Inclusion Criteria:
- 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.
- Participants must have a documented physician diagnosis of asthma for >=2 years that meets the National Heart, Lung, and Blood Institute, National Institute for Health and Care Excellence or Global Initiative for Asthma guidelines
- Have previously confirmed history of at least 2 exacerbations over the last 3 years prior to screening, with at least 1 of those exacerbations occurring in the previous year prior to Screening Visit 1.
- Exacerbation requiring treatment with systemic Corticosteroid (CS), for at least 3 days, despite the use of low to medium dose Inhaled corticosteroids (ICS)/ Long-acting beta2-adrenergic receptor agonist (LABA).
- A well-documented requirement for treatment with low to medium dose ICS/LABA (in the 12 months prior to screening visit. Treatment should be stable for 3 months prior to screening. If participants are taking Maintenance and Reliever Therapy/Single Maintenance and Reliever Therapy regularly, the total daily dose should be incorporated into the assessment of low or medium dose ICS.
- Study will limit enrolment to a maximum of 40 percent (%) of participants on low dose ICS/LABA.
- Sex and Contraceptive/Barrier Requirements Male or eligible female Participants:
- Male Participants: Contraception for male participants with female partners is not required.
- Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
- Is a participant of nonchildbearing potential (PONCBP) OR
- Is a participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective, with a failure rate of less than (<)1%, from at least 14 days prior to the first dose of study intervention until at least 35 weeks after the last administered dose of study intervention.
- A POCBP must have a negative highly sensitive serum pregnancy test at Screening Visit 1, Exit Visit 11 or Withdrawn from study visit, and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention.
- 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, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Capable of giving signed informed consent/assent as which includes compliance with the requirements Randomization inclusion criteria-
- Type 2 high disease at risk of asthma exacerbations as defined by either:
- An elevated peripheral blood eosinophils (EOS) count of >=500 cells/microliter (μL) at screening or >=500 cells/μL in the last 3 months prior to the screening visit.
OR
- An elevated peripheral blood EOS count of >=300 cells/μL at screening OR >=300 cells/μL in the last 3 months prior to the screening visit AND
- Fractional exhaled nitric oxide >=35 parts per billion (ppb) at screening. OR
- Documented current Chronic Rhinosinusitis with Nasal Polyps.
Exclusion Criteria:
- Participants have had 3 or more exacerbations in the last year prior to Visit 1.
- Participants on maintenance OCS or high dose ICS/LABA for asthma.
- Participants with a duration of asthma greater than (>)20 years.
- 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, bronchopulmonary aspergillosis, or a history of lung cancer. Participants with current diagnoses of emphysema or chronic bronchitis (Chronic Obstructive Pulmonary Disease other than asthma) are excluded.
- Participants with other conditions that could lead to elevated EOS such as hypereosinophilic syndromes including (but not limited to) Eosinophilic Granulomatosis with Polyangiitis (formerly known as Churg-Strauss Syndrome) or eosinophilic esophagitis.
- Participants who developed an exacerbation within 4 weeks before screening.
- Participants with a known, pre-existing parasitic infestation within 6 months prior to screening unless treated and evidenced to have been resolved.
- A known immunodeficiency (e.g. human immunodeficiency virus), other than that explained by the use of CS taken as therapy for asthma.
- A current malignancy or previous history of cancer in remission for less than 12 months prior to screening.
- Participants who have known, pre-existing, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, psychiatric, renal, gastrointestinal, hepatic, hematologic or any other system abnormalities that are uncontrolled with standard treatment.
- Participants with current diagnosis of vasculitis.
- Participants who have received treatment with any approved or investigational biologic monoclonal antibody (mAb).
- A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to the first dose of study intervention.
- Current smokers or former smokers with a smoking history of >=20 pack years (number of pack years = \[number of cigarettes per day/20\] \* number of years smoked) and vapers.
- Participants with allergy/intolerance to a mAb or biologic or any of the excipients of depemokimab.
- Participants who are pregnant or breastfeeding.
- Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
- Evidence of clinically significant abnormality in the hematological, biochemical or urinalysis screen at screening (Visit 0), as judged by the investigator.
Liver safety exclusion criteria:
- Alanine aminotransferase (ALT) >2\* Upper limit of normal (ULN).
- Total bilirubin >1.5\*ULN; For participants with Gilbert's syndrome: can be included with total bilirubin >1.5\*ULN as long as direct bilirubin is less than or equal to (<=)1.5\*ULN.
- Cirrhosis or current unstable liver or biliary disease as per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice.
Cardiac safety exclusion criteria:
- Electrocardiogram (ECG) Assessment: QTc corrected by Fridericia's formula (QTcF) >=450 millisecond (msec) or QTcF >=480 msec for participants with Bundle Branch Block in the 12-lead ECG central over-read from Screening Visit, or in the 12-lead ECG machine read at Visit 1.
- Participants are excluded if an abnormal ECG finding from central over read of the 12 lead ECG conducted at Screening Visit is considered to be clinically significant and would impact the participant's participation during the study, based on the evaluation of the investigator.
Randomization exclusion criteria:
- ECG Assessment: QTcF >=450 msec or QTcF >=480 msec for participants with Bundle Branch Block in the 12-lead ECG central over-read from Screening Visit, or in the 12 lead ECG machine read at Visit 1.
- ALT >2\*ULN.
- Total bilirubin >1.5\*ULN; For participants with Gilbert's syndrome can be included with total bilirubin >1.5\*ULN as long as direct bilirubin is <=1.5\*ULN.
- Participants with a clinically significant asthma exacerbation in the 7 days prior to randomization should have their randomization visit delayed until the investigator considers the participant's asthma to be stable.
- Maintenance Asthma Therapy: Any changes in the dose or regimen of baseline ICS and/or additional controller medication (except for treatment of an exacerbation) during the run-in period.