A Study of KT-621 Administered Orally to Adult Participants with Moderate to Severe Eosinophilic Asthma

Prior treatment

• Current smokers of nicotine/tobacco as well as non-nicotine products, participants with smoking history of ≥10 pack years, and participants using vaping products, including electronic cigarettes. Former smokers with a smoking history of < 10 pack years and users of vaping or e-cigarette products must have stopped for at least 26 weeks prior to the Screening visit (V1).
• An asthma exacerbation, requiring either treatment with systemic corticosteroids (intramuscular, intravenous, or oral) and/or hospitalization or an emergency/urgent medical care visit for acute asthma worsening, at any time from 4 weeks prior to the Screening visit (V1) up to and including the Baseline visit (V2).
• Has had any major surgery within 8 weeks prior to the Screening visit (V1) or has any planned surgical or medical procedure planned during the study
• Has a chronic or acute infection, including upper or lower respiratory tract infection, requiring treatment with systemic antibiotics, antiparasitics, antifungals, or antivirals that were completed within 4 weeks of Baseline or during the Screening period.

Other illness

• Has any medical or psychiatric condition which, in the opinion of the Investigator or the Sponsor's Medical Monitor, would place the participant at risk, interfere with participation in the study, or interfere with the interpretation of study results.
• Has a history of alcohol or drug abuse within 2 years of the Screening visit (V1).
• Has any cancer or a history of cancers within the last 5 years (except curatively treated with surgical excised squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin or cervix).
• Has had any of the following at Screening: a. Positive human immunodeficiency virus (HIV) antibody b. Positive hepatitis B (HBV) surface antigen (HBsAg) c. Positive total hepatitis B core antibody (HBcAb) d. Positive hepatitis C virus (HCV) antibody e. Have evidence of active or latent or inadequately treated infection with mycobacterium tuberculosis (TB)
• Known or suspected history of immunodeficiency disorder, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite infection resolution; or unusually frequent, recurrent or prolonged infections, per Investigator's judgment.
• Has a clinically significant history or evidence of any active or suspected parasitic infection within 4 weeks of the Baseline visit (V2) or has travelled within the 3 months before Baseline to areas of high parasitic exposure, as determined by local or international health guidelines or epidemiological data.

Lab values

• The presence of any clinically significant pulmonary disease other than asthma, including, but not limited to, active lung infection, chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity associated hypoventilation syndrome, lung cancer, alpha 1 antitrypsin deficiency, or primary ciliary dyskinesia. Additionally, any pulmonary or systemic condition other than asthma that is associated with elevated peripheral eosinophil counts, such as allergic bronchopulmonary aspergillosis/mycosis, Churg Strauss syndrome, or hypereosinophilic syndrome.
• Has any of the following findings at the Screening visit (V1): a. Inadequate hematological function, as follows: i. Platelet count < 100 × 10^9/L (< 100,000/µL) ii. Hemoglobin < 9 g/dL iii. Absolute neutrophil count < 1.5 × 10^9/L (< 1,500/µL) b. Inadequate liver function, as follows: i. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN) ii. Total bilirubin > 1.5 x ULN (participants with Gilbert's syndrome can be included with total bilirubin > 1.5 × ULN) as long as direct bilirubin is ≤ 1.5 x ULN)
• Has any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with participant safety, study evaluations, and/or study procedures. Examples include, but are not limited to, participants with short life expectancy, participants with uncontrolled diabetes (hemoglobin A1c ≥9%), partecipants with cardiovascular conditions (eg, heart failure, uncontrolled hypertension), severe renal conditions (eg, participants on dialysis), hepatobiliary conditions (eg, Child Pugh class B or C), neurological conditions (eg, demyelinating diseases), active major autoimmune diseases (such as, but not limited to, lupus, inflammatory bowel disease, rheumatoid arthritis), and other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases.

• Documented history of at least 1 asthma exacerbation requiring either treatment with systemic corticosteroids (intramuscular, intravenous, or oral) and/or hospitalization or an emergency/urgent medical care visit for acute asthma worsening within the past 52 weeks prior to Screening (V1).
• Absolute blood eosinophil count must be ≥0.30 x 10^9/L at Screening; up to 2 repeat assessments (3 total) are allowed during the screening period up to the Baseline visit (V2).
• Male or female assigned at birth, inclusive of all gender identities. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Must be 18 years old (or the legal age of consent in the jurisdiction in which the study is taking place) to 75 years of age, inclusive, at the time of signing the ICF.
• Must have a physician diagnosis of asthma for ≥ 52 weeks prior to the Screening visit (V1), based on the Global Initiative for Asthma (GINA) 2024 guidelines.
• Must be on a stable regimen of medium- to high-dose inhaled corticosteroid (ICS) defined as ≥500 µg fluticasone propionate DPI (or equivalent total daily dose) in combination with a long-acting β2-agonist (LABA). The regimen may include additional controller medication (e.g., leukotriene receptor antagonist [LTRA] and/or long-acting muscarinic antagonist [LAMA]). All background controller medications must have been used for ≥12 weeks prior to Screening (V1) and be at a stable dose and regimen with no change in dose or frequency of administration for ≥4 weeks prior to Screening (V1) and between Screening and Baseline (V2).
• Morning pre-bronchodilator FEV₁ 40–80% of predicted normal at Screening (V1) and at Baseline (V2), prior to randomization. Up to 2 repeat assessments (3 total) are allowed during the Screening period up to Baseline. If the criterion is not met at Baseline (V2), one additional repeat Baseline visit is permitted within 5 days; at a repeat Baseline visit all baseline assessments must be repeated in full. The qualifying Baseline visit will be used to determine timing of subsequent visits.
• ACQ-5 score ≥ 1.5 at the Screening visit (V1) and at the Baseline visit (V2), prior to randomization.
• Fractional exhaled nitric oxide (FeNO) ≥25 ppb at Screening (V1) and at Baseline (V2). Up to 2 repeat assessments (3 total) are allowed during Screening up to Baseline. If not met at Baseline (V2), one additional repeat Baseline assessment is permitted within 5 days; at a repeat Baseline visit all baseline assessments must be repeated in full.
• Demonstrated evidence of reversible airway obstruction by post-bronchodilator (albuterol/salbutamol) reversibility of FEV₁ at Screening (15–30 minutes after administration of 2–4 puffs of albuterol/salbutamol). Up to 2 repeat assessments (3 total) are allowed during Screening up to Baseline. If applicable, the repeat Baseline allowance described for Criteria 4–6 applies.