SUMMARY

• A DUE was a prospective, multicenter, double-blind, randomized, active-controlled, triple-dummy, parallel group, group-sequential, adaptive phase 3 study (NCT03904693) that evaluated the efficacy and safety of OPSYNVI as a single-tablet combination therapy (STCT) vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with pulmonary arterial hypertension (PAH).¹
  • Anemia was considered as a predefined treatment-emergent adverse event (TEAE) of special interest in the A DUE study. A total of 20 (18.7%) patients in the OPSYNVI group experienced anemia compared with 1 (2.9%) in the macitentan and 1 (2.3%) in the tadalafil monotherapy groups. Anemia (n=1; 0.9%) and decreased hemoglobin levels (n=1; 0.9%) were reported as adverse events (AEs) that led to premature study treatment discontinuation in the OPSYNVI group.^1,2
• A subgroup analysis of patients from the A DUE study based on their background therapy status (treatment-naïve, prior endothelin receptor antagonist [ERA], or prior phosphodiesterase type-5 inhibitor [PDE5i]) reported the incidence of anemia and deceased hemoglobin adverse events (AEs) for patients who were treatment-naïve or previously treated with an ERA or PDE5i.³
• An interim analysis of the open-label (OL) period of the A DUE study (data cutoff,
  April 28, 2023) evaluating the effect of OPSYNVI on exercise capacity (6 minute walk distance [6MWD]), N-terminal pro B-type natriuretic peptide (NT-proBNP), and its long-term safety and tolerability in patients with PAH, reported the incidence of anemia and decreased hemoglobin AEs, which are presented in the summary section below.⁴

CLINICAL DATA

The A DUE Study

A DUE was a prospective, multicenter, double-blind, randomized, active-controlled,
triple-dummy, parallel group, group-sequential, adaptive phase 3 study (NCT03904693) that evaluated the efficacy and safety of OPSYNVI as a STCT vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with PAH, including treatment-naïve patients and patients on prior ERA or PDE5i monotherapy at baseline (see Figure: Study Design).¹

Patients were excluded from A DUE if they had hemoglobin levels <100 g/L (<10 g/dL) at screening.²

Investigator Assessments of AEs

Per the A DUE Protocol, AEs were to be assessed by investigators for seriousness, intensity, and causal relationship to study treatment.⁵ A serious AE (SAE) must fulfill criteria defined by the International Council for Harmonisation guidelines.⁶ The intensity of each AE was graded on a three-point scale: mild, moderate, severe. Seriousness, rather than intensity, determined regulatory reporting obligations. Each AE must be assessed by the investigator as to whether or not there is a reasonable possibility of causal relationship to study treatment and reported as either related or not related. A TEAE is any AE temporally associated with the use of study treatment (from start of treatment until 30 days after study treatment discontinuation) whether or not considered by the investigator as related to study treatment.⁵

Results

Of the 294 patients screened between October 15, 2019, and August 23, 2022, 187 were randomized. Overall, 108 patients were assigned to receive OPSYNVI, 35 to macitentan
10 mg monotherapy, and 44 to tadalafil 40 mg monotherapy.¹

Safety

Anemia was considered as a predefined TEAE of special interest in the A DUE study. A total of 20 (18.7%) patients in the OPSYNVI group experienced anemia compared with 1 (2.9%) in the macitentan and 1 (2.3%) in the tadalafil monotherapy groups. Anemia (n=1; 0.9%) and decreased hemoglobin levels (n=1; 0.9%) were reported as AEs that led to premature study treatment discontinuation in the OPSYNVI group.^1,2

All cases of anemia, except 1, were classified as mild/moderate in intensity and were generally manageable without raising any safety concerns.¹ One case in the OPSYNVI group was classified as severe intensity involving a patient who experienced a hemorrhoidal hemorrhage for which the patient received a blood transfusion.^7-9

One case in the OPSYNVI group met the regulatory definition of SAE.¹⁰ The patient’s hemoglobin decreased by >5 g/dL from baseline to below 8 g/dL.^8,9 This SAE was classified as moderate intensity and led to discontinuation from study drug.^7-9 Transfusion was facilitated to this patient to correct the low hemoglobin levels caused by anemia.^1,8,9

Among the 22 anemia TEAEs of special interest that occurred in the A DUE trial, 6 were considered by the investigator to be related to study treatment, including the 1 SAE, 1 severe case, and 4 mild/moderate cases.^1,7 All other anemia TEAEs of special interest were considered by the investigator to be not related to study treatment.⁷

Baseline hemoglobin ranged from 11.0 to 17.7 g/dL amongst the 20 OPSYNVI patients who experienced anemia as a TEAE of special interest.¹¹

Of the 100 patients in the OPSYNVI group with ≥1 postbaseline hemoglobin test value during the 16-week double-blind period of the A DUE study, 11 (11%) and 2 (2%) reported hemoglobin levels ≤10 g/dL and ≤8 g/dL, respectively; 1 (2.9%) of 35 patients in the macitentan monotherapy group and 0 of 44 patients in the tadalafil monotherapy group, respectively, reported hemoglobin levels ≤10 g/dL.¹⁰

A DUE - Subgroup Analysis

Grünig et al (2023)³ conducted a subgroup analysis of patients from the A DUE study based on their background therapy status (treatment-naïve, prior ERA, or prior PDE5i) to evaluate the efficacy and safety of OPSYNVI vs macitentan 10 mg and tadalafil 40 mg monotherapies. Anemia and deceased hemoglobin AEs in the A DUE study were reported for patients who were treatment naïve or previously treated with an ERA or PDE5i.

See Table: Anemia and Decreased Hemoglobin AEs in the A DUE Study for rates of anemia and decreased hemoglobin adverse events in the subgroup analysis of treatment-naive, prior ERA, and prior PDE5i patients.³

Interim Analyses of the A DUE OL Study

Chin et al (2024)⁴ conducted an interim analysis of the ongoing 24-month OL period (data cutoff, April 28, 2023) of the phase 3 A DUE study, evaluating the effect of OPSYNVI on exercise capacity, NT-proBNP, and its long-term safety and tolerability in patients with PAH.

A total of 185 patients received OPSYNVI in the double blind (DB) and/or OL period, of whom 113 are ongoing in the OL study. Anemia and deceased hemoglobin AEs were reported in the interim analysis of the A DUE OL study. See Table: Anemia and Decreased Hemoglobin AEs in the Interim Analyses of the A DUE OLE Study.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 March 2024.