Background

NIO752 is an antisense oligonucleotide to tau, designed to reduce the levels of this protein by interfering with translation of tau mRNA. The antisense strategy assumes that decreasing the abundance of tau will slow the formation of tau aggregates and progression of tau pathology. NIO752 is in development to treat progressive supranuclear palsy, a primary tauopathy caused by accumulation of aggregates containing the 4-repeat tau isoform.

No preclinical work is published on NIO752, but tau antisense oligonucleotides (ASOs) 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).

Findings

In February 2021, Novartis began a Phase 1 study in 64 people with PSP. Patients in six sequential cohorts were to receive escalating doses of NIO752 or placebo, delivered by intrathecal injection four times over three months, with a nine-month follow-up. Safety assessments include adverse events as well as physical and neurological examinations, ECGs, vital signs, and standard clinical laboratory evaluations. Participants will be monitored for evidence of CSF infection. Run at multiple sites in North America, Germany, and the U.K., the trial finished in October 2024.

In February 2023, the company began a Phase 1b study to evaluate safety, pharmacokinetics and pharmacodynamics in 24 people with early Alzheimer’s. Participants must have positive CSF biomarker for amyloid and tau. After a single intrathecal dose of NIO752 or placebo, participants are being followed up for six months. Two dose cohorts are to be enrolled sequentially. The primary outcome is change in CSF total tau level after three months. Other assessments include pharmacokinetics (PKs), safety, and adverse event monitoring. Participants who finish the follow-up may enroll in an open-label extension and receive two additional NIO752 injections. The trial is fully enrolled with 25 participants, and scheduled to finish in October 2025.

In May 2024, a Phase 1 study was to begin measuring the effect of NIO752 on tau synthesis. Ten participants with sporadic for familial AD are to receive intrathecal NIO752 or placebo, and isotope-labeled leucine. Synthesis rates will be determined by the extent of isotope incorporation in serial CSF samples. As of November 2024, the study at University College London is listed as not yet recruiting; completion is intended in August 2025.

For details on NIO752 trials, see clinicaltrials.gov.