This is a first-in-human, Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study evaluating ARQ-234. The study is designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ARQ-234 in two populations: healthy volunteers and participants with moderate to severe atopic dermatitis (AD). Healthy volunteers will participate in Single Ascending Dose (SAD) Cohorts 1-5. Participants with moderate to severe AD will be enrolled in SAD Cohorts 6-7, Multiple Ascending Dose (MAD) Cohorts, and a Proof-of-Concept (POC) expansion cohort.

The study consists of 3 parts with staggered initiation:

• Part A - Phase 1a SAD: ARQ-234 will be assessed in single ascending dose cohorts in healthy volunteer participants and participants with atopic dermatitis.
• Part B - Phase 1b MAD: ARQ-234 will be assessed in multiple ascending cohorts in participants with atopic dermatitis.
• Part C - Phase 1b POC Expansion: ARQ-234 will be assessed in participants with atopic dermatitis.

Inclusion Criteria (All Participants):

• Able and willing to provide written informed consent.
• Adults 18-65 years (inclusive) at consent.
• Generally healthy at screening/baseline (no clinically significant findings on medical history, exam, vitals, ECG, or safety labs, per investigator).
• Contraception requirements: Females of childbearing potential: negative pregnancy tests at screening and baseline and agree to use highly effective contraception (plus barrier method) during the study and for 4 months after last dose. Males if sexually active with a pregnant partner or a female of childbearing potential, agree to condom use during the study and for 4 months after last dose.
• Body weight by study part: Part A (SAD) & Part B (MAD): 50-100 kg (inclusive), Part C (POC): 50-125 kg (inclusive)

Inclusion Criteria for atopic dermatitis (AD) Participants (Parts A Cohorts 6-7, Part B, Part C):

• Diagnosis of moderate-to-severe atopic dermatitis for ≥ 6 months prior to screening.
• Meets minimum disease severity at baseline: Part A Cohorts 6-7: BSA ≥7%, vIGA-AD 3-4, EASI ≥10 at Baseline, Parts B and C: BSA ≥10%, vIGA-AD 3-4, EASI ≥16 at Baseline.
• Inadequate response, intolerance, or medical inappropriateness of topical AD therapies (and/or prior systemic AD therapy failure within the last year may qualify as inadequate response).

Exclusion Criteria (All Participants):

• Any clinically significant medical or psychiatric condition that could increase risk, interfere with participation, or confound results (per investigator).
• Significant renal impairment or clinically significant hepatic impairment (per protocol/part-specific definitions).
• Clinically significant cytopenias or clinically significant abnormal liver tests at screening (per protocol).
• History of anaphylaxis/serious hypersensitivity (including significant hypersensitivity to local anesthetics).
• History of attempted suicide or significant current risk, per investigator).
• Chronic or significant infection history or positive screening tests for hepatitis B, hepatitis C, HIV, or tuberculosis (including positive QuantiFERON or history of active/latent TB).
• Known/suspected immunosuppression or history of invasive opportunistic infections or unusually frequent/recurrent/prolonged infections (per investigator).
• Recent herpes zoster that poses risk or may affect interpretation (per investigator).
• Malignancy within 5 years prior to screening
• Positive urine drug screen at screening (Part A/Part B only) or drug/alcohol abuse within 12 months, or other condition likely to impair compliance (per investigator).
• Unable to discontinue prohibited medications/treatments per protocol.
• Major surgery within 4 weeks prior to baseline or planned during participation.
• Participation in another trial or receipt of investigational product within 12 weeks (or 5 half-lives, whichever longer) before baseline.
• Prior cell-depleting therapy (e.g., rituximab) within 6 months prior to baseline (or until lymphocytes normalize, whichever longer).
• Blood products within 4 weeks prior to baseline or planned during participation.
• Live (attenuated) vaccines within 28 days prior to baseline or planned during the study.
• Pregnant or breastfeeding, or planning pregnancy during the study or within 4 months after last dose.
• Known/suspected allergy to ARQ-234 or its excipients.
• Unable to communicate/understand the local language or otherwise unsuitable per investigator.
• Family member of study staff or sponsor.

Exclusion Criteria for atopic dermatitis (AD) Participants (Parts A Cohorts 6-7, Part B, Part C):

• Skin disease(s) other than AD that would interfere with assessments.
• Active systemic/local infection, including actively infected AD, or infection requiring oral/IV antimicrobials within 14 days before baseline.
• Phototherapy/tanning bed use within 4 weeks prior to baseline.
• Biologic therapy for AD within 3 months or 5 half-lives (whichever longer) prior to baseline.
• Expected need for rescue therapy for AD within the first 2 weeks after baseline.
• History of eczema herpeticum within 12 months or ≥2 prior episodes.