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

• ClinicalTrials.gov Identifier: NCT04691154
• Recruitment Status: Recruiting
• First Posted: December 31, 2020
• Last Update Posted: January 28, 2022
• Sponsor: Pharmosa Biopharm Inc.
• Collaborator: PPD
• Information provided by (Responsible Party): Pharmosa Biopharm Inc.

Study Description

Brief Summary:

This single-arm, Phase 3, 2-part, open-label, multicenter study aims to demonstrate the safety and tolerability of L606 in patients with PAH switching from a stable Tyvaso dose. 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 in patients with PAH.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension	Combination Product: L606 inhalation suspension	Phase 3

Detailed Description:

This single-arm, Phase 3, 2-part, open-label, multicenter study aims to demonstrate the safety and tolerability of repeated doses of L606 in patients with PAH switching from a stable Tyvaso dose. 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 in patients with PAH. Part 1 of the study is short-term (2-week) evaluation of L606 in patients with PAH. Part 2 of the study will continue to assess the long-term safety and efficacy of L606 in patients with PAH. Results of Part 1 and Part 2 of the study will be presented in separate clinical study reports and clinical study report of Part 1 of the study will be submitted as part of new drug application.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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 Previously Stabilized on Inhaled Treprostinil Products
• Actual Study Start Date: August 1, 2021
• Estimated Primary Completion Date: October 31, 2022
• Estimated Study Completion Date: August 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: L606	Combination Product: L606 inhalation suspension; L606 inhalation suspension, twice daily dosing

Outcome Measures

Primary Outcome Measures :

1. Safety/Tolerability assessed by incidence of treatment-emergent AEs/SAEs [ Time Frame: 2 weeks ]
   Proportion of patients with PAH 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.

Secondary Outcome Measures :

1. Safety/Tolerability assessed by incidence of treatment-emergent AEs/SAEs [ Time Frame: 12 months ]
   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.
2. Pharmacokinetics assessed by steady-state PK parameters of treprostinil from Tyvaso and L606 [ Time Frame: 2 weeks ]
   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, assuming compliance with dosing requirements up to steady state.

Other Outcome Measures:

1. Efficacy of L606 assessed by 6MWD at steady-state morning trough and peak concentrations of treprostinil after switching from stable dose of Tyvaso to L606 for 2 weeks [ Time Frame: 2 weeks and 12 months ]
   The mean and mean difference (L606-baseline on stable Tyvaso) in 6MWD at steady state
2. Quality of Life assessed by PAH-specific Quality of Life questionnaire Cambridge Pulmonary Hypertension Outcome Review. [ Time Frame: 2 weeks and 12 months ]
   It is a validated PAH-specific instrument consisting of 65 items that assess overall symptoms (25 items), functioning (15 items), and QoL (25 items). The symptom and QoL scales have dichotomous ("True"/"Not true") response options and the scores in each subscale can range from 0 to 25, where low score indicates less severe symptoms or good QoL. The functioning scale has 3-point ("Able to do on own without difficulty"/"Able to do on own with difficulty"/"Unable to do on own") response options and the scores can range from 0 to 30, where low score indicates good functioning.
3. Treatment satisfaction of L606 assessed by Treatment Satisfaction Questionnaire (TSQM) [ Time Frame: 2 weeks and 12 months ]
   It is comprised of 14 items which represent 4 domains: effectiveness, side effects, convenience, and global satisfaction. The TSQM scores range from 0 to 100, with higher scores indicating greater satisfaction.
4. Efficacy of L606 assessed by Borg Dyspnea Score [ Time Frame: 2 weeks and 12 months ]
   The Borg Scale is a 10 point scale, with responses ranging from 0 (nothing at all) to 10 (very, very severe [maximal])
5. Efficacy of L606 assessed by New York Heart Association (NYHA) functional class [ Time Frame: 2 weeks and 12 months ]
   The NYHA functional classification helps evaluate the effect of cardiac symptoms on patient's daily activities.
6. Efficacy of L606 assessed by N-terminal prohormone B-type natriuretic peptide (NT-proBNP) [ Time Frame: 2 weeks and 12 months ]
   NT-proBNP is released from cardiac myocytes in response to mechanical load and wall stress and correlates with several pulmonary hemodynamic metrics. NT proBNP is inactive but has a longer half-life compared with BNP (70 minutes versus 22 minutes) and is relatively stable in stored blood samples, hence is preferred as a biomarker of heart failure.
7. Efficacy of L606 assessed by PAH symptoms [ Time Frame: 2 weeks and 12 months ]
   Fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea will be assessed prior to dosing at study site. The status of each sign and symptom will be assessed as 'present' or 'absent'. To assess overall change from baseline in signs and symptoms, a '1' will be assigned for each sign and symptom that is present at any postbaseline visit but absent at baseline, a '-1' will be assigned for each sign and symptom that is absent at any postbaseline visit but present at baseline, and a '0' will be assigned for no change. An overall change score at each postbaseline assessment will be calculated by summing these values for all signs and symptoms. The overall change score can range from -7 to +7.
8. Efficacy of L606 assessed by treatment failure due to worsening of PAH [ Time Frame: 2 weeks and 12 months ]
   Incidence rate of L606 treatment failure due to worsening of PAH, where worsening is defined as "discontinuation of L606 due to disease progression, death, transplantation, hospital stay due to worsening PAH, or initiation of additional approved PAH specific therapy" or "addition of a new PAH therapy".

