Study to Assess CMR316 in Healthy Volunteers and Patients With Idiopathic Pulmonary Fibrosis

A Phase 1/1B Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Nebulized CMR316 in Healthy Volunteers and Patients With Idiopathic Pulmonary Fibrosis

The purpose of this study is to assess the safety, tolerability and pharmacokinetics single and multiple inhaled doses of CMR316 in healthy volunteers and patients with Idiopathic Pulmonary Fibrosis (IPF).

This is a 3-part, single-center study; Part 1 will evaluate single ascending doses (SAD) and Part 2 will evaluate multiple ascending doses (MAD; once weekly dosing for 4 weeks) of nebulized CMR316 or placebo in healthy male and female subjects. Part 3 will assess multiple doses (once weekly dosing for 5 weeks) of nebulized CMR316 (open-label) in subjects with IPF.

Inclusion Criteria: Part 1 & 2

• Healthy men or non-pregnant, non-lactating healthy women of non-childbearing potential, 18-60 years of age.
• Must agree to use a highly effective method of contraception.
• Body Mass Index (BMI) 18-33 kg/m2 as measured at screening.
• Weight ≤100 kg at screening.
• Normal lung function, defined as: FVC and FEV1 > 80% predicted (based on age, height, race, sex, SaO2 > 95% on room air.
• Heart rate between 50 and 90 beats per minute (BPM).
• Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination) and screening safety procedures.

Inclusion Criteria: Part 3

• Diagnosis of IPF by American Thoracic Society/ERS (European Respiratory Society)/JRS (Japanese Respiratory Society)/ALAT (Latin America Thoracic Society) 2011 criteria within five years prior to consent.
• Men or non-pregnant, non-lactating women of non-childbearing potential.
• Age ≥ 40 years.
• Mild to moderate IPF as defined by predicted FVC ≥ 55% of normal and predicted DLCO > 40% of normal at Screening.
• Subjects receiving oral pirfenidone or nintedanib for treatment of IPF may participate if they have been on treatment with a stable, well-tolerated dose (as determined by the investigator), for at least 8 weeks prior to consent with no changes to therapy dose and schedule anticipated during the course of study participation.
• Must be able to understand a written informed consent, which must be obtained prior to any study procedures.
• Must be willing and able to comply with all study requirements

Exclusion Criteria: Part 1 & 2

• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
• Presence or history of clinically significant hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) or allergy as judged by the investigator. Subjects with a history of seasonal rhinitis (hay fever) or childhood asthma may participate if these conditions are not active or expected to be active during the subject's participation.
• History of clinically significant cardiovascular, skin, renal, hepatic, respiratory or gastrointestinal disease (except cholecystectomy), neurological or psychiatric disorder, illness/infection/hospitalization, or surgical procedure within 30 days prior to first dose of study drug. Subjects with a history of pancreatitis, heart failure, acute renal failure, bullous pemphigoid, or severe and disabling arthritis, conditions associated with postmarketing safety reports of oral gliptins, are excluded.
• Have poor venous access that limits phlebotomy.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin above upper limit of normal (elevated bilirubin in subject's with Gilbert Syndrome is allowed) or other clinically significant abnormal clinical chemistry, hematology, or urinalysis as judged by the investigator.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) antibody results.
• Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <90 mL/min using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 1: CKD-EPI Equation).
• Subjects with a corrected QT interval by Fredericia (QTcF) of >450 msec at screening or first admission.
• Positive highly sensitive serum pregnancy test at screening or highly sensitive urine pregnancy test at first admission. Those who are pregnant or lactating will be excluded.
• Subjects who have received any investigational medicinal product (IMP) in a clinical research study within 5 half-lives or within 30 days prior to first dose (whichever is longer).
• Subjects who have previously been administered IMP in this study. Subjects who have taken part in Part 1 are not permitted to take part in Part 2.
• Subjects who have taken, any over-the-counter drug or herbal remedies in the 15 days prior to first IMP administration. Subjects taking prescribed medication in the 90 days prior to first IMP administration. Subjects taking up to 4 g per day of acetaminophen may participate if discontinued at least 15 days prior to first IMP administration. Subjects taking DPP4 inhibitors are prohibited. Subjects taking strong CYP3A inhibitors are prohibited.
• History of any substance use disorder or alcohol use disorder in the past 2 years, as based on the diagnostic criteria in the Diagnostic and Statistical Manual Fifth Edition (DSM-5).
• Regular alcohol consumption in men >21 units per week and women >14 units per week (1 unit = 12 oz 1 bottle/can of beer, 1 oz 40% spirit, or 5 oz glass of wine).
• A confirmed positive alcohol breath test at screening or first admission.
• Current smokers and those who have a smoking history of ≥ 10 pack-years. A confirmed positive urine cotinine test at screening or first admission.
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
• Positive test result for common drugs of abuse on screening and first admission.
• Men with pregnant or lactating partners.
• Donation of a unit of blood (about 500 mL) within 2 months or donation of plasma within 7 days prior to first dose of study medication.
• Subjects who are, or are immediate family members of, a study site or Sponsor employee.
• Active respiratory infection requiring treatment with antibiotics within 4 weeks prior to signing of ICF.
• Lack of suitability for participation in the trial, for any reason, as judged by the Investigator.

Exclusion Criteria: Part 3

• Clinically significant deterioration between screening and Day 1.
• Use of any investigational drugs within 30 days or 5 half-lives prior to consent, whichever is longer.
• Serious adverse reaction or serious hypersensitivity to any DPP4 inhibitor (e.g., saxagliptin, sitagliptin) or the formulation excipients.
• Use of supplemental oxygen for resting hypoxemia.
• Evidence of significant renal impairment at screening, defined in this protocol as an estimated creatinine clearance (CLcr) of <50 mL/min using the CKD-EPI equation. Patients with renal insufficiency Clcr ≥ 50 mL/min with stable renal function (per clinical discretion, recommend based on average documented clinical chemistry values for at least 6 months) may participate.
• History of clinically significant and uncontrolled medical illness or clinically significant abnormal clinical chemistry, hematology, or urinalysis that represents a meaningful risk to the subject during this trial, as judged by the Investigator (e.g., heart failure).
• Subjects with a corrected QT interval by Fredericia (QTcF) of >450 msec at screening.
• Life expectancy < one year.
• Subject listed for lung transplant.
• Hospitalization or serious illness (as determined by the investigator) within the 3 months prior to consent.
• Alternative diagnoses that could lead to pulmonary fibrosis such as exposure to drugs, radiation, asbestos.
• Connective tissue disease that can lead to pulmonary fibrosis such as scleroderma or rheumatoid arthritis.
• Presence of clinically active, medically diagnosed asthma, chronic obstructive pulmonary disease, or active infection.
• Lack of suitability for participation in the trial, for any reason, as judged by the Investigator.
• History of severe hepatic impairment or AST or ALT greater than 3 times the upper limit of normal at screening.
• The use of required concomitant medications that represents a significant risk to produce an adverse drug interaction with CMR316, assessed by the investigator (in consultation with sponsor and sponsor's medical monitor). Specifically, subjects with Type 1 and Type 2 diabetes are excluded.
• Smoking within a year prior to consent.