Nueva droga previene el empeoramiento de la hipertensión arterial pulmonar en un gran ensayo clínico

Oral ralinepag is positioned for potential FDA approval following its strong results as a treatment for pulmonary arterial hypertension (PAH) in an international phase III trial.

Resultados del ensayo ADVANCE OUTCOMES

In ADVANCE OUTCOMES, ralinepag conferred a reduction in composite first clinical worsening events in a population of pretreated, low- or intermediate-to-low-risk patients mostly already on dual background PAH therapy (18% vs 36% for placebo; HR 0.45, 95% CI 0.33-0.62).

Ralinepag’s effects, apparent by week 8 and maintained through follow-up of over 1 year, were evident for the individual outcomes of disease progression (3% vs 11%), initiation of parenteral or inhaled prostacyclin-pathway therapy (3% vs 7%), and unsatisfactory long-term clinical response (4% vs 10%). Ralinepag was also associated with favorable changes in NT-proBNP and 6-minute walk distance (6MWD) results, according to Marc Humbert, MD, PhD, of Université Paris-Saclay, INSERM, and colleagues.

Seguridad del tratamiento

However, the caveat was safety, as treatment discontinuations citing adverse events as the primary reason reached 19% in the ralinepag group versus 3% with placebo. Most ralinepag discontinuations occurred during the dose-titration period, reflecting tolerability concerns typical of prostacyclin-pathway therapy, they reported in The Lancet.

The main study results of ADVANCE OUTCOMES were presented earlier this year at the American Thoracic Society annual meeting. On the basis of the trial, ralinepag’s maker United Therapeutics announced that it submitted an application for approval with the FDA last month.

Nueva opción de tratamiento

«These findings support ralinepag as an oral, once-daily prostacyclin-pathway treatment option upon FDA approval and suggest that the addition of prostacyclin-pathway therapy can reduce clinical worsening even in a largely pretreated population with relatively preserved baseline functional capacity,» said co-author Vallerie McLaughlin, MD, of University of Michigan in Ann Arbor, in a press release.

Ralinepag is an oral, once-daily, selective prostacyclin receptor agonist with multiple pathway effects spanning vasodilatory, anti-proliferative, and anti-inflammatory effects. It is a highly selective and potent receptor agonist, with much higher binding affinity for the prostacyclin receptor and greater boosting of cellular cyclic adenosine monophosphate concentrations than selexipag’s active metabolite. Notably, it can mimic the steady-state exposure of parenteral therapy.

Papel en el tratamiento de la HAP

PAH is a rare, progressive disease characterized by the narrowing or blockage of small pulmonary arteries, causing elevated blood pressure in pulmonary circulation and extra effort for the heart to pump. This may eventually lead to right heart failure and death. Several PAH therapies exist on the market; yet there are still unmet needs.

Even with 16 approved therapies across the nitric oxide, endothelin, prostacyclin, and activin pathways, morbidity and mortality in PAH remain high; there’s still real room for additional efficacious options. The bigger unmet need, though, is in the low- and intermediate-low-risk population specifically: patients who are already on background therapy but remain at ongoing risk of clinical progression to right ventricular dysfunction and death.

Conclusiones y próximos pasos

Ralinepag, as another layer atop background treatment, would fit the shift toward early diagnosis and treatment of lower-risk PAH in clinical practice. Furthermore, ralinepag’s once-daily dosing, versus twice-daily selexipag, is an attractive feature in the context of regimen complexity. Optimizing the titration protocol in practice will likely be key to improving retention on therapy given the discontinuation rate seen.

ADVANCE OUTCOMES was a double-blind phase III trial conducted across 169 pulmonary hypertension centers in 30 countries. Participants were adults with PAH diagnosed on the basis of mean pulmonary artery pressure >20 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance of >2 Wood units.

In summary, ralinepag presents a promising, new therapeutic option for patients with pulmonary arterial hypertension and addresses a critical need in lowering clinical worsening in pretreated populations. However, careful monitoring and individual titration will be essential for patient safety and ensuring treatment adherence.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult a healthcare provider for personal medical concerns.

Fuente: https://www.medpagetoday.com/cardiology/generalcardiology/122432