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Khondrion announces sonlicromanol Phase IIb progress supporting Phase III development in MELAS spectrum disorders


KhondrionannouncessonlicromanolPhaseIIbprogresssupportingPhase III development in MELAS spectrum disorders

  • Sonlicromanol for MELAS spectrum disorders – a rare, progressive primary mitochondrial disease – to move into a Phase III registrational study supported by favourable benefit-risk profile
  • Both randomised placebo-controlled Phase IIb study and ongoing Phase IIb open label extension study show statistically significant and/or clinically meaningful results in multiple outcome measures with acceptable safety profile
  • Though 28-day Phase IIb study did not meet primary endpoint of the attention domain score of cognitive functioning, the study demonstrated positive treatment effects in several other cognition and mood-related secondary endpoints
  • Positive results on cognition, mood, quality of life, pain, fatigue and balance control were observed after up to 52 weeks sonlicromanol treatment
  • Topline data to be presented today by Khondrion’s CEO, Prof. Dr. Jan Smeitink, at Wellcome’s Mitochondrial Medicine - Therapeutic Development Conference, Cambridge, UK

NIJMEGEN, the Netherlands – 22 November 2022: Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial diseases, today provides an update from (A) the 28-day double-blind, randomised, placebo-controlled, three-way cross-over KHENERGYZE Phase IIb study in 27 patients, and (B) the ongoing, open label extension KHENEREXT Phase IIb study (7 patients up to 52 weeks) (both studies jointly the “Phase IIb programme”). Sonlicromanol, Khondrion’s wholly-owned lead asset, is being investigated in the Phase IIb programme in adult patients with MELAS spectrum disorders as genetically confirmed by the m.3243A>G mutation in the mitochondrial DNA.

In line with previous studies, sonlicromanol was found to be safe and well tolerated in the Phase IIb programme, with no serious adverse effects. The overall evaluation of the shorter and longer term data from the programme shows patient benefits in several domains (cognition and mood, pain, fatigue and balance control) and marked improvements in global health and quality of life assessments, supporting sonlicromanol’s progression into Phase III clinical development in patients with MELAS spectrum disorders. In line with expectations in these slowly progressing rare diseases, analysis of the data shows more pronounced treatment effects after 52 weeks. These longer-term patient data are, therefore, instrumental in providing valuable insights for the design of the upcoming Phase III trial.

Dr. Mirian Janssen, one of the principal investigators,Radboud Centre for Mitochondrial Medicine (Nijmegen, the Netherlands), said: ‘’I amencouraged by these promising results, especially the improvement in quality of life measurements and NMDAS score over a longer period. The fact that the study-patients wish to continue using sonlicromanol and their personal motivation are also positive signs.I have had the privilege to work closely with many of these patients for many years and I am pleased to observe tangible improvements in those patients whohave now been treated with sonlicromanol for 52 weeks. I praise Khondrion for its pursuit of mitochondrial disease innovation, care to the patients in its trials and commitment to this development programme.”

Phase IIb programme results

A.   KHENERGYZEPhase IIb study in m.3243A>G MELAS spectrum disorders (adults)

  • Patients (n=27) treated with sonlicromanol (50 mg and 100 mg bid) for 28 days did not achieve a statistically significant improvement in the attention domain score of cognitive functioning, as assessed by the computerised Cogstate visual identification test, compared to those who received placebo.
  • Post-hoc analyses of the Phase IIb study data showed positive trends in several other cognition and mood-related secondary endpoints as well as in other domains including fatigue.
  • More specifically, statistically significant and clinically meaningful treatment effects versus placebo were obtained, amongst others for the Beck Depression Inventory (BDI, 100 mg bid, p=0.01) and the Cognitive Failure Questionnaire (CFQ, 100 mg bid, p=0.007).
  • The totality of data suggests better effectiveness of the 100 mg bid dose relative to 50 mg bid.
  • Acceptable safety profile confirmed.

B.   KHENEREXT Phase IIb open label extension study (ongoing)

  • An interim analysis from the ongoing Phase IIb open label extension study, examining the long-term safety and a broad set of efficacy parameters of sonlicromanol (100 mg bid) in patients who completed the KHENERGYZE Phase IIb study, confirmed the positive results shown in the Phase IIb study on BDI and CFQ over a longer period of time in a first cohort of 7 patients who received sonlicromanol for 52 weeks.
  • On the widely-used NMDAS score, specifically developed and validated to assess disease severity of adult patients with primary mitochondrial disease, the majority of subjects showed a meaningful improvement with a decrease up to 6 points after 52 weeks. In a Natural History Study conducted by De Laat et al. (J Med Genet 2021), it was observed that the NMDAS score in patients with m.3243A>G increased on average with 0.47 points per year, representing disease deterioration.
  • Regarding other global health and quality of life related outcome measures, like RAND SF36 and EQ-5D-5L, the majority of patients overall who were affected for these parameters at baseline showed clinically meaningful responses, while both the clinician- and patient-reported global impression of change improved in the majority of patients in an otherwise progressive disease.
  • In addition, the interim analysis showed marked improvements in multiple other outcome measures, including pain (Short-form McGill Pain Questionnaire), fatigue (Neuro-QoL short form) and balance control (Mini-Balance Evaluation Systems Test), with various endpoints showing statistically significant and/or clinically meaningful treatment effects.
  • Acceptable safety profile confirmed.

Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said: These results are an important milestone for Khondrion. While sonlicromanol’s effect on the primary endpoint within a 28-day period was insufficient in the Phase IIb trial, we believe the broader results from the Phase IIb programme, now up to 52 weeks, provide unequivocal evidence of the positive clinical impact and important patient benefit that sonlicromanol can provide. We are particularly encouraged by the positive signals onoverall disease severity, mood, cognition, fatigue, balance and pain, all belonging to the most burdensome symptoms patients experience in their daily lives, as mentioned in UMDF’sVoice of the Patient Report 2019. We look forward to discussing our plans with European and U.S. regulators in the near future, ahead of the initiation of the Phase III registrational trial which is currently foreseen in late 2023.

