged to be mild in severity were likewise more common on drug, at 62 versus 42 percent. Events with moderate severity were similar in both groups at 33 percent.

Symptoms that were more common on drug than placebo included nausea, vomiting, diarrhea, fatigue, confusion, and musculoskeletal pain. There were also three cases of mild tinnitus in the treatment group, and none on placebo. There were no adverse events labeled serious in treatment groups during the placebo-controlled portion of the trial. BIIB080 is now in Phase 2.—Madolyn Bowman Rogers

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References

News Citations

  1. First Hit on Aggregated Tau: Antisense Oligonucleotide Lowers Tangles
  2. Antisense Therapy Stifles CSF Tau in Mild Alzheimer’s Disease

Further Reading

Primary Papers

  1. Mummery CJ, Börjesson-Hanson A, Blackburn DJ, Vijverberg EG, De Deyn PP, Ducharme S, Jonsson M, Schneider A, Rinne JO, Ludolph AC, Bodenschatz R, Kordasiewicz H, Swayze EE, Fitzsimmons B, Mignon L, Moore KM, Yun C, Baumann T, Li D, Norris DA, Crean R, Graham DL, Huang E, Ratti E, Bennett CF, Junge C, Lane RM. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nat Med. 2023 Jun;29(6):1437-1447. Epub 2023 Apr 24 PubMed. Correction.

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