Actelion's Opsumit seeking to become only the second drug approved for the treatment of inoperable CTEPH.

Seeking to become only the second drug approved for the treatment of patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH; WHO Group 4), Actelion have submitted a supplemental NDA to the U.S. FDA seeking approval in these patients for their orally active endothelin receptor antagonist (ERA) Opsumit (macitentan). Opsumit is currently approved across the G7 major markets to delay disease progression and hospitalization in pulmonary arterial hypertension (PAH, WHO Group 1) patients. This filing will seek to expand the drug’s label to include improvement in exercise capacity and pulmonary vascular resistance (PVR) in inoperable CTEPH patients.

CTEPH is a rare and progressive form of PH and pulmonary endarterectomy (PEA) is the treatment of choice for all eligible patients. However, approximately 40% of CTEPH patients are deemed inoperable and Bayer/Merck’s guanylate cyclase stimulator Adempas (riociguat) is currently the only drug currently indicated for treatment of this patient group.
The approval for Adempas in inoperable CTEPH was supported by results from the Phase III CHEST-1 trial in 252 patients, where Adempas treatment significantly improved exercise capacity and PVR in CTEPH patients. Meanwhile, Opsumit’s filing for inoperable CTEPH is supported by the results of the 80-patient, Phase II MERIT-1 trial (NCT02021292), which demonstrated significant improvements with Opsumit treatment in PVR and six-minute walk distance (6MWD) compared with placebo.

One issue that may trouble the FDA is the lack of Phase III trial data; however, the general lack of therapeutic options for this patient group, the fact that patients in the MERIT-1 trial were allowed to receive PAH background therapy, including phosphodiesterase type 5 (PDE5) inhibitors or oral/inhaled prostanoids, and the fact that off-label prescribing of PAH therapies in these patients is a common occurrence, should all add weight to Opsumit’s approval argument.
DRG research estimates up to one-third of all U.S. CTEPH patients are prescribed off-label therapy. The 2017 Current Treatment: Physician Insight analysis also found that the most commonly-prescribed off-label therapy for CTEPH patients is the PDE5 inhibitor sildenafil, likely due to its low cost, proven efficacy and safety in treatment of PAH patients, and physician familiarity. With 61% of all patients in the MERIT-1 trial receiving background PH-specific therapy, and over half of those on a PDE5 inhibitor, approval of Opsumit for inoperable CTEPH may lead to increased use of combination therapy with an ERA and (off-label) PDE5 inhibitor in these patients, just as the AMBITION trial has led to a rise in earlier use of this combination in PAH patients.

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