A Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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HZNP-HZN-825-303 (HARBOR) comprises of 2 parts. Part 1 (Core Phase) is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial to evaluate the efficacy, safety and tolerability of HZN-825 in participants with Idiopathic Pulmonary Fibrosis (IPF). Part 2 (Extension Phase) is an optional, open-label, repeat-dose, multicenter extension of the Core Phase. The trial will include up to an 8-week Screening Period and a 52-week Double-blind Treatment Period in the Core Phase and 52 weeks of open-label HZN-825 treatment in the Extension Phase. During the Core Phase, participants will be screened within 8 weeks prior to the baseline (Day 1) Visit. Approximately 135 participants who meet the trial eligibility criteria will be randomly assigned in a 1:1:1 ratio on Day 1 to receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally for 52 weeks using the following 2 stratification factors: Concomitant use of approved IPF therapy (i.e., nintedanib or pirfenidone): yes or no Forced vital capacity (FVC) % predicted at Baseline: ≥70% or <70% Participants who complete the 52-week Double blind Treatment Period of the Core Phase of the trial will be invited to extend their participation in the 52-week Extension Phase of the trial.

Detailed Description
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Part 1 (Core Phase) The overall objective of the Core Phase is to investigate the efficacy, safety and tolerability of 2 dose regimens of HZN-825, a selective antagonist of lysophosphatidic acid receptor-1 (LPAR1), administered orally once daily (QD) or twice daily (BID) for 52 weeks in the treatment of participants with IPF. Part 2 (Extension Phase) The overall objective of the Extension Phase is to investigate the long-term efficacy, safety and tolerability of HZN-825, a selective antagonist of LPAR1, administered at a dose of 300 mg BID orally to participants with IPF in a 52-week open-label extension (OLE) following completion of the Core Phase of the trial. The dose for the Extension Phase may be modified based on the results of the Core Phase. Two types of Baseline are defined for the Extension Phase: OLE Baseline, defined as the latest measurement prior to the first dose of HZN-825 in the Extension Phase HZN-825 Baseline, defined as the latest measurement prior to the first dose of HZN-825 in either the Core Phase or the Extension Phase. For subjects who received placebo in the Core Phase, OLE Baseline will be the same as HZN-825 Baseline.

Official Title
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A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: HZN-825
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria in Core Phase: Male or female ≥18 years of age at Screening. Current diagnosis of IPF, as defined by American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) guidelines and determined by central review; the date of initial diagnosis of IPF should be ≤7 years prior to Screening. No recent changes or planned changes to the dose or regimen for IPF therapy, defined as: Receiving a stable dose of IPF-approved therapy (i.e., nintedanib or pirfenidone) for a minimum of 3 months prior to Day 1 with no plans to change the background regimen during trial participation, or Not currently receiving background IPF-approved therapy at Screening (either naïve to IPF-approved therapy or previously discontinued any IPF-approved therapy at least 4 weeks prior to Day 1 or drug-specific, 5 half-lives elimination period if longer than 4 weeks), and with no current plans to restart treatment during trial participation Participants receiving any additional agent for IPF therapy must be on a stable regimen for at least 3 months prior to Day 1 with no current plans to change the treatment regimen during trial participation. Any previously discontinued therapy used to treat IPF must have been discontinued at least 4 weeks prior to Day 1 or 5 half-lives for that specific therapy must have elapsed, whichever is longer, with no plans to restart the therapy during trial participation. Lung high-resolution computed tomography (HRCT) historically performed within 6 months prior to the Screening Visit and according to the minimum requirements for IPF diagnosis by central review based on participant's HRCT. If an evaluable HRCT is not available within 6 months prior to Screening, an HRCT will be performed at Screening to determine eligibility, according to the same requirements as the historical HRCT. HRCT shows ≥10% to <50% parenchymal fibrosis (reticulation) and the extent of fibrotic changes is greater than the extent of emphysema on the most recent HRCT scan (central reviewer determined). Meets all of the following criteria during the Screening Period: FVC ≥45% predicted of normal forced expiratory volume in 1 second (FEV1)/FVC ≥0.7 Diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin is ≥25% and ≤90% predicted of normal Estimated minimum life expectancy of ≥30 months for non-IPF-related disease, in the opinion of the Investigator. Vaccinations are up to date given age, comorbidities and local availability prior to trial drug dosing. