Background: GB5121 is an oral, brain-penetrant, potent, highly selective, irreversible, small molecule Bruton's tyrosine kinase inhibitor (BTKi) in development for hematologic malignancies with CNS involvement. Preclinical studies demonstrated that GB5121 exhibited several characteristics differentiating it from other BTKis, including rapid equilibrium into the brain, increased brain target occupancy, and fast inactivation rate. These characteristics combined with GB5121's kinase selectivity and activity in in vitro and in vivo DLBCL models support its clinical investigation in BTK-driven CNS lymphomas. This first-in-human study was designed to evaluate the single- and multiple-dose safety, tolerability, pharmacokinetics (PK; including CNS penetrance) and pharmacodynamics (PD), the effect of food, drug interactions, and cardiac safety of GB5121 to inform dosing and concomitant medications in clinical studies.

Methods: This is an ongoing Phase 1, double-blind, randomized, placebo-controlled, single ascending and multiple ascending dose (SAD, MAD) study in healthy subjects, with staggered dose escalations and adaptive dose selection. Safety is assessed throughout the study and PK and PD are characterized using serial blood samples collected up to 48 hours post-dose for GB5121 plasma concentrations, BTK target occupancy (TO), and target engagement (TE). Cerebrospinal fluid (CSF) samples are collected at 2 hours post-dose to characterize the relationship between GB5121 plasma concentrations and CNS penetrance. GB5121 PK parameters (e.g., AUClast, AUCinf, Cmax, Tmax, t1/2) are estimated by standard noncompartmental methods.

Results: Preliminary PK results from 3 completed SAD cohorts are presented, including 23 subjects (7 receiving 5 mg, 8 receiving 15 mg, and 8 receiving 45 mg: randomized in a 3:1 ratio to receive GB5121 or placebo) in a fed state (moderate-fat meal). A review of blinded safety data thus far indicated that the study drug was generally well tolerated with no serious adverse events or early study discontinuations reported. PK parameters are presented in Table 1. GB5121 was rapidly absorbed following oral administration with mean plasma Tmax ranging from 1-2 hours and exhibited a terminal half-life of approximately 3 hours. Single-dose GB5121 exposure (AUCinf) increased in a greater than dose-proportional manner from 5 to 15 mg and near dose-proportional from 15 to 45 mg. Mean GB5121 CSF:unbound plasma concentration ratios approximated 1, indicating unimpeded access of unbound drug in plasma into the CNS. The observed GB5121 plasma exposure, CNS penetrance, and preliminary TO and TE PD data were consistent with that of a translational PK/PD model.

Conclusions: Data from the first 3 SAD cohorts in healthy subjects indicated that low doses of GB5121 provided plasma exposure and CSF penetrance adequate to drive desired BTK inhibition in the CNS. Blinded safety data indicated that single-dose study drug administration was well tolerated across the dose range. PD analysis and additional evaluations are ongoing and final results will be presented. The safety and PK profiles of GB5121 support its continued evaluation in the ongoing Phase 1b/2 open-label, international study in adult subjects with relapsed/refractory primary/secondary CNS lymphoma, or primary vitreoretinal lymphoma (STAR CNS; NCT05242146).

Kirby:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Aranda:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Ward:Gossamer Bio: Consultancy; Loxo Oncology at Lilly: Consultancy; InClin: Consultancy; CTI Biopharma: Consultancy. Steinberg:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Hernandez:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Sosa:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Cravets:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rose:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Osterhout:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Ding:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Yusuf:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Fox:Gossamer Bio, Inc.: Consultancy, Current equity holder in publicly-traded company; Amphivena Therapeutics: Patents & Royalties; Sunesis Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Triursus: Consultancy; CPRIT: Consultancy; Viracta Therapeutics, Inc.: Consultancy, Current equity holder in publicly-traded company. Mathias:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company.

Author notes

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Asterisk with author names denotes non-ASH members.

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