Remodulin Pre-treatment Allows Higher Orenitram Doses

United Therapeutics shares top-line results of Phase 4 EXPEDITE trial

Teresa Carvalho, MS avatar

by Teresa Carvalho, MS |

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A short treatment with Remodulin (injectable treprostinil) before initiating Orenitram (oral treprostinil) allows pulmonary arterial hypertension (PAH) patients to achieve double the normal doses of the oral therapy without increasing side effects.

These are the findings of a preliminary analysis of top-line data from the Phase 4 EXPEDITE trial (NCT03497689), which involved 34 people with PAH.

Since higher blood levels of treprostinil — the active ingredient in both of the United Therapeutics’ therapies — have been associated previously with better outcomes, these results highlight a potential approach to safely and quickly increase Orenitram’s benefits.

“We’re delighted with the preliminary results from the EXPEDITE study, which provided patients a way to reach efficacious doses in a shorter period of time without having to commit to long-term pump therapy,” Meredith Broderick, United’s senior director of global medical affairs, said in a press release.

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“The EXPEDITE trial represents a framework to get carefully selected PAH patients on clinically impactful oral doses of a critical class of medication safely and so much more timely,” said John Kingrey, MD, the director of the pulmonary hypertension center at INTEGRIS Baptist Medical Center, Oklahoma City, one of the trial’s sites.

United plans to present detailed trial results at upcoming medical conferences and to publish them in peer-reviewed journals.

PAH is a progressive disease characterized by high blood pressure in the blood vessels that supply the lungs, which can cause damage to both the lungs and heart. Vasodilators, or agents that help widen blood vessels and encourage a proper blood flow, are a common PAH treatment.

Remodulin (with generics also available) is an injectable vasodilator therapy approved in the U.S. to ease symptoms associated with exercise in PAH patients, and to slow the clinical decline of those needing to discontinue Flolan, another injectable PAH medication.

The medication’s active ingredient, treprostinil, is a lab-made form of a vasodilator called prostacyclin.

It is administered as a continuous infusion directly under the skin (subcutaneous) or into the bloodstream (intravenous), using external or implantable pumps. This mode of administration is associated with lifestyle challenges, higher burden, and increased risk of complications, such as infections.

With this in mind, United developed an inhalable form of treprostinil, sold as Tyvaso, and an extended-release oral tablet formulation, sold as Orenitram. All are approved for PAH.

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Apart from the inhaled formulation, there is neither a target dose nor a ceiling dose of treprostinil to guide clinicians. Doses are therefore tailored for each patient based on tolerability and clinical improvement.

Notably, evidence to date suggests that higher doses of treprostinil are associated with better outcomes in people with PAH. As such, identifying ways to achieve higher daily doses of Orenitram is a clinically-relevant goal.

Orenitram, which usually is taken three times a day, is initiated at a low dose (0.125 mg) that can be increased gradually.

Also, a previous real-world study found that patients who transitioned from Remodulin to three-times-a-day dosing with Orenitram achieved the highest median total daily doses. This suggested that pre-treatment with Remodulin may enable patients to achieve higher doses of Orenitram and potentially benefit more from the oral therapy.

The multicenter, open-label Phase 4 EXPEDITE study tested this strategy in 34 people, ages 17–85 years, with PAH.

Participants initially were given subcutaneous or intravenous Remodulin for two to eight weeks (or about two months), with doses being continuously adjusted until reaching a minimum of 20 nanograms/kg/min.

After reaching that minimum Remodulin dose, patients were switched to Orenitram, taken three times a day, with doses being gradually increased for eight weeks to achieve the maximum tolerated dose.

The trial’s main goal was assessing the proportion of patients reaching an Orenitram dose of at least 4 mg three times daily, or a total daily dose of 12 mg, which have been associated with good outcomes at week 16 (about four months).

Secondary goals

Secondary goals included changes in disease severity, exercise capacity, shortness of breath, heart structure and function, levels of a heart damage biomarker, and health-related quality of life, as well as safety measures.

A total of 29 participants (85.3%) completed the study. Results showed that 79% of patients met the trial’s main goal by achieving a total daily dose of at least 12 mg at week 16.

Notably, the 12-mg daily dose is twice as high as that reported to be commonly achieved in the real-world setting after 16 weeks of treatment without a previous induction phase with Remodulin.

Orenitram, taken three times a day, was generally well-tolerated, with its safety profile being consistent with that reported in prior Orenitram trials involving PAH patients. Several treprostinil-related side effects, such as headache, nausea, and vomiting, were reported, but all tended to be reduced after switching from Remodulin to Orenitram.

“I’m so pleased with how my patients did with this approach, as it really did expedite (pun intended!) their path to achieving increased prostacyclin dosages,” Kingrey said.

“Along with our other phase 4 studies, EXPEDITE demonstrates our commitment to optimize available treatment options in order to help PAH patients better manage their disease,” Broderick said.

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