Phase III Trials in Pulmonary Arterial Hypertension Focus on Clinical Events Rather Than Symptom Control
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PRIORITY PRESS - 35th Annual Congress of the European Society of Cardiology (ESC)
Amsterdam, Netherlands / August 31-September 4, 2013
Amsterdam - In pulmonary arterial hypertension (PAH), trials are being increasingly designed to evaluate protection against disease progression rather than symptom control alone, according to data presented at the 2013 ESC. The trial data presented at the ESC can be directly traced to a 2009 expert consensus statement that called for this change (McLaughlin et al. J am Coll Cardiol 2009;54(suppl):S97-107). Prior to this recommendation, almost all trials used the 6-minute distance walk (6MWD) test as the primary end point, a precedent set with the first Phase III trial leading to an agent specifically approved for PAH (Barst et al. N Engl J Med 1996;334:296-301). After the 2009 recommendation, many trials have begun to employ composite primary end points that include mortality and other significant events. At the ESC, some of the first data from such trials were made available. This included a head-to-head comparison of two currently approved therapies and a Phase III trial of a novel endothelin receptor antagonist (ERA).
Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec
After the prostacyclin analog epoprostenol initiated the modern era of pulmonary arterial hypertension (PAH) therapy by demonstrating an improvement in the 6-minute walking distance (6MWD) test at 12 weeks (Barst et al. N Engl J Med 1996;334:296-301), subsequent PAH studies used the same functional end point. This focus has now shifted. Almost all new data presented on therapies for the treatment of PAH at the 2013 ESC emphasized events over functional improvement after 6 months or longer on therapy. The focus on events rather than symptoms may help clinicians select therapies most likely to slow disease progression.
In the head-to-head trial, which compared the endothelin receptor antagonist (ERA) bosentan to the phosphodiesterase-5 (PDE-5) inhibitor sildenafil, the traditional 6MWD test was an interim end point for the short-term analysis, but the composite long-term primary end point was time to clinical worsening (Mazzanti et al. ESC 2013 Abstract 1063). In this open-label trial, 205 patients with PAH were randomized to 125 mg bosentan twice daily or 20 mg sildenafil three times daily. The short-term 6MWD data, which did not show a difference between the two agents, were presented previously.
ERA and PDE-5 Inhibitor Perform Similarly
After a mean of follow-up of 26 months, the therapies were found to be surprisingly similar for event-free survival (EFS). Although median time to clinical worsening, defined as first occurrence of death from any cause, hospitalization for worsening of PAH, or addition of any new therapy for PAH, could not be calculated because of a low rate of total events so far, the two-year EFS was 72% and 73% for bosentan and sildenafil, respectively.
“The efficacy of bosentan and sildenafil were very similar both in the short-term functional end points and for the long-term study definition of clinical worsening,” reported Dr. Gaia Mazzanti, Department of Specialized, Diagnostic, and Experimental Medicine at the University of Bologna, Italy. She reported that the estimated 3-year event-free survival rates for bosentan and sildenafil were 41% and 47%, respectively, which did not differ significantly. Estimated overall survival rates at 3 years were 71% and 81%, respectively, which were also non-significantly different.
These data suggest that the ERA and PDE-5 inhibitors evaluated in this study provide similar protection against progression despite different mechanisms of action, but the high representation of mild to moderate disease at entry may be relevant to the low rate of events. In this population, 46% were in functional class I or II and the mean age was 53. The distribution of etiologies was relatively representative of PAH in the community. Specifically, 41% had idiopathic PAH, 25% had familial PAH, 18% had PAH associated with connective tissue disease, and the remainder had other etiologies.
Phase III Event-Based Trial in PAH
Details of the first Phase III study to employ a composite end point that included clinical events rather than symptoms were also presented at the ESC. Called SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), the trial was conducted with the experimental ERA macitentan and published just days before the ESC (Pulido et al. N Engl J Med 2013;369:809-18). At the ESC, the main findings were reinforced with data from several substudies.
