For rare mitochondrial disease, a small molecule shows promise

When a mutation occurs in mitochondrial DNA, it can disrupt the organelle’s ability to produce energy. If the balance of mutant to healthy mitochondria in a cell — known as heteroplasmy — shifts toward more mutant than healthy ones, it can lead to mitochondrial disease, a rare and debilitating group of disorders with no known cure. Because heteroplasmy can vary across cells, organs, and even among individuals within a family, mitochondrial diseases often present differently in each patient, making the development of treatments particularly difficult.

As the founder and Chief Executive Officer of Khondrion, Jan Smeitink leads the clinical-stage biopharmaceutical company’s efforts to discover new therapies targeting mitochondrial disease.

Credit: Khondrion

Aware of these challenges, Jan Smeitink, a pediatrician and mitochondrial biologist at Radboud University, decided to devote his career to tackling the disease. “I thought it’s now time to switch gears and start a company and try to really develop [new] drugs,” he said. In 2007, Smeitink founded Khondrion, a clinical-stage pharmaceutical company focused on developing therapies for mitochondrial diseases, where he now serves as Chief Executive Officer.

In the journal Brain, Smeitink and his team recently reported Phase 2b trial results of their drug sonlicromanol in treating people with a specific mitochondrial mutation, m.3243A>G, in the mitochondrial gene MT-TL1 (1). Sonlicromanol was safe, well-tolerated, and led to significant improvements in patient health. The discovery could offer a promising new avenue for treating this rare, devastating disorder.

The m.3243A>G variant is the most common mutation linked to mitochondrial disease. It disrupts the ability of a specific mitochondrial tRNA to synthesize proteins involved in producing energy from oxygen. Patients with the mutation generally experience a range of progressively worsening symptoms, from mild deafness to stroke-like episodes, for which no effective treatments are currently available (2).

Sonlicromanol is an oral brain-penetrant small molecule designed to target key pathways involved in mitochondrial energy production and oxidative stress in cells. The drug works by boosting ATP production in cells while reducing oxidative damage and inflammation, thereby preventing cell death.

In their study, the researchers first conducted a randomized controlled trial (RCT) to identify the most effective dose of the drug for treating disease symptoms. They then followed this with a 52-week open-label extension study to assess the drug's long-term safety, efficacy, and tolerability.

It was far beyond expectations.
– Jan Smeitink, Khondrion

The researchers found that sonlicromanol led to improvements in quality of life, mood, fatigue, and muscle function, using a range of standardized tests. The drug also markedly improved patient scores on the Newcastle Mitochondrial Disease Adult Scale (NMDAS), a test that is used to assess the severity of mitochondrial disease in adults. Typically, a patient’s NMDAS score increases over time, reflecting worsening symptoms and disease progression. However, after treatment with sonlicromanol, patients’ NMDAS scores began to trend downwards.

“That, I’ve never seen before,” said Smeitink. “I’ve seen thousands of patients with mitochondrial disease, and they [always] get worse and worse over time.” He added, “It was far beyond expectations.” However, sonlicromanol did not significantly improve cognitive function as measured by an identification task.

Herma Renkema oversees Khondrion’s preclinical development strategy as the company’s Chief Scientific Officer.

Credit: Khondrion

Herma Renkema, the Chief Scientific Officer of Khondrion and a coauthor on the study, attributed this to the large variability in baseline Cogstate scores among the study’s participants. When the researchers adjusted each subject’s score for baseline severity, they observed that sonlicromanol led to improved scores compared to the placebo.

Mike Murphy, a biochemist at the University of Cambridge who was not involved in the study, acknowledged the difficulties of testing a drug like sonlicromanol in patients with such varied symptom severities. “It’s very challenging to do any trial like this,” he said. “We've got a very variable cohort of patients and a small number [of them]. And if you look at the variation even in the mutation load, that was also quite challenging.”

Despite these difficulties, Murphy commended the team at Khondrion on their efforts to find treatments for patients with mitochondrial disease. “They’re hugely dedicated to making life better for patients,” he said.

Going forward, Smeitink and his colleagues are preparing to begin a Phase 3 clinical trial to assess sonlicromanol further. In November last year, Khondrion received FDA clearance for their Investigational New Drug (IND) application, allowing them to proceed to this critical trial phase. They plan to enroll 150 adult patients with the m.3243A>G variant.

“We expect to have the first patients in early in the second half of this year,” Smeitink said. “The sooner, the better.”

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