Phase 2 Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sotatercept (MK-7962) in Children from 1 to Less Than 18 Years of Age With PAH on Standard of Care

PAH applies to a group of diseases causing a progressive increase in PVR,
resulting in RV dysfunction and, ultimately, heart failure as well as premature
death.

This study has been transitioned to CTIS with ID 2023-504861-22-00 check the CTIS register for the current data.

This study will assess the safety and tolerability of sotatercept in pediatric
participants with PAH WHO Group 1 who receive PAH background therapy. In the
absence of treatment, the majority of patients succumb to heart failure within
a few years of diagnosis. There is currently no pharmacological cure for PAH.
Current background PAH therapy involves increasing blood flow through the
pulmonary vasculature via pharmacologic manipulation of various pathways to
relieve symptoms and slow clinical worsening of the disease. There is an unmet
need for additional PAH therapies because despite available options, the
disease continues to progress in most patients. Through a novel mechanism of
action, sotatercept targets an imbalance in activin/GDF and BMP pathway
signaling, opening a new treatment paradigm for PAH.

Genetic mutations in the BMPR2 are associated with the majority of cases of the
familial form of PAH and approximately 25% of IPAH cases. Specifically,
impairment of the BMPR2-associated signal pathway appears to lead to
uncontrolled proliferation of pulmonary VSMCs, the principal cause of PAH.
These data strongly suggest a key role of TGF-β family members in the
pathogenesis of PAH. Sotatercept acts to block activin ligands and GDFs, may
attenuate BMPs, and improves pulmonary vascular remodeling by restoring balance
to Smad signaling. Sotatercept binds to select ligands in the TGF-β superfamily
to suppress their signaling and restore balance between the opposing growth
promoting activin/GDF and growth-inhibiting BMP pathways.

This is a Phase 2, interventional, multicenter, open-label, single-group
assignment study in participants >=1 to <18 years of age with PAH WHO Group 1
(based on documented, historic diagnostic RHC). PAH WHO Group 1 consists of
IPAH, heritable PAH, drug/toxin-induced PAH, PAH associated with CTD, PAH-CHD
with shunt closure more than 6 months before the Screening Period, and PAH
associated with coincidental shunt. Eligible participants will have PAH
classified as WHO FC I or symptomatic PAH classified as WHO FC II to IV.

Four age-defined cohorts will be sequentially enrolled from oldest to youngest,
as follows:
• Cohort 1: >=12 to <18 years (N=12)
• Cohort 2: >=6 to <12 years (N=12)
• Cohort 3: >=2 to <6 years (N=12)
• Cohort 4: >=1 to <2 years (N=6)
Each subsequent younger-aged cohort will not begin enrollment until safety and
PK data (after 4 dosing visits) have been evaluated for, at a minimum, the
first 4 PK-evaluable participants (defined as participants with at least 1
evaluable postbaseline sample) in the immediately preceding, older-aged cohort.
The dose of sotatercept for each subsequent younger-aged cohort may be adjusted
to achieve similar exposures to those observed in adults based on review of
safety data by the eDMC and PK and safety data by the Sponsor*s siDMC.

N/A

For this study, patients will be exposed to invasive procedures such as blood
collection, physical examination, ECG monitoring, study medication
administration, parents or guardians will be asked to answer questions about
medication and the health status of their child and will be requested to visit
the hospital for check-up visits and / or a final telephone contact.

It cannot be guaranteed that participants in clinical studies will directly
benefit from treatment during participation, as clinical studies are designed
to provide information about the safety and effectiveness of an investigational
medicine. However, data from clinical studies in children are limited.

In the PULSAR study, more than 90% of participants received a dual or triple
PAH background therapy at baseline, targeting multiple existing therapeutic
pathways. Treatment with sotatercept led to hemodynamic and functional
improvements in these participants, including those who received maximum PAH
therapy with combinations of two/three medications and intravenous prostacyclin.
The results of PULSAR showed conclusive, preliminary evidence of the safety and
efficacy of sotatercept in adults. Because the underlying pathobiology is
similar between adult and pediatric patients with PAH WHO group 1, and because
the protein targets bound by sotatercept are identical in all people, the
effects of sotatercept in pediatric patients are expected to be similar to
those in adults.