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Late Clinical Development of KH176: an innovative orphan drug to reach mitochondrial disease patients & market

Periodic Reporting for period 2 - KHON2bTREAT (Late Clinical Development of KH176: an innovative orphan drug to reach mitochondrial disease patients & market)

Reporting period: 2019-10-01 to 2020-12-31

Mitochondrial diseases (MD) are chronic debilitating progressive multi-system disorders which might have their age of onset at any age. There is a high unmet medical need for treatment development for these devastating disorders as currently supportive care is the only option to be offered. MD are caused by specific nuclear DNA or the mitochondrial DNA gene defects. Consequently, the final biochemical pathway involved in energy production, the oxidative phosphorylation system, fails causing a multitude of harmful cellular consequences like disturbed redox metabolism, lipid peroxidation induced cell death and inflammation. A prototypic example of MD caused by a mitochondrial DNA mutation are the so-called MELAS spectrum disorders caused by a mutation in the transfer RNA of Leucine (m.3243A>G). The burden of this orphan MD for individual patients, their families and society are huge. First, high-energy requiring organs like the brain, the eyes, skeletal muscle start to dysfunction leading to e.g. cognitive decline, refractory epilepsy, vision loss, and exercise intolerance. As the disease progresses organ involvement increases finally leading to full dependence of individual patients with respect to daily life activities. There is a high unmet medical need to stop disease progression and finally cure these devastating disorders as currently supportive care is the only option to be offered. At Khondrion, a clinical stage biopharmaceutical company, we have developed new chemical entities of which the potential of one of these (KH176 or sonlicromanol) is currently being evaluated in a multi-center, phase 2b dose-finding study in adults with mitochondrial disease. Due to the Covid-19 pandemic a delay of the original predicted timelines has occurred and is discussed.

The goal of the study is to demonstrate a relevant clinical dose of KH176 in the mitochondrial disease patient population by studying an array of clinical readout parameters, all in preparation of the pivotal (Phase 3) trial. The project will allow Khondrion to secure a co-development deal with a (large) pharma company or investor financing for the pivotal clinical trial, market approval and market launch.
Since the start of the project (date 1- 10- 2018) all necessary requirements enabling the actual start of the clinical trial (first patient in Q1-2020) have been performed. These include among others design of the trial, European site selection, site visits and contract negotiations, GMP formulation studies, writing of the Investigator Brochure (IB) and updating the Investigational Medical Product Dossier (IMPD), preparation of the Informed Consent Letters and obtaining study approval by the regulatory and ethical bodies in the participating countries: The Netherlands, Germany and the UK. Next to that all licenses for the to be applied scales, questionnaires and computer assisted tools have been obtained and vendor selections for e.g. pharmacovigilance and data-management have been completed. Due to the pandemic the UK site is still closed with expected FPI Q1-2021. As a contigency plan we selected a 4th site (in progress) in order to try to keep within the timelines of the project. The German site has enrolled 4 patients, of whom currently 3 patients remain in the trial while the Dutch site has enrolled 9/9 patients in trial.
With the exception of idebenone for Leber’s Hereditary Optic Neuropathy, there are no approved prescription drug treatments for patients with primary mitochondrial disease (PMD) on the market. Khondrion is one of the leading mitochondrial disease companies in the world and the company’s strategy to focus their developments on one (the most frequently occurring) MD in adults (m.3243A>G spectrum disorders) will, with support of the H2020 SME grant, change the life of individual patients but, as expected, also substantially reduce healthcare costs. If successful the project will bring Europe in a leading position with respect to PMD treatments leading to increased employment within Khondrion and many companies indirectly involved.