A Phase IIa Randomised, Double Blind, Placebo Controlled, Parallel Arm, Multi-Centre Study to Evaluate the Efficacy and Safety of Mitiperstat (AZD4831), for 12-24 Weeks, in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a common, chronic pulmonary
disease which is characterised by airflow obstruction that is only partly
reversible, and usually progressive and associated with a decline in lung
function. COPD is now the third most common cause of death worldwide. It is
also associated with high morbidity and comorbidity and is currently the fifth
leading cause of DALYs worldwide. COPD is also associated with an enormous
economic burden, costing ~$50 billion in direct and indirect healthcare costs
in the USA alone.

COPD is caused by a complex interaction between genetics, early life, and
ongoing environmental exposure. The major environmental risk factor is inhaling
cigarette smoke and/or other pollutants, which trigger a chronic inflammatory
response in the lung that is associated with increased lung levels of oxidative
stress and proteolytic injury leading to various pathologic changes in the lung
that are heterogeneously expressed by patients. Patients with COPD can have
varying combinations of destruction of the alveolar walls (or emphysema), small
airway remodelling, and/or changes in the large airway (which manifests
clinically as a frequent productive cough characteristic of the chronic
bronchitis phenotype) that vary in severity between patients. The course of
COPD can be punctuated by acute exacerbations of COPD which are defined as a
sustained worsening of the patient*s condition from the stable state, and
beyond normal day-to-day variations, that is acute in onset and necessitates a
change in regular medication in a patient with underlying COPD. The initial
exacerbation leading to hospitalisation in a COPD patient is considered a
seminal event for the patients as it heralds the onset of subsequent
exacerbations that increase in frequency, and 50% of patients die within 3.6
years of their initial exacerbation.

In addition, COPD is also frequently associated with other metabolic or
cardiovascular comorbidities, which also contribute to impaired quality of life
and poorer survival. There is considerable overlap in the patterns of systemic
vascular inflammation seen in COPD and that of advancing atherosclerotic
disease and heart failure.

For these reasons, patients with COPD represent a huge unmet medical need.

AZD4831 is a potent, selective, irreversible, and dose-dependent inhibitor of
myeloperoxidase (MPO). MPO is a heme-containing enzyme that is stored within
the granules of neutrophils. Myeloperoxidase catalyses the oxidation of halide
ions by hydrogen peroxide leading to the generation of hypohalous acids which
are potent oxidants. Under normal conditions, MPO and the hypohalous acids that
it generates within neutrophil granules make crucial contributions to killing
of phagocytosed bacteria. However, during excessive inflammation, neutrophil
granule contents are extruded, and the extracellular hypohalous acids generated
by MPO promote lung inflammation and injure the lung. Delivering an MPO
inhibitor to guinea pigs that were exposed to cigarette smoke for 6 months
reduced lung oxidative stress levels and lung inflammation and also halted the
progression of emphysema and small airway fibrosis in the animals indicating
that MPO activity contributes significantly to the pathogenesis of COPD-like
disease in animals. MPO has also been linked to human COPD as MPO levels in
sputum are elevated in COPD patients versus controls and increase further
during exacerbations. In addition, extracellular MPO serum levels are
indirectly related to rate of decline in FEV1. Finally, preliminary results for
AZD4831 in related cardiovascular studies have shown an acceptable benefit/risk
profile of this compound and suggest potential benefits in comorbid conditions
commonly associated with COPD. Thus, the clinical development program for
AZD4831 will evaluate whether treating COPD patients with AZD4831 reduces
exacerbations, and improves symptoms, quality of life, lung function and other
clinically-relevant outcomes and comorbidities in patients with COPD.

To evaluate the effect of AZD4831 as compared to placebo on the time to first
COPDCompEx event in participants with moderate to severe COPD.

This is a Phase IIa, randomised, placebo-controlled, double-blind,
parallel-arm, event-driven study with an up to 24-week treatment time designed
to evaluate the efficacy and safety of AZD4831 administered QD using a tablet
in adult participants with confirmed moderate to severe symptomatic COPD
(FEV1/FVC < 0.7, >= 10 pack-years smoking history, and post-BD FEV1 >= 25%
predicted) who are at high risk of exacerbations despite being maintained on
optimised SoC inhaled therapies - triple inhaled therapy (ICS + LABA + LAMA) or
ICS + LABA dual therapy or LABA + LAMA dual therapy for participants who are
deemed unsuitable for ICS. The treatment will be over a minimum 12-week and
maximum 24-week period.
* Approximately 406 participants will be randomised into the study to evaluate
AZD4831 5 mg QD versus placebo.
* Being at high risk of exacerbations is defined as participants fulfilling one
or more of the following criteria:
* >= 1 moderate or severe exacerbation in the last 2 years (defined as requiring
systemic corticosteroids and/or antibiotics for at least 3 days duration [or 1
injection of depot formulation], or hospitalisation for reason of AECOPD in the
24 months prior to screening; see Section 5.1).
* Frequent productive cough (see Section 5.1).
* Post-BD FEV1 of < 50% predicted.
* Participants will be randomised 1:1 to AZD4831 5 mg QD or placebo QD.

Subjects will be randomized in a 1:1 ratio to either 5 mg AZD4831 or matching
placebo both administered once daily during treatment period. The treatment
will be over a minimum 12-week and maximum 24-week period.

The subject is asked to visit the site at least 7 times. Visit 6 (week 18) is a
virtual visit. The visit time will last maximal 1-4 hours.

Blood samples will be taken in this study. The total volume of blood that will
be collected is approximately 250 ml.
The subject will undergo:
physical examinations at 4 visits.
Clinic Spirometry (post-BD): 5 times
Virtual Spirometry (post-BD): 4 times will be performed at the participants
home prior to attendance at the site
MIR Spirobank SMART and UNIFY application to undertake twice daily,
unsupervised PEF-only measurements.


The subject will undergo a spontaneous sputum test at least 2 times during the
study
The subject will undergo a nasal lining fluid test at least 2 times during the
study.
HR-CT Scan of the thorax will be done: 1 time

The subject will be asked to fill out questionnaires at some hospital visits
with a maximum of 3 times.
The subject must fill out questionnaires every day (in the morning and evening)
in an e-Diary. This takes approximately 15 minutes a day.

The subject will receive the study medication at visit 3. Study medication will
be administered once daily during treatment period. The treatment will be over
a minimum 12-week and maximum 24-week period. The study medication may cause
allergic reactions, such as Maculopapular rash.