FDA Lifts Clinical Hold on IkT-148009 in Multiple System Atrophy

Milton H. Werner, PhD

According to a recent announcement, the FDA has lifted its clinical hold on IkT-148009 (Inhibikase Therapeutics) in multiple system atrophy (MSA), allowing for the company to proceed with its phase 2a “202” clinical trial. The news comes less than 2 months after the agency lifted a clinical hold on program assessing the agent in Parkinson disease (PD).^1,2

"We are grateful for the expeditious review by the FDA of our response to the Clinical Hold on IkT-148009 in MSA,” Milton H. Werner, PhD, president and chief executive officer, Inhibikase Therapeutics, said in a statement.1 “As with our work in Parkinson, preclinical models have highlighted the therapeutic potential of IkT-148009 in MSA. One of two ongoing model studies has shown a substantial neuroprotective benefit in response to c-Abl inhibition by IkT-148009. With the clinical hold lifted and the IND now open, we look forward to completing these studies prior to initiation of the Phase 2a trial in this patient population."

In early December 2022, the FDA placed the hold on the company’s PD and MSA programs for the agent, citing several points. At the time, the agency requested further evaluation of the existing safety and pharmacokinetic data of the 200 mg dose, a better understanding of how the trials will monitor adverse events that could affect vision in trial participants, and the need for material additions to the disclosures made to investigators and patients related to the clinical and safety measures completed to that point, including the potential vision risks.³

MSA is a rare form of Parkinsonism, which occurs in a different part of the brain and advances 3 times faster than ordinary PD. The disease is characterized by pathological alpha-synuclein aggregation, which may lead to cell dysfunction and degeneration of neurons. IkT-148009, an Abelson Tyrosine Kinase (c-Abl) inhibitor, has demonstrated substantial neuroprotective benefit and prevention of functional loss in preclinical mice models.

The planned ‘202’ trial will investigate the safety and tolerability of IkT-148009 in 2 doses in patients with MSA, using safety and tolerability as primary end points. Secondary end points include a hierarchy of motor and non-motor features in the central nervous system and gastrointestinal tract, including Total Unified MSA Rating Scale (UMSARS), assessment of quality of life, severity of symptoms arising from orthostatic hypotension, and neurofilament light levels in peripheral blood and spinal fluid. The study, which spans 25 sites in 4 European Union countries and the United States, will also assess the clinical effect of the agent on progression of atrophy using MRI.

IkT-148009 is also being assessed in the phase 2 trial 201 (NCT05424276), a double-blind, 12-week study that randomly assigned 120 patients with PD 1:1:1:1 to either 50, 100 or 200 mg of IkT-148009 given once daily, or placebo. Patients included in the study have untreated PD, indicated by Hoehn and Yahr scores of less than 3, who have not yet progressed to the need for symptomatic therapy. Spanning across 40 sites in North America, the trial’s primary end point includes safety, tolerability, and steady-state PK of IKT-148009; although, the trial will also measure a hierarchy of PD-related disease assessments in the brain and gut as secondary or exploratory end points.

Earlier this year, Inhibikase announced the publication of studies describing the potential of IkT-148009 as a disease-modifying therapy for PD and related disorders. Published online in the journal Science Translational Medicine, the agent was analyzed in animal models of slowly progressive, α-synuclein-dependent PD. All told, in mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation from baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation.⁴

REFERENCES
1. Inhibikase Therapeutics announces FDA has lifted the full clinical hold on IkT-148009 in multiple system atrophy. News release. March 8, 2023. Accessed March 9, 2023. https://www.prnewswire.com/news-releases/inhibikase-therapeutics-announces-fda-has-lifted-the-full-clinical-hold-on-ikt-148009-in-multiple-system-atrophy-301763757.html
2. Inhibikase Therapeutics announces FDA has lifted the full clinical hold on IKT-148009 in Parkinson’s disease. News release. Inhibikase Therapeutics. January 25, 2023. Accessed March 9, 2023. https://www.prnewswire.com/news-releases/inhibikase-therapeutics-announces-fda-has-lifted-the-full-clinical-hold-on-ikt-148009-in-parkinsons-disease-301729466.html
3. Inhibikase Therapeutics provides update to FDA clinical hold of IKT-148009 programs. News release. Inhibikase Therapeutics. December 7, 2022. Accessed January 25, 2023. https://www.prnewswire.com/news-releases/inhibikase-therapeutics-provides-update-to-fda-clinical-hold-of-ikt-148009-programs-301697459.html
4. Inhibikase Therapeutics announces publication demonstrating potential for c-Abl as a key therapeutic target in Parkinson’s Disease and related disorders. Inhibikase Therapeutics. January 25, 2023. Accessed March 9, 2023. https://www.prnewswire.com/news-releases/inhibikase-therapeutics-announces-publication-demonstrating-potential-for-c-abl-as-a-key-therapeutic-target-in-parkinsons-disease-and-related-disorders-301728359.html