Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension (STELLAR trial)

Design

Phase 3, multicenter, double-blind, randomized, placebo-controlled trial

N= 323

Objective

To investigate the efficacy, safety, and adverse-event profile of sotatercept in combination with stable background therapy in adult patients with symptomatic pulmonary arterial hypertension (PAH) compared to placebo

Study Groups

Sotatercept (n= 163)

placebo (n= 160)

Inclusion Criteria

Aged ≥18 years; diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension Group 1; symptomatic pulmonary arterial hypertension classified as WHO functional class II or III; minimum pulmonary vascular resistance (PVR) of ≥ 400 dynes·sec·cm^-5; pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg; on stable doses of background pulmonary arterial hypertension therapy and diuretics for ≥ 90 days; 6-minute walk distance ≥ 150 and ≤ 500 meters repeated twice at screening and both values within 15% of each other 

Exclusion Criteria

Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5; PAH Group 1 associated with human immunodeficiency virus (HIV), schistosomiasis-associated PAH and pulmonary veno-occlusive disease; uncontrolled systemic hypertension or systolic blood pressure< 90 mmHg; estimated glomerular filtration rate (eGFR)< 30 mL/min/m²; history of portal hypertension or chronic liver disease; received intravenous inotropes within 30 days prior to the screening

Methods

Eligible patients were randomly assigned (1:1) to receive sotatercept or placebo subcutaneously every 21 days in combination with stable background therapy. Sotatercept was administered at a starting dose of 0.3 mg/kg at visit 1 and was escalated to the target dose of 0.7 mg/kg at visit 2 (day 21±3). Patients continued to receive a dose of 0.7 mg/kg for the duration of the trial.

A maximum of 3 dose delays was allowed if hemoglobin level was above the upper limit of normal range and if platelet count was ˂ 50,000/mm³. At the visit following each dose delay, if platelet count was ˃ 50,000/mm³, the dose was reduced to 0.3 mg/kg and study drug treatment was restarted. 

Safety and efficacy were assessed at inclusion and every 3 weeks thereafter for 24 weeks. Adverse events that occurred up to and including day 56 after the last dose of sotatercept or placebo were reported. In cases of dose reduction due to an adverse event not related to study drug, the dose was re-escalated when the adverse event was resolved. After completion of the trial, patients were eligible to roll over into the ongoing SOTERIA trial (NCT04796337).

Duration

January 21, 2021 to December 6, 2022 

Follow-up at cutoff date (August 26, 2022): 24 weeks

Outcome Measures

Primary: Change in the 6-minute walk distance at week 24 

Secondary: Multicomponent improvement; change in pulmonary vascular resistance; change in N-terminal pro–B-type natriuretic peptide level; improvement in WHO functional class; time to death or clinical worsening; changes in the PAH–Symptoms and Impact (PAH-SYMPACT) Physical Impacts; cardiopulmonary symptoms

Baseline Characteristics

Sotatercept (n= 163)

Placebo (n= 160)

Age, years

Female

White

Body-mass index, kg/m²

PAH class

Idiopathic

Heritable

Associated with connective-tissue disease

Drug-induced or toxin-induced

Associated with corrected congenital shunts

50.9%

21.5%

17.8%

4.3%

5.5%

66.2%

15%

11.9%

2.5%

4.4%

WHO functional class

II

III

48.5%

51.5%

48.8%

52.2%

Background PAH therapy 

Prostacyclin infusion 

Monotherapy

Double therapy

Triple therapy

39.9%

5.5%

34.4%

60.1%

40.0%

2.5%

35%

62.5%

6-min walk distance, m

397.6 ± 84.3

404.7 ± 80.6

Laboratory parameters

Hemoglobin, g/dL

eGFR, ml/min/1.73 m²

NT-proBNP, pg/ml

13.9 ± 1.7

91.2 ± 34.6

1037.5 ± 2498.6

13.7 ± 1.6

88.3 ± 135.8

1207.8 ± 2694.4

Cardiac parameters

Pulmonary vascular resistance, dyn.sc.cm^-5

Cardiac output, L/min

Cardiac index, L/min/m²

Mean pulmonary artery pressure, mmHg

Right arterial pressure, mmHg

Pulmonary arterial wedge pressure, mmHg

781.3 ± 398.5

4.9 ± 1.3

2.7 ± 0.6

53.0 ± 14.6

8.0 ± 4.3

9.7 ± 3.2

745.8 ± 313.5

4.8 ± 1.2

2.7 ± 0.6

52.2 ± 13.0

8.5 ± 4.5

9.8 ± 3.1

Results

Endpoint 

Sotatercept (n= 163)

Placebo (n= 160)

Median change at week 24 (95% confidence interval [CI])

