The effectiveness and value of sotatercept for pulmonary arterial hypertension: A summary from the Institute for Clinical and Economic Review’s Midwest Comparative Effectiveness Public Advisory Council

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by increased blood pressure in the pulmonary arteries, which carry blood from the heart to the lungs.¹ The elevated pressure strains the right side of the heart and can lead to heart failure.¹ The cause of PAH is often unknown but can be inherited or related to other medical conditions, including connective tissue diseases, congenital heart defects, drug-induced toxicity, and HIV infection.¹ PAH affects women more often than men and typically develops in middle age.^2,3 The condition impacts more than 50,000 individuals in the United States.⁴ Common symptoms include shortness of breath, fatigue, chest pain, dizziness, and edema.⁵ Because of the nonspecific symptoms of the disease, as well as the invasiveness of the diagnostic procedure (right heart catheterization to measure pulmonary artery pressure), diagnosis of PAH is often delayed by an average of 1 to 2 years after symptom onset.^5,6

Current medical treatments aim to manage symptoms and improve quality of life. Medications such as prostanoids and prostacyclin receptor agonists, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors help dilate blood vessels and decrease pulmonary resistance, which in turn can improve exercise capacity and decrease symptoms.^6,7 The standard of care for PAH typically involves the use of upfront combination therapy with an endothelin receptor antagonist and phosphodiesterase-5 inhibitor, with additional therapies added on for patients at a higher risk of mortality.⁶ The high cost of these pharmacologic treatments, along with hospitalization costs and reduced work productivity, are a significant financial and quality-of-life burden to patients and caregivers.^7,8 Oxygen therapy and lung transplantation may also be recommended for some patients with severe PAH.⁶ With early diagnosis and appropriate treatment, long-term survival rates have improved but remain low.³

Sotatercept (Merck & Co., Inc.) is an investigational therapy with a new mechanism of action that is administered subcutaneously every 3 weeks. A decision on its regulatory approval is anticipated by March 26, 2024.⁹ The Institute for Clinical and Economic Review (ICER) evaluated sotatercept for PAH. This report presents the summary of our systematic literature review and cost-effectiveness analysis and highlights the key policy recommendations discussed at the public meeting of the Midwest Comparative Effectiveness Public Advisory Council (CEPAC) on December 1, 2023. The ICER Final Evidence Report on sotatercept for PAH is available at https://icer.org/wp-content/uploads/2023/05/PAH_Final-Evidence-Report_For-Publication_01082024.pdf.

Summary of Findings

CLINICAL EFFECTIVENESS

STELLAR was a pivotal 24-week, placebo-controlled phase 3 trial that studied sotatercept added on to background therapy (combination of commonly used therapies). The trial included 323 adult participants with PAH who were classified as World Health Organization (WHO) functional class II or III, indicating a mild to moderate severity of the disease. The trial population consisted of participants with a mean age of 47.9 years. A total of 79.3% of participants were female, and 61.3% were receiving triple therapy. On average, these participants had been living with PAH for 8.8 years.¹⁰

The 6-minute walk distance (6MWD) test, which evaluated participants’ cardiopulmonary function and their response to exercise, was the primary outcome. At 24 weeks, patients treated with sotatercept had a greater increase in the median 6MWD result than those receiving placebo (34.4 m vs 1.0 m; difference using a Hodges-Lehmann approach of 40.8 m).¹⁰ An increase of this magnitude is generally considered to be clinically meaningful.¹¹

Secondary endpoints evaluated in the trial at 24 weeks also generally favored sotatercept. Specifically, WHO functional class improvement was observed in 29.4% of the participants in the sotatercept group compared with 13.8% in the placebo group. There was an 84% reduction in the risk of clinical worsening with sotatercept as assessed by a composite endpoint of time to first clinical worsening event or death. Sotatercept also resulted in significant improvements in pulmonary vascular resistance and N-terminal pro B-type natriuretic peptide levels, both used to reflect disease severity. Additionally, data from an open-label extension study showed that sotatercept maintained its benefits in the 6MWD test, WHO functional class, pulmonary vascular resistance, and N-terminal pro B-type natriuretic peptide during a follow-up period of 1 year, demonstrating the durability of the treatment.¹² However, it was less clear how sotatercept affected quality-of-life measures. The difference between study arms in 1 of 3 domains was not significant, and it is not clear how well the quality-of-life measurement used in the study reflects the experience of patients with PAH.

