Detailed information about Sotatercept Subcutaneous (SC)

Cardiovascular

Sotatercept Subcutaneous (SC)

Merck/Bristol-Myers Squibb

Proposed indications

Pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1) in adults

FDA approval timeline

March 26, 2024

• Breakthrough therapy
• Orphan drug
• Priority review

Place in therapy

Sotatercept is a fusion protein comprised of the extracellular domain of activin receptor IIa (ActRIIa) attached to the Fc portion of human immunoglobulin G1 (IgG1). Activin ligands are involved in cell proliferation, apoptosis, and vessel wall inflammation in endothelial and smooth muscle cells of the lungs. When this activity is unbalanced, it leads to remodeling of pulmonary vasculature and PAH. Sotatercept sequesters activin ligands, thereby inhibiting activin signaling. It is proposed that this action can reverse vascular remodeling and improve vascular patency in PAH.

• If approved, sotatercept, will be a first-in-class activin signaling inhibitor and will potentially be the first disease modifying therapy to treat PAH.
• Sotatercept is being studied as an add-on therapy for patients established on stable doses of background PAH therapy, including a majority of patients already on triple therapy.
• The place in therapy for sotatercept is not yet clearly defined in terms of when to add it in the treatment paradigm.
• The Institute for Clinical and Economic Review (ICER) published a final evidence report on sotatercept for PAH and concludes that the addition of sotatercept to background therapy can improve clinical outcomes with relatively few harms, and sotatercept administered SC is less burdensome than many other PAH treatments.
• Sotatercept may be administered SC by a health-care provider or could potentially be self-administered, pending FDA approval.
• Efficacy in sicker populations and in those with connective tissue disease remains uncertain, along with durability of effect.
• The efficacy of sotatercept is being evaluated in newly diagnosed intermediate- and high-risk PAH patients and long-term efficacy is being studied in a follow-up phase 3 trial over 6.5 years.
• Sotatercept is also being studied to treat combined postcapillary and precapillary pulmonary hypertension (Cpc-PH) due to heart failure with preserved ejection fraction (HFpEF), in children with PAH (ages 1 to < 18 years old), and for management of anemia in hematologic diseases.

Reference charts:

WHO Classification of Pulmonary Hypertension (PH)
Group 1 PAH: Pulmonary arterial hypertension (PAH)
Group 2 PH: Pulmonary hypertension owing to left heart disease
Group 3 PH: Pulmonary hypertension owing to lung diseases and/or hypoxia
Group 4 PH: Chronic thromboembolic pulmonary hypertension (CTEPH)
Group 5 PH: Pulmonary hypertension with unclear multifactorial mechanisms

New York Heart Association (NYHA) Functional Classification
Class I: No symptoms with ordinary physical activity. No limitation of physical activity. Comfortable at rest.
Class II: Symptoms with ordinary physical activity. Slight limitation of physical activity. Comfortable at rest.
Class III: Symptoms with less than ordinary physical activity. Marked limitation of physical activity. Comfortable at rest.
Class IV: Symptoms with any physical activity or even at rest. Unable to perform any physical activity.

World Health Organization (WHO) Functional Assessment Classification
Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III: Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Understanding your data

Sotatercept is an investigational fusion protein acting as a ligand modulator for select transforming growth factor beta (TGF-β) superfamily members which rebalances pulmonary vascular homeostatis by facilitating growth inhibition and proapoptotic signaling. The fusion protein is comprised of the Fc domain of human IgG1 linked to the extracellular domain of human activin receptor IIa (ActRIIa) which can balance and stabilize vascular patency. There are several clinical trials evaluating sotatercept in PAH which include the following:

• NCT04576988 STELLAR: A phase 3, randomized, double-blind, placebo-controlled study to compare the efficacy and safety of sotatercept versus placebo when added to background PAH therapy for the treatment of PAH.
• NCT03496207 PULSAR: A phase 2, double-blind, placebo-controlled, randomized study to compare the efficacy and safety of sotatercept versus placebo when added to standard of care for the treatment of PAH.
• NCT04796337 SOTERIA: An open-label long-term follow-up study to evaluate the effects of sotatercept when added to background PAH therapy for the treatment of PAH.
• NCT04811092 HYPERION: A phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to background PAH therapy in newly diagnosed intermediate- and high-risk PAH patients.

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

• Age ≥ 18 years old
• Diagnosis of WHO PAH Group 1
• On stable doses of background PAH therapy and diuretics for ≥ 90 days

Common measurable exclusion criteria:

• Pregnant or breastfeeding
• Prior exposure to luspatercept
• Any history of the following:
  • Pneumonectomy
  • Portal hypertension
  • Pericardial constriction
  • Chronic liver disease, including hepatitis B and/or hepatitis C
  • Restrictive, constrictive, or congestive cardiomyopathy
  • Long QT syndrome

Appendix

Clinical deep dive

Disease state overview

Pulmonary arterial hypertension (PAH) is a rare disease caused by progressive hyperproliferation of cells in the arterial walls in the lung. This causes narrowing and increased pressure in the pulmonary arteries, leading to increased load on the heart. World Health Organization (WHO) classifies pulmonary hypertension (PH) into five groups based on etiology (Groups 1 to 5). While WHO Group 2, PH due to left heart disease, represents majority of the PH cases (68%), WHO Group I referring to PAH, represents 3% of the PH population. Additionally, WHO identifies PAH severity based on functional class (FC): FC-I severity represents symptom-free PAH; FC-II and FC-III convey symptoms (e.g., shortness of breath) with normal daily activities; and FC-IV indicates symptoms at rest and severe symptoms with physical activity. Majority of cases are expected to have FC-II and FC-III (about 65% combined). Symptoms of PAH include dyspnea, particularly during physical activity, chest pain, and syncope. Prognosis for PAH is poor, with a 5-year mortality rate estimated at 40%. In most individuals, PAH progresses to right sided heart dysfunction and death.

