Medication for the body's malfunctioning energy system in the works

There is hope for patients suffering from an energy metabolism disease. The company Khondrion, a spin-off from the Radboudumc in Nijmegen, has been working in recent years to develop a new medicine for these rare diseases. A preliminary study in children started this month. This caused Jan Smeitink, theme Metabolic diseases, a lot of frustration: he diagnosed and treated his patients as well as he could, except that there is no medication available.

Energy Factories

Smeitink is a pediatrician who specializes in mitochondrial diseases, also known as energy metabolism diseases. Mitochondria are found in almost every cell in the human body, where they convert sugars and fats into energy. You could think of them as the body's energy factories or batteries. In patients with an energy metabolism disease the mitochondria malfunction, causing the cells to receive too little energy and releasing harmful substances that eventually cause cells to die. This causes a variety of problems such as muscle weakness, fatigue, developmental or growth retardation, problems with vision or hearing, and heart problems. Often the first symptoms are seen in children, but sometimes the disease does not manifest itself until adulthood.

There are more than 300 known genes where faults lead to mitochondrial diseases, all of which are rare or extremely rare. Some mitochondrial diseases are so severe that children die of them at an early age. The course can also be more mild, with a longer life expectancy.

Repairing damage

Is it possible to repair these broken energy factories or at least prevent them from causing more damage in the body, in some cases even to the point of death? Smeitink resolved to seek the answer to that question himself.

In 2012 the company Khondrion started its work activities. Initially, Smeitink did this alongside his work as a pediatrician and professor at the Radboudumc. During his search for a medicine, Smeitink decided to focus on MELAS spectrum syndrome. In these patients, malfunctioning mitochondria can lead to cognitive problems (for example, difficulty concentrating or being able to plan and make decisions), stroke-like seizures, deafness, muscle weakness, fatigue and diabetes. The symptoms usually arise in late childhood or early adulthood. About 50,000 patients worldwide suffer from this form of mitochondrial disease. By comparison, Parkinson's involves about 7 million patients worldwide.

Khondrion tested a substantial series of new chemical compounds and their effects on mitochondria. You cannot prevent or eliminate faulty mitochondria, but you can potentially limit the harmful effects. “We received a grant from ZonMw in order to research this, and we are also supported by various charitable foundations. This enabled us to get started very quickly,” says Smeitink. Sonlicromanol emerged as the most promising of a number of candidate molecules. The results in the laboratory in cell and animal models also proved to be very promising.

Prestigious grant

"Yet after this study, it was extremely difficult to obtain funds for further research, even though this is necessary," Smeitink says. Eventually we managed to secure a prestigious European Horizon 2020 grant and a grant from the Economic Fund for Regional Development (ERDF). "But we have to be seriously economical with the funds we have. As a result, research is not processing as fast as we would like."

Yet significant and important steps are now being taken. Smeitink currently works full-time as CEO of Khondrion. “It was not possible to combine it with clinical duties at the hospital. The cooperation between the Radboudumc and our company is excellent. The hospital conducts the trials with sonlicromanol that has been developed by Khondrion and together we work on various research projects.

Clinical research

The drug has now been tested in humans and its results published in the medical professional medical papers. "First in healthy subjects, then in a small group of patients. We are looking forward to its potential efficacy on MELAS spectrum syndrome patients as well as on other mitochondrial diseases."

This year, Khondrion hopes to complete an international study – the phase 2b study – in adult patients in the Netherlands, Germany and England. They plan to study the drug’s effectiveness in a larger group of patients. The drug appears to improve patients’ cognitive function, making them more alert, for ont thing. But Smeitink also hopes for positive results on other bodily systems, such as motor function.

Trial in children

A study was recently started on children living with mitochondrial diseases. This is something that Smeitink considers very important because there is plenty of room for improvement here. The children participating in the study are affected by movement disorders and spasticity, among other things. Some of the children with a metabolic disease die before they reach the age of ten. Smeitink: “We cannot cure the disease. But we hope that the earlier we start treating it, the better the effect.”

If all goes well, Smeitink hopes that the drug will be approved for the market in three years, by which time it is hoped that a large proportion of patients can be helped.

The drug sonlicromanol has now received an orphan drug status rating from the European Medicines Agency (EMA) and the FDA. Once this is done, the research will be able to count on various incentive schemes for this type of drug. This makes it easier when it comes to applying for funding.

Source: Innovation Origins