Actelion Submits sNDA of Macitentan for Treatment of CTEPH

Actelion Pharmaceuticals Ltd. announced the submission of a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) seeking to expand the indication of macitentan (OPSUMIT) to include treatment of adults with inoperable chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4) to improve exercise capacity and pulmonary vascular resistance.

The submission is based on data from the MERIT-1 trial, which showed significant improvements in the primary and secondary endpoint of pulmonary vascular resistance and 6-minute walk distance (6MWD), respectively, versus background therapy.

“Inoperable chronic thromboembolic pulmonary hypertension is associated with a poor prognosis if left untreated,” Martin Fitchet, MD, global head, research and development, Actelion, said in a statement.

Almost 40% of CTEPH patients are deemed inoperable and current pharmacological treatment options are limited to only 1 therapy.

MERIT-1, a phase 2 prospective study, addresses a key unmet need in the disease and provides the first randomized controlled trial data involving patients on combination therapy.

The trial assessed the efficacy, safety and tolerability of 10-mg OPSUMIT in patients with inoperable CTEPH.

After 16 weeks of treatment, researchers found a significant reduction in pulmonary vascular resistance for OPSUMIT versus placebo (mean [SD] decrease from baseline —206 [450.4] dyn·s/cm5 vs. –86 [301.5]; p=0.041). Efficacy was consistent across all sub-groups including those receiving background pulmonary arterial hypertension specific therapy at baseline (61% of patients) and PD35 inhibitors (59% of patients).

The study showed a significant positive effect on exercise capacity. After 24 weeks of treatment, the mean change in 6MWD from baseline was an increase of 35 meters in OPSUMIT and 1 meter in placebo. At 24 weeks, the 6MWD least squares mean increase was 34 meters between OPSUMIT and placebo (95%, CL: 2.9, 65.2 m; p=0.03).

Overall, OPSUMIT was well tolerated and the safety was generally consistent with the known safety profile. The most frequently ≥ 10% reported adverse effects that occurred with higher frequency in OPSUMIT patients versus placebo were peripheral edema (23% vs. 10% placebo) and decrease in hemoglobin (15% vs. 0%).

OPSUMIT, an orally available endothelin receptor antagonist, is indicated in the US for treatment of pulmonary arterial hypertension, WHO Group 1 to delay disease progression.

The treatment is very likely to cause major birth defects and is contraindicated for use in pregnancy. In the US, OPSUMIT is distributed under a risk evaluation and mitigation strategy.