Khondrion Receives FDA Clearance of INDA for Pivotal Phase 3 Trial of Sonlicromanol for Treatment of Primary Mitochondrial Disease

Khondrion recently announced it has received clearance from the US FDA for its Investigational New Drug (IND) application for sonlicromanol. The IND supports the initiation of a pivotal Phase 3 trial in adult patients with PMD due to the m.3243A>G mutation, the most common genetic defect causing PMD. The company expects to initiate the trial in 2025.

Sonlicromanol, Khondrion’s lead proprietary drug candidate, is a potentially disease-modifying first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD.

The company’s multicenter Phase 2b program, recently published in the scientific journal Brain, highlighted strong patient benefits from sonlicromanol in multiple outcome measures. That program’s 52-week extension study, which continued to treat some patients out to 78 weeks, demonstrated durable improvements among patients receiving sonlicromanol in several relevant domains, including chronic fatigue and muscle weakness, two of the most burdensome symptoms of PMD as described by patients.

The drug candidate’s potential to treat these aspects of disease will be further investigated in the upcoming Phase 3 trial. The 52-week double-blind, randomized, placebo-controlled, multi-center, parallel-group Phase 3 trial is expected to enroll 150 adult patients with a genetically confirmed mitochondrial DNA tRNA^Leu(UUR) m.3243A>G variant. For this study, Khondrion has selected the Neuro-QoL Fatigue short form questionnaire and the Five Times Sit-to-Stand test as its two independent primary endpoints. These outcome measures, assessing patients’ most burdensome and frequent effects of disease (chronic fatigue and muscle weakness), have encouragingly shown clinically meaningful and statistically significant (p-value of 0.004 and 0.016¹, respectively) results in the 52-week open-label extension part of the Phase 2b program. Further details of the Phase 3 trial’s design can be found on ClinicalTrials.gov here.

Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said “The FDA’s clearance of our IND application for a pivotal Phase 3 trial marks another important milestone for Khondrion’s development of sonlicromanol, a disease-modifying therapy for primary mitochondrial disease that is so desperately needed by PMD patients. We look forward to sharing progress of our clinical program including its expected initiation next year.”

Sonlicromanol has been investigated in four clinical trials, three in adult PMD patients with m.3243A>G, as well as in the first wave of a 6-month Phase 2 study in children with genetically confirmed PMD suffering from motor symptoms. Encouragingly, seven patients in the Netherlands, who elected to participate in a named patient program following completion of the Phase 2b open label extension study out to 78 weeks, have been receiving sonlicromanol for more than two and a half years, thus confirming the drug’s favorable safety profile.

Khondrion is initially focusing the development of sonlicromanol on PMD patients with the m.3243A>G variant, which is the most common genetic defect causing multi-systemic PMD and has an estimated prevalence of 4.4:100,000. There are currently no approved therapies for PMD associated with the m.3243A>G variant. The Company’s longer-term objective is to make sonlicromanol widely available for the broader PMD patient community. PMDs are the most prevalent inherited neurometabolic disorders, estimated to affect at least 1 in 4,300 which translates into approximately 65,000 people in the US alone. Khondrion’s wholly-owned, proprietary drug candidate has received orphan drug designation in the US and Europe and has also been granted a rare pediatric disease designation.

Khondrion is a clinical stage biopharmaceutical company developing therapies for patients with primary mitochondrial disease (PMD). The company’s lead asset, sonlicromanol, is a potentially first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD.

One of the most advanced, disease-modifying drug candidates for mitochondrial disease in development, sonlicromanol has been tested in three clinical trials in patients with m.3243A>G PMD, as well as in the first wave of a 6-month Phase 2 study in children with genetically confirmed PMD and who suffer from motor symptoms.

Sonlicromanol has been granted orphan drug designations for the treatment of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Leigh disease and patients with maternally inherited diabetes and deafness (MIDD) in Europe, and for all inherited mitochondrial respiratory chain disorders in the U.S. It has also been granted a rare pediatric disease designation in the US for the treatment of MELAS.

Sonlicromanol and other compounds from Khondrion’s proprietary library have the potential to be developed for a wide range of diseases and conditions with the aim of benefiting patients whose daily lives are severely impacted by mitochondrial impairment. For more information, visit www.khondrion.com.

Mitochondrial disease occurs when mitochondria, found within all cells of the human body except erythrocytes, and responsible for producing the energy necessary for cells to function, are defective. This can result in a wide range of serious and debilitating illnesses occurring shortly after birth or later in life. Signs and symptoms of these can include cognitive problems, learning disabilities, blindness, deafness, heart failure, diabetes, fatigue, intolerance to exercise, muscle weakness and gait problems, and stunted growth.

Originally referred to as MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), primary mitochondrial disease associated with the m.3243A>G variant in the mitochondrial genome is now considered to include a spectrum of phenotypes including classic MELAS, MIDD syndrome (maternally inherited diabetes mellitus and deafness), MP (mixed phenotypes) and CPEO (chronic progressive external ophthalmoplegia). Learn more.