An open-label extension study to investigate efficacy, safety and tolerability of LTP001 in participants with pulmonary arterial hypertension

PAH is an orphan disease characterized by chronic elevation in pulmonary
arterial pressure, which eventually leads to remodeling of the pulmonary
vasculature, followed by right-sided heart failure.
LTP001 is a highly selective and potent, orally administered small molecule
designed to inhibit the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1).
SMURF1 is upregulated in vascular cells from patients with pulmonary arterial
hypertension (PAH). Increased activity of this ligase is expected to result in
impaired bone morphogenic protein (BMP) signaling by degradation of mediators
of the pathway activity.
Impaired BMPR2 signaling is suspected to play an important role within the
dysregulation of TGF-beta superfamily pathways that is found in the initiation
and progression of PAH. It creates an imbalance in TGFβ/BMP signaling favoring
TGFβ and may underlie vascular remodeling in PAH patients with and without
BMPR2 mutations. A number of therapeutic strategies have been proposed, beyond
the aspiration of gene therapy.
SMURF1 is upregulated in vascular cells from patients with PAH. The role of
SMURF1 is to target proteins in the BMP pathway for ubiquitination, thereby
triggering degradation of the BMP pathway signal, resulting in vascular smooth
muscle cell proliferation and remodeling.

To assess the long term safety of LTP001 in participants with pulmonary
arterial hypertension (PAH).

This is a non-randomized, open-label extension study over 52 weeks with LTP001
without a control treatment arm. Participants will be presented the opportunity
to consider the extension study at the End of Treatment (EOT) visit (Week 25)
of the parent study CLTP001A12201. The investigator will assess if the
participant will continue by verifying that the participant has completed the
parent study as planned. Moreover, at the EOT the investigator will determine
the eligibility for the extension study (i.e. that none of the treatment
discontinuation criteria were met and that the assessments at the EOT of the
parent efficacy study were completed according to the parent protocol). The
investigator may request information on the treatment of the parent study if it
is medically required to determine if the patient should continue in the
extension study. The treatment shall only be disclosed when all EOT data of the
parent study have been entered in the eCRF. The patient may directly continue
into the extension study.
The safety and efficacy of LTP001 will be checked at the following visits:
Weeks 5, 13, 26, 39 and 52, as specified in the Assessment Schedule. Safety and
tolerability assessments will take place at each visit. RHC will be performed
at week 26, 6MWT and echocardiography will be assessed at Weeks 26 and 52.
PAH-SYMPACT and emPHasis-10 will be collected for 7 days intervals with the
seventh day of collection occurring within the allotted visit window for all
Treatment visits (Weeks 5, 13, 26, 39 and 52). Following the end of treatment
period, participants will have one safety follow-up phone call approximately 30
days after the end of treatment visit at Week 52.

LTP001 6mg once dayly

Minimaal 6 bezoeken en 1 telefonisch contact. Totale studietijd is 53 weken.

Lichamelijk onderzoek: 5 keer
ECG: 5 keer
Rechter hart katheterisatie: 1 keer
Echocardiografie: 2 keer
6 min. loop test: 2 keer
Vragenlijsten: 5 keer
Bloedafnames: 5 keer