Sotatercept

With several pulmonary arterial hypertension (PAH) medicines already on the market, United Therapeutics is hoping to add ralinepag to the list after a Phase III readout showed the once-daily oral prostacyclin agonist significantly lowered the risk of clinical worsening events. The company plans to submit a filing to the FDA in the second half.The ADVANCE OUTCOMES trial enrolled 687 patients, most of whom were already receiving standard background therapy. Roughly 80% were on dual therapy, and 70% were classified as World Health Organization/New York Heart Association Functional Class II at baseline.Subjects randomised to ralinepag experienced a 55% reduction in the risk of the first adjudicated clinical worsening event versus placebo, meeting the primary endpoint. Clinical worsening was broadly defined as death, nonelective hospitalisation for worsening PAH, starting a parenteral or inhaled prostacyclin agent, disease progression, or unsatisfactory long-term response.Ralinepag works by activating prostacyclin receptors on pulmonary artery endothelial and smooth muscle cells to trigger downstream conversion of ATP to cAMP. United says ralinepag is six to eight times more potent at increasing cAMP levels than the active metabolite of Johnson & Johnson's Uptravi (selexipag). That elevated intracellular cAMP acts on pathways implicated in PAH progression to promote vasodilation and inhibit vascular remodeling, according to the company."It binds the [prostacyclin] receptor very tightly and has a really long half-life," noted Leigh Peterson, head of product development, during the company's recent earnings call, "so this translates to the once-a-day dosing and potentially more tolerability."The drug succeeded on key secondary endpoints as well. At week 28, ralinepag increased the odds of achieving clinical improvement by 47% versus placebo, alongside statistically significant gains in six-minute walk distance and reductions in NT-proBNP, a biomarker of cardiac strain. Safety outcomes were in line with known prostacyclin-related adverse events, and no new safety signals emerged. Full details will be shared at an upcoming conference."With its extended-release profile and pharmacokinetic characteristics that mimic the steady-state exposure of parenteral therapy, ralinepag provides disease-mitigating capabilities that target underlying PAH pathology and achieve impressive clinical benefits," said Derek Solum, senior director of product development and global lead for ADVANCE OUTCOMES.United already has several PAH therapies in its portfolio that vary by route and mechanism. These include drugs based on the synthetic prostacyclin analogue treprostinil; namely, Remodulin, given by infusion; Tyvaso, via dry-powder inhaler; and oral Orenitram. It also markets Adcirca (tadalafil), an oral PDE5 inhibitor for PAH.If approved, ralinepag would enter a market that has been reshaped by Merck & Co.'s Winrevair (sotatercept), an injectable activin signaling inhibitor whose sales have gone from $419 million in 2024 to $1.4 billion last year (see – Spotlight On: Merck & Co.'s fastest selling drugs in 2025 and Physician Views Results: Merck & Co.'s Winrevair set to move upstream).

GSK said it will acquire a 100% equity stake in Canadian clinical-stage biotech 35Pharma for $950 million in cash, securing rights to the latter's lead asset — an activin signalling inhibitor (ASI) being developed for pulmonary hypertension (PH). "We're delighted to add HS235 to our pipeline, a potential best-in-class medicine with a differentiated profile to reduce risk of bleeding and provide potential metabolic benefits clinically relevant to PH patients," said Tony Wood, chief scientific officer at GSK. The UK pharma, which markets the endothelin receptor antagonist Volibris (ambrisentan) for pulmonary arterial hypertension (PAH) outside the US, anticipates the global PH therapeutics market to reach $18 billion by 2032 — with ASIs likely to capture approximately half of that figure. The current ASI landscape is dominated by Merck & Co.'s Winrevair (sotatercept), the sole drug in its class approved for PAH in the US and EU, which racked up $1.4 billion in revenue last year (see — Spotlight On: Merck & Co.'s fastest selling drugs in 2025). HS235, which complements GSK's respiratory, immunology and inflammation portfolio, has completed early-stage testing in PAH, with studies in PH due to heart failure with preserved ejection fraction slated to begin soon. The molecule is designed for enhanced selectivity in the activin receptor pathway, thereby limiting binding with BMP9/10 ligands linked to bleeding and telangiectasia — a potential advantage for patients with PH on anticoagulants or antiplatelets. Early clinical data also indicated fat-selective weight loss, lean mass preservation and improved insulin sensitivity with HS235, alongside favourable changes in inflammation and adipokine profiles. The content above comes from the network. if any infringement, please contact us to modify.