FDA approves Opsynvi as 1st single-tablet PAH combo treatment

Macitentan plus tadalafil once-daily tablets are OK'd for use by adults

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has approved once-daily, fixed-dose tablets containing a combination of macitentan and tadalafil — to be marketed under the brand name Opsynvi — to treat adults with pulmonary arterial hypertension (PAH).

The approval marks the first single-tablet treatment combination to become available to people with PAH in the U.S.

The therapy is specifically approved for adults in the World Health Organization (WHO) functional class 2 or 3, its developer Johnson & Johnson said in a company press release. According to Opsynvi’s prescribing information, macitentan reduces the risk of clinical worsening and hospitalization, and tadalafil improves exercise ability.

“We’re thrilled to bring this single-tablet combination therapy to patients, as it has the potential to optimize disease management and fulfill a significant unmet need in supporting recently updated treatment guidelines that call for initial or early combination treatment,” said James F. List, MD, PhD, Johnson & Johnson‘s global therapeutic area head, whose team oversees programs including pulmonary hypertension.

Both molecules were already individually approved and sold separately for PAH, but are commonly prescribed together. Macitentan, sold by Janssen as Opsumit, is an endothelin receptor antagonist or ERA, while tadalafil, marketed as Adcirca for PAH in the U.S. by United Therapeutics, is a phosphodiesterase 5 inhibitor, or PDE5i.

Importantly, Opsynvi is not indicated for pregnant patients, and is available for women only through a restricted access program.

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2 medications in Opsynvi work in different ways in treating PAH

Opsynvi is indicated for PAH patients who are treatment-naïve, as well as those who were already taking PDE5i, ERA, or both. It may be used in patients who are currently treated with stable doses of both macitentan 10 mg and tadalafil 40 mg (20 mg twice) as separate tablets. The recommended dosage is one 10 mg/20 mg (starting dose) or 10 mg/40 mg (maintenance dose if starting dose is tolerated) tablet taken orally once daily with or without food.

Developer Janssen Pharmaceuticals, now Johnson & Johnson Innovative Medicine, believes the combined tablets offer a more convenient option for patients who might benefit from both classes of medications.

The introduction of a single tablet combining both [medications] is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy.

An ERA and a PDE5i each work in different ways to cause blood vessels to relax and widen. Guidelines recommended that the two classes of oral medications be used together as a first-line treatment for patients without significant existing heart or lung issues who have idiopathic (no known cause) PAH, heritable drug-associated PAH, or PAH associated with connective tissue disease.

However, that requires taking multiple pills to achieve the recommended daily doses of 10 mg macitentan and 40 mg tadalafil — which can limit patients’ adherence to the treatment regimen.

Opsynvi contains these same doses in a single, once-daily tablet. It’s expected to have similar efficacy as taking the two therapies separately, but in a simpler and more convenient treatment regimen.

“As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients,” said Kelly Chin, MD, director of the pulmonary hypertension program at UT Southwestern Medical Center, in Dallas, who served as an investigator in a Phase 3 clinical trial that supported the therapy’s approval.

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That trial, called A DUE (NCT03904693), enrolled 187 adults with PAH who were treatment naïve or had previously been on stable PDE5i or ERA monotherapy. All were in the WHO functional class 2 or 3.

Participants received a daily dose of Opsynvi, macitentan alone, or tadalafil alone for about four months. The results showed that the combination therapy led to significantly greater improvements in blood flow than either monotherapy regardless of patients’ treatment history, age, sex, race, or WHO functional class.

Opsynvi also led to significantly greater decreases in a biomarker of heart failure, and tended to be superior to either single treatment in terms of exercise capacity.

Johnson & Johnson also is seeking a similar approval for Opsynvi in the European Union.

The treatment combination earned its first clearance in 2021, when Health Canada approved it as a substitute for PAH patients already taking the two classes of therapies as separate tablets. It’s also cleared for that indication in Argentina.

The company further noted that it now offers PAH therapies addressing all three guideline-recommended pathways — nitric oxide, endothelin, and prostacyclin.

Opsynvi comes with four contraindications: It should not be used by pregnant women, patients with a history of hypersensitivity to macitentan, tadalafil, or any component of the product, individuals using any form of organic nitrate, and simultaneously with guanylate cyclase stimulators such as riociguat.

The therapy’s prescribing label comes with a boxed warning stating that it may cause fetal harm if administered to pregnant women, and advising against pregnancy during and one month after treatment. The release also notes that Opsyinvi is available for women only through a restricted program called Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS).

The most common side effects of the therapy are headache or migraine, swelling or fluid retention, and anemia. People with anemia do not have enough healthy red blood cells or hemoglobin to carry oxygen to the body’s tissues.

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