A Phase I, Randomized, SAD, MAD, and PK Study of Risvodetinib in Older Adults and Parkinson's Disease

Abstract

Background: Pre-clinical studies suggest that c-Abl activation may play an important role in the etiology of Parkinson's disease, making c-Abl an important target to evaluate for potential disease-modification.

Objective: To assess safety, tolerability, and pharmacokinetics of the c-Abl inhibitor risvodetinib (IkT-148009) in healthy subjects and participants with Parkinson's disease.

Methods: Part 1 (single ascending dose (SAD)) and Part 2 (7-day multiple ascending dose (MAD)) studies were in healthy volunteers. Participants were randomized 3 : 1 across 9 SAD doses and 3 MAD doses of risvodetinib (IkT-148009) or placebo. Part 3 was a MAD study conducted at two doses in 14 participants with mild-to-moderate PD (MAD-PD). Primary outcome measures were safety, tolerability and pharmacokinetics. Exploratory outcomes in PD participants included clinical measures of PD state, GI function, and cerebrospinal fluid (CSF) concentration.

Results: 108 patients were treated with no dropouts. The SAD tested doses ranging from 12.5 to 325 mg, while the MAD tested 25 to 200 mg and MAD-PD tested 50 to 100 mg in Parkinson's participants. All active doses had a favorable safety profile with no clinically meaningful adverse events. Single dose pharmacokinetics were approximately linear between 12.5 mg and 200 mg for both Cmax and AUC0 - inf without distinction between healthy volunteers and participants with PD. Exposures at each dose were high relative to other drugs in the same kinase inhibitor class.

Conclusions: Risvodetinib (IkT-148009) was well tolerated, had a favorable safety and pharmacology profile over 7-day dosing, did not induce serious adverse events and did not appear to induce deleterious side-effects in participants administered anti-PD medications.

Keywords: Parkinson’s disease; c-Abl inhibition; disease-modification; neurodegeneration; pharmacology; therapeutics.

Fig. 1

Plasma pharmacokinetic C_max and AUC_0 - inf as a function of single oral dose for risvodetinib (IkT-148009). Risvodetinib (IkT-148009) was administered once and the plasma pharmacokinetics measured from 0 to 96 h in 9 cohorts of 8 subjects each (3 : 1 randomized to placebo). Risvodetinib was administered as a single Type 0 gelatin capsules which delivered the indicated dose as the freebase. A) Mean±standard deviation of C_max (ng/mL) and B) Mean±standard deviation of AUC_0 - inf (ng-h/mL).

Fig. 2

Plasma pharmacokinetic C_max, AUC and C_min as a function of daily oral dose for 7-days for risvodetinib (IkT-148009). Risvodetinib (IkT-148009) was administered once daily for 7 days and the plasma pharmacokinetics measured on Day 1 and Day 7 in cohorts of 8 subjects each (3 : 1 randomized to placebo). A) Mean±standard deviation of C_max (ng/mL) on Day 1 and Day 7 as a function of dose; B) Mean±standard deviation of AUC_0 - inf for Day 1 and AUC_0 - τ for Day 7 as a function of dose and C) Trough concentration measured as a function of time. Measurements at 50 and 100 mg were done in participants with PD, while all other doses were measured in healthy volunteers.