Objective/Rationale:
IMD-026259 represents a proprietary highly potent and selective small molecule inhibitor of NF-kB pathway and 1 alpha (HIF-1alpha) mediated transcriptional activity. Comprehensive target identification studies, including affinity purification experiments, succeeded in identifying two potential target proteins for the MedChem optimized IMD-026259.
Multiple in vivo studies (MPTP and 6-OHDA, p.o.) demonstrated compelling efficacy; by preserving striatal dopamine levels in pre-clinical models, IMD-026259 shows the potential to act neuroprotective as to become a disease modifying therapeutic.
Project Description:
This project targets to clarify two key remaining issues for the development candidate IMD-026259 on its path toward IND: 1. improve confidence and rational for a new innovative molecular
mechanism for PD treatment and 2. complete toxicology evaluation regarding 1st and 2nd species and clear NOEL determination (therapeutic window identification), resulting in three operative milestones:
MS1: Validate previous oral 14d tox study in pre-clinical models and determine NOEL.
MS2: Perform tox evaluation in pre-clinical models. Tox study will be accompanied by metabolic profiling as to further secure dosing for human trials.
MS3: Conduct further target validation experiments for the molecular target candidates, identified out of a comprehensive target ID program, including affinity binding, with the up side being further research investigation of these targets in the PD disease context, independent from this program. For MS2 and 3, we plan to re-synthesize a larger batch of IMD-026259.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our target is to prepare IMD-026259 for clinical testing as a PD therapeutic. When tox data are favorable, the decision to conduct the 90d tox study could be made as the last prerequisite to apply for IND status at the FDA. We also will learn about the relevance of the molecular targets of IMD-026259 in the PD disease context; they potentially serve as new innovative research tools to identify other neuroprotection and disease modification therapeutics that are different in structure.
Anticipated Outcome:
We will learn about the validity of IMD-026259 to become a clinical development candidate. Target validation will support this drug development path and also may solidify the potential role of these innovative new molecular targets in PD, and open up new treatment avenues toward neuroprotection and disease modification.
Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity as a lead supporter providing funding for the InterMed project.
Final Outcome
Based on promising neuroprotective properties confirmed in pre-clinical models for the small molecule lead compound IMD-026259, strong focus was directed towards the safety properties and respective therapeutic window towards preparation for a safe clinical investigation. Further investigation towards the molecular target mechanisms (based on previous results) were conducted as to support biological and toxicological evaluation.
One pre-clinical model was repeatedly shown to be reasonably tolerant to IMD-026259 exposure indicating an acceptable therapeutic window for chronic application. However, a late stage pre-clinical model was shown to be sensitive to the previously shown efficacious dose, which represents an issue for chronic application of IMD-026259. Since such sensitivity has already been seen in a third pre-clinical model, suggesting a safe therapeutic window may not be possible, we do not feel comfortable to move ahead towards clinical investigation of IMD-026259. Since the molecular target also remains unclear, we do not see a clear rational to differentiate between efficacy and undesired side effects for further optimization of IMD-026259 and its applications. Consequently, we decided to terminate this project.