Randomized, Double-blind, Placebo-controlled Study of Nemolizumab in Chinese Subjects With Moderate-to-severe Atopic Dermatitis

Inclusion criteria

• Chinese subjects aged ≥ 12 years at the screening visit.
• Chronic AD for at least 2 years before the screening visit and confirmed according to American Academy of Dermatology Consensus Criteria (Eichenfield 2014, Appendix 1) at the time of the screening visit.
• EASI score ≥ 16 at both the screening and baseline visits.
• IGA score ≥ 3 (based on the IGA scale ranging from 0 to 4, in which 3 is moderate and 4 is severe) at both the screening and baseline visits.
• AD involvement ≥ 10% of body surface area (BSA) at both the screening and baseline visits.
• Peak (maximum) pruritus NRS score of at least 4.0 at the screening and baseline visit:

• Screening PP-NRS score will be determined by a single PP-NRS assessment (score ranging from 0 to 10) for the 24-hour period immediately preceding the screening visit.
• Baseline PP-NRS score will be determined based on the average of daily PP-NRS scores (score ranging from 0 to 10) during the 7 days immediately preceding baseline (rounding not permitted). A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.
• Documented history (within 6 months before the screening visit) of inadequate response to topical medications (TCS with or without TCI). Acceptable documentation includes patient records with information on TCS (with or without TCI) prescription and treatment outcome, or written documentation of the conversation with the subject's treating physician, if different than the investigator.

Inadequate response to TCS treatments (with or without TCI) is defined as:

• Failure to achieve or maintain remission or low disease activity (equivalent to IGA ≤ 2) despite treatment with a regimen of a medium- or high-potency TCS* (with or without TCI), applied for at least 4 weeks or for the maximum duration per prescribing information; or
• Requirement of a long-term treatment (> 4 weeks) with a high-potency TCS* (with or without TCI) to achieve or maintain remission or low disease activity (equivalent to IGA ≤ 2); Note: If subjects had received a TCI in addition to a TCS, documentation on failure to achieve or maintain remission or low disease activity (equivalent to IGA ≤ 2) is also required.

or c. If documentation of inadequate response to topical treatments is not available, subjects with a documented recent course of systemic treatment or phototherapy for AD (within 6 months before the visit) will also be considered as inadequate responders to topical treatments.

If documentation is inadequate, subjects may be rescreened after such documentation is obtained.

• Refer to Appendix 2 for a listing of permitted medium and high-potency TCS medications that are commercially available in China.
• Agree to apply an authorized TCS ± TCI from the screening visit and throughout the study as determined appropriate by the investigator.
• Women of childbearing potential (WOCBP) must agree either to commit to true abstinence throughout the study and for 12 weeks after the last IP injection, when this is in line with the preferred and usual lifestyle of the subject, or to use an effective and approved method of contraception throughout the study and for 12 weeks after the last IP injection. This criterion also applies to a prepubertal female subject who begins menses during the study. Adequate and approved methods of contraception applicable for the subject and/or her partner are defined below:

• Progestogen-only oral hormonal contraception
• Combination of male condom with cap, diaphragm, or sponge with spermicide
• Combined (estrogen- and progestogen-containing) oral, intravaginal, or transdermal hormonal contraception (double barrier methods)
• Injectable or implanted hormonal contraception
• Intrauterine devices
• Bilateral tubal ligation or tube insert (such as the Essure system) at least 3 months before the study
• Vasectomy of partner at least 3 months before the study W Emergency contraception to prevent pregnancy after unprotected intercourse are not acceptable methods for routine use.
• Female subjects of non-childbearing potential must meet one of the following criteria:

• Absence of menstrual bleeding for 1 year prior to screening without any other medical reason, confirmed with follicle stimulating hormone (FSH) level in the postmenopausal range.
• Documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 3 months before the study Note: Bilateral tubal ligation is not accepted as a reason for non-childbearing potential.
• Subject willing and able to comply with all of the time commitments and procedural requirements of the clinical study protocol.
• Understand and sign an informed consent form/assent form before any investigational procedure(s) are performed

