A Phase 3 Study to Evaluate the Safety and Tolerability of L606 in Subjects With PAH or PH-ILD

A Phase 3, 2-Part, Open-Label Study to Evaluate the Safety and Tolerability of Liposomal Treprostinil Inhalation Suspension (L606) in Subjects With Pulmonary Arterial Hypertension or Pulmonary Hypertension Associated With Interstitial Lung Disease

This Phase 3, 2-part, open-label, multicenter study aims to demonstrate the safety and tolerability of L606 in patients with PAH or PH-ILD. The study will determine the short-term and long-term safety and tolerability of L606 in this patient population; also evaluate the steady-state pharmacokinetics (PK) of L606 as compared to Tyvaso, effects on exercise ability, quality of life, and treatment satisfaction with L606.

This Phase 3, 2-part, open-label, multicenter study aims to demonstrate the safety and tolerability of repeated doses of L606 in patients with PAH or PH-ILD. The current Phase 3 study will help determine the short-term and long-term safety and tolerability of L606 in this patient population. The study will also evaluate the steady-state pharmacokinetics (PK) of L606 as compared to Tyvaso, effects on exercise ability (6-minute walk distance [6MWD] and Borg Dyspnea Score), quality of life (QoL), and treatment satisfaction with L606. Subjects who meet all the inclusion criteria and none of the exclusion criteria will be enrolled to one of the 2 cohorts: Cohort A: Subjects with PAH or PH-ILD receiving prior stable doses of Tyvaso (4 times daily) and willing to switch to L606 (twice daily). Cohort B: Subjects with PAH (not initially on prostacyclin therapy) who are likely to receive clinical benefit from inhaled treprostinil based on the opinion of the investigator. Cohort A subjects will sequentially participate in the MSP for 2 weeks and the OEP for 46 weeks. A subset of up to 15 subjects from Cohort A will also participate in a PK substudy. Cohort B subjects will sequentially participate in the MSP for 12 weeks and the OEP for 36 weeks.

treprostinil, Pulmonary Arterial Hypertension, inhalation, Pulmonary Hypertension Due to Lung Diseases

Proportion of patients with PAH or PH-ILD on a stable Tyvaso dose (4 times/day) who would develop treatment-emergent AEs/SAEs after switching to twice daily L606 dosing for up to 2 weeks.

Proportion of patients with PAH (not initially on prostacyclin therapy) who would develop treatment-emergent AEs/SAEs during 12 weeks with titration on twice daily L606.

To evaluate the safety and tolerability of twice daily L606 dosing for up to 48 Weeks in patients with PAH or PH-ILD who choose to continue twice daily dosing with L606 beyond 2 weeks of the MSP for Cohort A or patients with PAH (not initially on prostacyclin therapy) who choose to continue twice daily dosing with L606 beyond 12 weeks of the MSP for Cohort B.

Proportion of patients with PAH on a stable Tyvaso dose (4 times/day) who continue twice daily L606 dosing beyond 2 weeks, who would develop treatment-emergent AEs/SAEs for up to 12 months.

Ratio (L606 at Week 2/Tyvaso at Day 1) of geometric means of average steady-state plasma concentrations of treprostinil (calculated over the dosing interval as Cavg) in patients with PAH or PH-ILD, assuming compliance with dosing requirements up to steady state.

Efficacy of L606 assessed by 6MWD at steady-state morning trough and peak concentrations of treprostinil

Cohort A: In patients with PAH or PH-ILD transitioning from Tyvaso, the mean difference in 6MWD at steadystate: morning trough, peak, and peak minus trough after twice daily L606 for 2 weeks compared to baseline (Tyvaso at Day 1) Cohort B: In patients with PAH (not initially on prostacyclin therapy) after 12 weeks of twice daily L606 dosing, the mean difference in 6MWD at 60-90 minutes after morning dose compared to pre-dose baseline

Efficacy of L606 assessed by 6MWD at steady-state morning trough and peak concentrations of treprostinil (long-term)

Cohort A and Cohort B: In patients with PAH or PH-ILD choosing to continue twice daily L606 dosing for up to 48 weeks, the mean difference in 6MWD at steady-state trough after 48 weeks and at peaks at 60-90 minutes after morning dose at 12, 24, 36 and 48 weeks compared to baseline measurements.

Cohort A and Cohort B: Quality of Life assessed by PAH-specific Quality of Life questionnaire Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).

Cohort A: In patients with PAH or PH-ILD transitioning from Tyvaso, the difference in mean CAMPHOR (for total score, symptom, activity, and QoL components), after receiving a twice daily dose of L606 for 2 weeks compared to Tyvaso at Day 1. Cohort B: In patients with PAH (not initially on prostacyclin therapy) after 12 weeks with titration on twice daily dose of L606 compared to pre-dose. For Cohort A and Cohort B (long-term): In patients who choose to continue twice daily L606 dosing (for up to 48 weeks) compared to pre-transition/pre-dose.