6-Minute walk distance, m*

Pulmonary vascular resistance, dyn·sec·cm−5* 

NT-proBNP, pg/ml*

34.4 (33.0 to 35.5)

−165.1 (−176.0 to −152.0)

−230.3 (−236.0 to −223.0)

1.0 (−0.3 to 3.5)

32.8 (26.5 to 40.0)

58.6 (46.0 to 67.0)

Improvement at week 24, %

Multicomponent improvement**

WHO functional class**

38.9% (31.3 to 46.9)

29.4% (22.6 to 37.1)

10.1% (5.9 to 15.8)

13.8 (8.9 to 20.2)

Median changes in domain score at week 24

PAH-SYMPACT Physical Impacts 

PAH-SYMPACT Cardiopulmonary Symptoms 

−0.13 (−0.15 to 0.00)

−0.12 (−0.14 to −0.08)

0.01 (0.00 to 0.13)

−0.01 (−0.03 to 0.00)

Time to first occurrence of death or nonfatal clinical worsening event, hazard ratio (95% CI)*

0.16 (0.08 to 0.35)

--

*p<0.05

**p<0.001

Adverse Events

Common Adverse Events of sotatercept vs. placebo: headache (20.2% vs. 15%); nausea (9.8% vs. 11.2%); diarrhea (12.3% vs. 7.5%); fatigue (10.4% vs. 7.5%); epistaxis (12.3% vs. 1.9%); dizziness (10.4% vs. 1.9%); increased hemoglobin (5.5% vs. 0); thrombocytopenia (6.1% vs. 2.5%); bleeding events (21.5% vs. 12.5%); increased blood pressure (3.7% vs. 0.6%); telangiectasia (10.4% vs. 3.1%)

Serious Adverse Events: 14.1% vs. 22.5%; difference −8.4 (−16.9 to 0.1)

Percentage that Discontinued due to Adverse Events: 3 (1.8%) vs. 10 (6.2%); difference −4.4 (−9.5 to −0.1)

Study Author Conclusions

In this trial, treatment with sotatercept improved exercise capacity as determined by the 6-minute walk distance and showed clinical benefit across multiple efficacy end points. Sotatercept had a favorable benefit-risk ratio, findings that confirm and extend the results of previous studies.

InpharmD Researcher Critique

This phase 3 study was neither designed nor powered to evaluate the outcomes of mortality.

The specific inclusion/exclusion criteria limited the generalizability of the outcomes of this study to a broader patient population. The generalizability of the results is further limited to the white race, given the fact that only approximately 10% of included patients had other races and ethnicities.

Moreover, the study was subject to unblinding of investigators due to side effects such as telangiectasia or hematologic changes.

Pitre et al., 2024

Systematic review and network meta-analysis

N= 18 studies (all RCTs)

Objective: To compare the efficacy and safety of add-on sotatercept versus other add-on therapies for PAH using a network meta-analysis

Database search: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov

Inclusion criteria: Randomized trials involving patients with PAH treated with add-on sotatercept or other add-on PAH therapies

Exclusion criteria: Not specified in the abstract

Intervention: (dosing regimen unspecified) Placebo, sotatercept, endothelin receptor antagonists, inhaled prostanoids, oral prostanoids

Outcome: Reduction in clinical worsening

- Sotatercept demonstrated a significant reduction compared with placebo (relative risk [RR] 0.21; 95% confidence interval [CI] 0.11 to 0.41), high-certainty evidence

- Sotatercept reduced clinical worsening to a greater extent than endothelin receptor antagonists (RR 0.28; 95% CI 0.14 to 0.55), inhaled prostanoids (RR 0.4; 95% CI 0.07 to 0.67), and oral prostanoids (RR 0.32; 95% CI 0.16 to 0.67), all with moderate-certainty evidence

Improvements in 6-minute walk distance (6MWD):

- Sotatercept outperformed placebo (mean difference [MD] 36.89 m; 95% CI 25.26 to 48.51), endothelin receptor antagonists (MD, 18.38 m; 95% CI 5.92 to 30.84), and oral prostanoids (MD, 25.66 m; 95% CI= 13.71 to 37.61) Safety outcomes: Not specified within the abstract

Study authors’ conclusions: Sotatercept is an effective add-on therapy for PAH, likely superior to many approved add-on PAH therapies in reducing clinical worsening.

Comment/Critique: The study provides a comprehensive comparison of sotatercept with other PAH therapies using a robust network meta-analysis approach. However, the lack of direct comparisons and specific subgroup analyses may limit the applicability of the findings to individual patient scenarios. Caution is warranted in interpretation as only the abstract was available for scrutiny.

Study Sponsor: N/A