A 52-week, randomised, double-blind, double-dummy, parallel group,multi-centre, non-inferiority study assessing exacerbation rate, additional measures of asthma control and safety in adult and adolescent severe asthmatic participants with an eosinophilic phenotype treated with GSK3511294 (depemokimab) compared with mepolizumab or benralizumab

1. Age: Adults and adolescents >=12 years of age, at the time of signing the
informed consent/assent.[For countries where local regulations or the
regulatory status of study medication permit enrolment of adults only,
participants recruited will be >=18 years of age] Note for Germany, UK and
Norway Participants: In Germany, UK and Norway, only adult participants (>=18
years) are to be included in this clinical trial. Note for Austrian
Participants: In Austria, participants who are >=16 years are to be included in
this clinical trial.
2. Asthma: Participants who have a documented physician diagnosis of asthma for
>=2 years that meets the National Heart, Lung, and Blood Institute guidelines
[NHLBI, 2007] or GINA guidelines [GINA, 2020].
3. Anti-IL-5/5R Therapy: Receiving either mepolizumab 100 mg SC or benralizumab
30 mg SC for >=12 months prior to Screening and have a documented benefit to
therapy assessed by either:
• >=50% reduction in exacerbation frequency since initiating treatment,
ORhttps://www.toetsingonline.nl/to/ccmo_monitor.nsf/europe.gif?OpenImageResource
• >=50% reduction in maintenance OCS use since initiating treatment, OR
• no exacerbations in the past 6 months whilst receiving anti-IL-5/5R therapy
and an ACQ-5 score of <=1.5 at Screening.
4. Inhaled Corticosteroid: A well-documented requirement for regular treatment
with medium to high dose ICS in the 12 months prior to Visit 1 with or without
maintenance OCS. The maintenance ICS dose must be >=440 mcg fluticasone
propionate [FP] hydrofluoroalkane product [HFA] daily, or clinically comparable
[GINA, 2020; see Appendix 10 of the protocol]. Participants who are treated
with medium dose ICS will also need to be treated with a Long-acting
beta-agonist (LABA) to qualify for inclusion.
5. Additional Controller Medication: Current treatment with at least one
additional controller medication, besides ICS [e.g., LABA, LAMA, leukotriene
receptor antagonist (LTRA), or theophylline].
6. Male or eligible female.
• A female participant is eligible to participate if she is not pregnant or
breastfeeding, and 1 of the following conditions applies:
o Is a woman of non-childbearing potential (WONCBP) as defined in
Section 10.4.1 of the protocol
OR
o Is a woman of childbearing potential (WOCBP) and using a contraceptive method
that is highly effective, with a failure rate of <1%,as described in Section
10.4.2 of the protocol from at least 14 days prior to the first dose of study
intervention until at least 30 weeks after either: the first dose (if study
intervention was permanently discontinued prior to Week 26), or the dose at
Week 26.
• A WOCBP must have a negative highly sensitive serum pregnancy test at
screening Visit 1 and a negative highly sensitive urine pregnancy test within
24 hours before the first dose of study intervention. Additional requirements
for pregnancy testing during and after study intervention are located in
Section 8.3.5 of the protocol.
• Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
• The investigator should evaluate the potential for contraceptive method
failure (e.g., noncompliance, recently initiated in relationship to the first
dose of study intervention).
• The investigator is responsible for review of medical history,
menstrualhistory, and recent sexual activity to decrease the risk for inclusion
of awoman with an early undetected pregnancy.
• Note: If the childbearing potential changes after start of the study (e.g., a
premenarcheal female participant experiences menarche) or the risk of pregnancy
changes (e.g., a female participant who is not heterosexually active becomes
active), the participant must discuss this with the investigator, who should
determine if a female participant must begin a highly effective method of
contraception. If reproductive status is questionable, additional evaluation
should be considered.
7. Informed Consent: Capable of giving signed informed consent/assent as
described in Section 10.1 of the protocol which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in
the protocol.French participants: In France, a participant will be eligible for
inclusion in this study only if either affiliated to or a beneficiary of a
social securitycategory.

1. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically
important lung condition other than asthma. This includes (but is not limited
to) current infection, bronchiectasis, pulmonary fibrosis, XML File Identifier:
8gn94WbuVgZQJdjuTL83BkI1PnI=Page 24/38bronchopulmonary aspergillosis, or
diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary
disease other than asthma) or a history of lung cancer.
2. Eosinophilic Diseases: Participants with other conditions that could lead to
elevated eosinophils such as hyper-eosinophilic syndromes including (but not
limited to) Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly known
as Churg-Strauss Syndrome) or Eosinophilic Esophagitis.
3. Parasitic Infection: Participants with a known, pre-existing parasitic
infestation within 6 months prior to Visit 1 are to be excluded.
4. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency
virus - HIV), other than that explained by the use of CSs taken as therapy for
asthma.
5. Malignancy: A current malignancy or previous history of cancer in remission
for less than 12 months prior to screening (Participants that had localised
carcinoma of the skin which was resected for cure will not be excluded).
6. Liver Disease: Cirrhosis or current unstable liver or biliary disease per
investigator assessment defined by the presence of ascites, encephalopathy
,coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent
jaundice.
NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome,
asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if
participant otherwise meets entry criteria.
7. Other Concurrent Medical Conditions: Participants who have known,
preexisting, clinically significant cardiac, endocrine, autoimmune, metabolic,
neurological, renal, gastrointestinal, hepatic, haematological or any other
system abnormalities that are uncontrolled with standard treatment.
8. Vasculitis: Participants with current diagnosis of vasculitis. Participants
with high clinical suspicion of vasculitis at screening will be evaluated and
current vasculitis excluded prior to enrolment.
9. COVID-19: Participants that, according to the investigator's medical
judgment, are likely to have active COVID-19 infection should be excluded.
Participants with known COVID-19 positive contacts within the past 14 days
should be excluded for at least 14 days following the exposure during which the
participant should remain symptom-free.
10. Other mAbs used in the treatment of asthma: Participants who have received
omalizumab (Xolair), dupilumab (Dupixent), reslizumab (Cinqair/Cinqaero) or
Tezepelumab (Tezspire) within 130 days prior to Visit 1.
11. Other mAbs not used for the treatment of asthma: Participants who have
received any mAb within 5 half-lives of Visit 1. Authorised treatments for
COVID-19 are permitted and should be used in line with local regulatory
guidance.
12. Investigational Medications: Participants who have received treatment with
an investigational drug within the past 30 days or five terminal phase
half-lives of the drug whichever is longer, prior to visit 1 (this also
includes investigational formulations of marketed products).
13. ECG Assessment: QTcF >=450msec or QTcF >=480 msec for participants with
Bundle Branch Block in the central over-read 12-lead ECG at screening Visit 1.
14. Smoking history: Current smokers or former smokers with a smokinghistory of
>=20 pack years (number of pack years = (number of cigarettesper day / 20) x
number of years smoked). A former smoker is defined as a participant who quit
smoking at least 6 months prior to Visit 1. Pipes and/or cigars and/or
electronic cigarettes/vaping use cannot be used to calculate pack-year history.
Current and former use of these is exclusionary.
15. Alcohol/Substance Abuse: A history (or suspected history) of alcoholmisuse
or substance abuse within 2 years prior to Visit 1.XML File Identifier:
8gn94WbuVgZQJdjuTL83BkI1PnI=Page 25/38
16. Hypersensitivity: Participants with allergy/intolerance to a mAb or
biologic or any of the excipients of the investigational products listed in
section 6.1 of the protocol.
17. Pregnancy: Participants who are pregnant or breastfeeding. Participants
should not be enrolled if they plan to become pregnant during the time of study
participation. Requirements for pregnancy testing are located in Section 8.3.5
of the protocol.
18. Adherence: Participants who have known evidence of lack of adherence to
controller medications and/or ability to follow physician's
recommendations.