The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein–dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

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

“…The most frequent laboratory abnormality was a transient elevation in amylase and/or lipase, which is common to this drug class [ 17 ]. These observations are consistent with toxicology studies in rodent and non-human primates, respectively, where no histopathology in the pancreas was observed for daily dosing between 13 and 39 weeks duration [ 13 ]. In longer-term clinical studies, careful monitoring of these pancreatic enzyme values is warranted to detect the emergence of any risk from sporadic elevations in either enzyme, but given the similar exposures to risvodetinib in long-term toxicology studies and human clinical studies, it is not anticipated that pancreatic enzyme elevations will become adverse in humans.…”

“…The proposed therapeutic dose range for risvodetinib in humans was calibrated by comparison of the steady-state plasma pharmacokinetics observed in animal models of therapeutic efficacy to the clinical pharmacokinetics in humans [ 13 ]. Doses of 50 and 100 mg/kg/day were used to establish therapeutic efficacy in models of inherited or sporadic PD [ 13 ].…”

“…The proposed therapeutic dose range for risvodetinib in humans was calibrated by comparison of the steady-state plasma pharmacokinetics observed in animal models of therapeutic efficacy to the clinical pharmacokinetics in humans [ 13 ]. Doses of 50 and 100 mg/kg/day were used to establish therapeutic efficacy in models of inherited or sporadic PD [ 13 ]. Therapeutic doses in animal model studies that modified disease displayed steady-state C max and AUC 0 - inf values that could be achieved in humans by once daily dosing between 50 and 200 mg ( Supplementary Table 3 ), suggesting the possible therapeutic dosing range for treatment of PD.…”

“…Risvodetinib (IkT-148009) is a selective inhibitor of c-Abl that was designed to have a reduced affinity for transporters like PGP. In a series of prophylactic and therapeutic animal models, once-daily oral administration of risvodetinib blocked disease initiation and progression in the MPTP acute toxicity model [ 13 ] and was therapeutically effective following once daily oral administration in models of inherited or sporadic Parkinson’s-like disease [ 13 ]. These observations prompted clinical evaluation of the safety, tolerability and clinical pharmacokinetics following single and multiple oral doses of risvodetinib in older healthy adults and participants with mild-to-moderate PD who remained on symptomatic therapies.…”

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

“…Other c-Abl inhibitors such as IkT-148,009 and vodobatinib ( Table 2 ), are currently under development. The chronic oral treatment with IkT-148,009 was found to significantly reduce p-tyr39 and p-ser129 α-Syn levels thus preventing neurodegeneration in the brain of human A53T mutated α-Syn transgenic (tg) mice and of mice who received striatal injections of mouse recombinant α-Syn pre-formed fibrils (PFF; Karuppagounder et al, 2023 ). IkT-148009 is a derivative of the commercial anticancer imatinib and it has an IC50 of 33 nM for c-Abl, an improvement in potency of more than 20-fold over imatinib ( Werner and Olanow, 2022 ).…”