Summary Basis of Decision for Opsumit

Clinical Pharmacology

Macitentan (the medicinal ingredient of Opsumit) is an endothelin receptor antagonist. Endothelin and its receptors mediate a variety of effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as pulmonary arterial hypertension (PAH), the local endothelin system is overactive and is involved in vascular hypertrophy and in organ damage.

The clinical pharmacology included reports on the human pharmacodynamics and pharmacokinetics. The submitted clinical pharmacological data support the use of Opsumit for the specified indication in patients with PAH.

For further details, please refer to the Opsumit Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety were evaluated in a multicentre, double-blind, placebo-controlled, parallel-group, event-driven, Phase III outcome study. In this study, 742 patients with symptomatic PAH were randomized to receive placebo, 3 mg macitentan (the medicinal ingredient of Opsumit), or 10 mg macitentan (Opsumit), once daily. At baseline, the majority of enrolled patients (64%) were treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%). The primary efficacy endpoint was the time to first occurrence of a morbidity or mortality event up to the end of double-blind treatment (EOT), defined as death, or atrial septostomy, or lung transplantation, or initiation of intravenous or subcutaneous prostanoids, or other worsening of PAH. Other worsening of PAH was defined as the concurrent presence of all of the three following components: a sustained decrease in 6-minute walk distance (6MWD) of at least 15% from baseline; worsening of PAH symptoms, and need for new treatment for PAH. All events were confirmed by an independent adjudication committee, blinded to treatment allocation. The median treatment duration was 101 weeks, 116 weeks, and 118 weeks in the placebo group, macitentan 3 mg group, and macitentan 10 mg group, respectively; up to a maximum of 188 weeks on macitentan.

In the time-to-event analysis [that is (i.e.) time to reach the primary efficacy endpoint event], the hazard ratios for a morbidity or mortality event for the macitentan 3 mg and 10 mg groups versus (vs.) placebo were 0.704 (p = 0.0108) and 0.547 (p<0.0001), respectively. For the 10 mg dose (Opsumit), this corresponded to a 45% relative risk reduction. The proportion of patients in the 10 mg group without an event at 3 years (i.e. no evidence of disease deterioration) was 63.2% compared to 47% in the placebo group, corresponding to an absolute risk reduction of 16.2%.

The treatment effect of macitentan on the efficacy outcome was almost entirely due to a reduction in morbidity and primarily the occurrence of 'worsening of PAH'. Macitentan treatment had no significant effect on mortality (death as the first event occurred in 8.4%, 6.6%, and 6.8% in the macitentan 3 mg, macitentan 10 mg, and placebo groups, respectively). Similar results were noted for deaths from all causes at end of treatment; 17.1% in the macitentan 10 mg group, and 19.3% in the placebo group, corresponding to an absolute risk reduction of 2.2%.

At 3 years, treatment with macitentan 10 mg (Opsumit) as monotherapy was shown to result in an absolute risk reduction in the occurrence of a primary endpoint event of 20.9% compared to placebo (64.4% macitentan, 43.5% placebo). Treatment with macitentan 10 mg in combination with another PAH therapy resulted in an absolute risk reduction of 14.0% (62.6% macitentan, 48.6% placebo). All reductions were statistically significant. As was the case with monotherapy, the reductions observed were due almost entirely to effects on morbidity and not mortality.

Subgroup analysis of the primary efficacy endpoint with respect to sex, race, baseline PAH therapy, PAH etiology and geographic region were consistent with the overall analysis.

At 6 months, the placebo-corrected mean change in the 6 MWD from baseline was 22.0 metres (±92.58) for the macitentan 10 mg group. Although statistically significant (p = 0.0078), such an increase in the "traditional" assessment of efficacy of PAH drugs is seen as marginal and of questionable clinical significance.

For more information, refer to the Opsumit Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Opsumit (macitentan) was assessed in 863 patients in placebo-controlled studies for periods up to 188 weeks. Overall, the incidence of adverse events (AEs), serious adverse events (SAEs), deaths, or AEs leading to discontinuation of study treatment was comparable in the macitentan and placebo groups. In the pivotal Phase III study, described in the Clinical Efficacy section, the most common AEs (>3% compared to placebo) were nasopharyngitis, headache, anemia, bronchitis, urinary tract infection, pharyngitis and influenza. The majority of AEs were mild to moderate in intensity.

Compared to other drugs in the same endothelin receptor antagonist (ERA) class of drugs, no new, unexpected, or unusual clinical safety concerns arose during the review of the submitted studies. There are two safety concerns specifically related to the use of ERAs. The most important one, and possibly a class effect, is hepatotoxicity. The other and less of a concern is decreased hemoglobin, related to the expansion of plasma volume resulting from the right heart failure common to all cases of PAH coupled with the known pharmacodynamics of endothelin receptor antagonism.Both of these safety issues were monitored in the pivotal study and the resulting safety data were provided for our review. With regard to the potential hepatotoxicity of macitentan, Health Canada recruited an external consultant to provide an additional assessment of the data. The consultant's review included all non-clinical and clinical studies. Although cases of significantly elevated liver enzymes occurred, the cases were not found to meet the criteria of Hy's Law. These criteria are widely accepted as evidence of idiopathic drug-induced liver injury. The consultant's review concluded that macitentan is not associated with drug-induced liver injury. With regard to the anemia-inducing potential of macitentan, this effect was found to be similar in all respects to that of other ERAs. In the pivotal study, serious hemoglobin decreases occurred in approximately 3% of cases in the 10 mg treatment group vs. 0.8% in the placebo group, almost always occurred early in the course of the study and remained stable throughout treatment. The observed decreases were due to hemodilution resulting from an increase in plasma volume in conjunction with the pharmacodynamics of endothelin receptor antagonism.

In neither the pre-clinical nor clinical studies submitted was there any evidence of significant QT prolongation specifically related to the use of macitentan.

Overall, macitentan treatment was well-tolerated in the pivotal study. The safety profile of Opsumit is considered acceptable and manageable for patients with PAH whose PAH is either idiopathic or heritable, or associated with connective tissue disease or congenital heart disease. There are no signals of any significant idiopathic drug-induced liver injury. Appropriate warnings and precautions are in place in the approved Opsumit Product Monograph to address the identified safety concerns.

For more information, refer to the Opsumit Product Monograph, approved by Health Canada and available through the Drug Product Database.