A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms ("KHENERGYC")

Jan Smeitink, Rob van Maanen, Lonneke de Boer, Gerrit Ruiterkamp, Herma Renkema, Jan Smeitink, Rob van Maanen, Lonneke de Boer, Gerrit Ruiterkamp, Herma Renkema

Abstract

Background: METHODS: The KHENERGYC trial will be a phase II, randomised, double-blinded, placebo-controlled (DBPC), parallel-group study in the paediatric population (birth up to and including 17 years). The study will be recruiting 24 patients suffering from motor symptoms due to genetically confirmed PMD. The trial will be divided into two phases. The first phase of the study will be an adaptive pharmacokinetic (PK) study with four days of treatment, while the second phase will include randomisation of the participants and evaluating the efficacy and safety of sonlicromanol over 6 months.

Discussion: Effective novel therapies for treating PMDs in children are an unmet need. This study will assess the pharmacokinetics, efficacy, and safety of sonlicromanol in children with genetically confirmed PMDs, suffering from motor symptoms.

Trial registration: clinicaltrials.gov: NCT04846036 , registered April 15, 2021. European Union Clinical Trial Register (EUDRACT number: 2020-003124-16 ), registered October 20, 2020. CCMO registration: NL75221.091.20, registered on October 7, 2020.

Keywords: Children; Clinical study protocol; GMFM; KH176; Mitochondrial diseases; OXPHOS; Redox metabolism; Sonlicromanol.

Conflict of interest statement

Gerrit Ruiterkamp and Herma Renkema are employees of Khondrion, Rob van Maanen is a former employee of Khondrion, and Jan Smeitink is the founding CEO of this mitochondrial medicine company.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design

References

    1. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2:16080. doi: 10.1038/nrdp.2016.80.
    1. Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N Engl J Med. 2012;366(12):1132–1141. doi: 10.1056/NEJMra1012478.
    1. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148(6):1145–1159. doi: 10.1016/j.cell.2012.02.035.
    1. Papa S, Martino PL, Capitanio G, Gaballo A, De Rasmo D, Signorile A, et al. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol. 2012;942:3–37. doi: 10.1007/978-94-007-2869-1_1.
    1. Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Asp Med. 2004;25(4):365–451. doi: 10.1016/j.mam.2004.03.001.
    1. Schlieben LD, Prokisch H. The dimensions of primary mitochondrial disorders. Front Cell Dev Biol. 2020;8:600079. doi: 10.3389/fcell.2020.600079.
    1. Tinker RJ, Lim AZ, Stefanetti RJ, McFarland R. Current and emerging clinical treatment in mitochondrial disease. Mol Diagn Ther. 2021;25(2):181–206. doi: 10.1007/s40291-020-00510-6.
    1. Rahman S. Mitochondrial disease in children. J Intern Med. 2020;287(6):609–633. doi: 10.1111/joim.13054.
    1. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190–203. doi: 10.1002/ana.24551.
    1. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994;9(1):4–13. doi: 10.1177/088307389400900102.
    1. Okhuijsen-Kroes EJ, Trijbels JM, Sengers RC, Mariman E, van den Heuvel LP, Wendel U, et al. Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation. Neuropediatrics. 2001;32(4):183–190. doi: 10.1055/s-2001-17372.
    1. de Laat P, Rodenburg RR, Roeleveld N, Koene S, Smeitink JA, Janssen MC. Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant. J Med Genet. 2021;58(1):48–55. doi: 10.1136/jmedgenet-2019-106800.
    1. Sharma R, Reinstadler B, Engelstad K, Skinner OS, Stackowitz E, Haller RG, et al. Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity. J Clin Investig. 2021;131(2). 10.1172/jci136055.
    1. Beyrath J, Pellegrini M, Renkema H, Houben L, Pecheritsyna S, van Zandvoort P, et al. KH176 safeguards mitochondrial diseased cells from redox stress-induced cell death by interacting with the thioredoxin system/peroxiredoxin enzyme machinery. Sci Rep. 2018;8(1):6577. doi: 10.1038/s41598-018-24900-3.
    1. Bottani E, Lamperti C, Prigione A, Tiranti V, Persico N, Brunetti D. Therapeutic approaches to treat mitochondrial diseases: "one-size-fits-all" and "precision medicine" strategies. Pharmaceutics. 2020;12(11):1083. doi: 10.3390/pharmaceutics12111083.
    1. Martinelli D, Catteruccia M, Piemonte F, Pastore A, Tozzi G, Dionisi-Vici C, et al. EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome. Mol Genet Metab. 2012;107(3):383–388. doi: 10.1016/j.ymgme.2012.09.007.
    1. Frantz MC, Skoda EM, Sacher JR, Epperly MW, Goff JP, Greenberger JS, et al. Synthesis of analogs of the radiation mitigator JP4-039 and visualization of BODIPY derivatives in mitochondria. Org Biomol Chem. 2013;11(25):4147–4153. doi: 10.1039/c3ob40489g.
    1. Shabalina IG, Vyssokikh MY, Gibanova N, Csikasz RI, Edgar D, Hallden-Waldemarson A, et al. Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging. 2017;9(2):315–339. doi: 10.18632/aging.101174.
    1. Seo KS, Kim JH, Min KN, Moon JA, Roh TC, Lee MJ, et al. KL1333, a novel NAD(+) modulator, improves energy metabolism and mitochondrial dysfunction in MELAS fibroblasts. Front Neurol. 2018;9:552. doi: 10.3389/fneur.2018.00552.
    1. Leipnitz G, Mohsen AW, Karunanidhi A, Seminotti B, Roginskaya VY, Markantone DM, et al. Evaluation of mitochondrial bioenergetics, dynamics, endoplasmic reticulum-mitochondria crosstalk, and reactive oxygen species in fibroblasts from patients with complex I deficiency. Sci Rep. 2018;8(1):1165. doi: 10.1038/s41598-018-19543-3.
    1. Seminotti B, Leipnitz G, Karunanidhi A, Kochersperger C, Roginskaya VY, Basu S, et al. Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. Hum Mol Genet. 2019;28(6):928–941. doi: 10.1093/hmg/ddy403.
    1. Jiang X, Renkema H, Pennings B, Pecheritsyna S, Schoeman JC, Hankemeier T, et al. Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE(2) biosynthesis by sonlicromanol's metabolite KH176m. Sci Rep. 2021;11(1):880. doi: 10.1038/s41598-020-79466-w.
    1. Koene S, Spaans E, Van Bortel L, Van Lancker G, Delafontaine B, Badilini F, et al. KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers. Orphanet J Rare Dis. 2017;12(1):163. doi: 10.1186/s13023-017-0715-0.
    1. Janssen MCH, Koene S, de Laat P, Hemelaar P, Pickkers P, Spaans E, et al. The KHENERGY study: safety and efficacy of KH176 in mitochondrial m.3243A>G spectrum disorders. Clin Pharmacol Ther. 2019;105(1):101–111. doi: 10.1002/cpt.1197.
    1. Russell D, Rosenbaum P, Avery L, Lane M. Gross motor function measure (GMFM-66 and GMFM-88) user's manual: clinics in developmental medicine. London: Mac Keith Press; 2002.
    1. Smith YA, Hong E, Presson C. Normative and validation studies of the Nine-hole Peg Test with children. Percept Mot Skills. 2000;90(3 Pt 1):823–843. doi: 10.2466/pms.2000.90.3.823.
