Disease outcomes for patients with pulmonary arterial hypertension (PAH) have improved significantly in the last two decades with the discovery of a range of therapies targeting multiple disease pathways.1, 2 However, despite these new therapies, 1-year survival in patients with moderate and severe PAH remain at 10% and 21%, respectively.3 Consequently, research into PAH continues to focus on optimising the currently available PAH treatment regimens, in addition to investigating new compounds. These themes were focuses for PAH research presented at the 104th American Thoracic Society international congress, held in Dallas, Texas, United States on 17–22 May, 2019.
Actelion Pharmaceuticals and Johnson & Johnson presented new data from a post hoc exploratory analysis of the GRIPHON study, evaluating the oral IP prostacyclin receptor agonist, selexipag in patients with PAH.4 In the overall trial, which included 1,156 patients with PAH across 39 countries, selexipag reduced patient mortality and morbidity by 40% versus placebo; morbidity was determined by the need for hospitalisation, long-term oxygen therapy, initiation of intravenous prostanoid therapy, need for lung transplant or balloon atrial septostomy.5 In the post hoc analysis of the study, treatment effects were determined based on time from PAH diagnosis to treatment.4 Selexipag reduced the risk for morbidity/mortality by 40% (p<0.001) in patients, regardless of the time from diagnosis to treatment initiation. However, risk reductions in mortality/morbidity were greater in patients receiving treatment within six months of a diagnosis compared with those who received treatment later (55% and 30%, respectively). These results were consistent across subgroup analyses based on patient background PAH therapy.4
Supporting the importance of early intervention in PAH, a retrospective database analysis including 357 patients initiating prostacyclin-class therapies found that late initiators had higher disease burden than early initiators.6 Specifically, late initiators i.e. patients who began therapy more than one year from PAH diagnosis were older, had a higher comorbidity burden and were less likely to have received various therapy such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors than early initiators.6
Also presented was a study assessing the impact of triple therapy, including intravenous or subcutaneous prostacyclin and two oral drugs on the long-term survival of 1,295 patients with new incidental diagnoses of PAH.7 Triple therapy improved the actual overall survival rates at Year 1 and 3 to 94% and 90%, compared with predicted rates of 76% and 51%, respectively. In contrast, overall survival with dual/monotherapy was 90% and 72% at these same timepoints. Following adjustments for patient demographic and baseline characteristics, triple therapy was found to significantly reduce the risk of death over dual or monotherapy by 65% (p=0.003).7 This suggests that early aggressive treatment of PAH following diagnosis may improve patient outcomes.
United Therapeutics Corp presented data from the INSPIRE study, evaluating a new dry powder formulation of treprostinil, a synthetic prostacyclin analogue for the treatment of PAH.8 Currently treprostinil is approved for nebulised administration via nine breaths, four times daily, whereas the new dry powder formulation is designed for better deep-lung delivery, permitting delivery over one to two breaths, four times daily. In the Phase III open-label, multicentre INSPIRE study, 109 patients either transitioned from nebulised treprostinil to dry powder treprostinil or received dry powder treprostinil as an add-on to background therapy consisting of two or fewer non-prostacyclin oral PAH therapies. No treatment-related serious adverse events (SAEs) were found following 2 weeks of treatment and the safety profile of dry powder treprostinil was consistent with the current standard of care prostacyclin inhibitor therapy. Additionally, no SAEs were reported in patients receiving dry powder treprostinil during the follow-up period of up to 10 months. Finally, after 2 months of treatment, over 95% of patients transitioning from nebulised to dry powder treprostinil remained on therapy.
Results from early stage clinical studies investigating novel therapies for PAH were also presented. Arena Pharmaceuticals presented interim results from the ongoing open-label extension study to a previous Phase II study of the next-generation, oral, selective, and potent prostacyclin receptor agonist, ralinepag.9 Initial results suggest that patients receiving ralinepag have durable, long-term improvements in hemodynamics and walking distance, with median reductions from baseline in pulmonary vascular resistance of 214 dyn·s·cm−5(p=0.206) and mean improvements from baseline of 69.8 meters in 6-minute walk distance (p=0.010). Similar improvements were observed in patients switching from placebo in the Phase II study and no new safety signals were observed.9
Following on from previous work in healthy participants, a proof of concept pilot study examined the potential of inhaled albuterol as an add-on therapy in patients with PAH.10 In the six enrolled patients, albuterol decreased mean pulmonary arterial pressure by 23% from baseline (p<0.03), along with decreasing pulmonary vascular resistance by 44% from baseline (p<0.02) and increasing pulmonary blood flow from baseline by 14% (p<0.01). These changes lasted for approximately 2 hours and were accompanied by decreases in mean arterial pressure of 8.5% (p<0.02) at 30 minutes after albuterol administration, without changes in heart rate and oxygen saturation. Further placebo-controlled studies of long- and ultra-long β2-agonists in a large group of patients with PAH are required to further investigate potential treatment benefits.10
In summary, data presented highlight the importance of early PAH treatment to reduce not only the burden of disease morbidity, also but mortality. Additionally, the increasing focus on combining the range of available PAH treatments offers the promise of further reductions in disease mortality compared with single or dual therapy. New formulations of established treatments that offer greater convenience for patients, such as treprostinil, may reduce the burden of treatment. Finally, promising results from early clinical studies of new prostacyclin receptor agonists and β2-agonists suggest further improvements in disease outcomes and management options for patients with PAH are on the horizon.
1. Thenappan T, Ormiston ML, Ryan JJ, et al. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ 2018; 360: j5492.
2. Klinger JR, Elliott CG, Levine DJ, et al. Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest 2019; 155(3): 565-86.
3. Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50(2).
4. Gaine SP, Sitbon O, Channick RN, et al. A2502 / 101 – The Impact of Time from Diagnosis at Baseline on Long-Term Outcome in the GRIPHON Study: Selexipag in Pulmonary Arterial Hypertension. American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.
5. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine 2015; 373(26): 2522-33.
6. Anguiano RH, Stafkey-Mailey D, Saundankar V, et al. A2522 / 121 – Early Versus Late Initiation of Treatment with Prostacyclin-Class Therapy in Patients with Pulmonary Arterial Hypertension (PAH). American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.
7. Boucly A, Savale L, Weatherald JC, et al. A5585 – Impact of Initial Triple Combination Therapy on Long-Term Survival in Pulmonary Arterial Hypertension (PAH). American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.
8. Hill NS, Feldman JP, Sahay S, et al. A7402 / P1155 – INSPIRE: A Phase 3 Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of LIQ861 in PULMONARY ARTERIAL HYPERTENSION (PAH) (Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil NCT03399604). American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.
9. McLaughlin VV, Ristic AD, Jansa P, et al. A2509 / 108 – Interim Results from the Ongoing Open-Label Extension of the Phase 2 Trial Evaluating Ralinepag for the Treatment of Pulmonary Arterial Hypertension. American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.
10. De La Zerda DJ, Gutierrez Puentes IY, Hurwitz BE, et al. A2520 / 119 – Effect of Inhaled Albuterol on Pulmonary Vascular Resistance in Patients with Group 1 Pulmonary Arterial Hypertension on Oral Pulmonary Vasodilator Therapy: A Proof of Concept Study. American Thoracic Society International Conference; May 17-22, 2019. Dallas; 2019.