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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 (MACrO2)

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (MACrO2)

177

Ph 2: Mean age: 64.7 (SD: 9.97) yrs with 44 (55.0%) >=65 yrs; 71.3% female; 51 (63.8%) Asian, 28 (35.0%) White; 26 (32.5%) enrolled in the US, 32 (40.0%) Japan, 19 (23.8%) S. Korea; Cavitary nodular bronchiectatic 34 (42.5%); fibrocavitary 8 (10.0%). More placebo (PBO) pts had cavitary disease; epetraborole (EBO) group had more fibrocavitary disease. Cavity size was similar between the 2 groups. Ph 3: Mean age: 68.1 yrs with 64.9% >=65 yrs; 73.2% female; 63.9% Asian, 32.0% White; 34.0% enrolled in the US, 49.5% Japan, 13.4% S. Korea; Ph 3 pts overall had greater disease severity than Ph 2 pts. For pts with >=1 cavities, the frequency of cavity size >3.0 to <=5.0 cm was 40.4% (Ph 3) vs 21.4% (Ph 2); the fibrocavitary radiographic phenotype 20.6% (Ph 3) vs 10.0% (Ph 2)

After the 8-week screening period, patients(pts) were randomized to EBO+optimized background regimen (OBR) or PBO+OBR. EBO and matching PBO oral tablets were given in the fasting state (500 mg QD). The OBR was per standard of care, at the discretion of the Investigator. Pts were to receive at least 6 months (M) of blinded study drug, up to M16, depending on sputum culture results at M6. Pts were to return for a late follow-up visit 3 months after the last dose of study drug. Ph 2: 80 pts planned (40 EBO, 40 PBO); 39 pts were randomized to EBO and 41 to PBO, stratified by baseline use of amikacin liposomal inhaled suspension (ALIS) and age. Ph 3: Approximately 234 pts were to be randomized in a 2:1 ratio (156 EBO:78 matching PBO) and stratified by baseline use of ALIS and presence or absence of any fibrocavitary disease. However, due to a low microbiological response in Ph 2, the Sponsor prematurely terminated the study and the Ph 3 enrollment was truncated to 66 EBO and 31 PBO pts.

Ph 2: The most frequent treatment-emergent adverse events (TEAEs) in EBO pts were anemia (14/39, 35.9%), dizziness (7/39, 17.9%), and Hgb decreased (5/39; 12.8%). Most pts reported >=1 TEAEs; more EBO pts had a study drug-related TEAE vs PBO pts (30/39 [76.9%] vs 10/41 [24.4%], respectively). Overall, TEAEs were mild to moderate in severity. The rate of severe TEAEs was about 10%. TEAEs leading to premature treatment discontinuation were low (3 pts per group). The rate of serious TEAEs (TESAEs) was lower in the EBO group than the PBO group (4/39 [10.3%] vs 9/41 [22.0%]). The TESAEs reflected the underlying disease and pt severity of illness. No death or life-threatening event was reported in EBO pts. Ph 3: The most frequent TEAEs in EBO pts were anemia (16/66, 24.2%); and nausea and Hgb decreased (7/66, 10.6%, each). Most pts reported >=1 TEAEs; more EBO pts had a study drug-related TEAE (41/66 [62.1%] vs 10/31 [32.3%]). Most TEAEs were mild or moderate in severity; about 6% were severe. TEAEs leading to premature treatment discontinuation, often related to progressive TR-MAC-LD, occurred only in the EBO group (10/66, 15.2%). Four deaths (atypical mycobacterial infection, pneumonia aspiration, acute respiratory failure, hypoxia) and 1 life-threatening event (respiratory failure) occurred in EBO pts (none in PBO pts). The EBO safety profile reflected the advanced underlying MAC-LD disease and pt severity of illness, which were higher in Ph 3 than Ph 2, and greater in Ph 3 EBO pts than PBO pts.

Ph 2: The primary efficacy analyses were the MACrO2 PRO response at M6 (primary for US, secondary ex-US) and sputum culture conversion (SCC - 3 consecutive negative monthly MAC sputum cultures by M6) (primary ex-US, secondary for US). A numerically higher MACrO2 PRO response rate at M6 was observed in the EBO (15/38, 39.5%) vs the PBO group (10/40, 25.0%), weighted treatment difference 13.9%, p=0.1863. SCC rates were EBO (13.2%) and PBO (10.0%; weighted treatment difference 3.4%, p=0.6366). The secondary endpoint of PRO symptom/function-based clinical response was assessed using the QOL-B RD questionnaire. EBO pts showed a greater mean change from baseline to M6 in QOL-B Respiratory Symptoms Domain score (7.20) vs PBO pts (0.3; treatment difference 6.9, nominal p= 0.0365). Ph 3: The primary efficacy analysis in the US was change from baseline in QOL-B Respiratory Symptoms Domain Score, in which EBO pts showed a slightly greater mean change from baseline (5.14) compared with PBO pts (4.16) (treatment difference 0.98, p=0.7551). SCC rates were EBO (7.7%) vs PBO (9.7%) at M6 (weighted difference -2.0%, p=0.7374). Ph 3 secondary endpoints were not informative.

The Ph 3 study was prematurely terminated by the Sponsor due to low SCC rates in the Ph 2 study. Ph 3 analyses neither confirmed the Ph 2 signals of efficacy nor demonstrated microbiological efficacy. Potential explanatory factors for the lack of efficacy included higher than expected baseline EBO MAC MIC90s and high rates of OBR agent drug resistance. Compared with Ph 2 pts, Ph 3 pts had more baseline characteristics predictive of a poor outcome, including age >=65 years, BMI <18.5kg/m2, fibrocavitary MAC-

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071220118

Khedr Gabrielle

AN2 Therapeutics, Inc.

1800 El Camino Real, Suite D Menlo Park, CA, United States

gkhedr@an2therapeutics.com

Fujii Shinya

Medpace Japan K.K.

1-5-8, Jingumae, Shibuya-ku, Tokyo

+81-3-4563-7000

RSJapan1@medpace.com

Complete

Mar. 20, 2023

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

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:
a. Microbiological criteria:
- One Pre-Study MAC-positive respiratory specimen. Documentation of a MAC positive specimen collected per standard of care within 6 months prior to signing the informed consent form (ICF).
- One Screening MAC-positive expectorated or induced sputum sample.
b. 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
c. Radiographic criteria: Non contrast Chest CT scan within 6 months prior to signing the ICF with abnormalities consistent with MAC lung disease.
d. OBR criteria: An OBR is a combination regimen that consists of >-2 antimycobacterial agents. The patient-specific OBR must be administered for a minimum duration of 6 consecutive months that is either ongoing at the time of Screening or was stopped or paused no more than 12 months before screening. The OBR regimen administered during Screening must be continued after randomization.
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.

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 <-30 mL/min, as estimated by the Cockcroft Gault formula, at Screening.
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 x upper limit of normal (ULN) or total bilirubin >2 x 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.

Both

Treatment-refractory Mycobacterium avium complex (MAC) lung disease

Epetraborole 500 mg will be administered orally once daily.

Phase 2:
- By-subject sputum conversion monthly through Month 6 in the Micro-ITT Population
- Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole

Phase 3:
- By-subject sputum conversion based on 3 consecutive monthly negative sputum cultures for MAC by Month 6 in the Micro-ITT Population

+81-93-603-1611

Feb. 14, 2023

United States/South Korea/Australia