    1. Nagy S, Schmidt S, Hafner P, Klein A, Rubino-Nacht D, Gocheva V, et al. Measurements of motor function and other clinical outcome parameters in ambulant children with duchenne muscular dystrophy. J Vis Exp. 2019;143. 10.3791/58784.
    1. Tyson S, Connell L. The psychometric properties and clinical utility of measures of walking and mobility in neurological conditions: a systematic review. Clin Rehabil. 2009;23(11):1018–1033. doi: 10.1177/0269215509339004.
    1. Boyd RN, Graham HK. Objective measurement of clinical findings in the use of botulinum toxin type A for the management of children with cerebral palsy. Eur J Neurol. 1999;6(S4):s23–s35. doi: 10.1111/j.1468-1331.1999.tb00031.x.
    1. Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the Barry-Albright Dystonia Scale. Dev Med Child Neurol. 1999;41(6):404–411. doi: 10.1017/s0012162299000870.
    1. Schmitz-Hübsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia. Neurology. 2006;66(11):1717. doi: 10.1212/01.wnl.0000219042.60538.92.
    1. Dumas HM, Fragala-Pinkham MA, Haley SM, Ni P, Coster W, Kramer JM, et al. Computer adaptive test performance in children with and without disabilities: prospective field study of the PEDI-CAT. Disabil Rehabil. 2012;34(5):393–401. doi: 10.3109/09638288.2011.607217.
    1. Koene S, Hendriks JCM, Dirks I, de Boer L, de Vries MC, Janssen MCH, et al. International Paediatric Mitochondrial Disease Scale. J Inherit Metab Dis. 2016;39(5):705–712. doi: 10.1007/s10545-016-9948-7.
    1. Bédard M, Molloy DW, Squire L, Dubois S, Lever JA, O'Donnell M. The Zarit Burden Interview: a new short version and screening version. Gerontologist. 2001;41(5):652–657. doi: 10.1093/geront/41.5.652.
    1. Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology. Neurology. 2012;78(23):1860–1867. doi: 10.1212/WNL.0b013e318258f744.
    1. Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11(4):909–918. doi: 10.1002/jcsm.12559.
    1. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007;4(7):28–37.
    1. Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manip Physiol Ther. 2004;27(1):26–35. doi: 10.1016/j.jmpt.2003.11.003.
    1. EuroQol. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199–208. doi: 10.1016/0168-8510(90)90421-9.
    1. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) Qual Life Res. 2011;20(10):1727–1736. doi: 10.1007/s11136-011-9903-x.
    1. Eiser C, Morse R. The measurement of quality of life in children: past and future perspectives. J Dev Behav Pediatr. 2001;22(4):248–256. doi: 10.1097/00004703-200108000-00007.
    1. Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications. Health Qual Life Outcomes. 2003;1:54. doi: 10.1186/1477-7525-1-54.
    1. Thompson C, Lombardi D, Sjostedt P, Squires L. Best practice recommendations regarding the assessment of palatability and swallowability in the development of oral dosage forms for paediatric patients. Ther Innov Regul Sci. 2015;49(5):647–658. doi: 10.1177/2168479015573585.
    1. Lifesphere EDC system and Central Coding . Vendor: Arisglobal. 2022.
    1. Fujii T, Nozaki F, Saito K, Hayashi A, Nishigaki Y, Murayama K, et al. Efficacy of pyruvate therapy in patients with mitochondrial disease: a semi-quantitative clinical evaluation study. Mol Genet Metab. 2014;112(2):133–138. doi: 10.1016/j.ymgme.2014.04.008.
    1. Koene S, van Bon L, Bertini E, Jimenez-Moreno C, van der Giessen L, de Groot I, et al. Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop. J Inherit Metab Dis. 2018;41(6):1267–1273. doi: 10.1007/s10545-018-0229-5.
    1. Mancuso M, McFarland R, Klopstock T, Hirano M. International Workshop: Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16–18 November 2016, Rome, Italy. Neuromuscul Disord. 2017;27(12):1126–1137. doi: 10.1016/j.nmd.2017.08.006.
    1. Sage-Schwaede A, Engelstad K, Salazar R, Curcio A, Khandji A, Garvin JH, Jr, et al. Exploring mTOR inhibition as treatment for mitochondrial disease. Ann Clin Transl Neurol. 2019;6(9):1877–1881. doi: 10.1002/acn3.50846.
    1. Liufu T, Wang Z. Treatment for mitochondrial diseases. Rev Neurosci. 2020; [published online ahead of print. 10.1515/revneuro-2020-0034.
    1. Lyseng-Williamson KA. Idebenone: a review in Leber's hereditary optic neuropathy. Drugs. 2016;76(7):805–813. doi: 10.1007/s40265-016-0574-3.
    1. Viscomi C, Zeviani M. Strategies for fighting mitochondrial diseases. J Intern Med. 2020;287(6):665–684. doi: 10.1111/joim.13046.
    1. Wang Y, Hu LF, Zhou TJ, Qi LY, Xing L, Lee J, et al. Gene therapy strategies for rare monogenic disorders with nuclear or mitochondrial gene mutations. Biomaterials. 2021;277:121108. doi: 10.1016/j.biomaterials.2021.121108.
    1. Russell OM, Gorman GS, Lightowlers RN, Turnbull DM. Mitochondrial diseases: hope for the future. Cell. 2020;181(1):168–188. doi: 10.1016/j.cell.2020.02.051.
    1. de Haas R, Das D, Garanto A, Renkema HG, Greupink R, van den Broek P, et al. Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease. Sci Rep. 2017;7(1):11733. doi: 10.1038/s41598-017-09417-5.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe