A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Astegolimab in Patients with Chronic Obstructive Pulmonary Disease

•Signed Informed Consent Form •Age 40-90 years at time of signing Informed
Consent Form •Ability to comply with the study protocol •Documented physician
diagnosis of COPD made at least 12 months prior to screening •History of
frequent exacerbations, defined as having had two or more moderate or severe
exacerbations occurring within a 12-month period in the 24 months prior to
screening. Exacerbations should have been treated with systemic corticosteroids
and/or antibiotics. A moderate COPD exacerbation is defined as new or increased
COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) that lead to
treatment (duration => 3 days) with systemic corticosteroids (oral, IV, or IM)
at a dose of >10 mg/day prednisolone equivalent and/or antibiotics. Prior use
of antibiotics alone does not qualify as a moderate exacerbation, unless the
use was specifically for the treatment of worsening symptoms of COPD. A severe
COPD exacerbation is defined as new or increased COPD symptoms that lead to
hospitalization (duration >24 hours) or lead to or death. •Post-bronchodilator
FEV1 =>20 and <80% of predicted normal value at screening, as verified by
over-reader •Post-bronchodilator FEV1/FVC < 0.70 at screening, as verified by
over-reader •mMRC score => 2 at screening •Current smoker or former smoker with
a minimum of 10 pack-year history (e.g., 20 cigarettes/day for 10 years) A
former smoker is defined as meeting the criteria above but has not used inhaled
tobacco products or inhaled marijuana within 6 months prior to screening,
through use of cigarettes, cigars, electronic cigarettes, vaporizing devices,
or pipe. Note that at screening, patients who meet the protocol definition of
current smoker will receive smoking cessation counseling. •History of one of
the following combinations of optimized, stable, standard-of-care COPD
maintenance therapy for at least 4 weeks prior to screening, with no
anticipated changes in therapy prior to initiation of study drug and throughout
the study: Inhaled corticosteroid (ICS) => 500 mcg/day fluticasone propionate
dose-equivalent plus long-acting beta-agonist (LABA). - Long-acting muscarinic
antagonist (LAMA) plus LABA. - ICS => 500 mcg/day fluticasone propionate
dose-equivalent plus LAMA plus LABA •Demonstrated ability to use and comply
with electronic diary (eDiary) requirements, defined as completion of all
questions on at least 5 out of 7 consecutive days within the 14 days after the
screening visit Patients unable to demonstrate compliance with the eDiary
within the first 2 weeks of screening will be screen failed. Patients will have
the opportunity to demonstrate eDiary compliance if re-screened. •For women of
childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception, as defined below: Women must
remain abstinent or use contraceptive methods with a failure rate of <1% per
year during the treatment period and for 12 weeks after the final dose of
Astegolimab. A woman is considered to be of childbearing potential if she is
postmenarchal, has not reached a postmenopausal state (=> 12 continuous months
of amenorrhea with no identified cause other than menopause), and is not
permanently infertile due to surgery (i.e., removal of ovaries, fallopian
tubes, and/or uterus) or another cause as determined by the investigator (e.g.,
Mu*llerian agenesis). The definition of childbearing potential may be adapted
for alignment with local guidelines or regulations. Examples of contraceptive
methods with a failure rate of <1% per year include bilateral tubal ligation,
male sterilization, hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices. The
reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of
contraception. If required per local guidelines or regulations, locally
recognized adequate methods of contraception and information about the
reliability of abstinence will be described in the local Informed Consent Form.
•For men: agreement to remain abstinent (refrain from heterosexual intercourse)
or use a condom, and agreement to refrain from donating sperm, as defined
below: With a female partner of childbearing potential or pregnant female
partner, men must remain abstinent or use a condom during the treatment period
and for 12 weeks after the final dose of Astegolimab to avoid exposing the
embryo. Men must refrain from donating sperm during this same period. The
reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence. •For patients enrolling in the Airway Biomarker
Substudy(at participating sites): ability to produceat least 1mL of sputum
spontaneously or via sputum inductionat screening

Pregnant or breastfeeding, or intending to become pregnant during the study or
within 12 weeks after the final dose of study drug. Women of childbearing
potential must have a negative serum pregnancy test result at screening and a
negative urine pregnancy test on Day 1 prior to initiation of study drug.
