a new source of energy

Targeting the key underlying mechanisms in mitochondrial disease.

our approach

Khondrion’s development programme is based on more than 10 years of academic research, leveraging the increased understanding of the underlying mechanisms of primary mitochondrial disease in combination with the development of new cellular readouts.

Khondrion’s drug development strategy is based on counteracting these cellular consequences to stall disease progression and to restore normal cellular function.

Our lead compound sonlicromanol was developed based on a comprehensive screening programme after we had first determined the most prominent disease-causing factors present across most of the now known pathogenic variants in genes causing mitochondrial diseases – i.e. increased radical species production, alterations in the cellular redox-state, and inflammation

Sonlicromanol was selected based on both its radical trapping capacity and its ability to reduce cellular redox stress out of more than 250 new compounds that were tested in genetically and biochemically characterised cultured primary skin fibroblasts.

technology platform

Khondrion’s in-house discovery engine is using unique live-cell imaging technologies and disease models to build a portfolio of promising compounds. Active discovery programmes are underway developing new therapies, biomarkers, and new read-out technologies in the field of mitochondrial diseases.

pipeline

Sonlicromanol

Khondrion’s wholly-owned investigational lead asset, sonlicromanol (formerly known as KH176), is a potential first-in-class medicine and one of the most advanced disease-modifying drug candidates for primary mitochondrial disease in clinical development.

Sonlicromanol targets the key underlying mechanisms of mitochondrial disease based on its scientifically validated and unique triple mode of action:

  • Redox modulation to help restore the cell’s metabolism
  • Radical trapping preventing lipid peroxidation induced ferroptotic cell death
  • Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition resulting in anti-inflammatory effects

Sonlicromanol development programme

  • KHENERGY – Early clinical proof of concept was achieved for sonlicromanol in the Company’s Phase IIa KHENERGY study. The study generated consistent pharmacokinetic, safety and tolerability data and sonlicromanol demonstrated significant cognition and mood -related patient improvements. Publication of the KHENERGY study results.
  • KHENERGYZE – In January 2020 Khondrion commenced its international multi-centre Phase IIb KHENERGYZE study of sonlicromanol in adult patients with MELAS spectrum disorders. The study’s objective is to reconfirm and expand on the positive findings from the KHENERGY study. The double-blind, randomised, placebo-controlled 3-way cross-over study will study the effect of sonlicromanol in 27 adult patients with a  3243A>G mutation which is responsible for MELAS spectrum disorders as well as pre-confirmed cognitive impairment using a cognition-related inclusion test. In addition to the endpoints that were assessed in the Phase IIa study, the KHENERGYZE study will add several cognition related endpoints developed by Cogstate which are broadly validated in a number of CNS indications as well as several outcome parameters in other domains that were not studied before. Khondrion announces first patients dosed in Phase IIb study of sonlicromanol for mitochondrial diseases.
  • KHENEREXT – Patients who have successfully completed the KHENERGYZE study will be offered to participate in a 12 month open label extension study, announced in October 2021. The main objective of this trial is to enable continued sonlicromanol treatment for those patients while collecting additional insightful longer-term data.  Khondrion announces first patients dosed in KHENEREXT Phase IIb extension study examining long-term safety and efficacy of oral sonlicromanol in mitochondrial disease patients.
  • KHENERGYC – In April 2021 Khondrion commenced its paediatric Phase II study to explore the pharmacokinetics, safety and efficacy of sonlicromanol in children. The double blind, placebo-controlled study is investigating the effect of sonlicromanol in 24 children (from birth to 17 years) with genetically confirmed primary 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 movement disorders. 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. Khondrion announces first patients dosed in 6-month paediatric Phase II study of sonlicromanol for mitochondrial diseases.

 

Sonlicromanol has been granted Orphan Drug Designations for the treatment of MELAS, Leigh disease and patients with MIDD in Europe and for all inherited mitochondrial respiratory chain disorders in the USA. It has also been granted a Rare Pediatric Disease designation by the US FDA for the treatment of MELAS.

Preclinical research

Khondrion is exploring the potential of its pipeline to target other diseases.

Press release – Khondrion announces publication in Scientific Reports outlining an additional anti-inflammatory mode of action for its lead phase IIb-stage drug candidate sonlicromanol

Press release – Khondrion announces publication in PLOS ONE of new research showing normalisation of prostate cancer stem cell mPGES-1 overexpression and inhibition of cancer spheroid growth by sonlicromanol’s active metabolite

scientific articles

“Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons.”

Klein Gunnewiek TM, Verboven AHA, Pelgrim I, Hogeweg M, Schoenmaker C, Renkema H, Beyrath J, Smeitink J, de Vries BBA, Hoen PAC’, Kozicz T, Nadif Kasri N.

Stem Cell Reports. 2021 Sep 14;16(9):2197-2212. doi: 10.1016/j.stemcr.2021.07.002. Epub 2021 Jul 29.

PMID: 34329596 Free PMC article.

 

“Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE 2 biosynthesis by sonlicromanol’s metabolite KH176m”

X. Jiang, H. Renkema, B. Pennings, S. Pecheritsyna, J.C. Schoeman, T. Hankemeier, J. Smeitink & J. Beyrath

Sci Rep. 2021 Jan 13;11(1):880. doi: 10.1038/s41598-020-79466-w.

“Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons.”

Schwartzentruber A, Boschian C, Lopes FM, Myszczynska MA, New EJ, Beyrath J, Smeitink J, Ferraiuolo L, Mortiboys H.

Sci Rep. 2020 Sep 23;10(1):15485. doi: 10.1038/s41598-020-72345-4.

“Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?”

Smeitink, J.; Jiang, X.; Pecheritsyna, S.; Renkema, H.; van Maanen, R.; Beyrath, J.

Preprints 2020, 2020040180 (doi: 10.20944/preprints202004.0180.v1)


“Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients”

Jan Smeitink, Saskia Koene, Julien Beyrath, Christiaan Saris, Douglas Turnbull, Mirian Janssen

JIMD reports, 2019, volume 46, issue 1


“Rescue from galactose-induced death of Leigh Syndrome patient cells by pyruvate and NAD+”

Eligio F. Iannetti, Jan A. M. Smeitink, Peter H. G. M. Willems, Julien Beyrath & Werner J. H. Koopman

Cell Death & Disease, 2018, volume 9, 1135.


“The KHENERGY study: Safety and efficacy of KH176 in mitochondrial m.3243A>G spectrum disorders.”

Mirian CH Janssen, Saskia Koene, Paul de Laat, Pleun Hemelaar, Peter Pickkers, Edwin Spaans, Rypko Beukema, Julien Beyrath, Jan Groothuis, Chris Verhaak, Jan Smeitink

Clinical Pharmacology & Therapeutics, 2018, July 30th


“KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery”

Julien Beyrath, Mina Pellegrini, Herma Renkema, Lisanne Houben, Svetlana Pecheritsyna, Peter van Zandvoort, Petra van den Broek, Akkiz Bekel, Pierre Eftekhari & Jan A. M. Smeitink

Scientific Reports 2018, April 26; 8:6577


“KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers”

Saskia Koene, Edwin Spaans, Luc van Bortel, Griet van Lancker, Brant Delafontaine, Fabio Badilini, Julien Beyrath and Jan Smeitink.

Orphanet Journal of Rare diseases 2017 Oct 2; 12:163


“Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease.”

de Haas R, Das D, Garanto A, Renkema HG, Greupink R, van den Broek P, Pertijs J, Collin RWJ, Willems P,
Beyrath J, Heerschap A, Russel FG, Smeitink JA.

Scientific Reports 2017 Sep 15;7(1):11733.


“Multiplexed high-content analysis of mitochondrial morphofunction using live-cell microscopy”

Eligio Iannetti, Jan Smeitink, Julien Beyrath, Peter Willems, Werner Koopman.

Nature Protocols (2016) 11, 1693-1710


“Mitochondrial disorders in children: toward development of small‐molecule treatment strategies”

Werner Koopman, Julien Beyrath, Cheuk‐Wing Fung, Saskia Koene, Richard Rodenburg, Peter Willems, Jan Smeitink.

EMBO Molecular Medicine (2016) emmm.201506131.


“Toward high-content screening of mitochondrial morphology and membrane potential in living cells”

Eligio Iannetti, Peter Willems, Mina Pellegrini, Julien Beyrath, Jan Smeitink, Lionel Blanchet, Werner Koopman.

The International Journal of Biochemistry and Cell Biology, 63 (2015) 66-70.


“Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics”

Sarah Foriel, Peter Willems, Jan Smeitink, Annette Schenck, Julien Beyrath.

The International Journal of Biochemistry and Cell Biology, 63 (2015) 60-65.


“Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning”

Lionel Blanchet, Jan A.M. Smeitink, Sjenet E. van Emst-de Vries, Caroline Vogels, Mina Pellegrini, An I. Jonckheere, Richard J.T. Rodenburg, Lutgarde M.C. Buydens, Julien Beyrath, Peter H.G.M. Willems and Werner J.H. Koopman.

Scientific Reports, 26;5:8035 (2015).


“New treatments for mitochondrial disease—no time to drop our standards”

Gerald Pfeffer, Rita Horvath, Thomas Klopstock, Vamsi K. Mootha, Anu Suomalainen, Saskia Koene, Michio Hirano,Massimo Zeviani, Laurence A. Bindoff,Patrick Yu-Wai-Man, Michael Hanna, Valerio Carelli, Robert McFarland, Kari Majamaa, Douglas M. Turnbull,
Jan Smeitink and Patrick F.Chinnery

Nature Review Neurology 9, 474–481 (2013).


“Monogenic mitochondrial disorders”

Koopman WJ, Willems PH, Smeitink JA.

New England Journal of Medicine. 366(12):1132-41 (2012).


“Towards the harmonization of outcome measures in children with mitochondrial disorders.”

Koene S, de Laat P, van Tienoven DH, Vriens D, Brandt AM, Sweep FC, Rodenburg RJ, Donders AR, Janssen MC, Smeitink JA.

Developmental Medicine & Child Neurology. 55(8): 698-706 (2013).


“Serum FGF21 levels in adult m.3243A>G carriers: clinical implications.”

Koene S, de Laat P, van Tienoven DH, Vriens D, Brandt AM, Sweep FC, Rodenburg RJ, Donders AR, Janssen MC, Smeitink JA.

Neurology. 83(2):125-33 (2014).