Exclusion criteria

• Body weight < 30 kg.
• Cutaneous infection within 1 week before the baseline visit, any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks before the baseline visit.
• Known or suspected history of immunosuppression, or unusually frequent, recurrent, severe, or prolonged infections, as per investigator's judgment.
• History of lymphoproliferative disease or history of malignancy of any organ system within the last 5 years, except for (1) basal cell carcinoma, squamous cell carcinoma in situ (Bowen's disease), or carcinomas in situ of the cervix that have been treated and have no evidence of recurrence in the last 12 weeks before the baseline visit, or (2) actinic keratoses that have been treated.
• Presence of confounding skin condition that may interfere with study assessments (e.g. Netherton syndrome, psoriasis, cutaneous T-cell lymphoma [mycosis fungoides or Sezary syndrome], contact dermatitis, chronic actinic dermatitis, dermatitis herpetiformis).
• Pregnant women (positive serum pregnancy test result at the screening visit or positive urine pregnancy test at the baseline visit), breastfeeding women, or women planning a pregnancy during the clinical study.
• Any medical (e.g., serious cardiac/hepatic/lung [including uncontrolled asthma]/hematologic disease) or psychological condition or any clinically relevant laboratory abnormalities, such as but not limited to elevated ALT or AST (> 3 × upper limit of normal [ULN]) in combination with elevated bilirubin (> 2 × ULN), during the screening period that may put the subject at significant risk according to the investigator's judgment, if he/she participates in the clinical study, or may interfere with study assessments (e.g. poor venous access or needle-phobia).
• Planned or expected major surgical procedure during the clinical study.
• Having received any of the following treatments within the specified timeframe before the baseline visit:

Treatment(s) Timeframe Coal tar products 2 weeks Topical PDE-4 inhibitor 2 weeks Non-authorized TCS 2 weeks Topical medications, including authorized TCS/TCI, with occlusive dressings (e.g., wet wraps) 2 weeks Systemic corticosteroids (corticosteroid inhalers and intraocular corticosteroids are permitted) 4 weeks Phototherapy or tanning beds 4 weeks Immunosuppressive or immunomodulatory drugs (e.g., cyclosporin A, oral tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, Janus kinase inhibitors) 4 weeks or 5 half-lives (whichever is longer) Biologics and their biosimilars (e.g., etanercept, adalimumab, infliximab, omalizumab) 8 weeks or 5 half-lives (whichever is longer) Dupilumab 10 weeks Live-attenuated vaccines 4 weeks Drugs with a sedative effect such as benzodiazepines, imidazopyridines, barbiturates, sedative antidepressants (e.g., amitriptyline), SSRIs (e.g., paroxetine), or SNRIs, except if these treatments were taken at a stable dose for at least 3 months before screening (Stable treatment with antihistamines with sedative effect is allowed.) 1 week Gabapentinoids (e.g., gabapentin, pregabalin) 4 weeks Cannabinoids 2 weeks Cannabinoids alternative medicine for AD (e.g., traditional Chinese medicine) 2 weeks Aromatic Hydrocarbon Receptor [AhR] modulator (e.g. tapinarof ) 2 weeks

Abbreviations: AD = atopic dermatitis; PDE-4 = phosphodiesterase-4; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.

Note: Subjects should not interrupt ongoing treatment with medications important for the subject's health for the sole purpose of participating in this study.

• Subjects unwilling to refrain from using prohibited medications during the clinical study.
• Requiring rescue therapy for AD during the screening period or expected to require systemic rescue therapy during the treatment period.
• Previous treatment with nemolizumab.
• History of hypersensitivity (including anaphylaxis) to an immunoglobulin product (plasma-derived or recombinant, e.g., monoclonal antibody) or to any of the IP excipients.
• History of intolerance to low- or medium-potency TCS or for whom TCS is not advisable (e.g., hypersensitivity, significant skin atrophy).
• Currently participating or participated in any other study of an investigational drug or device, within the past 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) before the screening visit.