Objective: Report on the non-clinical in vivo pharmacokinetic and pharmacodynamic biomarker response to PROteolysis TArgeting Chimera (PROTAC®) molecules designed to induce degradation of leucine rich repeat kinase 2 (LRRK2) for the treatment of Parkinson’s disease (PD).

Background: Mutations in LRRK2, resulting in gain-of-function increase in kinase activity, are a common cause of familial and sporadic PD.   In addition, an increase in LRRK2 expression driven by a single nucleotide polymorphism in the LRRK2 locus is associated with a higher risk for developing PD. LRRK2 is a large multidomain protein and plays a role in diverse cellular processes including endolysosomal regulation, autophagy, mitophagy and neuroinflammation.  Human genetics and preclinical animal model data suggest that reduction of 50% of LRRK2 protein may impact pathology and dysfunction in PD. Therefore, degradation of LRRK2 in the brain may be beneficial for the treatment of PD. We have identified potent, orally bioavailable LRRK2 PROTAC degraders that cross the blood brain barrier in preclinical species and biodistribute to brain regions impacted in PD.

Method: Orally bioavailable LRRK2 PROTAC degraders were assessed in non-clinical in vivo pharmacology studies in rodents and non-human primates to evaluate LRRK2 degradation and pathway engagement in samples relevant for clinical biomarker analysis.  LRRK2 levels and phospho-RAB10 were measured in peripheral blood mononuclear cells (PBMCs) by Meso Scale Discovery assay and capillary immunoassay, respectively.  LRRK2 levels in cerebrospinal fluid (CSF) were measured by single molecule array assay.  Urine di-22:6 bis(monoacylglycerol) phosphate (BMP) levels were measured by LC-MS/MS. PROTAC plasma and CSF exposure levels were measured by LC-MS/MS.

Results: Acute and chronic oral administration of LRRK2 PROTAC molecules induced robust reductions of LRRK2 protein in CSF, confirming PROTAC brain exposure and pharmacology. LRRK2 and phospho-RAB10 reductions were observed in PBMC extracts, demonstrating peripheral target and pathway engagement. Reductions of urine BMP levels following chronic dosing were observed, confirming effects of LRRK2 reduction on lysosome biology.

Conclusion: These results support translational approaches for the future assessment of LRRK2 PROTAC molecules as a potential disease modifying therapy for the treatment of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-protac-degrader-molecules-induce-robust-biomarker-responses-in-preclinical-in-vivo-pharmacology-studies-following-acute-and-chronic-oral-dosing/