Efficacy and Safety Evaluation of Humanised IgG1 Kappa Monoclonal Antibody Against Thymic Stromal Lymphopoietin in Moderate-to-Severe Atopic Dermatitis

Trial ID: 2024-520302-19-00
Protocol: ATI-045-AD-201
Sponsor: Aclaris Therapeutics Inc.

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Diseases & Conditions

Dermatitis atopic

Objectives

The primary objective of this study is to evaluate the **efficacy** of ATI-045 compared to placebo in patients with moderate-to-severe **atopic dermatitis**. This will be measured by the change in the Eczema Area and Severity Index (EASI) score. The EASI score is a clinically relevant measure as it quantifies the extent and severity of eczema, providing a standardized method to assess treatment outcomes in atopic dermatitis.

Secondary objectives include:

To evaluate the treatment effect of ATI-045 compared to placebo on additional clinical outcome measures.
To assess the safety and tolerability of ATI-045, including the characterization of its immunogenicity profile in patients with moderate-to-severe atopic dermatitis.

Participants

The clinical trial involves a total of **42 participants** diagnosed with **atopic dermatitis**. The study population comprises both male and female adults, aged between 18 and 70 years. Participants were selected based on their chronic condition, with a history of inadequate response to topical treatments or where such treatments are medically inadvisable. All participants have moderate-to-severe atopic dermatitis, as indicated by an Eczema Area and Severity Index (EASI) score of 16 or higher and a validated Investigator Global Assessment (vIGA) score of 3 or more. Additionally, they exhibit a minimum of 10% body surface area involvement and a weekly average of the daily Peak Pruritus Numerical Rating Scale (PP-NRS) score of 4 or higher. Participants are required to maintain a stable dose of non-medicated topical moisturizer and adhere to specific contraceptive measures if applicable. The trial includes a vulnerable population, ensuring comprehensive monitoring and ethical considerations throughout the study.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of ATI-045 in patients with moderate-to-severe **atopic dermatitis**. The trial will involve the administration of ATI-045, a **solution for injection** containing a humanised IgG1 kappa monoclonal antibody against thymic stromal lymphopoietin, compared to a placebo. The study is expected to last for approximately 24 weeks, with participant involvement extending from the initial screening visit through to the end-of-study visit.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease severity, and treatment history. Eligible participants will then be randomized to receive either ATI-045 or placebo. The primary endpoint is the percent change from baseline in the Eczema Area and Severity Index (EASI) score at Week 24. Secondary endpoints include the proportion of patients achieving validated Investigator Global Assessment (vIGA) treatment success, EASI reductions of 50%, 75%, and 90%, and changes in the Peak Pruritus Numerical Rating Scale (PP-NRS) score.

Follow-up visits will occur at regular intervals to monitor treatment efficacy and safety, including the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The end-of-study visit will conclude the trial, with final assessments of efficacy and safety parameters. Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial is structured to ensure rigorous data collection and analysis, adhering to the highest standards of clinical research methodology.

Treatment

The clinical trial involves the administration of **ATI-045**, a **humanised IgG1 kappa monoclonal antibody against thymic stromal lymphopoietin**. This experimental medication is provided in the form of a **solution for injection**. The administration route is **subcutaneous**, with a maximum daily dose of 600 mg and a total maximum dose of 4200 mg over the treatment period. The treatment duration is set for a maximum of 24 weeks. The medication is classified as a biological product and is not formulated specifically for pediatric use. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** comparator, referred to as "Placebo to ATI-045". The placebo is designed to match the experimental treatment in appearance but does not contain the active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo administration follows the same subcutaneous route and dosing schedule as the experimental medication to ensure consistency in the trial conditions.

Efficacy

The efficacy of ATI-045 in patients with moderate-to-severe **Atopic Dermatitis** will be assessed through a randomized, double-blinded, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the percent change from baseline in the Eczema Area and Severity Index (EASI) score at Week 24. Secondary endpoints include the proportion of patients achieving validated Investigator Global Assessment (vIGA) treatment success, defined as a score of 0 or 1 with a reduction of at least 2 points from baseline at Week 24, and the proportion of patients with a 75% reduction in EASI score (EASI75) relative to baseline at Week 24.

