Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease

Overview

This pivotal Phase 2/3, double-blind, placebo-controlled study of epetraborole + OBR (Optimized Background Regimen) versus placebo + OBR in patients with treatment-refractory MAC lung disease. This study will enroll adult patients with treatment-refractory MAC lung disease who meet all eligibility criteria (including clinical, radiographic, and microbiological criteria).

Full Title of Study: “A Phase 2/3, Randomized, Double-blind, Placebo-controlled, Multicenter, Prospective Study to Assess the Efficacy, Safety, and Pharmacokinetics of Orally Administered Epetraborole in Patients With Treatment-refractory Mycobacterium Avium Complex Lung Disease”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Triple (Participant, Care Provider, Investigator)
• Study Primary Completion Date: May 2024

Detailed Description

In the Phase 2 part of the study, approximately 80 patients will be randomized in a 1:1 ratio (40 patients receiving active epetraborole tablets and 40 patients receiving matching placebo tablets). The Phase 2 part of the study includes a blinded psychometric analysis plan to assess the psychometric properties of a novel PRO instrument. In addition, symptom-based clinical responses will be assessed using blinded data, to inform the measurement of clinical response in the Phase 3 part of the study. The Phase 3 part of the study will test the superiority of epetraborole + OBR compared to placebo + OBR. In this part of the study, approximately 234 patients are planned to be randomized in a 2:1 ratio (156 patients receiving active epetraborole tablets and 78 patients receiving matching placebo tablets). The current symptom-based clinical response definition (using the novel PRO) in Phase 3 is a placeholder to be verified after Phase 2 analyses based on data through Month 6. In addition, the Sponsor will determine if the sample size for Phase 3 should be adjusted and will verify the Phase 3 epetraborole dosage regimen based on the observed plasma epetraborole exposure. Phase 3 data analyses will include a review of patient-reported outcomes, microbiological, safety, and PK data collected at multiple time points through Month 6. Patients in Phase 3 will continue double-blinded study drug for 12 months after the first negative MAC culture that defines sputum culture conversion; study drug will be discontinued in patients who remain MAC culture positive despite 6 months of therapy with study drug.

Interventions

• Drug: Epetraborole
  • 500 mg taken orally QD
• Drug: Placebo
  • Placebo taken orally QD

Arms, Groups and Cohorts

• Active Comparator: epetraborole + OBR
  • epetraborole + Optimized Background Regimen
• Placebo Comparator: placebo + OBR
  • Placebo + Optimized Background Regimen

Clinical Trial Outcome Measures

Primary Measures

• Phase 2: Change from baseline to month 6 of novel Patient Reported Outcome instrument
  • Time Frame: Baseline to Month 6
  • Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument bewteen baseline and month 6.
• Phase 3: Change from baseline to month 6 of novel Patient Reported Outcome instrument
  • Time Frame: Baseline to Month 6
  • Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at month 3 and month 6.
• Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of epetraborole
  • Time Frame: Up to Month 16
  • Number of Participants with indicated Adverse Events in subjects receiving 500 mg Once Daily Dose of epetraborole

Secondary Measures

• Phase 2: Percentage of Participants Achieving Culture Conversion at Month 6
  • Time Frame: Up to Month 6
  • By-subject sputum conversion monthly through Month 6 in the Micro-ITT Population. Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC.
• Phase 2: Microbiological changes
  • Time Frame: Baseline to Month 6
  • By-subject microbiological changes monthly through Month 6 in the Micro-ITT Population. Microbiological changes will be assessed using decrease in MAC colony counts of ≥1 category
• Phase 3: Microbiological changes
  • Time Frame: Baseline to Month 6
  • By-subject microbiological changes monthly through Month 6 in the Micro-ITT Population. Microbiological changes will be assessed using decrease in MAC colony counts of ≥1 category
• Phase 2: PK analysis of volume of distribution [Vd]
  • Time Frame: One month
  • To evaluate the volume of distribution [Vd] in epetraborole recipients in the PK Population
• Phase 2: PK analysis of maximum plasma drug concentration [Cmax]
  • Time Frame: One month
  • To evaluate the maximum plasma drug concentration [Cmax], in epetraborole recipients in the PK Population
• Phase 2: PK analysis of the area under the concentration-time curve [AUC]
  • Time Frame: One month
  • To evaluate the area under the concentration-time curve [AUC]) in epetraborole recipients in the PK Population
• Phase 3: Percentage of Participants Achieving Culture Conversion at Month 6
  • Time Frame: Up to Month 6
  • Microbiological response will be evaluated using decrease in semiquantitative culture MAC colony counts of ≥1 grade to determine if epetraborole + OBR is superior to placebo + OBR in reduction of colony counts
• Phase 3: PK analysis of volume of distribution [Vd]
  • Time Frame: One month
  • To evaluate the volume of distribution [Vd] in epetraborole recipients in the PK Population
• Phase 3: PK analysis of maximum plasma drug concentration [Cmax]
  • Time Frame: One month
  • To evaluate the maximum plasma drug concentration [Cmax], in epetraborole recipients in the PK Population
• Phase 3: PK analysis of the area under the concentration-time curve [AUC]
  • Time Frame: One month
  • To evaluate the area under the concentration-time curve [AUC]) in epetraborole recipients in the PK Population
• Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of epetraborole
  • Time Frame: Up to Month 16
  • Number of Participants with indicated Adverse Events in subjects receiving 500 mg Once Daily Dose of epetraborole

