Results of the Phase III STELLAR study show therapeutic progress

In pulmonary arterial hypertension, sotatercept improved primary and secondary endpoints, and thus numerous disease parameters, in a phase 3 study, in addition to standard combination therapy. The molecule targets a new mechanism of action.

Pulmonary arterial hypertension is a disease characterized by proliferative remodeling of the small pulmonary arteries and progressive narrowing of the lumens [2]. The resulting increase in pressure in the pulmonary arteries stresses the heart and leads to right ventricular failure and death. Currently available treatments include phosphodiesterase-5 inhibitors, endothelin receptor antagonists, soluble guanylate cyclase stimulators, and agents targeting the prostacyclin pathway [3,4]. Administered alone or in combination, these treatments improve pulmonary hemodynamics, exercise capacity, and progression-free survival in patients with pulmonary arterial hypertension. The median survival time is between five and seven years after diagnosis [5]. The persistently high morbidity and mortality underscore the need for additional treatment options targeting novel signaling pathways involved in pulmonary vascular remodeling.

Pulmonary vascular remodeling affects all layers of the vascular wall and is mainly driven by increased proliferation and decreased apoptosis of endothelial and smooth muscle cells [6]. Recent research has highlighted the role of altered signal transduction by members of the transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein type II receptor, activin receptor type IIA (ActRIIA), and the ActRIIA ligands activin A, activin B, growth differentiation factor 8 (GDF8), and GDF11. A shift toward proliferative and antiapoptotic signaling by these TGF-β superfamily members is thought to be an important mechanism driving pulmonary vascular remodeling in patients with pulmonary arterial hypertension [7–9].

Balance between pro- and anti-proliferative signals

Sotatercept is a first-in-class fusion protein consisting of the Fc domain of human IgG linked to the extracellular domain of human ActRIIA, which acts as a ligand trap for selected members of the TGF-β superfamily. Inhibition of these ligands by sotatercept is thought to rebalance pulmonary vascular homeostasis toward growth-inhibitory and proapoptotic signaling. In animal models of pulmonary hypertension, sotatercept inhibited cell proliferation, promoted apoptosis, and alleviated inflammation in vascular walls, leading to reverse remodeling and restoration of vascular permeability [9–11].

Phase 2 PULSAR study already showed encouraging results

In the Phase 2 PULSAR study, which enrolled 106 patients receiving background therapy for pulmonary arterial hypertension, pulmonary hemodynamics (including pulmonary vascular resistance and pulmonary arterial pressure) improved, serum levels of N-terminal natriuretic peptide type B (NT-proBNP) and exercise capacity (as measured by 6-minute walk distance) by 24 weeks of treatment with sotatercept administered subcutaneously every three weeks at a dose of 0.3 or 0.7 mg per kilogram of body weight [12]. Improvements were observed within the first 24 weeks of treatment and were maintained over a period of 18 to 24 months with continued sotatercept therapy [13].

Following the encouraging results of the Phase 2 study, sotatercept has now been put to the clinical test in Phase 3 in the double-blind STELLAR study. “Our study data establish the clinical utility of sotatercept as a new approach to PAH in combination with established drugs, a true paradigm shift,” said study first author Prof. Marius Höper, deputy director of the Department of Pneumology and Infectious Diseases at Hannover Medical School, at the 2023 ACC Congress in New Orleans [1].

Of the 434 patients eligible for the study, 323 were randomized and assigned (1:1 ratio) to either sotatercept (163 patients) or placebo (160 patients) in combination with stable background therapy. Sotatercept or placebo (saline) was administered by subcutaneous injection every 21 days. Sotatercept was administered at an initial dose of 0.3 mg per kilogram at visit 1 and escalated to the target dose of 0.7 mg per kilogram at visit 2 (day 21, with a time window of ± 3 days). Patients continued to receive a dose of 0.7 mg per kilogram throughout the study period unless a reduction in dose was warranted by the protocol.

Patient demographic and clinical characteristics at baseline were generally similar in the two groups. The study population was relatively young (mean age 47.9 ± 14.8 years), with a mean time since diagnosis of 8.8 years. Overall, 198 of the 323 randomized patients (61.3%) received triple therapy and 129 (39.9%) received prostacyclin infusion therapy at study inclusion.

Improvement of numerous disease components

The observed mean change from baseline in 6-minute walk distance at week 24 was 40.1 m (95% confidence interval) in the sotatercept group and -1.4 m (95% confidence interval) in the placebo group (Fig. 1) [14]. In the prespecified analysis of the primary end point, the median change from baseline in 6-minute walk distance was 34.4 m in the sotatercept group and 1.0 m in the placebo group. The results of a post-hoc analysis of 6-minute walk distance were consistent with those of the prespecified analysis: The median change from baseline at week 24 was 34.4 m in the sotatercept group and 5.4 m in the placebo group. The magnitude of the treatment effect on 6-minute walk distance was independent of treatment missing data due to death or nonfatal clinical deterioration and similar in most predefined subgroups.

The first eight secondary endpoints were also significantly positively affected

The number of patients who met all three criteria of the multicomponent improvement endpoint at week 24 was 63 of 162 (38.9%) in the sotatercept group and 16 of 159 (10.1%) in the placebo group (p<0.001).

Compared with placebo, significant improvements in change from baseline at week 24 in pulmonary vascular resistance, NT-proBNP levels, WHO functional class, and simplified French risk model were observed with sotatercept treatment.

There was a significant difference in the distribution of time to first occurrence of death or nonfatal clinical worsening in the sotatercept and placebo groups (p<0.001 by log-rank test). The Kaplan-Meier curves showed that separation began early (around week 10) and persisted for the rest of the study. After a median follow-up of 32.7 weeks in all groups, the hazard ratio was 0.16 (95%) in the sotatercept group compared with the placebo group.

With respect to the PAH-SYMPACT quality of life questionnaire, at week 24, sotatercept showed greater improvements than placebo in the domains of “physical effects” and “cardiopulmonary symptoms.” No significant difference was found between groups on the PAH-SYMPACT cognitive/emotional impact score (p=0.16).

Side effects that occurred more frequently in the verum group included nosebleeds, drowsiness, telangiectasia, increased hemoglobin, decreased platelets, and increased blood pressure. However, these were not serious, Höper reported.

Not an entirely representative patient population

The STELLAR study also appeared simultaneously with its presentation at the ACC Congress in the New England Journal of Medicine (NEJM). However, NEJM editorial authors led by Prof. Darren Taichman cautioned that the findings do not apply to all PAH patients. The collective consisted mainly of clinically relatively stable patients in WHO functional class II or III (87%); however, patients with PAH in the setting of mixed collagenoses, which represent a substantial proportion in practice, were underrepresented (15%). Furthermore, the long-term durability of the treatment response is unknown; further vigilance is therefore warranted [15].

Congress: ACC 2023

Literature:

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