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial. Key Inclusion Criteria in Extension Phase: Completed the Double-blind Treatment Period (Week 52) of the Core Phase of the trial; subjects prematurely discontinued from trial drug in the Core Phase of the trial for reasons other than safety or tolerability may be included at the discretion of the Investigator after completing scheduled visits, including Week 52 assessments. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the Extension Phase of the trial. Key Exclusion Criteria Core Phase: Any of the following cardiovascular diseases: uncontrolled, severe hypertension (≥160/100 mmHg), within 6 months of Screening myocardial infarction within 6 months of Screening unstable cardiac angina within 6 months of Screening Interstitial lung disease (ILD) associated with known primary diseases (e.g., sarcoidosis, amyloidosis and coronavirus disease 2019 [COVID-19]), connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, Sjogren's, dermatomyositis, scleroderma), exposures (e.g., radiation, silica, asbestos and coal dust) or drugs (e.g., amiodarone). Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed). The participant must be 3 months beyond any acute infection with COVID-19 if there has been a prior infection. Clinically significant pulmonary hypertension requiring chronic medical therapy. Use of any of the following therapies within 4 weeks prior to Screening, during the Screening Period or planned during the trial: prednisone at steady dose >10 mg/day or equivalent or cyclosporine. Change in regimen or dosage of any immunosuppressant during the Screening Period through the end of trial participation will require consultation with and approval by the trial Medical Monitor. Use of rifampin within 2 weeks prior to Day 1 or planned during the trial. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ). Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 4 weeks after last dose of trial drug. Females must refrain from egg/ova donation for 4 weeks after the last dose of trial drug and males must refrain from sperm donation for 3 months after the last dose of trial drug. Pregnant or lactating women and women who plan to become pregnant or breast feed during the trial and within 4 weeks after the last dose of trial drug. Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject. Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial. Known history of positive test for human immunodeficiency virus (HIV). Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus [anti-HCV] and positive RNA HCV). Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis. Previous organ transplant (including allogeneic and autologous marrow transplant). International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limit of normal (ULN) or partial thromboplastin time >1.5 × ULN at Screening. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × ULN. Estimated glomerular filtration rate <30 mL/min/1.73 m^2 at Screening. Total bilirubin >1.5 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is ≤3.0 mg/dL. Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment according to the Child-Pugh scoring system. Any confirmed Grade 3 or higher laboratory abnormality. Any laboratory abnormality at Screening that, in the opinion of the Investigator, would preclude the participant's entry in the trial. Exposure to an experimental drug (with the exception of HZN-825) or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is the longest, prior to Day 1. Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial. Key Exclusion Criteria Extension Phase: Anticipated use of another investigational agent for any condition during the course of the trial. New diagnosis of malignant condition after enrolling in Trial HZNP-HZN-825-303 (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ). Estimated minimum life expectancy ≤18 months, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HZN-825 300 mg once daily (QD)<br>Two 150 mg oral tablets given in the morning with a meal and two matching placebo tablets given in the evening with a meal; total daily dose 300 mg HZN-825. | Drug: HZN-825<br>* Core Phase: Participants will receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally in the morning and evening with a meal for 52 weeks according to randomization schema. Extension Phase: Participants will receive open-label HZN-825 150 mg orally in the morning and evening with a meal for 52 weeks.<br>|
| Experimental: HZN-825-300 mg twice daily (BID)<br>Two 150 mg oral tablets given in the morning with a meal and two 150 mg oral tablets given in the evening with a meal; total daily dose 600 mg HZN-825. | Drug: HZN-825<br>* Core Phase: Participants will receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally in the morning and evening with a meal for 52 weeks according to randomization schema. Extension Phase: Participants will receive open-label HZN-825 150 mg orally in the morning and evening with a meal for 52 weeks.<br>|
