Anti-ST2 (MSTT1041A) in COPD (COPD-ST2OP)

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence and is projected to be the third-leading cause of death and disability worldwide by 2030. The costs to society for treating COPD are high, accounting for approximately 3.4% of the total health care budget of the European Union. Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic burden of COPD. More than 500,000 hospitalisations and 100,000 deaths are attributed to AECOPD in the US each year. In addition to a substantial economic burden, AECOPD is also responsible for much of the morbidity and mortality from COPD.

Interleukin-33 (IL-33) is an alarmin released from the epithelium following damage. IL-33 is an IL-1 family alarmin cytokine constitutively expressed at epithelial barrier surfaces where it is rapidly released from cells during tissue injury. IL-33 signals through a receptor complex of IL-1 receptor-like 1 (IL1RL1) (known as ST2) and IL-1 receptor accessory protein (IL1RAcP) to initiate MyD88-dependent inflammatory pathways. The role of the IL33/ST2 axis in COPD is uncertain. IL33 has been implicated in eosinophil recruitment to the airway and maturation in the bone marrow largely via its effects upon innate lymphoid cells. IL33 increased following experimental cold in asthma and thus might play a role in the consequent inflammatory response and possible susceptibility to secondary bacterial infection in obstructive lung disease. Both eosinophilic inflammation and viral infection drive COPD exacerbations and therefore targeting the IL33/ST2 axis might reduce COPD exacerbations.

The main aim of this trial is to evaluate whether anti-ST2 will impact on airway inflammation in COPD and therefore reduce the frequency of exacerbations. For the purposes of this trial, exacerbations are defined as flare-ups of symptoms involving the use of healthcare resulting in treatment with steroids and/or antibiotics and/or hospitalisation or death due to COPD.

This is a single-centre, double-blind, placebo- controlled, parallel group, randomised controlled trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with moderate to very severe COPD (GOLD II-IV). Anti-ST2 will be administered via subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44) during the 48-week treatment period. Participants will be followed up for 60 weeks (i.e. 48 week treatment period and 12 week follow-up), with secondary outcome measures at baseline, 4, 12, 24, 36, 48 and 60 weeks and at exacerbation events presenting prior to treatment initiation.

After signing the informed consent at the initial visit, patients will enter a screening period which should last for up to 2 weeks unless extension of the screening period is necessary under certain circumstances. Patients who qualify to participate in the study will be randomised into a 48-week treatment period in which they will receive either 490 mg anti-ST2 or a matching placebo. Patients will be evaluated for an additional 12 weeks following completion of the randomised treatment period. Treatment groups will remain blinded until the 60-week follow-up period is completed, and trial database is locked.

This trial is sponsored by the University of Leicester, coordinated by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) - Respiratory and Leicester Clinical Trials Unit (LCTU) and funded by Genentech, Inc.

The primary objective of the study is to evaluate the efficacy of anti-ST2 versus placebo on frequency of moderate-to-severe exacerbations (health care utilisation resulting in treatment with systemic corticosteroids and/or antibiotics or hospitalisation, respectively) as add-on to standard of care.

Secondary objectives: another key objective is to assess the safety and tolerability of subcutaneous (SC) doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD.

Additionally, to assess the effects of anti-ST2 versus placebo both during stable visits and at the exacerbation events on the following:

1. Symptoms
2. Health status
3. Lung function
4. Inflammatory cell differentials i. Sputum cell count ii. Blood cell count
5. Airway morphometry
6. Pharmacogenomics

Exploratory objectives include:

1. Systemic inflammation
2. Upper airway inflammation
3. Airway infection and ecology
4. Breath volatile organic compound profiling
5. Quantitative airway geometry and densitometry
6. Pharmacogenomics
7. Pharmacokinetics and ADA level
8. Pharmacogenomics response analysis in subgroups determined by SNPs for alleles associated with the IL33/ST2 axis.

Subgroup objectives: to evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) \[SGRQ-c\], and lung function \[FEV1\] in subgroups defined by baseline blood eosinophil count.

Eligibility Criteria:
Inclusion Criteria:

1. Symptoms typical of COPD when stable (baseline mMRC dyspnoea score ≥ 2)
2. GOLD COPD stage 2-4
3. Smoking pack years ≥ 10 years
4. Age \> 40 years
5. Receiving standard-of-care drug therapy as per British Thoracic Society (BTS) guidance for COPD
6. A history of ≥ 2 moderate-to-severe exacerbations in the last 12 months.
7. Be able to give valid written consent; compliant with study procedures and study visits.
8. Able to understand written and spoken English

Exclusion Criteria:

1. Significant known respiratory disorders other than COPD that in the view of the investigator will affect the study
2. Patients whose treatment is considered palliative (life expectancy \<12 months)
3. Known hypersensitivity to the active substance of the investigational product (IP) or any of the excipients
4. Known history of anaphylaxis
5. Patients with a COPD exacerbation and/or pneumonia within the 4 weeks prior to visit 1
6. Have, in the opinion of investigator, uncontrolled co-morbid conditions, such as diabetes mellitus, hypertension and heart failure \[e.g. New York Heart Association (NYHA) class III (e.g. less than ordinary activity causes fatigue, palpitation, or dyspnoea), and class IV (e.g. Symptoms of heart failure at rest)\] that will affect the study.
7. Myocardial infarction, unstable angina or stroke within 12 month prior to screening
8. Diagnosis of malignancy within 5 years of visit 1 (except for excised localised carcinoma of skin not including malignant melanoma)
9. Clinically significant ECG changes, which in the opinion of investigator warrants further investigations
10. Laboratory abnormalities, which in the opinion of investigator warrants further investigations
11. Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
12. Pregnant, breastfeeding, or lactating women. Women of child-bearing potential (i.e. not surgically sterilised or post- menopausal) must have a negative blood serum pregnancy test performed at the screening visit and must agree to use two methods of birth control, (one of which must be a barrier method).
13. Participation in an interventional clinical study within 3 months of visit 1 or receipt of any investigational medicinal product within 3 months or 5 half- lives.
14. Upon questioning the patient has blood born infection (e.g. HIV, hepatitis B or C)