What question did this study set out to answer?

To determine if OB-001 can improve the brain distribution of several kinase inhibitors in a mouse model.

April 5, 2026

Abstract 5873: OB-001 boost the brain penetration of multiple TKIs

Key Points

To determine if OB-001 can improve the brain distribution of several kinase inhibitors in a mouse model.
Male CD-1 mice received oral doses of various kinase inhibitors after pretreatment with vehicle or OB-001.
Plasma and brain concentrations were measured over 24 hours using LC-MS/MS.
Pharmacokinetic parameters and fold-changes in brain and plasma area under the curve (AUC) were analyzed.
OB-001 resulted in significant increases in cerebral AUC for multiple kinase inhibitors: 4, 33, 5, 11, and 4-fold increases for Osimertinib, Adagrasib, Tucatinib, Mobocertinib, and Lorlatinib, respectively.
No significant changes in plasma AUC were observed for Osimertinib and Adagrasib, with minimal increases for others.
Findings suggest OB-001 enhances CNS drug efficacy without increasing systemic toxicity.

Abstract

Abstract Background: Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib all demonstrate clinically meaningful CNS activity across numerous cancer types. However, all four agents show incomplete and variable CNS penetration, with reported CSF:plasma or Kp,uu values typically well below unity, largely due to ABCB1/ABCG2 efflux at the blood-brain barrier. OB-001 is a novel KinetiSol amorphous solid dispersion first-in-class efflux transporter inhibitor. We evaluated whether OB-001 can selectively enhance the brain distribution of kinase inhibitors. Methods: Male CD-1 mice received one of oral Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib following 2-h pretreatment with vehicle or OB-001 (10 mg/kg). Plasma and perfused-brain concentrations were quantified to 24 h by LC-MS/MS. Pharmacokinetic parameters were derived by noncompartmental analysis, and fold-changes in area under the curve (AUC) between brain and plasma were compared. Results: OB-001 led to a 4, 33, 5, 11 and 4 -fold increase in Brain AUC for Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib respectively. No change in plasma AUC was observed for Osimertinib and Adagrasib with less than 2-fold increase obserevd for Tucatinib, Mobocertinib and Lorlatinb. Conclusions: OB-001 selectively boosts brain exposure without substantially increasing systemic exposure. These data demonstrate that theoretically a pharmacokinetic window can be achevied with OB-001 whereby enhanced brain metatsases efficacy could be acheived for numerous kinase inhibitors without effecting systemic toxicity. These findings support OB-001 as a first-in-class CNS-targeted efflux modulating adjunct capable of elevating brain drug exposure beyond what is achievable by existing kinase inhibitors alone. OB-001 has strong translational rationale for combination development with Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib—to further extend CNS disease control in numerous cancer types. Citation Format: Hitesh Mistry, Jim Millen, Josh Fleet, Mark Brimble, . OB-001 boost the brain penetration of multiple TKIs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5873.

Bookmark

Cite This Study

Mistry et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fdbfa79560c99a0a4030 https://doi.org/https://doi.org/10.1158/1538-7445.am2026-5873

Bookmark