I would like to express my heartfelt gratitude to each of the patients, and their families who have played a part in these studies, and to the patient advocacy groups, the clinical study teams in Nijmegen, Munich, Newcastle and Copenhagen, and Foundations and Governmental bodies for their special contributions to our research. And a huge thank you to the talented team at Khondrion for their continued hard work, furthering this field of research, and for their commitment to finding the new treatments that are so needed for patients.”

A presentation of topline data from this sonlicromanol Phase IIb programme update will be given by Prof. Dr. Jan Smeitink today at Wellcome’s Mitochondrial Medicine – Therapeutic Development Conference, Cambridge, UK. The full data will be submitted for peer-reviewed publication.

– ENDS –

Notes to editors

About the Phase IIb programme in adult patients with MELAS spectrum disorders

KHENERGYZE – A 28-day double-blind, randomised, placebo-controlled, multi-centre, three-way cross-over Phase IIb study examining cognitive function in adult patients with a specific genetically confirmed DNA mutation in the mitochondrial transfer RNALeu(UUR) (MT-TL1m.3243A>G). This mutation is responsible for MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders, including classical MELAS, MIDD (maternally inherited diabetes and deafness) syndromes, and mixed phenotypes.

Further details are available on (NCT04165239) and (2019-000599-40).

KHENEREXTAn open-label extension study, enabling continued sonlicromanol treatment for patients who had completed the KHENERGYZE Phase IIb study and the collection of longer-term data. Alongside safety, the study also gathers a broad set of primary and secondary functional clinical outcome measures, including cognition, fatigue and motor-function related parameters.

Further details are available on (NCT04604548) and (2020-000832-23).

Additional pediatric study(ongoing)

KHENERGYC – A placebo-controlled, double-blind Phase II study to explore the pharmacokinetics, safety and efficacy of sonlicromanol in children with a genetically confirmed primary mitochondrial disease and suffering from motor symptoms. The 6-month study, supported by Dutch Patient Foundations and an EFRO Grant (PROJ-00582), is investigating the effect of sonlicromanol in 24 children (from birth to 17 years) with genetically confirmed mitochondrial disease of which the gene defect is known to hamper the functioning of one or more oxidative phosphorylation system enzymes and who are suffering from motor symptoms. The study’s primary objective is to evaluate the effect of sonlicromanol on motor function using a range of validated, quantitative assessments including the Gross Motor Function Measure-88 and the Nine Hole Peg Test.

Further details are available on (NCT04846036) and (2020-003124-16).

About Khondrion

Khondrion is a clinical stage biopharmaceutical company developing therapies for patients with inherited mitochondrial diseases. Based on proprietary science and a deep biological understanding of mitochondrial dysfunction, the company is advancing its lead drug candidate sonlicromanol. Sonlicromanol is a first-in-class, oral small molecule targeting key underlying mechanisms of mitochondrial disease based on its uniquely differentiated triple mode of action: reductive distress modulation to help restore the cell’s metabolism, oxidative distress modulation preventing ferroptotic cell death, and selective mPGES-1 inhibition resulting in anti-inflammatory effects.

One of the most advanced disease-modifying drug candidates for mitochondrial disease in development, sonlicromanol has recently completed a Phase IIb study in adult patients with m.3243A>G MELAS spectrum disorders. In combination with interim 52-week data from the ongoing Phase IIb open-laben extension study, analysis of the results has shown marked improvements in multiple endpoints which merit further study in a Phase III registrational trial. Sonlicromanol is also studied in a 6-month Phase II study in children with genetically confirmed primary mitochondrial diseases and who suffer from motor symptoms. The compound has been granted orphan drug designations for the treatment of MELAS, Leigh disease and patients with maternally inherited diabetes and deafness (MIDD) in Europe, and for all inherited mitochondrial respiratory chain disorders in the US. 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

About mitochondrial disease

Mitochondrial disease occurs when mitochondria, found within all cells of the human body 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. Orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders including MIDD (maternally inherited diabetes and deafness), and other respiratory chain / oxidative phosphorylation disorders, are all examples of mitochondrial disease. MELAS spectrum disorders are some of the most frequently observed primary mitochondrial diseases, in which all patients are characterised by an underlying point mutation (m.3243A>G) in the maternally inherited MT-TL1 gene.

Forward-looking statements

This press release may contain certain forward-looking statements regarding, among other things, the results, conduct, progress and timing of the company’s clinical trials and presentation of data from clinical trials for sonlicromanol. Although the company believes its expectations are based on reasonable assumptions, all statements other than statements of historical fact included in this press release about future events are subject to (i) change without notice and (ii) factors beyond the company’s control. These statements may include, without limitation, any statements preceded by, followed by or including words such as “target,” “believe,” “expect,” “aim,” “goal,” “intend,” “may,” “anticipate,” “foreseen,” “estimate,” “plan,” “project,” “will,” “can have,” “likely,” “potential,” “should,” “would,” “could” and other words and terms of similar meaning or the negative thereof. Forward-looking statements are subject to inherent risks and uncertainties beyond the company’s control that could cause the company’s actual results, performance or achievements to be materially different from the expected results, performance or achievements expressed or implied by such forward-looking statements. Except as required by law, the company assumes no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.


Khondrion BV

Prof. Dr. Jan Smeitink, CEO


Tel: +31-24-7635000

Consilium Strategic Communications
David Daley, Melissa Gardiner, Kris Lam
Tel: +44 20 3709 5700

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