Participating in This Clinical Trial

Inclusion Criteria

1. Male or female patients who are 18 years of age or older. 2. Willing and able to provide written informed consent. 3. Patients with a diagnosis of treatment-refractory MAC lung disease consisting of all of the following (a) Microbiological, (b) Clinical, and (c) Radiographic criteria: 1. Microbiological criteria:

• One Pre-Study MAC-positive respiratory specimen. Documentation of a MAC positive specimen collected per standard of care within 6 months of screening. – One Screening MAC-positive expectorated or induced sputum sample. 2. Clinical criteria: At least 2 of the following patient-reported clinical symptoms: – Cough with sputum production – Cough without sputum – Chest congestion – Hemoptysis – Dyspnea – Fatigue – Night sweats or unusual sweating 3. Radiographic criteria: Chest CT scan within 8 weeks prior to randomization with abnormalities consistent with MAC lung disease. 4. Patients who are willing to comply with all the study activities and procedures throughout the duration of the study and comply with all planned study visits and study procedures from Screening through the LFU Visit. 5. All patients must agree to use an effective method of birth control. 6. Patients expected to survive with continued antimycobacterial therapy and appropriate supportive care from Screening through the LFU Visit, in the judgment of the Investigator. Exclusion Criteria:

1. Patients with a presence of any suspected or confirmed disease or condition at Screening or the time of randomization that, in the opinion of the Investigator, may confound the assessment of symptom-based clinical response. 2. Patients with active pulmonary malignancy or any malignancy that required or would require chemotherapy or radiation therapy within 1 year prior to randomization through the LFU Visit. 3. Patients with creatinine clearance (CrCl) of ≤50 mL/min, as estimated by the Cockcroft Gault formula, at Screening or at the time of randomization. 4. Patients with hemoglobin <10.0 g/dL or <6.2 mmol/L at Screening; donation of blood or plasma within 28 days prior to randomization; or symptomatic loss of blood or hemorrhage within 28 days prior to randomization. 5. Patients with severe hemoptysis within 28 days prior to randomization, defined as >100 mL over any 24-hour period or severe or extremely severe hemoptysis. 6. Patients with severe hepatic impairment, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >2 × ULN, or clinical signs of cirrhosis or end-stage hepatic disease. 7. Patients who are pregnant or breastfeeding. 8. Patients with a mean QT interval corrected using Fridericia's formula (QTcF) >480 msec based on triplicate 12-lead ECGs at Screening. 9. Patients with an immunodeficiency or an immunocompromised condition and risk for an opportunistic pulmonary infection. 10. Patients with an anticipated start of new non-study antimycobacterial therapy to be administered at any time between Screening and Month 6. 11. Patients who have received any investigational medication during the 30 days or 5 half lives, whichever is longer, prior to randomization. 12. Patients with any prior exposure to epetraborole. 13. Patients with any condition that, in the opinion of the Investigator, interferes with the ability to safely complete the study or adhere to study requirements, including the patient's inability or unwillingness to comply with all study assessments and visits.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • AN2 Therapeutics, Inc
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Contact(s)
  • Bibiana Castaneda, MD, 650-331-9090, bcastaneda@an2therapeutics.com