A Phase 2 Trial of ENV-101 in Patients With Lung Fibrosis (WHISTLE-PF Trial)

This trial is a 6-month, randomized, double-blind, controlled, dose-ranging trial of ENV-101 in adult patients with idiopathic pulmonary fibrosis (IPF). Patients are allowed to continue treatment with approved standard of care (e.g., nintedanib, pirfenidone) during the trial. Patients will be randomized to one of 3 dose levels of ENV-101 or placebo at baseline. The objectives of this trial are to characterize the efficacy, antifibrotic activity, and safety of ENV-101 to select the Phase 3 dose of ENV-101.

• ENV-101 (Drug), also known as taladegib: oral tablet, dosed once a day
• Placebo (Drug): oral tablet, dosed once a day

Primary outcomes

• Change in percent predicted forced vital capacity (ppFVC) compared to placebo [Baseline and Week 24]: ppFVC is a measure of lung function

Secondary outcomes

• Absolute change in FVC (mL) compared to placebo [Baseline and Week 24]: FVC is a measure of lung function
• Time to disease progression (absolute decline in ppFVC >10%, IPF-related hospitalization, or death) compared to placebo [Baseline and Week 24]
• Absolute change in the Living with Pulmonary Fibrosis Symptoms (L-PF Symptoms) Questionnaire Cough domain score compared to placebo [Baseline and Week 24]: The L-PF Symptoms Questionnaire Cough domain consists of 6 questions regarding a subject's experience with cough over the prior 24 hours. Questions have response options on a five-point numeric rating scale with an anchor of 0 ("Not at all") to 4 ("Extremely"). Total score for the Cough domain is normalized to the range 0 to 100, with higher scores indicating greater impairment.
• Absolute change in the L-PF Symptoms Questionnaire Dyspnea domain score compared to placebo [Baseline and Week 24]: The L-PF Symptoms Questionnaire Dyspnea domain consists of 12 questions regarding a subject's experience with dyspnea (shortness of breath) over the prior 24 hours. Questions have response options on a five-point numeric rating scale with an anchor of 0 ("Not at all") to 4 ("Extremely"). Total score for the Dyspnea domain is normalized to the range 0 to 100, with higher scores indicating greater impairment.
• Absolute change in the L-PF Symptoms Questionnaire Fatigue domain score compared to placebo [Baseline and Week 24]: The L-PF Symptoms Questionnaire Fatigue domain consists of 5 questions regarding a subject's experience with fatigue over the prior 24 hours. Questions have response options on a five-point numeric rating scale with an anchor of 0 ("Not at all") to 4 ("Extremely"). Total score for the Fatigue domain is normalized to the range 0 to 100, with higher scores indicating greater impairment.
• Absolute change in the L-PF Symptoms module score compared to placebo [Baseline and Week 24]: The L-PF Symptoms module is a 23-item patient-reported outcome measure designed to assess the severity of dyspnea (12 items), cough (6 items), and fatigue (5 items) experienced by a subject over the prior 24 hours. Questions have response options on a five-point numeric rating scale with an anchor of 0 ("Not at all") to 4 ("Extremely"). Total score for the Symptoms module is normalized to the range 0 to 100, with higher scores indicating greater impairment.
• Absolute change in the L-PF Impacts module score compared to placebo [Baseline and Week 24]: The L-PF Impacts module consists of 21 questions regarding a subject's experience with the impacts of pulmonary fibrosis on daily life over the prior week. Questions have response options on a five-point numeric rating scale with an anchor of 0 ("Not at all") to 4 ("Extremely"). Total score for the Impacts module domain is normalized to the range 0 to 100, with higher scores indicating greater impairment.
• Absolute change in total lung capacity (TLC) by chest high-resolution computed tomography (HRCT) imaging compared to placebo [Baseline and Week 24]: HRCT is a method of imaging which is more precise than chest x-ray in the diagnosis and monitoring of diseases of the lung tissue and the airways.
• Absolute change in % quantitative interstitial lung disease (QILD) by chest HRCT imaging compared to placebo compared to placebo [Baseline and Week 24]
• Absolute change in % quantitative ground glass opacity (QGG) by chest HRCT imaging compared to placebo [Baseline and Week 24]
• Absolute change in % quantitative lung fibrosis (QLF) by chest HRCT imaging compared to placebo [Baseline and Week 24]

Sex: All, ages: 40 Years to any

Inclusion Criteria:

* Patients ≥ 40 years old with an IPF diagnosis as confirmed by the Investigator.
* Percent predicted FVC of ≥ 45% at study start.
* Percent predicted diffusing capacity of lung for carbon monoxide (DLCO) ≥ 25%, adjusted for hemoglobin (Hgb) at study start.
* Ability to perform spirometry tests.
* Either stable treatment with standard of care (SoC) \[i.e., antifibrotics, immunosuppressants (PPF only)\] for at least 3 months prior to study start or not treated with SoC for at least 8 weeks prior to study start.

Exclusion Criteria:

* Evidence of other known causes of interstitial lung disease (ILD).
* Forced expiratory volume in one second (FEV1)/FVC ratio <0.7 at study start.
* History of malignancy, including carcinoma during the preceding 5 years from study start, with the following exceptions:

  1. Prior history of in situ melanoma, basal or squamous cell skin cancer if treated with curative therapy.
  2. Patients with prostate cancer that are managed by surveillance.
  3. Patients with ductal carcinoma in situ, treated surgically with curative intent.
* Patients with moderate to severe hepatic impairment (Child-Pugh B and C).
* Smoking (including vaping) within 6 months of study start; current smoker, or unwillingness to refrain from smoking during the clinical trial duration.
* Active or suspected alcohol or drug abuse in the opinion of the Investigator.
* Currently enrolled in another investigational device or drug trial, or less than 3 months from study start since ending another investigational device or drug trial(s) or receiving other investigational treatment(s).
* Presence of active infection at study start or confirmed active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
* Major surgery requiring hospitalization (according to the Investigator) performed within 3 months prior to study start or planned during the course of the trial. Being on a transplant list is allowed.
* Occurrence of serious illness requiring hospitalization within 90 days prior to study start.
* Current or previous use (within 28 days prior to study start) of the following:

  1. Endothelin receptor antagonist
  2. Riociguat
  3. Prostacyclin or prostacyclin analogue
  4. Radiation to the lungs
  5. Oral corticosteroids >15 mg/day
* Use of cyclophosphamide or tocilizumab within 8 weeks, or rituximab within 6 months, prior to study start.
* Use of drugs that are known moderate or stronger CYP3A4 inhibitors or inducers within 14 days prior to study start. Patients must also agree not to eat fruits that inhibit CYP3A4 such as grapefruit, Seville oranges, pomelo and star fruit.
* Patients of reproductive potential who are sexually active and unwilling to use birth control for the duration of the study and for 3 months after their final dose of study drug.
* Females that are pregnant or nursing.
* Patients that are unwilling to refrain from blood or blood product donation for the duration of the study and for 30 days after their final dose of study drug.
* Males who are unwilling to refrain from sperm donation and females who are unwilling to refrain from egg donation for the duration of the study and for 3 months after their final dose of study drug.
* Patients with a history of a severe allergic reaction or anaphylactic reaction or known hypersensitivity to any component of ENV-101.
* Patients who have previously taken ENV-101.

• Lisa Lancaster, M.D., Study director, Endeavor Biomedicines