Short-term treatment with oral KH176 was safe and well-tolerated by mitochondria disease patients, and lessened their symptoms of depression while also having a positive effect in alertness and mood, a Phase 2 clinical trial shows.
The study with those findings, “The KHENERGY study: Safety and efficacy of KH176 in mitochondrial m.3243A>G spectrum disorders,” was published in the journal Clinical Pharmacology & Therapeutics.
The small and orally administered KH176 molecule, developed by Khondrion, targets reactive oxygen species (ROS) produced by mitochondria and was developed as a potential strategy to help control the oxidative and redox, harmful events common in mitochondrial disease.
Previous studies have shown that in patient-derived fibroblasts (a type of cell), KH176 had a protective effect against this oxidative deviation.
Moreover, in a mouse model depleted for the NDUFS4 gene, whose loss of function is linked to Leigh syndrome and Mitochondrial Complex I Deficiency, treatment with KH176 improved the animals’ rotarod and gait performance.
The KHENERGY Phase 2 clinical trial (NCT02909400) tested KH176’s tolerability, safety, and its profile once inside the body, in 19 patients who are carriers of the most prevalent mitochondrial gene mutation, called m.3243A>G, who have MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), MIDD (maternally inherited diabetes and deafness) syndromes, or other mitochondria diseases.
Patients were randomized to twice-daily oral dose of 100 mg KH176 for 28 days (10 patients), or to a placebo control (nine patients). After a washout period, they were given a second round of KH176 or placebo for another 28 days.
The average age of the patients was 44 years and the most common symptoms associated were myopathy (muscle disease), exercise intolerance and fatigue. Two patients had impairments in normal walking and six patients had diabetes, of whom five received insulin treatment.
The daily dose of 100 mg of KH176 was well-tolerated with no serious adverse effects reported. However, measurement of the heart beat after seven days treatment showed a significantly lower average heart rate when compared to placebo patients.
Researchers assessed the KH176 effects on gait and other motor functional outcomes, including step-length and the variability in step-time and width. However, no differences were found between the KH176 treated group and the placebo.
The same lack of effect was found for additional parameters, including the 6-minute walking and the 6-minute mastication test, and the maximal grip strength test. No effects were detected in tests for respiratory function, and the treatment had no effect in lessening mitochondria’s disease burden and severity, measured by patients’ scores in the Newcastle Mitochondrial Disease Adult Scale.
The short-term therapy with KH176 improved depression and had a positive effect on alertness and mood.
“As depressive symptoms are quite prevalent in patients with mitochondrial disease, a reduction of the mitochondrial disease-related depressive symptoms, as observed, may be of clinical importance,” researchers wrote.
“Clinical trials of longer duration are needed to confirm a true treatment effect on mood related outcomes and to understand whether the improved mood is a primary effect of KH176 or secondary to improvement of other mitochondrial disease-related symptoms,” the study concluded.
KH176 received orphan drug designation for Leigh disease and MELAS in Europe, and for all inherited mitochondrial respiratory chain diseases in the U.S.