Regulatory Decision Summary for Opsynvi

The clinical data package to support the New Drug Submission for Opsynvi for the proposed indication included data from three completed bioequivalence studies (using United States-sourced Adcirca [Study AC-077-101], European Union [EU]-sourced Adcirca [Study AC-077-103], and Canadian-sourced Adcirca [Study 67896062PAH1006]), in healthy volunteers. The data from these studies demonstrated the bioequivalence between the free combination of macitentan 10 mg and tadalafil 40 mg and the Opsynvi fixed dose combination (FDC).

Supportive safety data included an open-label, prospective, Phase 4 study (OPTIMA) and real world evidence based on secondary analysis of pooled data from the OPsumit USers (OPUS) Registry and the Organisation for PhD Education in Biomedicine and Health Sciences in the European System (OrPHeUS), retrospective medical chart review.

OPTIMA was a prospective, multicenter, single-arm, open-label Phase 4 study evaluating the effects of dual free combination therapy with macitentan and tadalafil on efficacy and safety in treatment-naïve, newly diagnosed adult participants with PAH. A total of 46 patients completed the treatment of 16 weeks, and 39 completed the study extension period. Patients were predominantly female (65.2%) with idiopathic PAH etiology as most common (63.0%), and at baseline were World Health Organization Functional Class (WHO FC) II (21.7%) or III (78.3%). The mean exposure to macitentan and tadalafil up to the end of study was ~18 months, including the extension period. Most frequent adverse events (AE) were peripheral oedema (28.3%), headache (23.9%), diarrhoea (19.6%), dyspnoea (15.2%), anaemia (13.0%) and asthenia (13.0%). Haemoglobin decreases were reported in five (10.9%) patients, with no decreases to ≤8 grams per millilitre (g/mL). No patients discontinued study treatment due to decreased hemoglobin. Aspartate aminotransferase levels above three times the upper limit of normal (ULN) without bilirubin elevation above double the ULN were reported in one patient but did not lead to treatment discontinuation. No changes from baseline were noted for creatinine.

The objectives of the secondary analysis of pooled data from OPUS and OrPHeUS were to characterize the safety profile of the free combination therapy of macitentan and tadalafil (M + T), and macitentan with a special focus on hepatic safety. The patients in the M + T cohort and macitentan cohort were very similar in terms of gender (female ~76%), median age (~60) and most common PAH etiology was idiopathic (~50%). The median observed exposure to free combination was 14.5 months, with 44.7% of patients receiving free combination therapy for at least 12 months. The hospitalization rate for M + T cohort (95% confidence interval (CI)) (33.0 [29.5, 37.2]) per 100 person-years was similar to macitentan cohort (34.0 [31.1, 37.2]) per 100 person-years. Similarly, all cause death rate was 9.5 (8.3, 11.1) per 100 person-years for M + T and 10.1 (9.0, 11.4) per 100 person-years for macitentan cohort. The incidence rates of hepatic adverse events (HAE) and hepatic adverse events of special interest (HAESI) were 6.2 and 3.8 per 100 person-years, respectively, in the M + T cohort, and 5.8 and 3.4 per 100 person-years, respectively, in the macitentan cohort. Ten patients (0.8%) in the M + T cohort and 14 patients (0.6%) in the macitentan cohort met the biochemical criteria of a potential Hy’s law case during the study. Adverse events other than HAE were captured only in the OPUS registry. The most frequently reported AEs were dyspnea (21.5%), headache (12.0%), and peripheral edema (10.0%) in the M + T cohort and dyspnea (17.3%), headache (9.2%), and peripheral edema (8.9%) in the macitentan cohort. No previously unknown safety signal appeared in patients receiving the free macitentan and tadalafil combination, compared to patients receiving macitentan without phosphodiesterase (PDE)-5 inhibitor therapy. Frequency of AE was similar between the M + T cohort and macitentan cohort.

Despite the limitations of safety data based on real world evidence, the safety profile was consistent with what has been seen previously with macitentan in combination with PDE-5 inhibitors.

As the comparative bioavailability of macitentan and tadalafil was demonstrated between the Opsynvi fixed dose combination tablet and concomitant use of Opsumit (macitentan) and Adcirca (tadalafil) as a free combination in healthy subjects under fasting conditions, the product monograph (PM) for Opsynvi relies on the information from the PMs of its components Adcirca (tadalafil) and Opsumit (macitentan). The safety data from real world evidence (secondary analysis of OPUS and OrPHeuS studies) and OPTIMA study are consistent with what is seen with macitentan in combination with PDE-5 inhibitors.

Based on the information submitted for review, the benefit/risk ratio of Opsynvi is favorable when used according to its approved indication.