Additional secondary endpoints involve changes in the weekly average of the daily Peak Pruritus Numerical Rating Scale (PP-NRS) score, with specific focus on the proportion of patients achieving a 4-point improvement or greater from baseline at Week 24. Other measures include the proportion of patients with EASI reductions of 50% (EASI50) and 90% (EASI90) relative to baseline, as well as changes in body surface area (BSA) affected by the disease at Week 24. The incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will also be monitored from the first dose of the study drug until the patient's last visit. Furthermore, clinical laboratory evaluations, 12-lead ECGs, vital signs, and the presence of anti-ATI-045 antidrug antibodies (ADA) will be assessed to ensure comprehensive safety and efficacy evaluation.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female adults aged ≥ 18 and ≤ 70 years, inclusive at the time of consent.
Chronic AD that has been present for ≥ 6 months before the screening visit and with no significant AD flares during the past 4 weeks before screening.
EASI score ≥ 16 at the screening and the baseline visit (W0D1).
vIGA score ≥ 3 (scale of 0 to 4) at the screening and the baseline visit.
Minimum weekly average of the daily PP-NRS score ≥ 4 in the 7 days before the baseline visit.
≥10% body surface area (BSA) of AD involvement at the screening and baseline visit.
Photographs at screening are representative of the disease diagnosis and extent
History of inadequate response to treatment for AD with topical medications; or determination that topical treatments are otherwise medically inadvisable. Note: History of inadequate response to or lack of tolerability (as assessed by the investigator based on information obtained from medical chart, patient’s physician, or directly from the patient), of a stable regimen (≥ 4 weeks or for the duration recommended by the product prescribing information) of one or more topical treatments (e.g., moderate to high potency TCSs and/or TCIs) before the Screening visit, or for whom topical treatments are otherwise inadvisable.
The patient has applied a stable dose of non-medicated topical moisturizer (ideally once or twice daily) for ≥ 7 days prior to the baseline visit and agrees to continue using the same moisturizer daily at the same frequency throughout the study.
Willing and able to comply with all clinic visits and study-related procedures and questionnaires.
Provide signed informed consent.
A male patient who is non-sterilized and sexually active with a female partner of childbearing potential agrees to use a condom and a highly effective contraception from screening, throughout the duration of the study treatment and for 180 days after the last dose of study drug.
A female patient of childbearing potential who is sexually active with a non-sterilized male partner agrees to routinely use highly effective contraception from screening, throughout the duration of the study treatment and for 120 days after the last dose of study drug.