Sotatercept treatment was generally well-tolerated. There were higher occurrences of telangiectasia, bleeding events, and increased hemoglobin levels in the sotatercept group compared with the placebo group. However, none of these adverse events were deemed severe, and none led to treatment discontinuations. Long-term open-label data reflected similar safety findings, with low rates of treatment-emergent adverse events and discontinuations.¹²

UNCERTAINTIES BECAUSE OF LIMITATIONS IN THE CLINICAL EVIDENCE

The current data are insufficient to evaluate the effect of sotatercept on mortality. Longer-term data would be needed to establish the impact of sotatercept on mortality and long-term outcomes. Additionally, more data are needed to better understand sotatercept’s place in therapy, including whether its effects are truly “disease-modifying,” whether the treatment can eventually be discontinued, and whether the treatment is effective in sicker PAH populations (eg, WHO functional class IV) or in newly diagnosed or less stable patients with PAH. Lastly, there are generalizability concerns regarding sotatercept’s treatment benefit. Various subpopulations of PAH were underrepresented in the STELLAR trial compared with real-world PAH demographics, including connective tissue disease– associated PAH, congenital heart disease–associated PAH, and drug- or toxin-induced PAH. Some of these subtypes have historically responded less well to prior PAH treatments; therefore, it is crucial to collect data on sotatercept’s effects in these subpopulations.^13-15

LONG-TERM COST-EFFECTIVENESS

We developed a decision analytic model to estimate the cost-effectiveness of sotatercept added to background therapy, compared with background therapy alone, for patients with PAH. The analysis took a lifetime time horizon from a health care sector perspective. The model consisted of health states defined by WHO functional class and death. All patients started in either WHO functional class II or III. During the first 24 weeks, functional class could improve, worsen, or stay the same. After 24 weeks, functional class could only worsen or stay the same. Once a patient reached WHO functional class IV, an infused prostacyclin was added to their treatment regimen.

The key assumptions were that functional class improvement occurred only during the first 24 weeks, and subsequent improvement could only occur during the cycle immediately after initiating an infused prostacyclin. We also assumed that an individual would discontinue sotatercept after they had been in WHO functional class IV for longer than 12 weeks.

Compared with background therapy alone, treatment with sotatercept produced greater time without symptoms at rest, quality-adjusted life-years (QALYs), life-years, and equal-value life-years (evLYs) (Table 1). However, with an annual placeholder cost of $400,000, sotatercept resulted in substantially higher total costs. The incremental cost-effectiveness ratios were $1,805,000 per evLY gained and $2,380,000 per QALY gained (Table 2).

TABLE 1.

Base Case Model Outcomes for Sotatercept Plus Background Therapy as Compared With Background Therapy Alone

Treatment	Intervention cost	Nonintervention costs	Total costs	Years without symptoms at resta	QALYs	Life-years	evLYs
Sotatercept plus background therapy	$2,002,000b	$1,011,000	$3,013,000	5.02	3.41	5.46	3.69
Background therapy alone	$0	$880,000	$880,000	2.98	2.51	4.27	2.51

^a Defined as the years spent in World Health Organization functional classes I, II, and III.

^b Assuming a placeholder price of $400,000 per year.

evLY = equal-value life-year, QALY = quality-adjusted life-year.

TABLE 2.

Incremental Cost-Effectiveness Ratios for the Base Case

Treatment	Cost per additional year without symptoms at rest	Cost per QALY gained	Cost per life-year gained	Cost per evLY gained
Sotatercepta plus background therapy	$1,046,000	$2,380,000	$1,792,000	$1,805,000

^a Assuming a placeholder price of $400,000 per year.

evLY = equal-value life-year; QALY = quality-adjusted life-year.

Sotatercept’s effect on slowing the worsening in functional class had the largest influence on these ratios. None of the 1,000 probabilistic iterations were cost-effective at thresholds of $50,000-$200,000 per QALY or evLY with a placeholder price of $400,000 per year. Scenarios that considered societal-level factors and more optimistic assumptions around sotatercept’s effect on functional class improvement showed improved cost-effectiveness. Because of the high nonintervention costs (eg, background therapy and health state costs), there was no positive price for sotatercept that would meet thresholds of $50,000 or $100,000 per QALY or evLY gained. After excluding all nonintervention costs, sotatercept was associated with a health benefit price benchmark range of $17,900-$35,400. The health benefit price benchmark is the price range that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY or per evLY gained.

KEY UNCERTAINTIES IN THE MODELING OF LONG-TERM COST-EFFECTIVENESS

The long-term cost-effectiveness of sotatercept is largely dependent on its long-term effects on functional class and its price. However, trial evidence is limited to 24 weeks, and a price is not yet known. Longer-term data are needed to reduce uncertainty in sotatercept’s ability to improve and slow the worsening of functional class over time. Scenario analyses tested assumptions around long-term effectiveness. Even when optimistically assuming that sotatercept halts disease progression at 24 weeks or improves functional class over a lifetime, sotatercept exceeded typical cost-effectiveness thresholds at a placeholder price of $400,000 per year. Additionally, a published model coauthored by the manufacturer of sotatercept assumed that sotatercept has a long-term impact on morbidity and mortality.¹⁶ However, as noted in the clinical evidence, current data have not yet established the mortality benefit of sotatercept. As such, our analysis did not assume that sotatercept would have an independent effect on reducing mortality. In our model, sotatercept was associated with more life-years than background therapy alone because of the increased time spent in less severe health states. However, these less severe health states still carry a high risk of mortality and are associated with costly background therapies. Therefore, sotatercept was associated with greater total costs even though it was associated with reduced infused prostacyclin use as a result of the reduced time spent in WHO functional class IV.

