A trial to evaluate efficacy and safety of buloxibutid in people with idiopathic pulmonary fibrosis.

The ASPIRE trial is a 52 week randomized, double-blind, placebo-controlled, parallel-group, multicenter trial in which the efficacy, safety, and pharmacokinetics of orally administered buloxibutid, either on top of stable IPF therapy or as monotherapy, are assessed in participants with IPF.

Trial website: www.aspire-ipf.com

Buloxibutid is an oral angiotensin II type 2 (AT2) receptor agonist and has been shown to improve lung function in IPF over 36 weeks.

Buloxibutid agonizes the AT2 receptor on alveolar epithelial type 2 cells (AEC2s), which are believed to play a central role in the disease. Buloxibutid has been demonstrated preclinically to improve AEC2 viability, alveolar integrity via surfactant secretion and epithelial repair via replenishment of gas exchange alveolar epithelial type 1 cells (AEC1s). This leads to decreasing downstream profibrotic signaling, enhancing resolution of existing fibrotic tissue via upregulation of collagenase matrix metalloproteinases, and addressing vascular disfunction associated with the disease.

The trial will include participants who are on stable licensed IPF therapy or who are currently not treated with a licensed IPF therapy. The latter group will include participants intolerant or not responsive to licensed IPF therapies, participants ineligible to receive these therapies, and participants who have voluntarily declined to receive a licensed IPF therapy after being fully informed of the potential benefits and risks of such therapy. Due to the potential risk of drug-drug interactions (DDIs), concomitant treatment with pirfenidone is not allowed in this trial. Participants who are not on antifibrotic therapy at study start may initiate such treatment during the study.

The trial is planned to enroll 360 participants, 120 participants on oral buloxibutid 100 mg BID, 120 participants on oral buloxibutid 50 mg BID, and 120 participants on oral placebo BID for 52 weeks. The treatment will be blinded and treatment allocation will be randomized.

The primary measurement will be based on spirometry, measuring the forced vital capacity (FVC).

The trial consists of 3 consecutive periods: a screening period of up to 6 weeks, a 52-week treatment period, and a follow-up period of 2-4 weeks after the 52-week visit. The study procedures have been planned with focus on optimizing patient convenience while allowing a safe conduct and strict scientific rigor.

Trial website: www.aspire-ipf.com

Inclusion Criteria

1. Age ≥ 40 years at the time of signing the informed consent.

2. Diagnosed with IPF within 7 years prior to visit 1, as per applicable ATS/ERS/JRS/ALAT guidelines at the time of diagnosis.

3. HRCT scan within 36 months prior to visit 1 with central reading confirming either a or b, and c

   1. A pattern consistent with usual interstitial pneumonia (UIP) according to ATS/ERS/JRS/ALAT 2022 guideline (Raghu et al., 2022) UIP or probable UIP.

   2. A pattern indeterminate for UIP according to ATS/ERS/JRS/ALAT 2022 guidelines (Raghu et al., 2022) and a historical biopsy (surgical lung biopsy or transbronchial lung cryobiopsy) consistent with IPF.

   3. Extent of fibrosis > extent of emphysema.

4. FVC ≥50% predicted at visit 1.

5. DLCO (corrected for hemoglobin) ≥30% predicted at visit 1.

6. Either:

   1. On a stable dose of licensed IPF therapy for at least 8 weeks prior to visit 1 and expected to remain on this background treatment after randomization. Due to the risk of DDIs, concomitant treatment with pirfenidone is not allowed in this trial.

   2. Not currently receiving treatment for IPF with a licensed therapy for any reason, including prior intolerance, non-responsiveness, ineligibility, lack of access or voluntarily decline. Any such previous treatment must have been discontinued >8 weeks prior to visit 1.

7. Anticipated life expectancy of at least 12 months at visit 1 and not anticipated to require a lung transplant during the trial period (being on a transplant list does not exclude a participant from the trial).

8. Contraceptive use by women of childbearing potential (WOCBP) which is highly effective and consistent with local regulations regarding the methods of contraception for those participating in clinical trials.

For Uk and countries within the Eu: Male participants, if heterosexually active with

a female partner of childbearing potential, or a pregnant or breastfeeding partner,

must agree to use barrier contraception (male condom) and abstain from sperm

donation for the duration of the treatment period and for at least 2 weeks after the

last dose of the trial drug.

1. Written informed consent, consistent with ICH-GCP and local laws, obtained before the initiation of any trial-related procedure.

Exclusion Criteria

Participants are excluded from the trial if any of the following criteria apply:

1. Concurrent serious medical condition that in the opinion of the investigator constitutes a risk or a contraindication for participation in the trial or that could interfere with the trial objectives, conduct or evaluation, including active or suspected malignancy or history of malignancy within 5 years prior to visit 1, except appropriately treated basal cell carcinoma of the skin, fully resected and cured squamous cell carcinoma of the skin, "under surveillance" prostate cancer or in situ carcinoma of uterine cervix.

2. Airways obstruction with a pre-bronchodilator forced expiratory volume in one second (FEV1)/FVC ratio 3 times upper limit of normal (ULN) or total bilirubin >1.5 times ULN at visit 1.

3. Severe renal impairment (i.e., estimated glomerular filtration rate (eGFR) ≤35 ml/min/1.73 m2 at visit 1 according to Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).

4. Prolonged QTcF (QT interval with Fridericia's correction) (>450 ms), AV-block II or III, uncontrolled arrhythmia, or other clinically significant abnormality in the resting ECG at visit 1, as judged by the investigator. Patients with implantable cardiovascular devices (e.g. pacemaker) affecting the QT interval time may be enrolled in the trial based upon investigator judgement, following cardiologist consultation if deemed necessary, and only after discussion with the medical monitor.

5. Heart failure NYHA Class IV, acutely decompensated right heart failure, PH with syncopal episode, confirmed myocardial infarction, unstable angina or uncontrolled hypertension, within 6 months prior to visit 1.

6. Known hypersensitivity or intolerance to buloxibutid or to any other components of the test product, including excipients.

7. Pregnant or breast-feeding female participants.

8. Acute IPF exacerbation within 3 months prior to visit 1 and/or during the screening

period, as defined by Collard et al., 2016:

1. Acute worsening or development of dyspnea typically