New Mitochondrial Therapy Based on Bioenergetics Advancing in Range of Clinical Trials

In the pipeline at Stealth BioTherapeutics is a new therapy, MTP-131, with the potential to treat individuals with mitochondrial disease and other diseases affected by mitochondrial dysfunction. The systemic version of MTP-131 (also known as Bendavia) is in clinical trials for skeletal muscle and cardio-renal diseases. The topical eye drop version (also known as Ocuvia) is on track to initiate clinical trials into Fuchs’ corneal endothelial dystrophy and Leber’s hereditary neuropathy in early 2016.

“Our lead compound, MTP-131, is being tested in therapeutic areas where mitochondria have the highest impact: heart, skeletal muscle, and the eye,” said Dr. Mark Bamberger, chief scientific officer of Stealth BioTherapeutics. “In collaboration with mitochondrial experts, we are looking at the organs with the most mitochondria (e.g., the heart) or that produce the most energy (e.g., muscle tissue and the eye). Mitochondrial function is involved in many different diseases. The key is which disease areas to focus.”

Stealth BioTherapeutics has provided positive proof of concept in some areas of mitochondrial disease through clinical trials. Last February, at the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH NIDDK) Meeting, Stealth BioTherapeutics and Mayo Clinic representatives discussed interim results of a single-center trial with 12 acute renal stenosis patients. During the trial, six patients received a two-hour infusion of MTP-131 before undergoing stent placement to alleviate blockage in the renal artery. The patients treated with MTP-131, compared to those treated with placebo, saw improved cortical renal blood flow and renal blood oxygenation.

The positive results may be due partly to where MTP-131 goes when it is administered to patients. “MTP-131 crosses the plasma membrane [of cells] and localizes specifically to the mitochondria,” said Dr. Bamberger. “This localization has been reproduced multiple times.” Probing further into the mechanism of action, the research team discovered that MTP-131 associates with the inner membrane of the mitochondria, where the respiratory complexes that generate ATP are located.

As stated by Dr. Bamberger, the question was then asked: “What’s unique about that inner membrane? As it turns out, it’s the only place where the phospholipid cardiolipin is found.” Cardiolipin, a molecule that composes approximately 20% of the inner mitochondrial membrane’s phospholipid content, differs from other phospholipid molecules such as phosphatidylcholine because it has two “phospho” head groups and four acyl chains. This unique structure gives cardiolipin a conical shape that forms a curve in the inner membrane of the mitochondria when the molecules are adjacent to each other, and helps hold the respiratory complexes in place. The binding of MTP-131 to cardiolipin may help the respiratory complexes operate more efficiently, in addition to other potential effects.

This mechanism of action sets MTP-131 apart from other investigational mitochondrial disease therapies because it directly affects bioenergetics rather than scavenges reactive oxygen species (ROS). Whereas therapeutics that neutralize ROS can potentially decrease ROS to harmfully low levels (some ROS activity is necessary in cells for signaling purposes), MTP-131 normalizes ROS levels by increasing the efficiency of mitochondria. In one experiment with old and young mice, it was shown that the mitochondria of old mice reached nearly the same level of ATP generation as that of young mice an hour after treatment with MTP-131, rising from approximately two-thirds the level of young mice.

MTP-131 appears to have therapeutic effects only in abnormal or stressed mitochondria, potentially reducing the risk for side effects in patients. Additional safety studies in clinical trials are needed to determine any adverse effects of treatments.

A virtual company without any laboratories of its own, Stealth BioTherapeutics outsources for clinical and animal model work, explained Brian Blakey, the company’s chief business officer. Collaborating with institutions such as Cornell University, Henry Ford Hospital, the University of Washington at Seattle, Mayo Clinic, and Duke University, Stealth BioTherapeutics and its 40 employees have been able to move “fast and furious into the clinic,” with hopes of jumping into larger Phase 3 trials soon.