| Placebo Comparator: Placebo BID<br>Matching placebo tablets (2) given in the morning with a meal and matching placebo tablets (2) given in the evening with a meal; total dose 4 placebo tablets. | Drug: Placebo<br>* Core Phase: Participants will receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally in the morning and evening with a meal for 52 weeks according to randomization schema. Extension Phase: Participants who received matching placebo in the Core Phase will receive open-label HZN-825 150 mg orally in the morning and evening with a meal for 52 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Change in Forced Vital Capacity (FVC) percent (FVC %) predicted from Baseline to Week 52 |  | Baseline to Week 52 | 
| Extension Phase: Change from the Open Label Extension (OLE) baseline, defined as the latest measurement prior to the first dose of HZN-825 in the extension phase in FVC % predicted from Baseline to Week 104 |  | Baseline to Week 104 | 
| Extension Phase: Change from the HZN-825 baseline, defined as the latest measurement prior to the first dose of HZN-825 in either the core phase or the extension phase in FVC % predicted from Baseline to Week 104 |  | Baseline to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Change from baseline in the 6MWT (Six-Minute Walk Test) results to Week 52 | The 6-minute walk test measures the distance that a participant can quickly walk on a flat, hard surface in 6 minutes. This test evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units and muscle metabolism. The 6MWT will be performed according to ATS guidelines for the 6MWT. | Baseline to Week 52 | 
| Core Phase: Change from baseline in K-BILD (King's Brief Interstitial Lung Disease) scores to Week 52 | The King's Brief Interstitial Lung Disease Questionnaire is a self-completed health status questionnaire comprising 15 items and a 7-point Likert response scale that was developed and validated specifically for patients with IPF. The questionnaire has 3 domains: psychological, breathlessness, and activities and chest symptoms. The K-BILD domains and total score range from 0 to 100; 100 represents best health status. The minimal clinically important difference for the K-BILD total score as determined by both anchor and distribution methods is a change of 5 units. | Baseline to Week 52 | 
| Core Phase: Change from baseline in L-IPF (Living with IPF[Idiopathic Pulmonary Fibrosis]) scores to Week 52 | The questionnaire evaluates how living with IPF has impacted the quality of life of the participant with IPF. There are two modules, a 15-item symptom module with 3 domains (dyspnea, cough, and energy) all with a 24-hour recall and a 20-item impacts module with 1-week recall. All items in both modules have response options in a 5-point (0-4) numerical rating scale, where 0 = not at all and 4 = all the time. | Baseline to Week 52 | 
| Core Phase: Change from baseline in LCQ (Leicester Cough Questionnaire) scores to Week 52 | The LCQ is a participant-reported questionnaire evaluating the impact of cough on quality of life. The LCQ comprises 19 items and takes 5-10 minutes to complete. Each item assesses symptoms or the impact of symptoms over the last 2 weeks on a 7-point Likert scale. Scores in 3 domains (physical, psychological, and social) are calculated as a mean for each domain (range: 1-7). A total score (range: 3 to 21) is also calculated. Higher scores indicate better quality of life. | Baseline to Week 52 | 
| Core Phase: Time to first hospitalization due to respiratory distress up to Week 52 |  | Baseline to Week 52 | 
| Core Phase: Time to first onset of the composite endpoint of PFS (progression-free survival) from Baseline up to Week 52, where progression includes decline in FVC % predicted ≥10% or death |  | Baseline to Week 52 | 
| Core Phase: Incidence of treatment emergent adverse events (TEAEs) |  | Day 1 to Week 52 | 
| Core Phase: Incidence of serous adverse events (SAEs) |  | Day 1 to Week 52 | 
| Core Phase: Incidence of adverse events of special interest (AESIs): orthostatic hypotension |  | Day 1 to Week 52 | 
| Core Phase: Incidence and frequency of use of concomitant medication(s) |  | Day 1 to Week 52 | 
| Core Phase: Change in abnormal and clinically significant vital signs as reported as TEAEs |  | Day 1 to Week 52 | 
| Core Phase: Change in abnormal clinical safety laboratory test results as reported as TEAEs |  | Day 1 to Week 52 | 
| Core Phase: Change in abnormal and clinically significant 12-lead electrocardiogram (ECG) or echocardiogram measurements as reported as TEAEs. |  | Day 1 to Week 52 | 
| Extension Phase: Incidence of AESIs: orthostatic hypotension |  | Day 1 to Week 104 | 
| Extension Phase: Incidence of TEAEs |  | Day 1 to Week 104 | 
| Extension Phase: Incidence and frequency of use of concomitant medication(s) |  | Baseline to Week 104 | 
| Extension Phase: Change from trial baseline in abnormal and clinically significant vital signs reported as TEAEs |  | Baseline to Week 104 | 
| Extension Phase: Change from trial baseline in abnormal and clinically significant 12-lead ECG) measurements as reported as TEAEs. |  | Baseline to Week 104 | 
| Extension Phase: Change from trial baseline in abnormal clinical safety laboratory test results as reported as TEAEs |  | Baseline to Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Fibrosis, Idiopathic Pulmonary Fibrosis