FDA Approves Sotatercept in the Management of Patients With PAH
In this video, Zeenat Safdar, MD, MS, a STELLAR trial investigator, discusses the STELLAR trial results, which supported the FDA approval of sotatercept. Sotatercept is the first activin signaling inhibitor therapy approved for the management of patients with pulmonary arterial hypertension (PAH). While close monitoring for adverse effects, like changes in hemoglobin and platelet levels is advised, this approval offers hope for patients and health care providers in managing patients with PAH, with availability expected in the United States by the end of April 2024.
Additional Resources:
Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558
Zeenat Safdar, MD, MS, is a professor of medicine at Houston Methodist Hospital and Houston Methodist Lung Center (Houston, TX).
TRANSCRIPTION:
Zeenat Safdar, MD, MS: My name is Dr Zeenat Safdar. I'm a professor of medicine at Houston Methodist Hospital and Houston Methodist Lung Center.
Consultant360: What is pulmonary arterial hypertension?
Dr Safdar: Pulmonary arterial hypertension, it's a rare disease. It leads to vascular remodeling in the lungs. This vascular remodeling leads to the thickening of the vessels in the lungs and leads to increased pulmonary vascular resistance. And because of that, it leads to right heart failure. So, as you can imagine, it's a progressive disease. It happens in females, predominantly a female disease. No hormonal imbalances have been identified with this disease, but as I mentioned, it's more progressive. There are medications available to treat it, to try to get the patients to breathe better.
The most common symptoms that patients present with is shortness of breath, and palpitations, and more severe symptoms that they can present is presyncope and syncope. It's a detrimental disease, a bad diagnosis to have, and something we really need to take care of with patients with pulmonary arterial hypertension.
There are some genetic mutations associated with it, but all and all, we have about 14 drugs currently available to treat it, and they target three pathways: the endothelin pathway, the prostacyclin pathway, and the nitric oxide pathway.
C360: What is the significance of the FDA approval of sotatercept for the management of patients with PAH?
Dr Safdar: It's a very exciting time for us because we have been taking care of patients with pulmonary arterial hypertension for a very, very long time and we only had these three targeted pathways and drugs which are available, which are addressing these pathways, and we never had any other medication that had led to FDA approval. So, this is a really exciting time for us. Sotatercept is an activin signaling inhibitor. It's a protein. It is injected subcutaneously every three weeks. And it is something that you can give on top of their current medications.
So, most of these patients that were on the clinical trial were on background therapy of two drugs or three drugs. Despite being on maximum background therapy, these patients were still in heart failure, and they still were not doing well. There was still an area in which they needed improvement in their disease state. And in the studies, it has been clearly shown that sotatercept treatment had actually helped these patients a lot.
C360: Please provide an overview of the STELLAR trial, which supported the FDA approval.
Dr Safdar: So, I would start with the phase two study, if you don't mind, because I think the phase two study was a very positive study. There were 106 patients enrolled in a 24-week study of sotatercept and placebo, so 1:1 randomization.
The doses were 0.3 mg/kg and target dose was 0.7 mg/kg and the primary endpoint was a reduction in PVR. This study was very positive, which was very encouraging. The reduction in PVR [pulmonary vascular resistance] was quite significant, and that led to the phase three study, the STELLAR study, which is sotatercept for pulmonary arterial hypertension patients. And in this study, about more than 300 patients were enrolled, again, in a 24-week study with a primary endpoint of a six-minute walk distance.
And in this study, what's interesting is that the primary endpoint was positive and most of the secondary endpoints were also positive, including the 6-minute walk distance, reduction in BNP [N-terminal pro-B-type natriuretic peptide levels], the improvement in function class, and the delay in clinical worsening, and deaths. So, it's very exciting data that we have over here.
C360: What is the mechanism of action in sotatercept?
Dr Safdar: Sotatercept is a unique molecule. It is an activin inhibitor. It works to rebalance the endothelium. So, what happens in pulmonary arterial hypertension is that normally there is a proliferation and anti-proliferation going on in a process–apoptosis going on in the pulmonary vessel wall. So, there's a signaling that tells the cells that, “Okay, now stop growing. We have enough cells available now. You don't need to grow anymore.” But in any patient with pulmonary arterial hypertension, the normal regulation of this growth is lost, so there's more proliferation and less anti-proliferative signaling and there's less apoptosis. So, the cells, the smooth cells, and the endothelial cells keep drawing on top of each other leading to the narrowing of the vessel lumen and that leads to an increase in the PVR.