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Able to understand and complete study requirements and provide written informed consent.
• Males and females ≥18 and ≤75 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 Group 1 pulmonary hypertension (PH) per European Society of Cardiology/European Respiratory Society Guidelines for the diagnosis and treatment of PH
• Documentation of having PAH as confirmed by right heart catheterization (RHC) within 12 months prior to screening and meeting the following criteria:
• New York Heart Association functional class II, III, or IV at the screening visit.
• Documented stable doses
• Can complete a screening 6MWD of ≥150 meters
• Forced expiratory volume in 1 second (FEV1) >65% of predicted and FEV1/forced vital capacity (FVC) ratio >65% at screening.

Key Exclusion Criteria:

• Pregnant or lactating female at screening or baseline.
• Left ventricular ejection fraction of ≤45% on a historical echocardiogram within 6 months of screening. Patients who recovered their LVEF culd be allowed, as judged by investigator.
• History of sleep apnea, parenchymal lung disease, 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.
• Use of any investigational drug/device or participation in any other investigational study with therapeutic intent within 30 days or 5 half-lives, whichever is longer, prior to signing the ICF.
• Systolic blood pressure <90 mmHg or ≥160 mmHg at baseline.
• Screening electrocardiogram (ECG) with QTcF >450 ms for male subjects or >480 ms for female subjects.
• 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 6-minute walk test (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.

Contacts and Locations

Contacts

Contact: Pei Kan, PhD; 886-2782-7561; peikan@pharmosa.com.tw

Contact: Sydney Chuang; 886-2782-7561; sydney@pharmosa.com.tw

Locations

United States, Arizona

Arizona Pulmonary Specialists; Recruiting

Phoenix, Arizona, United States, 85012

Principal Investigator: Jeremy P Feldman, MD

Sponsors and Collaborators

Pharmosa Biopharm Inc.

PPD

Investigators

• Principal Investigator: Jeremy P Feldman, MD; Arizona Pulmonary Specialists
• Principal Investigator: Elizabeth Gay, MD; Brigham and Women's Hospital
• Principal Investigator: Michael G Risbano, MD; UPMC Montefiore

More Information

• Responsible Party: Pharmosa Biopharm Inc.
• ClinicalTrials.gov Identifier: NCT04691154
• Other Study ID Numbers: PBI L606p3
• First Posted: December 31, 2020
• Last Update Posted: January 28, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pharmosa Biopharm Inc.:

treprostinil; Pulmonary Arterial Hypertension; inhalation

Additional relevant MeSH terms:

Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Vascular Diseases; Cardiovascular Diseases; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases