Khondrion Doses First Patient in Phase 2b Trial Testing Sonlicromanol for Mitochondrial Diseases

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Khondrion has dosed the first patient in a Phase 2b clinical trial evaluating sonlicromanol, its lead investigational therapy for treating a range of mitochondrial diseases in adults.

Sonlicromanol is being developed as a treatment for MELAS — mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes — and MIDD, or maternally-inherited diabetes and deafness, syndromes.

The study will specifically include carriers of a common mitochondrial gene mutation — m.3243A>G in the MTTL1 gene. It will test the effect of different doses of sonlicromanol and its benefits in the cognition of patients, in particular their attention skills.

Participants are being recruited in Europe. More information can be found here. Results from the study are expected in the second half of 2020.

“The start of our phase 2b trial is another significant milestone for Khondrion as we aim to bring this important treatment to patients suffering from these devastating mitochondrial diseases,” Jan Smeitink, MD, PhD, founder and CEO of Khondrion, said in a press release.
“This study is targeting the most frequently encountered group of mitochondrial disorders, estimated to affect around 50,000 people in Europe, U.S. and Japan. Their impact on everyday life can be significant, particularly from cognitive impairment which affects everything we do involving thought or memory — whether that’s getting ready for work, chatting with friends or planning for the future,” Smeitink said.
“We believe Sonlicromanol has the potential to be an important disease-modifying treatment option and could address a significant unmet medical need and improve the lives of patients with mitochondrial diseases,” he added.

Previously known as KH176, Sonlicromanol is an oral small molecule designed to counteract the toxic effects of reactive oxygen species (ROS) — chemically reactive molecules that contain oxygen.

Mitochondria, the structures that provide energy to cells, are one of the main sources of ROS inside cells. One potential mechanism at the basis of mitochondrial diseases is the existence of unbalanced levels of ROS. This could result in an imbalance of the chemical processes of reduction-oxidation (redox) inside cells and lead to oxidative stress, which damages cells and tissues.

Sonlicromanol was developed to control the oxidative and redox imbalances in cells with mitochondrial disease and protect them from harm. It works by safeguarding lipids (a type of fats) from damage, counteracting inflammation, and preventing cell death — all processes associated with mitochondrial diseases.

The compound has been granted orphan drug designation in Europe for the treatment of MELAS spectrum disorders, Leigh disease, and MIDD, and in the U.S. for all inherited mitochondrial respiratory chain disorders.

The first trial of sonlicromanol was a Phase 1 study (NCT02544217) that showed the molecule was well-tolerated in healthy men.

The KHENERGY Phase 2a trial (NCT02909400) evaluated sonlicromanol’s tolerability, safety, and availability in the body, in 19 patients with MELAS,  MIDD, or other mixed types of mitochondrial diseases.

The participants were randomly assigned to receive twice-daily oral doses of 100 mg sonlicromanol for 28 days (10 patients) or a placebo control (nine patients). After a washout period, they were given a second round of sonlicromanol or placebo for another 28 days.

The study’s data showed sonlicromanol was well-tolerated with no serious side-effects. However, heart rates were lower seven days after treatment.

The treatment had no significant benefits on gait, strength, and other motor functions, or in respiratory capacity or clinical scores of disease severity.

However, short-term therapy with sonlicromanol lessened symptoms of depression and had a positive effect on alertness and mood.

These findings encouraged Khondrion to advance the potential therapy into the Phase 2b KHENERGYZE trial (NCT04165239), which is ongoing in Europe.

A double-blind, randomized, placebo-controlled trial, KHENERGYZE plans to recruit 27 adults with a specific mitochondrial mutation, MT-TL1 m.3243A>G, which is one of the most prevalent.

This mutation is responsible for MELAS spectrum disorders, including MELAS and MIDD syndromes, and other conditions with mixed characteristics.

The participants will be randomly assigned to twice-daily 50 mg of sonlicromanol, 100 mg of sonlicromanol, or a placebo for 28 days. After a washout of 14 days, patients will be crossed-over to one of the two other regimens, so that each group of patients goes through all three different treatments.

The primary objective is to evaluate the dose-effect of sonlicromanol on the participants’ cognitive function, which refers to all mental processes that deal with thought or memory.

The study’s main goal is to determine the benefit for patients’ attention skills — the ability to selectively focus on certain stimuli or information while ignoring, or avoiding getting distracted by others.

Other potential effects of sonlicromanol will be studied, including its impact on learning, hearing, smelling, anxiety and depression, disease severity, and quality of life.

KHENERGYZE is being launched at three mitochondrial disease centers in Europe. These are the Radboud University Medical Center, in the Netherlands, Newcastle University, in the U.K., and the Ludwig-Maximilians-University of Munich, in Germany.

The announcement of trial results is expected in the second half of 2020.

Khondrion also plans to investigate sonlicromanol’s potential in children, with a pediatric study expected to start later in 2020.