OREANDA-NEWS. Actelion Ltd announced today that it will be initiating a Phase III study to evaluate the effect of macitentan on delaying disease progression in children with PAH using a pediatric formulation of macitentan (Opsumit).

TOMORROW (pediaTric use Of Macitentan tO delay disease pRogRessiOn in PAH Worldwide) is a multicenter, controlled, randomized, open-label event-driven study to assess the efficacy, safety and pharmacokinetics of macitentan versus standard of care in children with PAH.

The study will enroll children between the age of 1 month and 18 years in more than 20 countries. Initially, only children aged between 2 and < 18 years will be enrolled, and pharmacokinetic profiles collected in the study for up to 40 patients will allow Actelion to determine the doses for younger patients. Once the dose is determined, the study protocol will be amended to include children below 2 years of age. The children will be randomized in a 1:1 ratio into two treatment groups - macitentan administered as a pediatric formulation or standard of care as per local practice. The pediatric formulation of macitentan is a round dispersible tablet that is neutral in taste. It is available in three different dose strengths, containing 0.5 mg, 2.5 mg and 5.0 mg macitentan. To make them easier for children to swallow, the tablets can be dispersed in water on a spoon.

The trial is expected to last up to 6 years, with children being enrolled until 187 primary efficiency endpoint events have occurred. The primary efficacy endpoint is defined as the time to the first Clinical Event Committee (CEC) confirmed outcome event.

Maurice Beghetti, Head of Paediatric Cardiology at the University Hospital of Geneva, commented: "Clinical studies in children come with big challenges, such as the influence of growth stage and body weight on the dosage scheme and on potential side effects. PAH is a rare disease in adults and even more so in children, so pediatric PAH physicians have to mostly rely on research data collected in adults when weighing up treatment options for their younger patients. There is a significant medical need for showing the benefit of adequately adapted formulations and doses of PAH-specific medications in order to provide children with PAH with the most appropriate treatment. TOMORROW as a robust study assessing long-term treatment with the appropriate pediatric formulation of macitentan will deliver the sought-after data on all fronts."

Dunbar Ivy, Director of the Pediatric Pulmonary Hypertension Program at Children's Hospital Colorado, commented: "As there is no globally approved treatment for PAH in children, it was not possible to define a single unique treatment as reference drug or standard background. The design of the TOMORROW study will ensure that children receive the best available standard of care therapy or macitentan, a treatment that is well supported by long-term efficacy and safety data in adults. This will render the study ethical, informative, and feasible and I welcome Actelion's effort to broaden the pediatric knowledge base, which will help both physicians and their young PAH patients in the long term."

Jean-Paul Clozel, MD and CEO of Actelion, commented: "We take our leadership in PAH as a responsibility and have now committed to the first long-term, event-driven study in children with PAH using a pediatric formulation of macitentan. The design of the TOMORROW clinical trial allows the safe and comprehensive assessment of children over a long period of time. This is another example of our long-term commitment to the PAH community and our intention to broaden the use of macitentan to new patient populations."

ABOUT THE TOMORROW STUDY
TOMORROW (pediaTric use Of Macitentan tO delay disease pRogRessiOn in PAH Worldwide) is a multicenter, open-label, randomized, event-driven study to assess the efficacy, safety and pharmacokinetics of macitentan versus standard of care in children with pulmonary arterial hypertension. The study will enroll patients with an age range from 1 month to 18 years in more than 20 countries. The patients will be randomized in a 1:1 ratio into two treatment groups - macitentan or standard of care as per local practice. The trial is expected to last up to 6 years, with patients remaining in the study until the target number of primary efficacy endpoints is met. The primary efficacy endpoint is defined as time to the first Clinical Event Committee (CEC) confirmed disease progression event, comprising:

  • Death (all causes), or

  • Atrial septostomy or Pott's anastomosis, or registration on lung transplant list, or

  • Hospitalization due to PAH, or

  • Clinical worsening of PAH

Due to the open-label nature of the study, the management of investigational centers as well as data management, data analysis and coordination of the CEC will be conducted by a CRO. The primary endpoints of the study will be adjudicated by a blinded CEC, in a similar approach to that used in the Phase III SERAPHIN study, where macitentan was studied in adult patients with PAH. An interim analysis for early efficacy or futility is planned when at least 131 CEC-confirmed first disease progression events (70% information fraction) have occurred. If Actelion completes the study as outlined, the company can apply for the extension of the marketing exclusivity for Opsumit both in the US and the European Union.

ABOUT OPSUMIT® (MACITENTAN)
Opsumit (macitentan), an orally available endothelin receptor antagonist, resulted from a tailored drug discovery process in Actelion's laboratories.

In the US, Opsumit is indicated for the treatment of PAH, WHO Group I to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO FC II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

In Europe, Opsumit is indicated, as monotherapy or in combination, for the long-term treatment of PAH in adult patients of WHO Functional Class (FC) II to III. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease.

ABOUT THE PEDIATRIC FORMULATION OF MACITENTAN
The pediatric formulation is a round dispersible tablet that is neutral in taste. It comes in three different dose strengths (containing 0.5 mg, 2.5 mg and 5.0 mg macitentan). To make them easier for children to swallow, the tablets can be dispersed in water on a teaspoon.

PRODUCT AVAILABILITY & REGULATORY STATUS
Opsumit is commercially available in over 35 markets, including the US (since November 2013), Germany (since January 2014) and Japan (since June 2015). The registration process for other countries is ongoing.

AVAILABLE CLINICAL DATA
SERAPHIN, a global, pivotal Phase III study, was designed to evaluate the efficacy and safety of macitentan in patients with symptomatic PAH, through the primary endpoint of time to first morbidity and all-cause mortality event.

A total of 742 patients were randomized to placebo (n=250), macitentan 3 mg (n=250), or macitentan 10 mg (n=242). The primary endpoint occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for macitentan 3 mg versus placebo was 0.70 (97.5% CI, 0.52 to 0.96; p=0.0108) and the hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5% CI, 0.39 to 0.76; p<0.0001). Worsening of pulmonary arterial hypertension was the most frequent primary endpoint event. Patients were allowed to receive PAH background therapy throughout the study, either PDE-5 inhibitors or oral/inhaled prostanoids. The effect of macitentan on the endpoint was observed irrespective of background therapy for pulmonary arterial hypertension. The most commonly reported adverse drug reactions with Opsumit were nasopharyngitis (14.0%), headache (13.6%) and anemia (13.2%).

PULMONARY ARTERIAL HYPERTENSION (PAH)
PAH is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The symptoms of PAH are non-specific and can range from mild breathlessness and fatigue during normal daily activity to symptoms of right heart failure and severe restrictions on exercise capacity and ultimately reduced life expectancy. PAH is one group within the classification of pulmonary hypertension (PH). This group includes idiopathic PAH, heritable PAH and PAH caused by factors which include connective tissue disease, HIV infection and congenital heart disease.

The last decade has seen significant advances in the understanding of the pathophysiology of PAH, which has been paralleled with developments of treatment guidelines and new therapies. Drugs targeting the three pathways that have been established in the pathogenesis of PAH are endothelin receptor antagonists (ERAs), prostacyclin receptor agonists, and phosphodiesterase-5 inhibitors. PAH treatments have transformed the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago to delayed disease progression today. Improved disease awareness and evidence-based guidelines developed from randomized controlled clinical trial data have highlighted the need for early intervention, goal-oriented treatment and combination therapy.