Off-label Adempas for Pediatric PAH Supported by Phase 3 Trial Data

Approved for adults, Adempas was well-tolerated by children in PATENT-CHILD

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Adempas (riociguat), an approved therapy for adults with pulmonary arterial hypertension (PAH), was well-tolerated in children and adolescents with PAH, with no new safety signals, according to data from PATENT-CHILD — the first pediatric trial of the therapy.

The medication, used off-label for pediatric PAH patients with doses tailored to body weight, led to similar concentrations of Adempas in the blood as those seen in adults.

Exploratory efficacy analyses also supported therapeutic potential, with positive trends seen in improved exercise capacity and less heart damage. The study, however, was not powered to assess efficacy.

“Previous data regarding the use of riociguat [Adempas] in children have been limited to isolated case reports. The PATENT-CHILD study provides valuable preliminary evidence to start to fill this gap,” the researchers wrote.

The study, “Riociguat in children with pulmonary arterial hypertension:the PATENT-CHILD study,” was published in the journal Pulmonary Circulation.

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Treatment of PAH in children is challenging, with most targeted PAH therapies used off-label, meaning the therapy has not been officially approved for this patient population.

“Despite the availability of various treatment options for adult patients with PAH, few have been rigorously evaluated and then approved for pediatric use,” the researchers wrote.

Adempas, developed by Bayer, is approved for adults with PAH and chronic thromboembolic PH. It acts as a vasodilator, a compound that widens blood vessels, reducing blood pressure in the lungs. Data from the Phase 3 CHEST-1 study (NCT00855465) showed that Adempas significantly lowered patients’ pulmonary vascular resistance — a measure of the effort required for blood to flow through lung arteries — and increased their exercise ability.

How was Adempas tested in children with PAH?

Now, an international team of researchers reported the results of an open-label (no placebo) Phase 3 trial — called PATENT-CHILD (NCT02562235) — that evaluated the safety, tolerability, and pharmacological profile of Adempas in children with PAH (ages 6 to 17).

Participants were receiving standard-of-care PAH treatment for at least 12 weeks (three months) before the trial’s start. The most frequently used medications were bosentan (sold as Tracleer and generics, 63%) and Revatio (sildenafil, 38%).

In total, 24 children (11 girls, mean age of 12.8 years) received at least one dose of Adempas and were included in this analysis. Eighteen of them were classified as World Health Organization functional classification (WHO-FC) II — the higher the classification, the worse the symptoms.

Adempas was administered orally for 24 weeks, including a dose-adjustment phase of eight weeks followed by 16 weeks of maintenance therapy. Oral formulations were given to two groups: the adult dose to children weighing at least 50 kg (around 110 lb) and other doses adjusted for body weight to those weighing less.

The median (range) cumulative Adempas exposure was 649 mg, with 46% of children receiving a cumulative riociguat dose of 400–800 mg.

Twenty-one patients completed treatment and joined the trial’s long-term extension, which is underway.

Besides safety, tolerability, and pharmacological properties, exploratory efficacy measures also were evaluated and included the 6-minute walking distance test (6MWT), levels of brain natriuretic peptide (NT-proBNP) — a heart damage biomarker that serves as a prognostic marker of PH — quality of life, time to clinical worsening, and WHO-FC.

When compared to the start of the trial (baseline), the distance walked in the 6MWT increased by a mean of 23 meters. Data from 14 patients showed that the mean level of NT-proBNP was 66 picograms per milliliter lower at the end of the study. There was no change in WHO-FC.

Two participants experienced clinical worsening and were hospitalized due to right-sided heart failure. Quality of life showed a slight improvement, as shown by an increase in the mean scores in the Short-Form 10 Child Health Questionnaire and the Pediatric Quality of Life Inventory.

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A total of 20 patients (83%) reported adverse events (AEs), mostly of mild or moderate intensity and in agreement with the safety profile seen in adults. Headache was the most frequent (seven patients, 29%), followed by abdominal pain, common cold, and upper respiratory tract infections — each seen in four patients, 17%.

Four patients (17%) experienced a serious AE, including two with right ventricular failure. All serious AEs were resolved or recovered by the end of the study. A case of right ventricular failure and another of low blood pressure were deemed linked to the therapy.

Pharmacological analysis revealed that the concentrations of riociguat in the blood were consistent with those reported in adult patients.

Among 14 children given at least one dose of riociguat oral suspension and responding to a questionnaire at 24 weeks, four said they did not like the drink or would not like to drink it again.

Overall, the findings from this trial “demonstrate a suitable dosing strategy for riociguat in children and adolescents with PAH. Although the study was not powered for assessing efficacy, positive trends were seen,” the researchers wrote.

“The results of the data from the [long-term extension] phase of the study are awaited with interest,” they added.


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