Background

LY3954068 is a small interfering RNA (siRNA) that targets expression of the microtubule-associated binding protein tau. No information is available about the makeup of LY3954068. In general, siRNAs are double-stranded RNA molecules about 20 to 25 nucleotides long, which bind to complementary sequences on mRNA and induce RNA interference, resulting in degradation of target mRNAs. As such, LY3954068 is designed to reduce the levels of tau protein. This strategy assumes that decreasing the abundance of tau will slow the formation of tau aggregates and progression of tau pathology. LY3954068 is being studied for the treatment of neurodegenerative diseases.

No preclinical work is published on LY3954068. More generally, one published study tested the effects of a MAPT siRNA delivered directly to the brains of P301S tau-expressing mice. After a single injection, the siRNA partially spread through the hippocampus and suppressed tau expression, with no signs of neurotoxicity or neuroinflammation (Xu et al., 2014). MAPT siRNA improved recovery after spinal cord injury in rats (Chen et al., 2023). However, another study claimed it impaired the migration of Schwann cells after nerve injury in rats, interfered with cytoskeletal protein expression and distribution, and compromised myelin and lipid debris clearance in these cells (Yi et al., 2019).

An alternative approach to reducing tau expression uses antisense oligonucleotides to block mRNA translation (DeVos et al., 2013; DeVos et al., 2017). Two of these are in early stage clinical trials (BIIB080; NIO752).

Findings

In August 2024, Lilly began a first-in-human study of LY3954068 in 32 people with early symptomatic Alzheimer's Disease. Participants must have a Clinical Dementia Rating of 0.5 or 1, and a TAUVID™ PET scan indicating tau pathology. In the first part of the study, they will receive a single intrathecal injection of siRNA or placebo, and be followed up for six months. The primary outcome is number of participants with adverse events. Secondary endpoints are plasma and CSF pharmacokinetics, and change in CSF tau concentration. An optional multiple-dose arm will test two injections, with additional follow-up. Completion is expected in February 2027.

For details on this trial, see clinicaltrials.gov.