Objective: To evaluate the therapeutic potential of the selective, brain penetrant c-Abl inhibitor IkT-148009 in mouse models of progressive PD and the safety and tolerability in older healthy subjects and Parkinson’s patients.

Background: Parkinson’s disease (PD) pathology involves accumulation of misfolded α-synuclein within affected neurons. Animal models of PD suggest that activation of c-Abl plays an essential role in the initiation and progression of α-synuclein pathology, driving neurodegeneration. The role of c-Abl activation and the disease-modifying potential of c-Abl inhibition by IkT-148009 was evaluated in multiple mouse models of progressive PD (1), prompting clinical evaluation of the safety and tolerability of IkT-148009 in 88 older healthy subjects and 25 Parkinson’s patients.

Method: Mouse models evaluated the disease-modifying potential of IkT-148009 in inherited or sporadic PD (1, 2).  Clinical SAD studies were carried out in 72 healthy subjects between 12.5 mg and 325 mg, MAD studies in 16 healthy subjects at 12.5 mg and 25 mg once daily for 7 days, 14 Parkinson’s patients on concomitant anti-Parkinsonian therapy at 50 mg and 100 mg once daily for 7 days and 11 untreated Parkinson’s patients at 50 mg, 100 mg and 200 mg for up to 11 weeks.

Results: The outcomes of mouse model efficacy studies provided the basis for advancing into the clinic (1).  In the clinic, 7 possibly drug-related adverse events were observed, none of clinical significance and no SAEs were reported.  Clinical PK analysis established that IkT-148009 is well absorbed orally, has a 24 hr half-life, reached steady-state in 4-5 days with very high exposures and was linearly dose proportional between 12.5 mg and 200 mg once daily.  The therapeutic dosing range was determined to reside between 25 mg and 200 mg once daily.

Conclusion: In model studies, IkT-148009 drove functional recovery concomitant with clearance of the underlying alpha-synuclein pathology, consistent with the mechanism of disease initiation and progression recently described (2).  Clinically, IkT-148009 was shown to be relatively safe and induced no serious or clinically significant adverse events across a wide dosing range.  These outcomes warrant the continued evaluation of IkT-148009 as a potential disease-modifying therapy for PD.

References: (1) DOI: 10.1126/scitranslmed.abp9352
(2) DOI: 10.1002/mds.28858

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-the-therapeutic-potential-of-ikt-148009-in-parkinsons-disease/