So, what sotatercept does is that it acts through the TGF pathway, which is a proliferative pathway, and it is a ligand path for TGF molecules so that that it rebalances the endothelin to an antiproliferative and apoptotic pathway that leads to a reduction in this overgrowth of these cells. It enhances the BNP-R signaling, which is the antiproliferative signaling in these vessel walls. And there's exciting data, especially animal data, that shows that with this happening, there is decreased inflammation, there's decreased growth of these cells, and there's actually reverse remodeling in the vessel wall and improvement in the right heart failure.
C360: What were the results of the trial?
Dr Safdar: One of the important points is that most of these patients were on background therapy, as I mentioned. So, 60% were, on triple therapy, and 35% were on double therapy. This is really important. 40% of these patients who were enrolled in the STELLAR clinical trial for sotaterceptwere on prostacyclin infusion therapy.
So, despite being on this maximum amount of therapy, which is what we have clinically available right now approved by the FDA, these patients that were enrolled to go on to sotatercept in this clinical trial, they actually showed a marked improvement in all the clinical outcomes that were tested, in most of them, especially the walk distance, the delay in clinical worsening, the improvement in their functional class, reduction in the BNP levels. All of these suggest that the right heart failure that these patients go into has been improved.
So, I think it's a very, very good example of how a new pathway can be tested and can be introduced and can help these patients to actually regain some kind of normality in their living and improve their heart function and their vascular remodeling in their lungs.
It is important to also remember that there were some side effects or adverse effects associated with this medication. Every medication has a side effect, but one of the important side effects that clinicians need to remember is thrombocytopenia and an increase in hemoglobin level. And these usually happen early.
So, the current recommendation is that for the first five doses of this medication, the physician checks the hemoglobin and platelet levels in these patients.
As this is a weight-based medication, it has to be given as a sub-q injection every three weeks. So, every three weeks, five times, the CVC needs to be done for these patients. There are guidelines available in the package inserts that we need to be aware of so that we can properly address any increases and changes in these levels.
C360: What is next for research on this topic?
Dr Safdar: So, the other pathway that has been evaluated, that is being treated right now, and investigated is a platelet drive growth factor… targeting that. And there are two molecules that are out there.
One, some of you may know is imatinib, which has been there for a very long time. It's an oral medication. Imatinib was tested for pulmonary arterial hypertension, and the results were published in the New England Journal of Medicine in 2005. But it has some controllability issues. The patients didn't tolerate it well. There was a lot of discontinuation, and there were about eight subdural hematomas that were reported in that paper. And FDA did not approve this medication as an oral tablet.
Since then, pharmaceutical companies have come up with an inhaled formulation of this medication. So, inhaled imatinib is being investigated currently, which will limit the oral bioavailability, so limit the side effects. All these side effects that happen with oral imatinib happen in patients who are on anticoagulation. So, it's important to remember that patients while on anticoagulation are not being enrolled in the study.
And a similar molecule to inhaled imatinib is another inhaled drug which, is related to platelet-derived growth factor also. That is called seralutinib and that is also an inhaled medication that is also being investigated. The phase 2 trial for that drug was a positive reduction in PVR and phase 3 studies are ongoing currently.
C360: As a trial investigator, what is your personal reaction to the FDA approval?
Dr Safdar: We are very happy and very excited for the patients because now we have another drug, which is targeting a brand-new pathway that's FDA-approved, and that can help patients who are already on maximum therapy.
C360: What are the overall take-home messages from our conversation today?
Dr Safdar: It's an exciting time for both the physicians and the patients because now we have this drug available that we have been researching for many years, many clinical trials that resulted in negative phase two studies. So, it never went to a phase three study.
So, when this drug, a phase two study was positive, we were all very excited, we were all very enthusiastic about it and positive. And now with the result of this phase three study being so positive, I think it has helped us really bring a light of hope for our patients, for their families.
I think it's really exciting time, and I would like to add that the patients who were started on these medications and who were involved in this clinical trial were on background therapy. So, this drug is not approved for the treatment-naive patients.
C360: Is there anything else you’d like to add?
Dr Safdar: I think physicians and specialty nurses will play an important role in educating the patient and teaching the patient how to reconstitute the medicine because… I wouldn't say it's a difficult reconstitution, but I think it's something that needs to be taught how to do it properly to maintain the efficacy of this drug and also to keep an eye out for any bleeds, any low platelets, any increased hemoglobins, those are the things that I would like all the physicians, NPs, and the nurses to be aware of when they are prescribing this medication.