Background

BIIB113 is a small molecule inhibitor of O-GlcNACase, or OGA, an enzyme that catalyzes the removal of O-GlcNAc sugar modifications from proteins.

OGA inhibitors promote glycosylation of tau, which prevents its aggregation and appears to stabilize the protein in a soluble, non-pathogenic form (e.g., see Yuzwa et al., 2012). O-GlcNAc modification was reported to reduce the aggregation and toxicity of the α-synuclein protein as well (Marotta et al., 2015; Levine et al., 2019). This modification appears to promote formation of an α-synuclein fibril strain that does not propagate and is not neurotoxic in vivo (Balana et al., 2024). Thus, OGA inhibitors could potentially slow or prevent the progression of neurodegeneration due to these proteins. Biogen is developing this inhibitor to treat Alzheimer’s disease.

No preclinical work on BIIB113 is published. At the March 2024 AD/PD conference, the company showed unpublished preclinical data indicating that BIIB113 achieved 85 percent target occupancy, increased the glycnacylation of tau, and reduced tau pathology by 43 percent, in the human tau-expressing rTG4510 mouse line. These results are similar to published reports on other structurally different OGA inhibitors (e.g. Permanne et al., 2022). Biogen has disclosed structures of hundreds of OGA inhibitors in several patent applications (summarized in Bartolomé-Nebreda et al., 2021).

Biogen also developed an OGA PET ligand to assess target engagement in the clinic (Cook et al, 2023).

Findings

In January 2022, Biogen began Phase 1 with a safety and pharmacokinetic study in 72 healthy volunteers. The trial compared single doses of 0.5, 3, 15 and 50 mg, and two weeks of 50 mg daily with placebo in up to nine cohorts. One SAD cohort tested food effects, and one MAD cohort was elderly. The company also measured BIIB113 binding to brain OGA after single and multiple doses, using the PET ligand 11[C]BIO-1819578. Run at three sites in Sweden and the U.K., the finished in July 2023, and results were presented at the March 2024 AD/PD conference (Mar 2024 news). Single and multiple doses up to 50 mg were safe and well tolerated. Adverse events were mild or moderate, with headache the most frequent. One person discontinued treatment in the MAD cohort, due to tremor. Pharmacokinetics were dose-proportional. The drug half-life was 30 hours, and blood levels reached steady state after one week. Food and age did not affect pharmacokinetics. Multiple daily doses of 0.5 mg maintained greater than 90 percent brain target occupancy up to 48 hours after the last dose.

In December 2023, Biogen completed an interaction study with drugs that alter cytochrome p450 3A activity. The study in 90 healthy men tested the effect of simultaneous dosing with itraconazole or phenytoin on the pharmacokinetics of BIIB113, and of BIIB113 on midazolam.

For details on these trials, see clinicaltrials.gov and the WHO registry.