Policy Discussion

The Midwest CEPAC convened on December 1, 2023, to publicly deliberate on the clinical effectiveness and cost-effectiveness of sotatercept for PAH. The Midwest CEPAC is an independent appraisal committee composed of medical evidence experts, including clinicians, methodologists, and patient advocates. Their deliberations included input from clinical experts and patient representatives with PAH expertise and formal comments from the manufacturer and the public.

Following the discussion, the Midwest CEPAC panel members deliberated on key questions raised by ICER’s report. All panelists (13-0) found that the current evidence is adequate to demonstrate a net health benefit for sotatercept added to background therapy when compared with background therapy alone.

The Midwest CEPAC also voted on “potential other benefits” and “contextual considerations” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about the long-term value for money that are not adequately captured in analyses of clinical and/or cost-effectiveness. They highlight several factors beyond the results of cost-effectiveness modeling that the Midwest CEPAC panel felt were particularly important for judgments of overall long-term value for money. The results for these votes are shown in Table 3. Value votes were not taken at the Midwest CEPAC public meeting because a net price for sotatercept was not available.

TABLE 3.

Votes on Other Benefits and Contextual Considerations for Sotatercept

When making judgments of overall long-term value for money, what is the relative priority that should be given to any effective treatment for PAH on the basis of the following contextual considerations?
Contextual consideration	Very low priority	Low priority	Average priority	High priority	Very high priority
Acuity of need for the treatment of individual patients based on short-term risk of death or progression to permanent disability	0	0	0	6	7
Magnitude of the lifetime impact on individual patients of the condition being treated	0	0	1	4	8
What are the relative effects of sotatercept added to background therapy vs background therapy alone on the following outcomes that inform judgments of the overall long-term value for money of sotatercept?
Potential other benefit or disadvantage	Major negative effect	Minor negative effect	No difference	Minor positive effect	Major positive effect
Patients’ ability to achieve major life goals related to education, work, or family life	0	0	0	6	7
Caregivers’ quality of life and/or ability to achieve major life goals related to education, work, or family life	0	0	0	8	5
Patients’ ability to manage and sustain treatment given the complexity of regimen vs the currently available third-line or fourth-line treatments	0	1	2	10	0
Society’s goal of reducing health inequities	1	4	8	0	0

PAH = pulmonary arterial hypertension.

Following the discussion of the evidence, a policy roundtable was convened to deliberate on how best to apply the evidence to the use of sotatercept for PAH. The policy roundtable members included 2 patient advocates, 1 clinical expert, and 2 payer representatives. The full set of policy recommendations can be found in the Final Evidence Report at https://icer.org/wp-content/uploads/2023/05/PAH_Final-Evidence-Report_For-Publication_01082024.pdf.

Select key policy recommendations are as follows:

1. Given that sotatercept has only been tested over a relatively short duration as an add-on therapy in a subset of patients with PAH and is likely to be very expensive, it is reasonable for payers to use prior authorization as a component of coverage. Prior authorization criteria should be based on the US Food and Drug Administration label, clinical evidence, specialty society guidelines, and input from clinical experts and patient groups. The options for specific elements of the coverage criteria within the insurance coverage policy are discussed in ICER’s Final Evidence Report at https://icer.org/wp-content/uploads/2023/05/PAH_Final-Evidence-Report_For-Publication_01082024.pdf.

2. Given sotatercept’s different mechanism of action from other third- and fourth-line agents, clinical experts did not deem it reasonable to require a trial of therapies, including a different third-line agent (eg, prostacyclin or selexipag), before initiating sotatercept therapy. The clinical expert and patient representatives at ICER’s public meeting stated that delayed and restricted access to treatment because of step therapy requirements for patients with PAH could lead to clinical deterioration.

3. Given that many patients with PAH will need to travel to obtain appropriate diagnosis and treatment, payers should consider wraparound coverage, including transportation, to ensure equal access to treatment.

4. The high oxygen flow needs of patients with PAH are best met with liquid oxygen, which is relatively more expensive because of the specialized transportation and equipment required. Payers and Medicare policymakers should help advocate for increased access to liquid oxygen through the reform of supplemental oxygen reimbursement policies, including setting differential reimbursement rates for liquid oxygen.