Regulatory Decision Summary for Opsumit

This Supplement to a New Drug Submission was filed to obtain market authorisation for a new formulation of Opsumit (macitentan), oral dispersible tablets for suspension (1 milligram [mg] and 2.5 mg). In addition, the sponsor proposed to extend the indication to include the long-term treatment of pediatric pulmonary arterial hypertension (PAH) patients aged 1 month to less than 18 years of age of World Health Organization Functional Class (WHO FC) I-III whose PAH is idiopathic or heritable, or associated with connective tissue disease or congenital heart disease.

During the initial review period, the submission was assessed using the international Access Consortium New Active Substance Medicines Work Sharing Initiative (NASWSI). Health Canada reviewed the clinical and non-clinical parts of the submission, and the UK Medicines and Healthcare Products Regulatory Agency reviewed the quality part of the submission. Each regulatory agency peer reviewed parts of the submission that were reviewed by the other regulatory agency. Following the review of all data, a Notice of Non-compliance (NON) was issued due to significant deficiencies pertaining to 1) comparative bioavailability and quality information, and 2) insufficient data to support the safety and dosing of Opsumit in patients less than 2 years of age.

In response to the NON, the sponsor removed the 1 mg tablet and provided additional comparative in vitro dissolution data. Health Canada authorized Opsumit with the following modifications to the proposed pediatric strengths and the indication: 2.5 mg dispersible tablets for suspension for the long-term treatment of PAH (WHO Group I) in pediatric patients aged 2 to less than 18 years of WHO Function Class II-III whose PAH is idiopathic or heritable, or associated with connective tissue disease or congenital heart disease.

The effect of Opsumit (macitentan) in pediatric patients with pulmonary arterial hypertension (PAH) was evaluated in the randomized, multicentre, open-label on-going TOMORROW study. At the end of core period analysis (EOCP; February 2024 data cutoff), a total of 148 participants 2 years of age and older were randomized 1:1 to receive either Opsumit (n = 72) or standard of care (SoC) PAH therapies (n = 75). The mean treatment duration was 183.4 weeks in the Opsumit arm and 130.6 weeks in the SoC arm. The baseline demographics and characteristics were generally acceptable for the proposed target pediatric PAH population, and they were relatively balanced between randomized treatment groups.

Given recruitment challenges, the design of the TOMORROW study was amended from an event-driven study to a pharmacokinetic (PK), safety, and efficacy study with a fixed duration. As a result, the primary endpoint was revised to the assessment of the PK of Opsumit, and the original primary endpoint of time to first disease progression event was revised as a secondary endpoint. Accordingly, the study was not powered to demonstrate the efficacy of Opsumit in pediatrics with PAH, and safety data was limited by a lower level of recruited patients resulting from the study design change.

The efficacy data from the TOMMORROW study showed non-statistically significant trends favouring the effect of Opsumit in time to disease progression events and other secondary efficacy endpoints (e.g., quality of life tests, WHO FC scores, N-terminal pro-B-type natriuretic peptide). When considering the limited and statistically unpowered efficacy results, and probable confounding associated with permitting endothelin receptor antagonists as part of “planned/ongoing” standard of care therapies for PAH in the SoC arm, the totality of efficacy data only provided supportive evidence towards the efficacy of Opsumit in pediatrics 2 years of age and older with PAH. Consistent with the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) E11 (R1) guideline, the efficacy of Opsumit in pediatrics 2 years of age and older with PAH was mainly corroborated by an extrapolation approach based upon exposure-matching to the adult efficacious dose range, given the similarity of the disease in children and adults, as well as on supportive efficacy and safety data from the TOMORROW study.

The EOCP safety results of the TOMORROW study showed a higher rate reporting at least one adverse event (AE) in the participants randomized to Opsumit (67 [93.1%] Opsumit vs. 51 [68.0%] SoC). The sponsor suggested that a number of confounding factors contributed to this imbalance (e.g., open-label design, lack of exposure adjustment, not adding disease progression events, etc.). The majority of AEs were mild to moderate in intensity. Predefined AEs of special interest were more frequently observed in the Opsumit arm compared to SoC arm: anemia (11 [15.3%] vs. 2 [2.7%]), edema/fluid retention (4 [5.6%] vs. 1[1.3%]), hepatic disorders (3 [4.2%] vs. 3 [4.0%]), and hypotension (3 [4.2%] vs. 1 [1.3%]). The preferred term upper respiratory tract infection (31.9% Opsumit), rhinitis (8.3% Opsumit), and gastroenteritis (11.1% Opsumit) were identified pediatric-specific adverse drug reactions. An analysis of post-market literature and data from the TOMORROW study and the prior pivotal adult PAH study (SERAPHIN) concluded that there is a new signal for increased uterine bleeding in women of child-bearing potential. Serious AEs were similarly distributed across system organ classes for the two treatment arms, with differences in frequency between treatment arms below 5% for all system organ classes except Infections and infestations. Serious AEs occurring in more than one participant in the Opsumit arm were pneumonia (5 [6.9%]), anemia, gastritis, and non-cardiac chest pain (2 each [2.8%]). A total of thirteen participants 2 years of age and older died up to the EOCP (7 in the Opsumit group, six in the SoC group). Out of the thirteen deaths, six in the Opsumit arm and four in the SoC arm were due to PAH disease progression confirmed by the Clinical Events Committee, and no deaths were related to Opsumit. Overall, the TOMORROW study and its limited EOCP results were underpowered to make solid conclusions regarding differences in safety endpoints between treatment arms. However, the totality of evidence was supportive for the safety of Opsumit in patients 2 years of age and older with PAH. The identified risks in pediatrics and women of child-bearing potential were mitigated by warnings on the label.

A Notice of Non-Compliance (NON) was issued in December 2024 due to an absence of acceptable quality and comparative bioavailability data extrapolating (bridging) the TOMORROW study’s safety and efficacy data generated with strengths of the early clinical service formulation (CSF) to the proposed final market image (FMI) 1 mg and 2.5 mg strengths. In addition, no conclusions could be made about the safety profile of Opsumit in patients less than 2 years of age based on the small number of patients studied and short clinical trial experience with Opsumit. Finally, the sponsor’s proposed indication for PAH of WHO FC I-III patients should have mirrored the approved adult indication for PAH of WHO FC II-III for Health Canada to utilize a pediatric extrapolation approach, as per ICH E11 (R1).

In response to the NON, the sponsor removed the 1 mg FMI tablet and provided additional comparative in vitro dissolution data. The dissolution data was sufficient to support the granting of a waiver from conducting comparative bioavailability studies between the 2.5 mg and 5.0 mg CSF tablets, thereby resolving the remaining bridging deficiencies. The proposed pediatric indication was restricted to patients 2 years of age and older with PAH of WHO FC II-III, and an alternative weight-based pediatric dosing regimen that utilizes the 2.5 mg FMI dispersible tablet was proposed for patients 2 to under 18 years of age; the alternative regimen was acceptable for the proposed pediatric population given the totality of available PK data and safety evidence.

An updated Risk Management Plan was reviewed and considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Opsumit 2.5 mg dispersible tablets for suspension for the proposed pediatric indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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