Pulmonary arterial hypertension (PAH) is a progressive disease involving proliferative remodeling of the pulmonary vessels and elevations in pulmonary vascular resistance (PVR). Despite recent treatment advances, the associated morbidity and mortality rates of the disease are still high. In this touchCARDIO interview, we speak with Prof. Marius Hoeper (Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany) to explore the potential of sotatercept, a fusion protein that targets activins and growth differentiation factors implicated in PAH. The phase 3 STELLAR trial investigated sotatercept, in combination with stable background therapy for the treatment of adult patients with PAH.
Watch more: Prof. Marius Hoepers discusses on treatment gaps in pulmonary arterial hypertension
The abstract entitled ‘The STELLAR Phase III Trial: A Study Of Sotatercept In Combination With Background Therapy For The Treatment Of Pulmonary Arterial Hypertension’ (Abstract number 413-15) was presented at ACC.23 Together With WCC (ACC.23/WCC) in New Orleans, 4–6 March 2023
Questions:
- What are the aims, design, and eligibility criteria of the STELLAR trial? (0:18)
- How well were the primary and secondary endpoints achieved? (1:42)
- Were there any notable adverse events or side effects observed in the trial? (2:58)
- What are the implications of these findings for clinical practice and patient care? (4:30)
- What questions remain unanswered and what are the future plans in the development of sotatercept in the treatment of pulmonary arterial hypertension? (5:19)
Disclosures: Marius Hoeper is a consultant for Acceleron, Actelion, AOP, Bayer, Ferrer, Janssen, and MSD; on the advisory board for Acceleron, Actelion, AOP, Bayer, Ferrer, Janssen, and MSD; receives honoraria/honorarium from Acceleron, Actelion, AOP, Bayer, Ferrer, Janssen, and MSD; and is a dpeaker’s bureau participant with Acceleron, Actelion, AOP, Bayer, Ferrer, Janssen, and MSD.
Support: Interview and filming supported by Touch Medical Media. Interview conducted by Katey Gabrysch.
Filmed as a highlight of ACC 2023
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Transcript
Subtitles and transcript are autogenerated
I am Marius Hoeper, Upper Respiratory Physician from Hanover Medical School, Hanover, Germany. I have been taking care of patients with pulmonary hypertension for the past 30 years.
What are the aims, design, and eligibility criteria of the STELLAR trial? (0:18)
The aim of STELLAR was to basically confirm the results of the phase II study, which was called the PULSAR phase II study where sotatercept shows that sotatercept improves hemodynamics and excess capacity as assessed by the 6 minute walk distance in patients with pulmonary arterial hypertension and functional class two or three who were pretreated with PNH medications. The STELLAR study was a phase III randomized, double blind, placebo controlled study, that included patients with PNH functional class 2-3, 6 minute walk distance between 150 and 500 meter and PVR of 400 dyn·sec/cm5 or more despite receiving medical therapy. The primary endpoint of the study was change in 6 minute walk distance from baseline at week 24, and the study had, in addition to that, 9 secondary endpoints that were studied hierarchically, and were assessed at week 24, excluding, time to death of the first clinical worsening event, which was assessed at the cut-off date, which was the date when the last patient had completed two week 24 visit.
How well were the primary and secondary endpoints achieved? (1:42)
The STELLAR study met its primary endpoint on the difference in change in a 6 minute walk distance at week 24 was about 40 meter favouring sotatercept. In addition, the study also met 8 of the 9 pre-specified secondary endpoints, including improvements in so-called multi-component improvement endpoint, which was a predefined composite endpoint of changes in 6 minute walk distance and improvements in PVR, NT-proBNP, and WHO FC improved as well. As did hemodynamics, and vascular resistance. There were improvements in the French risk score and also improvements in two out of three domains of the PAH-SYMPACT Cognitive–Emotional Impact tool, which is a disease specific quality of life tool. Finally, there was quite substantial reduction in time to clinical worsening with the risk reduction of 84% or hazard ratio of 0.16 favouring sotatercept.
Were there any notable adverse events or side effects observed in the trial? (2:58)
That there were some unique side effects in the trial overall and treatment associated adverse events were more common with sotatercept than placebo, whereas treatment related, serious or severe adverse events as well as adverse events that led to study drug discontinuation were more common in the placebo group. So overall, the sotatercept treatment was quite well-tolerated. However, there were side effects that were noted, especially a higher frequency of bleeding complications mostly in epistaxis, and also the development of telangiectasia which were seen in 14% of the sotatercept patients and the cutoff date compared to 3% of the placebo group. So this was certainly in effect, it was related to sotatercept, which is something that needs to be watched closely in the years to come. In addition to that, studies have had the expected effects on blood count, especially usually slight increases in hemoglobin levels and slight decrease declines or decreases in the platelet counts that in most of these patients were not clinically relevant in the study, but also something that needs to be controlled whenever the medication is going to apply to clinical practice.
What are the implications of these findings for clinical practice and patient care? (4:30)
I think given the benefit risk profile that we’re seeing with this medication in both the phase II as well as the phase III study, I think it’s very likely that sotatercept is going to be the next approved therapy for patients with pulmonary arterial hypertension. And I expect that to become one of the new mainstays of PAH therapy. I believe that in newly diagnosed patients that will still use combination therapy as first line therapy, but I also expect that physicians are then going to use sotatercept as an early add on therapy.
What questions remain unanswered and what are the future plans in the development of sotatercept in the treatment of pulmonary arterial hypertension? (5:19)
There are many unanswered questions. Firstly, coming back to the side effect profile of sotatercept, we have no experience with the first patients from the phase II study and the 5-year open label extension study. These are small numbers of patients for the time being, and then from the start study, of course, and to mean observation time was 7.5 months. So certainly, we cannot make any firm conclusions about the long term effects and the potential long term side effects of this medication. But we have ongoing studies, and they will look into that.
In addition to that, we have ongoing additional phase III studies. One is called PANIS, enrolling patients with very advanced pulmonary hypertension disease. The other one is called HEPARIN, which is also quite interesting as this investigates patients with more recently diagnosed pulmonary hypertension. Remember that STELLAR included patients that had a diagnosis on average 9 years previously, so they had prevalent disease. One might envision that administering a drug like sotatercept, but earlier during the course of the disease, will give us even more efficacy, although this is something that it has to be demonstrated. This trial is ongoing and enrolling.
