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

NCT03615040 | Completed Phase 2 Results DMC FDA Drug

• 6 other identifiers: 06712018-000919-24GB40568U1111-1210-133524475818/EM/0189
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

COPD Exacerbation

Keywords

COPD; Exacerbations; ST2 MAb; RG6149; MSTT1041A; Anti-ST2; Phase IIa; Placebo controlled

Outcome Measures

Primary Outcomes (1)

• Number of Moderate to Severe Exacerbation (Defined as Requiring Treatment With Systemic Corticosteroids and/or Antibiotics in the Community or Hospital or Hospitalisation).

  Where a COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics and/or * inpatient hospitalisation or death due to COPD

  0-48 weeks

Secondary Outcomes (17)

• Adverse Event Rate in the 48 Weeks of the Trial From First Dose

  Weeks 0 , 4, 12, 24, 26, 48

• Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose

  Weeks 0 , 4, 12, 24, 26, 48

• St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score

  Weeks 0, 4, 12, 24, 36, 48

• COPD Assessment Test (CAT) (Questionnaire)

  Weeks 0, 4, 12, 24, 36, 48

• Modified Medical Research Council (mMRC) Dyspnea Scale

  Screening, weeks 0, 4, 12, 24, 36, 48

Other Outcomes (15)

• Non-contrast Thoracic CT Derived Outcomes [Exploratory Outcome]

  Screening and week 48

• Sputum Mediator Profiling (Biomarkers) [Exploratory Outcome]

  Weeks 0, 4, 12, 24, 36, 48

• Blood Biomarkers [Exploratory Outcome]

  Screening, weeks 4, 12, 24, 36, 48

Study Arms (2)

Anti-ST2

EXPERIMENTAL

Anti-ST2 (MSTT1041A) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.

Drug: MSTT1041A

Placebo

PLACEBO COMPARATOR

Placebo (no active component) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.

Drug: Placebo

Interventions

MSTT1041A DRUG

MSTT1041A (RO7187807; formerly made by Amgen \[AMG\] and referred to as AMG 282) is a novel biopharmaceutical that blocks signaling of interleukin (IL)-33, an inflammatory cytokine of the IL-1 family and member of the newly discovered "alarmin" class of molecules. IL-33 is released from airway epithelial cells in response to allergens, irritants, and infection. IL-33 release can trigger acute exacerbations in both asthma and COPD. MSTT1041A has the ability to block inflammation,prevent exacerbations, and improve lung function and quality of life. Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile vial is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM sodium acetate, 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2.

Also known as: RO7187807, ST2 MAb, Anti-ST2, AMG 282, RG6149

Anti-ST2

Placebo DRUG

Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% (w/v) sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial configuration.

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Significant known respiratory disorders other than COPD that in the view of the investigator will affect the study
• Patients whose treatment is considered palliative (life expectancy \<12 months)
• Known hypersensitivity to the active substance of the investigational product (IP) or any of the excipients
• Known history of anaphylaxis
• Patients with a COPD exacerbation and/or pneumonia within the 4 weeks prior to visit 1
• 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.
• Myocardial infarction, unstable angina or stroke within 12 month prior to screening
• Diagnosis of malignancy within 5 years of visit 1 (except for excised localised carcinoma of skin not including malignant melanoma)
• Clinically significant ECG changes, which in the opinion of investigator warrants further investigations
• Laboratory abnormalities, which in the opinion of investigator warrants further investigations
• Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
• 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).
• 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.
• Upon questioning the patient has blood born infection (e.g. HIV, hepatitis B or C)

Sponsors & Collaborators

• University of Leicester: lead
• Glenfield Hospital, Leicester: collaborator
• Genentech, Inc.: collaborator

Study Sites (1)

Biomedical Research Centre- Respiratory, Glenfield Hospital

Leicester, Leicestershire, LE3 9QP, United Kingdom

Location

Related Publications (1)

• Yousuf AJ, Mohammed S, Carr L, Yavari Ramsheh M, Micieli C, Mistry V, Haldar K, Wright A, Novotny P, Parker S, Glover S, Finch J, Quann N, Brookes CL, Hobson R, Ibrahim W, Russell RJ, John C, Grimbaldeston MA, Choy DF, Cheung D, Steiner M, Greening NJ, Brightling CE. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med. 2022 May;10(5):469-477. doi: 10.1016/S2213-2600(21)00556-7. Epub 2022 Mar 24.

  PMID: 35339234 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

astegolimab

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

* Small sample size (n=81) at a single site, therefore not powered to detect a reduction in exacerbation frequency that was observed. * Participants were required to have had a minimum of 2 exacerbations in the previous 12 months, so the findings are not representative for a wider clinical population. * In response to COVID-19, collection of secondary/exploratory outcomes were reduced, with spirometry and sputum induction discontinued.

Results Point of Contact

• Title: Professor Chris Brightling
• Organization: University of Leicester

ceb17@le.ac.uk

+44 116 250 2704

Study Officials

• Christopher Brightling, Prof

  University of Leicester

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: A or B
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single-centre, double-blinded, placebo-controlled, parallel group, randomised controlled trial

Study Record Dates

• First Submitted: May 4, 2018
• First Posted: August 3, 2018
• Study Start: October 11, 2018
• Primary Completion: May 29, 2020
• Study Completion: December 31, 2020
• Last Updated: June 21, 2022
• Results First Posted: May 24, 2022

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)