This phase 2b study is designed to evaluate the safety and efficacy of KT-621 in adult and adolescent participants with moderate-to-severe atopic dermatitis (AD), a common form of eczema. The main goals of this study are to learn how effective KT-621 is at reducing the severity and extent of AD, the safety and tolerability of KT-621, how KT-621 behaves in the body, and how the body responds to KT-621. This is a 16-week double-blind, placebo-controlled study with a 52-week open-label period.

Inclusion Criteria:

• Must be 12 to 75 years of age, inclusive, at the time of signing the IAF (informed assent form) and/or ICF (informed consent form).
• Must have chronic AD that has been present for at least 3 years (for participants ≥ 18 years of age) or 1 year (for participants < 18 years of age) before the Screening visit.
• Must have an EASI score ≥ 16 at the Screening and Baseline visits.
• Must have a vIGA-AD score ≥ 3 (scale of 0 to 4) at the Screening and Baseline visits.
• Must have at least 10% BSA of AD involvement at the Screening and Baseline visits.
• Must have a weekly average Peak Pruritus NRS value ≥ 4 at the Baseline visit.
• Must have a history within the 6 months prior to the Baseline visit of either an inadequate response to, or inability to take, topical medications for the treatment of AD.
• Must apply a stable dose of moisturizer at least twice daily for at least 7 consecutive days immediately prior to the Baseline visit. Participants should be willing to continue using moisturizer twice daily during the study.
• Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, other study-related procedures, and questionnaires, including completing the electronic diary (e-diary), for the duration of the study as required by the study protocol.
• Must agree to contraceptive requirements in compliance with the clinical study and local requirements.

Exclusion Criteria:

• Must not have an unstable course of AD (spontaneously improving or rapidly deteriorating) as determined by the Investigator in the 4 weeks before the baseline visit.
• Must not have other skin conditions, such as contact dermatitis, psoriasis, tinea corporis, or lupus erythematosus, that may interfere with study assessments.
• Must not have a clinically relevant history of respiratory, gastrointestinal (GI), renal, hepatic, hematological, lymphatic, endocrinological, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, ophthalmological, or connective tissue diseases or disorders.
• Must not have any surgical or medical procedure planned during participation in the study.
• Must not have a history of alcohol or substance abuse within the previous 2 years.
• Must not be pregnant or breastfeeding; must not be a woman planning to become pregnant or breastfeed during the study.
• Must not have a history of lack of response to any medication targeting interleukin (IL)-4, IL-13, and/or janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways (e.g. dupilumab, tralokinumab, upadacitinib, abrocitinib) at approved doses after at least 16 weeks of therapy.
• Must not have results from clinical laboratory safety tests that are outside the local reference range at Screening.
• Must not have been dosed with any investigational drug or device in a clinical study within 8 weeks or 5 half-lives (whichever is longer) of KT-621 administration.
• Female participants of childbearing potential must not have a positive or undetermined pregnancy result at the Screening and baseline visits.
• Must not have any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results.
• Must not be taking or have taken any prespecified prohibited therapies within a specific timeframe as evaluated by the Investigator.
• Must not have a known sensitivity to any of the components of KT-621.
• Must not be a member of the investigational team or his/her immediate family.