The phase 1 study, REASON, in Parkinson’s disease patients evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ascending and multiple doses of ION859 (also known as BIIB094), an RNA-targeted therapy designed to reduce LRRK2 protein in the CNS.

The LRRK2 gene produces the LRRK2 protein involved in several cellular processes implicated in Parkinson’s disease, including the phosphorylation of Rab10, which is involved in lysosomal functions and immune responses. Mutations in the LRRK2 gene are the most common genetic cause of Parkinson’s disease. 

Part A Single Ascending Doses (SAD) of 10 to 150 mg with 85 days of follow-up. Part B: Multiple Ascending Doses of 40, 80, and 120 mg ION859, administered monthly, were delivered for 12 weeks. Patients were subsequently followed for 24 weeks to examine pharmacodynamic rebound.

40 Patients living with Parkinson's Disease were enrolled in the SAD. 42 patients were enrolled in MAD with stratification by LRRK2 mutation status. MAD: Patients mean age 61 (range 44-78) years; disease duration 3.8 (0, 7) years; 39 of 42 (92%) completed study treatment.  Most AEs were of mild-moderate severity and not treatment-limiting. Serum concentrations of ION859 increased with higher doses. CSF LRRK2 and pRab10 reductions were largely dose-dependent, with 59% and 50% maximal suppression, respectively. The suppression of LRRK2 and pRab10 was maintained at the 3-month follow-up.  The reduction of LRRK2 also corresponded with reductions in CSF Cathepsins, suggesting that LRRK2 lowering may also modulate lysosomal biology. No differential effects in patients with or without LRRK2 mutations were observed.  

ION859 reduces total LRRK2 and the LRRK2 substrate pRab10 in CSF. The safety and pharmacodynamic profile support its advancement into later-stage development for patients with Parkinson’s disease.