SUMMARY

• Researchers involved in the rationale, formulation, and clinical development of OPSYNVI explain that adherence to the prescribed therapy has an impact on clinical outcomes and reducing the pill/tablet count and frequency of consumption has an impact on patient’s adherence to therapies in general and to pulmonary arterial hypertension (PAH) therapies in particular. One way to simplify treatment is to utilize fixed-dose combination (FDC, also known as single-tablet combination therapy [STCT]) products that combine multiple treatments into a single tablet.^1-7
• The A DUE authors proposed that a simplified PAH treatment regimen in the form of a single OPSYNVI tablet containing a FDC of macitentan 10 mg and tadalafil 40 mg given once daily vs loose dose combination of 3 tablets (one macitentan 10 mg and 2 tadalafil 20 mg tablets) would reduce pill burden, thereby, offering a convenient treatment option, and potentially improving treatment adherence in patients with PAH.²
• Three phase 1 pharmacokinetic (PK) studies established bioequivalence between macitentan 10 mg/tadalafil 40 mg FDC (M/T FDC 10/40) and single-component tablets of macitentan 10 mg and tadalafil 40 mg (coadministered as 3 tablets) in healthy subjects.^4,5
• Another phase 1 PK study established bioequivalence between macitentan 10 mg/tadalafil 20 mg FDC (M/T FDC 10/20) and single-component tablets of macitentan 10 mg and tadalafil 20 mg (coadministered) in healthy subjects.⁷
• Results from analyses based on patients’/clinicians’ experience with a STCT of OPSYNVI over loose dose combination therapy of macitentan 10 mg and tadalafil 40 mg have been summarized below.^8,9

CLINICAL DATA

The A DUE authors proposed that a simplified PAH treatment regimen in the form of a single OPSYNVI tablet containing a FDC of macitentan 10 mg and tadalafil 40 mg given once daily vs loose dose combination of 3 tablets (one macitentan 10 mg and 2 tadalafil 20 mg tablets) would reduce pill burden, thereby, offering a convenient treatment option, and potentially improving treatment adherence in patients with PAH.²

The bioequivalence data from the 3 phase 1 PK studies^4,5 support switching patients already receiving dual combination therapy in the form of stable doses of macitentan 10 mg and tadalafil 40 mg, coadministered as separate tablets, to OPSYNVI 10 mg/40 mg as a STCT.^10,11 Therefore, these studies preclude the need for the phase 3 A DUE study to compare the efficacy and safety of OPSYNVI 10 mg/40 mg as a STCT to that of the loose dose combination of macitentan 10 mg and tadalafil 40 mg.^4,5

Results from the 4 phase 1 PK studies comparing FDC vs loose dose combination therapies are summarized below.

Grill et al (2020)⁴ conducted two phase 1, single-center, open-label (OL), single-dose,
2-period, randomized, crossover studies (AC-077-101 [conducted in the United States] and
AC-077-103 [conducted in the European Union]) that aimed to demonstrate bioequivalence between M/T FDC 10/40 and single-component tablets of macitentan 10 mg and tadalafil 40 mg in healthy subjects. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of area under the plasma concentration-time curve from time 0 to infinite time (AUC_0-∞), area under the plasma concentration-time curve from time 0 to time of the last measured concentration above the lower limit of quantification (AUC_0-t), and maximum observed plasma analyte concentration (C_max) for FDC-2 and single-component tablets were within the bioequivalence limits (80%-125%) in both the studies.

Csonka et al (2021)⁵ conducted a single-center, OL, single-dose, 2-period, randomized, crossover phase 1 study that aimed to demonstrate bioequivalence between tadalafil as part of the M/T FDC 10/40 and single-component tablets of macitentan and tadalafil in healthy subjects. The study also evaluated the effect of food on M/T FDC 10/40 in healthy subjects.

