(S-090) An Empirical Drug Autoinduction Model to Characterize the Population Pharmacokinetics of TEV-56286 (Emrusolmin) in Healthy Participants and Patients

Asama Hunter – Teva Branded Pharmaceuticals LLC; Itay Perlstein – Teva Branded Pharmaceuticals LLC; Dvora Izgelov – Teva Branded Pharmaceuticals LLC; Rajendra Singh – Teva Branded Pharmaceuticals LLC

Objectives: Multiple system atrophy (MSA) is an α-synucleinopathy characterized by severe motor dysfunction and autonomic system failures. TEV-56286 (emrusolmin) is an orally administered small molecule developed for the treatment of MSA. TEV-56286 specifically binds to early-stage amyloidogenic aggregates observed in neurodegenerative diseases. In MSA, these small aggregates are composed of misfolded α-synuclein, which is assumed to be the pathogenic core aggregating protein driving the disease. The pharmacokinetic (PK) profile of TEV-56286 has shown a decrease in exposure over time (time-dependent PK), suggestive of autoinduction processes. The objective of this analysis was to characterize the population pharmacokinetics (popPK) of TEV-56286 in healthy adult participants and participants with Parkinson’s disease who present similar gastrointestinal tract motility properties as patients with MSA.

Methods: The TEV-56286 popPK analysis was performed using pooled data from 145 participants across three Phase 1 trials, which assessed safety, tolerability, and PK. These included 1) a first-in-human study (single ascending dose [SAD] ranging from 50–300 mg, multiple ascending doses [MAD] ranging from 100–300 mg, and food effect at a 150 mg dose) in healthy participants, 2) multiple-dose Phase 1b study in participants with Parkinson’s disease, including food effect, and 3) drug-drug interaction study that assessed TEV-56286 as a CYP1A2 and CYP3A4 perpetrator and as a CYP1A2 victim drug in healthy participants. The data were analyzed using a nonlinear mixed-effects model (NONMEM v 7.4.3). Potential covariates were assessed. The model evaluation was based on goodness-of-fit (GOF) plots and visual predictive checks (VPCs).

Results: A two-compartment model linked with a hypothetical enzyme compartment adequately described the time course of TEV-56286 (emrusolmin) autoinduction in both healthy participants and those with Parkinson’s disease. The relationship between clearance and concentration was characterized by Michaelis-Menten kinetics. Covariate analysis indicated that food effect reduced the absorption rate constant (Ka) by 30%, with only 14% impact on overall exposure (area under the curve), while co-administration with a CYP1A2 inhibitor drug decreased the Michaelis-Menten elimination rate (Vmax) by 85%. The effect of dose was lower in Vmax and the first-order rate constant for enzyme pool degradation (kENZ).

Conclusions: The PK of TEV-56286 (emrusolmin) in healthy participants and participants with Parkinson’s disease was adequately characterized using a two-compartment model linked with a hypothetical enzyme compartment. This popPK model can support study design including dosing selection in the Phase 2 trial in patients with MSA and future product development.

Citations: None

Keywords: population pharmacokinetics, autoinduction, multiple system atrophy