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Exclusion Criteria

Treatment with any of the following: a. Intravenous immunoglobulin within 12 weeks prior to the baseline visit (W0D1) b. Systemic antibiotics within 2 weeks prior to the baseline visit (W0D1) c. Topical antibiotics within 1 week prior the baseline visit (W0D1) d. Topical medicated treatment that could affect atopic dermatitis should be prohibited for at least 2 weeks prior to baseline visit. Example: topical corticosteroids, crisaborole, calcineurin inhibitors, ruxolitinib, roflumilast, tars, antimicrobials, medical devices, and bleach baths. e. Topical products containing urea within 1 week prior to baseline visit (W0D1) f. Doxepin, hydroxyzine, or diphenhydramine within 1 week prior to the baseline visit (W0D1) g. Patient has used systemic treatments (other than biologics) that could affect AD less than 4 weeks or 5 half-lives (whichever is longer) prior to the baseline visit (W0D1), including, but not limited to, retinoids, calcineurin inhibitors, methotrexate, cyclosporine, hydroxycarbamide (hydroxyurea), azathioprine, oral/injectable corticosteroids, baricitinib, upadacitinib, and abrocitinib. h. Biologics for AD treatments (such as dupilumab, tralokinumab, lebrikizumab, investigational biologics) within 5 half- lives or 12 weeks, whichever is longer prior to the baseline visit (W0D1) i. An investigational drug (non-biologic) within 4 weeks or within 5 half-lives (if known), whichever is longer prior to the baseline visit (W0D1) j. Phototherapy and photochemotherapy for AD within 4 weeks prior to the baseline visit (W0D1) k. A live (attenuated) vaccine within 12 weeks prior to the baseline visit (W0D1)
Abnormal (clinically significant) electrocardiogram (ECG) at the screening visit. Entry of any patient with an abnormal (not clinically significant) ECG must be approved and documented by signature of the Investigator. In the case of a corrected QT interval (Fridericia) (QTcF) > 450 ms or > 470 ms (patients with bundle branch block) or PR interval outside the range of 115 to 220 ms, assessment may be repeated once for eligibility determination.
Positive test result for hepatitis B surface antigen (HbsAg), Hepatitis B core Antibody (HBcAb), antihepatitis C virus (HCV), or for human immunodeficiency virus (HIV), or a known history of HIV infection at the screening visit. Patients with a history of hepatitis B vaccination without a history of hepatitis B are allowed to enroll in the study.
Known presence of active tuberculosis or a history of tuberculosis disease. History of tuberculosis exposure/infection (e.g. positive purified protein derivative test or an alternative test like Interferon Gamma Release Assay) is not an exclusion, though history of positive test will require prior documented completed prophylactic treatment. In case of known latent tuberculosis (or prior indeterminate result), or positive/indeterminate result at screening when done, participants will be allowed to participate only after a consultation with a TB specialist or infectious diseases specialist, and their written approval. Note: In North America, this is only based on history – there is no testing or imaging required as part of this exclusion criterion, outside North America QuantiFERON GOLD TB test will also be done at screening.
Diagnosed with a helminthic parasitic infection within 6 months prior to the screening visit or at high risk of these infections as per the judgement of the Investigator.
Major surgical or major dental procedure within 8 weeks prior to the screening visit or a planned major surgery during the study.
Patient is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study. Female patients must agree to not have egg retrieval from W0D1 until at least 120 days after the last dose of study product.
Male patient intends to donate sperm during this study or within 180 days since the last dose of study drug.
History of malignancy, except for adequately treated basal or squamous cell skin cancer or in situ cancers; or any other cancer from which the patient has been disease free for at least 5 years prior to the baseline visit.
The patient has donated or lost ≥ 450 mL of blood (including plasmapheresis) or had a transfusion of any blood product within 90 days prior to the baseline visit.
Poorly controlled hypertension, not suitable for participation in this study in the judgement of the Investigators at screening assessment.
History of anaphylaxis following biologic therapy.
Patient has excessive sun exposure, is planning a trip in a sunny climate, or has used tanning booths within 4 weeks prior to W0D1, or is not willing to minimize natural and artificial sunlight exposure during the study. Use of sunscreen products and protective apparel are recommended when exposure cannot be avoided
The patient plans to use any other prohibited medication or undergo any prohibited procedure during the study.
Current or any recent (within last 12 months prior to screening) substance (including alcohol) abuse disorder. Note: Marijuana use is allowed, if not considered substance abuse by the investigator. If a patient uses marijuana, it is recommended that patient refrain from all marijuana use for 24 hours prior to any study site visit.
23.The patient is compulsorily detained for a medical or psychiatric illness.
24.The patient or their immediate family are personnel at the study site.
Patient has a known or suspected allergy to any component of the investigational product
Other dermatologic conditions that might confound a diagnosis of AD or a treatment assessment as per the Investigator.
Uncontrolled chronic disease that might require burst of oral corticosteroids, e.g., comorbid severe uncontrolled asthma or a history of ≥ 2 asthma exacerbations within the last 12 months requiring systemic [oral and/or parenteral] corticosteroid treatment or hospitalization for > 24 hours).
Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit, or superficial skin infections within 1 week prior to the baseline visit. NOTE: patients may be rescreened after infection resolves.
Any clinically significant illness that may affect the safety, increase the risk for seizure or lower the seizure threshold, or potentially confound the study results, as per the Investigator, such as cardiovascular, neurologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, immunologic, endocrine, or psychiatric disease or disorder, or other abnormality. It is the responsibility of the Investigator to assess the clinical significance of a patient’s condition; however, consultation with the Medical Monitor may be warranted.
Clinically significant laboratory abnormalities including but not limited to: a.Hemoglobin < 10.0 g/dL b.White blood cell count < 2.5 ×10^9 /L (< 2500/mm3) c.Absolute neutrophil count of < 1.0 × 10^9 /L (< 1000/mm3) d.Absolute lymphocyte count of < 0.5 × 10^9 /L (< 500/mm3) e.Platelet count <100,000/μL f.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values ˃ 2 times the upper limit of normal (ULN) g.Alkaline phosphatase (ALP) > 3 × ULN h.Total bilirubin level > 2 × ULN unless participant has been diagnosed with Gilbert syndrome, and this is clearly documented
History of allergy to corticosteroids, diphenhydramine, hydroxyzine, cetirizine, or fexofenadine.