Epidemiology

PAH is uncommon compared to other forms of PH. Although the exact prevalence of PAH is unknown, the Pulmonary Hypertension Association Registry estimates about 30,000 persons in the U.S. are diagnosed with the disease. Additionally, it is estimated that 500 to 1,000 new cases of PAH are diagnosed each year, in the U.S., with most occurring in women 30 to 60 years of age. Approximately half of PAH cases have no known cause (idiopathic), and an estimated 6% to 20% of patients have a family history of the disease. The remaining cases of PAH are caused by drugs or toxins or are associated with other conditions, such as connective tissue disease, congenital heart disease, or pulmonary hypertension.

Treatment

There is no cure for PAH. In severe cases, lung or heart-lung transplant may be recommended. Several medications are available to treat symptoms of PAH by promoting vasodilation. They include oral/inhaled and IV/SC prostacyclin pathway agonists (e.g., epoprostenol, iloprost, selexipag [Upravi®], treprostinil), oral endothelin receptor antagonists (ERAs) (e.g., ambrisentan, bosentan, macitentan), IV and oral phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil), and oral soluble guanylate cyclase stimulator (riociguat [Adempas®]). Other agents, such as select calcium channel blockers, anticoagulants, and diuretics, are also used in patients with PAH. Five-year survival rate is limited to about 60% which highlights the need for alternative therapies; specifically targeting pulmonary vascular remodeling pathways.

Drug and clinical trial overview

The double-blind, placebo-controlled, phase 3 STELLAR trial evaluated sotatercept in 323 adults with PAH (WHO functional class [FC] II or III). Patients were randomized 1:1 to sotatercept or placebo as add-on to background therapy, which could be mono-, double, or triple therapy with medications for PAH. Sotatercept was administered SC at a starting dose of 0.3 mg/kg, which was increased every 3 weeks to a target dose of 0.7 mg/kg. Notably, 99.4% of patients assigned to sotatercept received the target dose. The mean patient age was 47.9 years, and mean time from diagnosis was 8.8 years among enrolled patients. At trial start, 61.3% were on triple therapy, and 39.9% were on prostacyclin infusion therapy. In the prespecified analysis of the primary endpoint, the median change from baseline in 6MWD at week 24 was +34.4 meters in the sotatercept group and +1 meter in the placebo group (p<0.001). The mean change from baseline in 6MWD at week 24 was +40.1 meters with sotatercept and -1.4 meters with placebo. Compared to placebo, there were significant improvements with sotatercept in secondary endpoints, including pulmonary vascular resistance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and WHO functional class. The risk of death or nonfatal clinical worsening events was 84% lower with sotatercept compared to placebo. Two deaths (1.2%) were reported in the sotatercept arm and 7 (4.4%) in the placebo arm; however, the study was not designed nor powered to assess the effects of sotatercept on mortality. No deaths were considered to have been caused by sotatercept. Treatment emergent adverse events (TEAEs) reported with sotatercept included epistaxis, dizziness, telangiectasia, increased Hb levels, thrombocytopenia, and increased blood pressure.

The double-blind, placebo-controlled, phase 2 PULSAR trial evaluated sotatercept in 106 patients with moderate to severe PAH. Patients were randomized to sotatercept or placebo as add-on to background therapy, which could include mono-, double, or triple therapy with medications for PAH. The primary endpoint was pulmonary vascular resistance (PVR). Baseline PVR was 778.6 dyn/sec/cm⁻⁵ (normal PVR range is 100 to 200 dyn/sec/cm⁻⁵.) After 24 weeks, the least squares (LS) mean difference in the primary endpoint between sotatercept 0.7 mg/kg and placebo was -239.5 dyn/sec/cm⁻⁵ (p<0.001). The most common TEAEs with sotatercept were thrombocytopenia and increased Hb. One death was reported in the sotatercept 0.7 mg group due to cardiac arrest. Clinical efficacy was maintained in the open-label extension period for up to 24 months.

In addition, in the ongoing, open-label extension study SOTERIA, patients either continued sotatercept or were switched from placebo to sotatercept. Top-line results revealed that among 131 patients with 1 year of treatment data (most from phase 2 PULSAR and SPECTRA trials), the changes from baseline to week 24 in 6MWD, NT-proBNP and WHO-FC were generally maintained at 1 year. Serious TEAEs were reported in 19.3% of the safety population, including 4 deaths (1%).

Pipeline (late-stage development)