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A New Treatment for Patients with Severe Mitochondrial Disease

Mitochondria generate most of the energy in cells throughout the body, so defects in these intracellular structures can have far-ranging, sometimes devastating, consequences. Hundreds of mitochondrial diseases are currently known. They occur in both children and adults, and can affect multiple organs, including brain, heart, skeletal muscles, gastrointestinal tract, kidneys, peripheral nerves, eyes, and skin.

For these reasons, the clinical trial currently being conducted by Dr. Richard H. Haas, MD at the CTRI, and its encouraging preliminary results, are viewed with much interest by the clinicians, scientists, and families in the mitochondrial disease community. Along with Dr. Zuela Zolkipli-Cunningham and Dr. Gail Reiner, he is assessing the effects of EPI-743, an experimental agent developed by Edison Pharmaceuticals, as part of an international multicenter trial. The PI of the study, Dr. Greg Enns, is based at Stanford University.

According to Dr. Haas, a Professor in the Departments of Pediatrics and Neurosciences at the UC San Diego School of Medicine, the severity of the disease depends on the organs affected. “Most of us in the field view mitochondrial disease as similar to premature aging,” he says. “Whereas adults might most often be affected in the muscles and heart, children are mostly affected in the brain.” Dr. Zuela Zolkipli-Cunningham, an Instructor in the Department of Neurosciences and a pediatric neurologist, noted that “The earlier onset of mitochondrial disease in some children significantly impacts their neurodevelopment.” Developmental deficits include speech impairment, and often confine these children to wheelchairs. Most of the patients in the current study are likely to enter hospice within 6 months. “It’s tough to see them like that—kids are supposed to be bundles of energy, tiring out the adults first, not the other way around,” observed Vicky Lam, RN, Nurse Supervisor at the CTRI clinic. “And caregiver burden is usually pretty heavy with this population, especially since most of the families are from out of town and are willing to travel across the country to seek care for their children.”

Some Background

There are two categories of mitochondrial disease: primary, due to a genetic defect; and secondary, as a component of other diseases like diabetes, Parkinson’s, and cancer. The children in the current study have diverse primary mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), Leigh’s Disease, and illnesses derived from deletions or depletions of mitochondrial DNA. However, the diseases typically share some common manifestations, such as disruptions in the electron transport chain (this is a series of molecular reactions inside mitochondria that give off energy). Besides interfering with energy production, impairment of electron transport can increase the number of free radicals (harmful molecules which also accumulate in the normal aging process).

So a goal of therapy for patients with mitochondrial disease is to remove or “scavenge” these free radicals, using antioxidants like coenzyme Q10 (CoQ10). In fact, the standard of care is a regimen of CoQ10, a high dose of the B vitamin riboflavin, and carnitine (plus supplemental folate for those patients with cerebral folate deficiency). However, CoQ10 is notoriously insoluble. So Edison Pharmaceuticals, the sponsor of the study, has formulated a version of CoQ10 that is more easily absorbed (it crosses the blood-brain barrier), and which seems to be a strong antioxidant. This soluble form of CoQ10 is combined with vitamin E to form the experimental agent EPI-743.

CoQ10 may help in another way. In addition to its antioxidant properties, CoQ10 happens to be one of the molecular players in the electron transport chain. So supplementation with CoQ10 may improve respiratory chain function in affected individuals, especially those patients who have abnormally low amounts of CoQ10 in their muscles.

The EPI-743 Open-Label Study

This international multicenter trial involves a total of approximately 120 children and adults with mitochondrial disease, 8 of whom participate at the CTRI. Treatment consists of oral EPI-743 over 13 weeks. In addition, subjects take their usual regimen of high dose B vitamins including riboflavin and carnitine, but without their conventional CoQ10. The primary endpoint is quality of life, measured by the Newcastle Pediatric Mitochondrial Disease Survey.

“Since this is an open-label study, the results must be viewed with caution; but we are seeing benefits in development,” says Dr. Haas. This is consistent with three published reports on a similar regimen. Gail Reiner, Nurse Practitioner III and Research Coordinator for the study, added that “Ten-year-old Derek spoke for the first time in his life this week. ‘Hi,’ proud and four times. Amazing.” The treatment appears well-tolerated; some subjects experience gastrointestinal issues, but these have been readily resolved.

After 13 weeks, the patients will continue on therapy, with follow-up probably every 3 months. Beyond this open-label EPI-743 study, a new clinical trial has just started—the first randomized, double-blinded, controlled trial in Leigh’s Disease, including centers at Stanford University, Seattle Children’s Hospital, Akron Children’s Hospital, and Baylor College of Medicine. The endpoints include quality of life, survival rate, neuromuscular function, respiratory function, drug safety, and biomarkers. For more information on this new trial, please visit Safety and Efficacy Study of EPI-743 in Children With Genetically Confirmed Leigh Syndrome. Patients and their families can find information on mitochondrial diseases from the United Mitochondrial Disease Foundation.

About UC San Diego Altman Clinical and Translational Research Institute:

UC San Diego Altman Clinical and Translational Research Institute (ACTRI) is part of a national Clinical and Translational Science Award consortium, led by the National Institutes of Health National Center for Advancing Translational Science. Established in 2010, ACTRI provides infrastructure and support for basic, translational and clinical research throughout the San Diego region to bring discoveries from the laboratory to the bedside, and facilitates training and education of the next generation of researchers. ACTRI carries out its activities in collaboration with institutional and corporate partners and currently has more than 1,500 members.