Cohort A: In patients with PAH or PH-ILD transitioning from Tyvaso, the difference in mean TSQM score (effectiveness, side effects, convenience, and global satisfaction components) after receiving twice daily doses of L606 for 2 weeks or at treatment discontinuation. Cohort B: In patients with PAH after receiving a twice daily dose of L606 for 12 weeks or at treatment discontinuation, the mean TSQM score irrespective of compliance with the dosing regimen or taking of prohibited medication. For Cohort A and Cohort B: In patients with PAH or PH-ILD who choose to continue twice daily L606 dosing beyond 2 weeks of the MSP for Cohort A or patients with PAH who choose to continue twice daily L606 dosing beyond 12 weeks of the MSP for Cohort B, the mean TSQM score at 12 weeks or at treatment discontinuation, irrespective of compliance with the dosing regimen or taking of prohibited medication.

Mean and mean difference in Borg Dyspnea Score from baseline at steady-state morning trough, peak, and peak minus trough after the 6MWT and twice daily L606 dosing during (A) 2 weeks for Cohort A or (B) peak only at 12 weeks for Cohort B troughs and peaks after the 6MWT, for up to 48 weeks in patients who choose to continue L606 dosing beyond (A) 2 weeks for Cohort A or (B) 12 weeks for Cohort B Mean and mean difference from Day 1 in Borg Dyspnea Score at each time point before the 6MWT and the mean changes in Borg Dyspnea Score from before to immediately after 6MWT.

Proportion of patients with each grade of NYHA functional class on Day 1 (baseline), end of MSP (Cohorts A and B), and across the OEP (ie, start of the OEP to 48 weeks).

Mean and mean difference in NT-proBNP levels from Day 1 (baseline) to the end of MSP (Cohorts A and B), and across the OEP (ie, start of the OEP to 48 weeks).

Mean and mean difference in PAH or PH-ILD symptoms score from Day 1 (baseline) to the end of MSP (Cohorts A and B), and across the OEP (ie, start of the OEP to 48 weeks).

Incidence rate of L606 treatment failure due to worsening of PAH or PH-ILD, where worsening is defined as discontinuation of L606 due to disease progression, death, transplantation, hospital stay due to worsening PAH or PH-ILD, or initiation of additional approved or new PAH or PH-ILD therapy.

Key Inclusion Criteria: Able to understand and complete study requirements and provide written informed consent. Males and females ≥18 and ≤80 years of age at the time of informed consent. All sexually active male subjects and female subjects of childbearing potential must use an acceptable, highly effective method of contraception. Diagnosed with PAH belonging to at least 1 of the following subgroups of Group 1 pulmonary hypertension (PH) per European Society of Cardiology/European Respiratory Society Guidelines for the diagnosis and treatment of PH at least 1 year prior to screening. or PH-ILD Group 3 European Society of Cardiology/European Respiratory Society Guidelines for the diagnosis and treatment of PH. Subjects with Group 3 PH that is not related to underlying ILD are not eligible. Subjects with PAH: Documentation of having PAH as confirmed by RHC within 12 months prior to screening and meeting the following criteria: i. Mean PAP >20 mmHg. ii. Pulmonary arterial wedge pressure ≤15 mmHg. iii. Pulmonary vascular resistance >3 Wood units. Subjects with PH-ILD: Confirmation of the underlying ILD must be based on HRCT imaging conducted within the past 12 months prior to randomization with demonstration of diffuse parenchymal lung disease and documented by the Investigator or radiology report. Subjects may have any form of ILD or CPFE. NYHA functional class II, III, or IV at the screening visit. Can complete a screening 6MWD of ≥150 meters For subjects with PAH: >65% of predicted and FEV1/FVC ratio >65% at screening. For subjects with PH-ILD: >40% of predicted and FEV1/FVC ratio >70% at screening. Key Exclusion Criteria: LVEF of ≤45% on a historical echocardiogram within 6 months of screening. History of sleep apnea, or left-sided heart disease (including but not limited to aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, or coronary artery disease) per investigator's discretion. Experienced an acute exacerbation of disease or hospitalization for any reason within 30 days of signing the ICF or prior to baseline. Systolic blood pressure <90 mmHg or ≥160 mmHg at baseline. Screening electrocardiogram (ECG) with QTcF >525 ms. Musculoskeletal disorder (eg, arthritis affecting the lower limbs, recent hip or knee joint replacement) or any disease that would likely be the primary limit to ambulation or subject is connected to a machine that is not portable enough to allow for a 6MWT. Alanine aminotransferase or aspartate aminotransferase levels >3 × upper limit of normal reference range, clinically significant liver disease/dysfunction, or known Child-Pugh Class C hepatic disease. Estimated glomerular filtration rate <30 mL/min/1.73 m2 or requires dialysis.