sonlicromanol (KH176) / Khondrion - LARVOL DELTA

Targeting the Electron Transport System for Enhanced Longevity. (PubMed, Biomolecules) - "Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress."

Journal • Review • Inflammation

KH176-301: KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases (clinicaltrials.gov) - P3 | N=150 | Not yet recruiting | Sponsor: Khondrion BV | Trial completion date: Jul 2027 ➔ Jan 2028 | Initiation date: Jan 2025 ➔ Aug 2025 | Trial primary completion date: Jul 2027 ➔ Jan 2028

Trial completion date • Trial initiation date • Trial primary completion date • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Otorhinolaryngology

The KHENERGYC Study (clinicaltrials.gov) - P2 | N=24 | Suspended | Sponsor: Khondrion BV | Active, not recruiting ➔ Suspended

Trial suspension • CNS Disorders • Metabolic Disorders • CRP • FGF • GDF15

Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation. (PubMed, Brain) - "Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline."

Journal • P2b data • CNS Disorders • Depression • Fatigue • Inherited Retinal Dystrophy • Leber Hereditary Optic Neuropathy • Metabolic Disorders • Mood Disorders • Ocular Inflammation • Ophthalmology • Optic Neuritis • Psychiatry

KH176-301: KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases (clinicaltrials.gov) - P3 | N=150 | Not yet recruiting | Sponsor: Khondrion BV

New P3 trial • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Otorhinolaryngology

The KHENERGYC Study (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Khondrion BV | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Metabolic Disorders • CRP • FGF • GDF15

The KHENEREXT Study (clinicaltrials.gov) - P2 | N=11 | Completed | Sponsor: Khondrion BV | Active, not recruiting ➔ Completed | Phase classification: P2b ➔ P2 | Trial completion date: Sep 2023 ➔ Jun 2023 | Trial primary completion date: Sep 2023 ➔ Jun 2023

Phase classification • Trial completion • Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Ophthalmology • Otorhinolaryngology

Targeting AMPK/eNOS pathway and mitochondria by sonlicromanol protects myocardial cells against ischemia-reperfusion injury. (PubMed, Gen Physiol Biophys) - "However, AMPK inhibition significantly reduced sonlicromanol protective actions. Cardioprotection by sonlicromanol was achieved by moderating inflammatory and oxidative responses, and AMPK/eNOS/mitochondrial signaling is a crucial regulator of these actions."

Journal • Cardiovascular • Coronary Artery Disease • Myocardial Ischemia • Reperfusion Injury • IL1B • NOS3 • TNFA

The KHENERGYC Study (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: Khondrion BV | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • CNS Disorders • Metabolic Disorders

The KHENEREXT Study (clinicaltrials.gov) - P2b | N=15 | Active, not recruiting | Sponsor: Khondrion BV | Recruiting ➔ Active, not recruiting | N=27 ➔ 15 | Trial completion date: Mar 2023 ➔ Sep 2023 | Trial primary completion date: Mar 2023 ➔ Sep 2023

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Ophthalmology • Otorhinolaryngology • CRP

The KHENERGYZE Study (clinicaltrials.gov) - P2b | N=27 | Completed | Sponsor: Khondrion BV | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Metabolic Disorders • Myositis

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"). (PubMed, BMC Neurol) - P2 | "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."

Journal • P2 data • PK/PD data • Metabolic Disorders • Pediatrics

The KHENERGYZE Study (clinicaltrials.gov) - P2b | N=27 | Active, not recruiting | Sponsor: Khondrion BV | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Metabolic Disorders • Myositis

The KHENERGYC Study (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: Khondrion BV | Trial completion date: Sep 2022 ➔ Dec 2023 | Trial primary completion date: Jul 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • CNS Disorders • Metabolic Disorders

The KHENEREXT Study (clinicaltrials.gov) - P2b; N=27; Recruiting; Sponsor: Khondrion BV; Not yet recruiting ➔ Recruiting; Trial completion date: Dec 2022 ➔ Mar 2023; Trial primary completion date: Sep 2022 ➔ Mar 2023

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Ophthalmology • Otorhinolaryngology • CRP

The KHENERGYZE Study (clinicaltrials.gov) - P2b; N=27; Recruiting; Sponsor: Khondrion BV; Trial primary completion date: Dec 2021 ➔ Apr 2022

Clinical • Trial primary completion date • CNS Disorders • Metabolic Disorders • Myositis

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons. (PubMed, Stem Cell Reports) - "This was intricately linked with changes in the neuronal transcriptome. Overall, we provide insight in transcriptomic changes in iPSC-derived neurons with high m.3243A>G heteroplasmy, and show the pathology is partially reversible by sonlicromanol."

Journal • Cardiovascular • CNS Disorders • Metabolic Disorders

Sonlicromanol's active metabolite KH176m normalizes prostate cancer stem cell mPGES-1 overexpression and inhibits cancer spheroid growth. (PubMed, PLoS One) - "KH176m inhibited the expression of mPGES-1 and reduced the growth of spheroids derived from the CSC. Based on the results obtained we propose selective mPGES-1 targeting by the sonlicromanol metabolite KH176m as a potential novel treatment approach for cancer patients with high mPGES-1 expression."

Cancer stem cells • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD24 • CD44

The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury. (PubMed, Cardiovasc Drugs Ther) - "Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished."

Journal • Cardiovascular • Coronary Artery Disease • Metabolic Disorders • Myocardial Ischemia • Reperfusion Injury

The KHENERGYC Study (clinicaltrials.gov) - P2; N=24; Recruiting; Sponsor: Khondrion BV

New P2 trial • CNS Disorders • Metabolic Disorders

The KHENERGYZE Study (clinicaltrials.gov) - P2b; N=27; Recruiting; Sponsor: Khondrion BV; Trial completion date: Jun 2021 ➔ Mar 2022; Trial primary completion date: Mar 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Metabolic Disorders • Myositis

The KHENEREXT Study (clinicaltrials.gov) - P2b; N=27; Not yet recruiting; Sponsor: Khondrion BV; Initiation date: Jan 2021 ➔ Apr 2021

Clinical • Trial initiation date • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Ophthalmology • Otorhinolaryngology • ALB • CRP

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE biosynthesis by sonlicromanol's metabolite KH176m. (PubMed, Sci Rep) - "Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond."

Journal • Immunology • Inflammation • Metabolic Disorders • IL1B

Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid β-oxidation. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4 mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases."

Journal • Preclinical • Hepatology • Metabolic Disorders

The KHENEREXT Study (clinicaltrials.gov) - P2b; N=27; Not yet recruiting; Sponsor: Khondrion BV

Clinical • New P2b trial • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Ophthalmology • Otorhinolaryngology • CRP