FDA Grants Orphan Drug Designation to Livantra for Pulmonary Arterial Hypertension

This morning, August 14, 2018, the US Food and Drug Administration (FDA) granted an orphan drug designation in a second indication to Martin Pharmaceuticals’ repurposed, reformulated liquid version of the drug trimetazidine (LIVANTRA) for the treatment of pulmonary arterial hypertension (PAH).

“The metabolic theory of PAH is rapidly gaining a wider following,” said Sven Jacobson, CEO of Martin Pharmaceuticals exclusively to Rare Disease Report^Ò. “This orphan drug designation is an important achievement as we advance our development plans for LIVANTRA to combat PAH. We believe LIVANTRA may significantly enhance currently available treatment options for this desperately at-need patient population.”

LIVANTRA restores cellular homeostasis via its ability to inhibit beta-oxidation of fatty acids, which enhances glucose oxidation and prevents a decrease in intracellular ATP levels. Principally, trimetazidine dihydrocholoride has been used for the treatment of angina pectoris.

The drug has proven effective in 2 animal models of PAH—chronic hypoxia (CH) and monocrotaline (MCT) models.

In the CH model, mice were placed into chambers with 10% oxygen (normal air is 21% oxygen) for the duration 3 weeks to induce PAH. For the CH model, investigators used both normal mice and engineered mice lacking an enzyme referred to as malonyl-CoA decarboxylase (MCD-/- mice). MCD-/- mice were resistant to PAH, according to Martin Pharmaceuticals, “because β-oxidation is permanently impaired, which alleviates the Randle cycle inhibition of PDH, promoting glucose oxidation and reducing the proliferative and anti-apoptotic state underlying PAH.”

Trimetazidine was then administered for an additional 3-week period. Investigators found that the drug significantly improved the mean pulmonary arterial pressure, decreased right ventricular thickness, and boosted exercise performance, compared with the control mice. Furthermore, functional performance was found to have improved to a level comparable to MCD-/- mice, which investigators deemed to be reflective of untreated controls and did not develop PAH. Pulmonary arterial wall thickness and architecture of trimetazidine-treated normal PAH animal models were also more comparable to non-PAH controls than untreated normal PAH animal models.

For the second MCT model, investigators administered MCT to rats for the duration of 3 weeks using standard protocols in order to induce PAH. After PAH was established, the animals were split into 2 groups: those that would receive trimetazidine and those that would receive control. The rats treated with the drug showed significant improvements in reducing pulmonary arterial pressure and pulmonary artery thickness, as well as ventricular thickness.

A progressive, life-threatening disorder, PAH occurs when the very small arteries throughout the lungs narrow, increasing the resistance to blood flow through the lungs as a result. Ultimately, damage to the right ventricle of the heart can occur due to the increased blood pressure, making it difficult for the heart to pump blood through the lungs to be oxygenated. Approximately 35,000 to 60,000 people in the United States live with PAH, and The National Institutes of Health Registry has reported a 3-year mortality rate of approximately 50%.

Previously, LIVANTRA was granted an orphan drug designation by the FDA for the treatment of acute-on-chronic liver failure (ACLF).