Bioequivalence (Group 1: FDC vs Free Combination [Fasted])

The mean plasma concentrations and exposure PK parameters: AUC_0-∞, area under the plasma analyte concentration-time curve from time 0 to time of the last quantifiable concentration (AUC_0-last), C_max, time to reach maximum plasma concentration (t_max), and terminal half-life (t_1/2) for tadalafil and macitentan were similar for FDC vs tadalafil as part of the free combination tablet. For both tadalafil and macitentan, the 90% CIs for the GMRs of AUC_0-∞, AUC_0-last, and C_max were within the bioequivalence limits (80%-125%).

Food Effect (Group 2: FDC [Fed vs Fasted])

The mean AUC, t_max, and t_1/2 values for tadalafil and macitentan were comparable under fed vs fasted conditions; however, the mean C_max values were approximately 42.5% and 15.9% higher, respectively, under fed vs fasted conditions. The 90% CIs for the GMRs of AUC_0-∞ and AUC_0-last for tadalafil and macitentan were within the bioequivalence limits (80%-125%) under fed vs fasted conditions. The GMRs of C_max for tadalafil and macitentan were 44.97% and 16.10% higher, respectively, under fed vs fasted conditions.

Ford et al (2024)⁷ conducted a single-center, randomized, OL, 3-way crossover, single-dose, phase 1 study that aimed to demonstrate bioequivalence on primary PK parameters between M/T FDC 10/20 and single-component tablets of macitentan 10 mg and tadalafil 20 mg coadministered in healthy subjects. The study also evaluated the effect of food on primary PK parameters of M/T FDC 10/20 in healthy subjects.

Bioequivalence (FDC vs Free Combination [Fasted])

The 90% CIs for the GMRs of C_max, AUC_0-last, and AUC_0-∞ for tadalafil and macitentan were within the bioequivalence limits (80%-125%) under fasted conditions.

Food Effect (FDC [Fed vs Fasted])

The 90% CIs for the GMRs of C_max, AUC_0-last, and AUC_0-∞ were within the bioequivalence limits (80%-125%) following the administration of M/T FDC 10/20 with a high-fat, high-calorie meal. However, the absorption rate in fed vs fasted condition for tadalafil was slightly delayed, with a median t_max of 5 hours for FDC fed vs 3 hours for FDC fasted and 2.81 hours for free combination fasted.

Descriptive results evaluating patients’/clinicians’ experience of STCT are summarized below.

Langleben et al (2022)⁸ described the clinical experience with OPSYNVI in patients with PAH. As of August 2022, 7 patients from the outpatient pulmonary hypertension clinic at a Jewish General Hospital (Montreal, Quebec, Canada) transitioned from dual therapy (macitentan 10 mg and tadalafil 40 mg) to OPSYNVI. Patients were in the age range of
42-76 years and 6 out of 7 were female. Duration of OPSYNVI treatment ranged from 19 to 98 days. Patients found OPSYNVI to be “more convenient”, and compliance was described to be “excellent.” The transition from dual therapy to OPSYNVI was described as “smooth” and the therapy itself was “well tolerated.”

Davis et al (2023)⁹ conducted an interim analysis to explore patients’ and clinicians’ experience (in terms of adherence and convenience) with OPSYNVI as a STCT. As of October 2023, 27 participants (patients, n=14; clinicians, n=13) from the ongoing
OL extension (OLE) of the A DUE study were interviewed. All participants provided positive feedback regarding the STCT and preferred the single tablet in the OLE to the 4 tablets in the double-blind period (1 STCT + 3 placebos; 1 macitentan 10 mg + 3 placebos; 2 tadalafil 20 mg + 2 placebos) irrespective of the country or treatment in the double-blind period.

Patients stated the STCT was “convenient”, “helped adherence”, and had a “positive impact” on their day-to-day lives. They discussed how taking a greater number of tablets made them feel “sicker” compared with the STCT. Patients noted the STCT “improved” their psychological well-being by reducing the stress of keeping a tab regarding the multiple tablets. Clinicians noted the high pill burden in PAH can cause emotional distress in their patients, whereas patients had a higher treatment satisfaction with STCT. Clinicians predicted the STCT will be “well received” in clinical practice and endorsed prescribing STCT for their patients, with the majority also endorsing its use in treatment-naïve patients.

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.