•Current documented diagnosis of asthma according to the Global Initiative for
Asthma guidelines or other accepted guidelines within 5 years prior to
screening •History of clinically significant pulmonary disease other than COPD
(e.g., pulmonary, fibrosis, sarcoidosis, chronic pulmonary embolism or primary
pulmonary hypertension, alpha-1-antitrypsin deficiency) •Clinically significant
abnormalities requiring clinical follow-up as indicated by chest X-ray or chest
CT scan performed within 6 months prior to screening Chest X-ray must be
performed at screening if results from a chest X-ray or chest CT scan performed
within 6 months prior to screening are not available. •Presence of risk factors
for aspiration pneumonia (e.g., neurologic disease such as uncontrolled
epilepsy) in the opinion of the investigator •History of long-term treatment
with oxygen at > 4.0 liters/minute. While breathing supplemental oxygen,
patient should demonstrate an oxyhemoglobin saturation of => 89%. •History of a
severe allergic reaction or anaphylactic reaction to a biologic agent or known
hypersensitivity to any component of the study drug •Lung volume reduction
surgery or procedure within 12 months prior to screening •Participation in or
planned participation in a new pulmonary rehabilitation program within 4 weeks
prior to screening and throughout the study treatment period. Patients who are
in the maintenance phase of a rehabilitation program are eligible. •History of
lung transplant •Occurrence of protocol-defined moderate or severe COPD
exacerbation, COVID-19, upper or lower respiratory infection, pneumonia, or
hospitalization of => 24 hours duration within 4 weeks prior to initiation of
study drug •Any prior treatment with Astegolimab •Treatment with oral, IV, or
IM corticosteroids (>10 mg/day prednisolone equivalent) within 4 weeks prior to
initiation of study drug •Treatment with investigational therapy within 3
months or 5 drug-elimination half-lives (whichever is longer) prior to
screening •Treatment with a licensed biologic agent (e.g., omalizumab,
dupilumab, and/or anti-IL-5 therapies) within 3 months or 5 drug-elimination
half-lives (whichever is longer) prior to screening •Initiation of a
methylxanthine preparation, maintenance macrolide therapy, and/or PDE4
inhibitor within 4 weeks prior to screening •Initiation of or change in
non-biologic immunomodulatory or immunosuppressive therapy within 3 months
prior to screening •Treatment that is considered palliative (e.g., for life
expectancy <12 months) •Use of any of the following treatments within 4 weeks
prior to screening, or any condition that is likely to require such treatment
during the course of the study, unless the treatment is deemed acceptable by
the investigator, in consultation with the Medical Monitor: - Treatment with
immunoglobulin or blood products. - Treatment with any live or attenuated
vaccine (including any approved, live SARS-CoV-2 vaccine) within 4 weeks prior
to screening or during the screening period, or anticipated need for live,
attenuated vaccine during the course of the study, unless the vaccine is deemed
medically necessary and no inactivated vaccine alternatives are available.
•Administration of non-live SARS-CoV-2 vaccine (with full marketing
authorization or temporary), including those delivered by non-replicating viral
vectors, within 7 days prior to initiation of study drug •Planned surgical
intervention during the study •Positive hepatitis C virus (HCV) antibody test
result accompanied by a positive HCV RNA test at screening •Unacceptable test
results for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody
(HBsAb), and total hepatitis B core antibody (HBcAb) at screening, defined as
meeting either of the following criteria: - Positive HBsAg test at screening. -
Negative HBsAg test at screening, with negative HBsAb test accompanied by
positive total HBcAb test, followed by quantitative hepatitis B virus (HBV) DNA
=> 20 IU/mL. Inability to perform HBV DNA test is exclusionary. Patients with a
negative HBsAg test and positive HBsAb test are eligible. •Known
immunodeficiency including, but not limited to, HIV infection Patients must
have a negative HIV test result at screening or within 3 months prior to
screening. •Known evidence of active or untreated latent tuberculosis
•Substance abuse, as determined by the investigator, within 12 months prior to
screening •History of malignancy within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death (e.g.,
5-year overall survival rate > 90%), such as adequately treated carcinoma in
situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, or
ductal carcinoma in situ •Any other serious medical condition or abnormality in
clinical laboratory tests that, in the investigator's judgment, precludes the
patient's safe participation in and completion of the study •Unstable cardiac
disease, myocardial infarction, or New York Heart Association Class III or IV
heart failure within 12 months prior to screening •History or presence (as
verified by over-reader)of an abnormal ECG that is deemed clinically
significant by the investigator, including complete left bundle branchblock or
second- or third-degree atrioventricular heart block •QT interval corrected
through use ofFridericia*s formula (QTcF)(as verified by over-reader)>450 ms if
patient is male or QTcF >470 ms if patient is female For male or female
patients with QRS >120: QTcF >480 ms. •History of ventricular dysrhythmias or
risk factors for ventricular dysrhythmias such as structural heart disease
(e.g., severe left ventricular systolic dysfunction, significant left
ventricular hypertrophywith strain), or family history of sudden unexplained
death or long QT syndrome