Of substudies, one reconfirmed the limitations of the 6MWD test as a prognostic tool (Galiè et al. ESC 2013 Abstract 1061). In SERAPHIN, the primary end point was a composite of death, atrial septostomy, lung transplantation, initiation of treatment with prostanoids, or worsening of PAH. In the substudy, 6MWD was evaluated in the context of this outcome.
While the main results of SERAPHIN, which randomized 742 patients to 10 mg of macitentan, 3 mg of macitentan, or placebo, associated the higher dose of macitentan with a 45% reduction (HR 0.55, 95% CI 0.39 – 0.76; P<0.001) in the primary end point relative to placebo, the change in 6MWD from baseline at 3 or 6 months was not correlated. Although baseline 6MWD was prognostic in this study as it has been in others, change in 6MWD on treatment, when compared by quartiles, was not. These data serve to re-emphasize the 2009 expert consensus recommendation to switch from exercise testing to event-driven studies in order to test whether therapies are favorably altering the natural history of PAH.
In a second SERAPHIN substudy that evaluated 187 of the 742 participants with right heart catheterization, sustained improvements from baseline in pulmonary vascular resistance (PVR) and cardiac index (CI) (both P<0.0001) were achieved with either dose of macitentan over a period in which both hemodynamic measures declined on placebo (Tobicki et al. ESC 2013 Abstract 1062). Attention to favorable changes in hemodynamics as they relate to risk of structural changes in the heart and lungs is consistent with efforts to better understand the relative ability of PAH therapies to prevent PAH progression.
Phase III Tadaladil Program Measures Events
New data presented from the Phase III study program with the PDE-5 inhibitor tadalafil also focused on events in long-term follow-up (Galiè et al. ESC 2013 Abstract 338). While the initial randomized, placebo-controlled PHIRST trial employed change in the traditional 6MWT over 16 weeks to evaluate benefit, PHIRST-2 has been designed as an open-label follow-up to gather data on safety and long-term protection against events. The events evaluated included death, lung transplantation, atrial septostomy, hospitalization for PAH, or worsening requiring new PAH therapy.
Of the 286 enrolled in the study, 217 (76%) were available for evaluation after a mean of 818 days of exposure (62% of patients initiated tadalafil in PHIRST-2 on concomitant bosentan), according to Dr. Galiè, who also presented these data. The observed probability of having no event was 80%, 64%, and 56% at 1 year, 2 years, and 3 years, respectively. Most events over the course of follow-up involved need for new PAH therapy, but death accounted for 14% of cases of deterioration. Dr. Galiè characterized the survival probability of 73% at 4 years as consistent with other active therapies.
In an on-going Phase III study of subcutaneous (SC) treprostinil for inoperable CTEPH, the primary outcome is the traditional 6MWD rather than events, but this end point is being measured at 6 months rather than 12 or 16 weeks of follow-up once standard in Phase III trials, and secondary end points include events as well as physiological stabilization as captured with hemodynamic measures (Sadushi-Kolici et al. ESC 2013 Abstract 1065). In the interim analysis presented at ESC on 54 of the 92 enrolled patients enrolled in the study, the activity of the 30 ng/kg/min target dose was encouraging, providing both a sustained increase in 6MWD at 6 months an increase in PVR. In the control arm, 6MWD was largely unchanged while PVR deteriorated from baseline.
Four years after a consensus recommendation to test treatments for their ability to prevent PAH-related events rather than merely control symptoms, the first such trials are now being completed. These trials have the potential to provide a better understanding of the relative ability of therapeutic options to prevent disease progression, an important goal in an irreversible disease process. Of such studies presented at the 2013 ESC, data were presented from a head-to-head trial comparing two approved therapies, a Phase III placebo-controlled trial with an experimental ERA, and a Phase III placebo-controlled trial with a PDE-5 inhibitor.