Research Research themes Metabolic disorders The successful road to development of drug candidate KH176, and beyond: A potential drug for mitochondrial disorders

Years of fundamental research within the Radboud Center for Mitochondrial Medicine at the Radboudumc resulted in a chemical hit molecule, a water-soluble vitamin E, demonstrating beneficial biological activity in mitochondrial disease cell lines when compared to control cell lines from healthy volunteers. To accelerate the hit to lead to clinical trial development it was necessary to disengage these research activities from its university setting. In good collaboration with the Technology Transfer Office and the Board of Directors of the Radboudumc this decision resulted in the operational start of Khondrion in November 2012. Financial support to start this strategic partnership was obtained from the Dutch government and national funding bodies. The obtained public knowledge of the identified chemical hit molecule served as starting point for an extensive, Radboudumc-independent lead optimization (LO) and Medicinal Chemistry program by Khondrion. Using the Structure Activity Relationship (SAR) approach, new LMW compounds were developed to improve the primary (bio)activity in Khondrion’s biological assays (a.o. modulating redox), using patient and control cell lines. Of the more than 250 newly synthesized compounds, KH176 demonstrated the best activity and also possessed good physicochemical properties (e.g. solubility). Therefore, KH176 was moved forward as Khondrion’s drug development candidate (DC) and was patented (Chromanyl derivatives for treating mitochondrial disease, WO2014011047). As this potential drug is developed to treat rare diseases lacking effective treatment, also an Orphan Drug Designation was received from both EMA and FDA. Following completion of the preclinical drug development program, KH176 has been successfully tested in phase I and phase II studies. Khondrion will continue to perform in-house drug discovery programs for the development of new therapies in the field of mitochondrial- and mitochondrial-related disorders (i.e. Parkinson) and the design and execution of clinical trials.
Patients and parents from affected children are important stakeholders in Khondrion’s drug development process. For them the progress in medicine development is always too slow and therefore it is of great importance to inform them by firsthand communication. For this reason, regular meetings are organized with the stakeholders and representatives of Khondrion to inform them about the progress of medicine development (KH176), and even more important to guide them through the expected timelines as we have to deal with legislations of the Dutch government and medicine agencies. It is of utmost importance to manage their expectations, but also to keep them motivated to proceed with their fundraising activities. Khondrion’s employees voluntary contribute to activities and events to show their commitment to the families and these organizations. Every year an Energy4All magazine is released, in which everyone can read the status of medicine development in interviews with employees of Khondrion and theme members involved in trials, and in stories of patients to emphasize the necessity of a cure. The magazine is also used to create more awareness for this rare disease. Campaigns in regional newspapers help to enlarge this awareness. We aim to ‘spread the word’, because more publicity means more chance to generate more finances to support and speed up medicine development.