Robert F. Kennedy famously said, “The purpose of life is to contribute in some way to making things better.” And when you’re in the rare disease business, you measure how you’re “making things better” on a micro, but no less vital, scale.
For Vij Senthilnathan, a PTC leader in clinical operations working on the small molecule therapy PTC743 (vatiquinone), now in a Phase 3 global clinical trial for patients with mitochondrial disease and associated refractory epilepsy – a.k.a. the MIT-E Trial, small measurements keep her motivated: “Every cell in the body of a child with mitochondrial epilepsy can be affected by this rare disease,” she explains.
Some children are unable to communicate with their muscles. Some children drool a lot. Even for the child to look at you is a milestone to the parent.
“But that’s not a milestone we can take to the FDA (Food and Drug Administration),” Senthilnathan adds. “In novel rare disease we don’t always know enough about the disease, and there is often no accurate natural history data. It can be hard to know what to measure and what ‘good’ looks like. This is a great barrier to clinical trial design and endpoint selection for rare indications like this.”
The PTC743 development program has been running for over a decade—and has been a pioneering program in drug development for mitochondrial disease. PTC743 is an oral compound that targets the oxidoreductase enzymes critical to inflammation, oxidation, and cell death (ferroptosis) which have been shown to be associated with seizures in mitochondrial disease. If the clinical trials are ultimately successful, vatiquinone has the potential to reduce seizures and improve quality of life for patients.
The 743 Story
Vatiquione development was initiated by BioElectron over a decade ago. In 2009, a young girl at the terminal stages of mitochondrial disease was treated with 743, as part of an emergency use protocol. Over the next several years, the therapy was studied in a number of different open-label clinical trials targeting various mitochondrial disease subtypes and other inherited oxidative stress disorders.
Senthilnathan joined the 743 clinical operations team in 2014. In 2019, PTC Therapeutics acquired Bio-Electron’s assets, including not only PTC743 (vatiquinone), but a number of other clinical and preclinical compounds targeting inflammation and oxidative stress.
MIT-E Is Mighty
The global MIT-E trial was designed to leverage a number of important findings about the reported treatment effects of PTC743 from previous studies. Matthew Klein, MD, MS, FACS, PTC’s chief development officer, and Martin Thoolen, the clinical development lead for 743 – both 743 veterans of more than a decade – spent several months meeting with regulatory authorities worldwide to discuss the clinical learnings and align on clinical measurements or endpoints to study that may be able to demonstrate clinical benefit for patients.
In 2020, this double-blind, placebo-controlled trial commenced in children with genetically-confirmed mitochondrial disease and refractory epilepsy, such as Leigh syndrome, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, Alpers syndrome, MERRF (myoclonus epilepsy with ragged-red fibers) syndrome, and PCH6 (Pontocerebellar hypoplasia type 6). The FDA has granted vatiquinone orphan drug designation, and rare pediatric disease designation.
Learning More Every Step of the Journey
“Over the years, we learned that staying connected with clinical investigators and patient advocacy groups (PAGs) will give us a better understanding of the endpoints that matter,” Senthilnathan explains. “We gained insights about the difficulties families living with mito face and the challenges of having highly infirmed patients travel to trial sites for participation.”
To be enrolled in the MIT-E Trial, patients with mitochondrial disease must exhibit frequent seizures lasting over a 28-day period. “We locked our primary endpoint as reduction in seizure frequencies,” Senthilnathan says, adding that epilepsy is a very important symptom, significantly impairing the quality of life.
In the most extreme cases of epilepsy, such as status epilepticus, prolonged seizures are likely to cause some brain injury and cognitive impairment. The reduction of seizures is therefore critical to the patients and caregivers who endure them.
743 Today and Tomorrow
To date, over 500 children and adults have been treated with 743. The longest treatment has spanned over 11 years in a child with Leigh syndrome secondary to SURF1 mutation. The data collected from previous PTC743 studies indicated that treatment was associated with a reduction in seizure frequency as well as other aspects of disease morbidity such chronic hospitalization.
The MIT-E Trial is active and recruiting; and four locations in the United States have opened to enrollment:
- Akron Children’s Hospital in Akron, Ohio
- Seattle Children’s Hospital in Seattle, Washington
- University of Texas Health Science in Houston, Texas
- Children’s of Minnesota in Minneapolis, Minnesota
Additional sites in North American and Europe and sites in Europe will be opening in the near future.
Despite the challenges that come with orphan drug development, the 743 team hopes to be the first to develop a therapy for children with mitochondrial diseases. “In the beginning, I got a job I liked,” Senthilnathan says. “But over the years, I have gotten attached to the people in the mito community.
“When I joined PTC, I was so thankful that it meant 743 was going to Phase 3,” she explains. “There are a lot of ups and downs in clinical trial operations, but we stand today with a common goal to get the FDA approval.”