Companies working on inhaled version of PAH treatment ralinepag
Dry powder may have advantages over tablet formulation
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Mannkind said it is creating an inhaled formulation of ralinepag, an experimental oral pulmonary arterial hypertension (PAH) treatment, for developer United Therapeutics.
The inhaled version, ralinepag DPI, will be a dry powder that delivers the drug directly to the lungs, providing an alternative to the tablet formulation.
The announcement comes on the heels of positive data from United’s pivotal Phase 3 ADVANCE OUTCOMES clinical trial, which demonstrated that ralinepag tablets significantly reduced the risk of clinical worsening in PAH compared with a placebo. United Therapeutics plans to seek regulatory approval of ralinepag DPI for PAH.
“We have been working on the ralinepag DPI formulation for the past six months and are excited to finally be able to share this announcement,” Michael Castagna, CEO of Mannkind, said in a company press release. “We are pleased to apply our dry powder development expertise to advance ralinepag DPI.
PAH is a progressive disease in which the small blood vessels in the lungs narrow and thicken, forcing the heart to work harder to pump blood. Over time, this strain can lead to right heart failure. PAH treatment typically aims to widen the lung’s arteries and slow disease progression.
Potential to ‘redefine’ treatment
Ralinepag belongs to a class of drugs called prostacyclin receptor agonists, which work by relaxing the blood vessels in the lungs to reduce blood pressure.
The ADVANCE OUTCOMES trial (NCT03626688) enrolled 687 people with PAH who were randomly assigned to receive daily ralinepag or a placebo. Most participants were receiving dual background therapy and were designated as functional class 2 at the study’s start, meaning they experienced symptoms such as shortness of breath only during activities like climbing stairs.
Results showed ralinepag cut the risk of clinical worsening by 55%. Clinical worsening is a combined measure that includes disease progression, hospitalization due to worsening, and death. The drug also increased the likelihood that patients would improve within about 7 months, improved exercise capacity, and lowered levels of a heart strain marker.
“Supported by the strength of the pivotal ADVANCE OUTCOMES results, we believe ralinepag has the potential to redefine the PAH treatment landscape,” said Martine Rothblatt, PhD, chairperson and CEO of United Therapeutics. “We view ralinepag DPI as an important component of long-term success to help broaden real-world use and support patients over time.”
Inhaled ralinepag could offer advantages over a tablet. Because the drug is deposited directly in the lungs, it may be more effective. The companies also believe that the long duration of ralinepag’s activity in the body could support once-daily dosing.
Researchers are finalizing the inhaled formulation for non-clinical laboratory testing. Those studies will be followed by a Phase 1 trial in healthy volunteers to confirm that the inhaler delivers ralinepag into the bloodstream at levels comparable to those achieved with the tablet. Results from that study will then guide a larger trial in PAH patients evaluating safety and pharmacological properties.
Under the terms of the collaboration agreement, United leads global development, regulatory, and commercialization activities, while Mannkind handles formulation and supply.
United recently made a $5 million payment to Mannkind to accelerate the program’s development. Mannkind is eligible to receive up to $35 million in development milestone payments, plus 10% royalties on net sales of any approved product.
This isn’t the first time the two companies have worked together. A previous collaboration produced Tyvaso DPI, an approved inhaled therapy for PAH and pulmonary hypertension associated with interstitial lung disease.
“This program further validates MannKind’s role as a partner of choice for inhaled delivery of complex and high-value therapeutics,” Castagna said.
United Therapeutics also intends to develop the therapy for pulmonary hypertension associated with interstitial lung disease, as well as idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.
