Nemolizumab

12.1 Mechanism of Action Nemolizumab-ilto is a humanized IgG2 monoclonal antibody that inhibits IL-31 signaling by binding selectively to IL-31 RA. IL-31 is a naturally occurring cytokine that is involved in pruritus, inflammation, epidermal dysregulation, and fibrosis. Nemolizumab-ilto inhibited IL-31-induced responses including the release of proinflammatory cytokines and chemokines.

1 INDICATIONS AND USAGE NEMLUVIO is an interleukin-31 receptor antagonist indicated for: Prurigo Nodularis The treatment of adults with prurigo nodularis. ( 1.1 ) Atopic Dermatitis The treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors when the disease is not adequately controlled with topical prescription therapies. ( 1.2 ) 1.1 Prurigo Nodularis NEMLUVIO is indicated for the treatment of adults with prurigo nodularis. 1.2 Atopic Dermatitis NEMLUVIO is indicated for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors when the disease is not adequately controlled with topical prescription therapies.

2 DOSAGE AND ADMINISTRATION Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO. ( 2.1 ) Prurigo Nodularis: Adult Patients Weighing Less Than 90kg: The recommended subcutaneous dosage is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. ( 2.2 ) Adult Patients Weighing 90kg or More: The recommended subcutaneous dosage is an initial dose of 60 mg (two 30 mg injections), followed by 60 mg given every 4 weeks. ( 2.2 ) Atopic Dermatitis: The recommended subcutaneous dosage is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. ( 2.3 ) After 16 weeks of treatment, for patients who achieve clear or almost clear skin, a dosage of 30 mg every 8 weeks is recommended. ( 2.3 ) Use NEMLUVIO with topical corticosteroids and/or topical calcineurin inhibitors. When the disease has sufficiently improved, discontinue use of topical therapies. ( 2.3 ) Administer NEMLUVIO by subcutaneous injection. ( 2.5 ) NEMLUVIO must be reconstituted prior to administration. ( 2.6 ) 2.1 Vaccination Prior to Treatment Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO [ see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage for Prurigo Nodularis Adult Patients Weighing Less Than 90 kg: The recommended subcutaneous dosage of NEMLUVIO for adult patients weighing less than 90 kg is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. Adult Patients Weighing 90 kg or More: The recommended subcutaneous dosage of NEMLUVIO for adult patients weighing 90 kg or more is an initial dose of 60 mg (two 30 mg injections), followed by 60 mg given every 4 weeks. 2.3 Recommended Dosage for Atopic Dermatitis The recommended subcutaneous dosage of NEMLUVIO in adults and pediatric patients 12 years of age and older is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. After 16 weeks of treatment, for patients who achieve clear or almost clear skin, a subcutaneous dosage of 30 mg every 8 weeks is recommended. Concomitant Topical Therapies: Use NEMLUVIO with topical corticosteroids and/or topical calcineurin inhibitors. When the disease has sufficiently improved, discontinue use of topical therapies. 2.4 Missed Dose If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. 2.5 Important Administration Instructions NEMLUVIO is administered by subcutaneous injection. NEMLUVIO is intended for use under the guidance of a healthcare provider. Prior to the first injection, provide patients and/or caregivers with proper training on the preparation and administration of NEMLUVIO. Patients may self-inject NEMLUVIO after receiving training on subcutaneous injection techniques. In pediatric patients 12 years of age and older, administer NEMLUVIO by or under the supervision of a trained adult or caregiver. For the initial dose, administer each of the two NEMLUVIO injections at different injection sites. Administer NEMLUVIO subcutaneously into the front upper thighs or abdomen avoiding the 2-inch (5 cm) area around the navel. NEMLUVO may be subcutaneously injected into the upper arm, but this should only be performed by a caregiver or healthcare professional. Alternate the injection site with each injection. Do not inject NEMLUVIO into skin that is tender, inflamed, swollen, damaged or has bruises or scars or open wounds. Refer to the Instructions for Use for complete administration instructions with illustrations [ see Instructions for Use ]. 2.6 Preparation for Use of NEMLUVIO Before injection, remove NEMLUVIO carton from the refrigerator and allow to reach room temperature (30-45 minutes). Inspect NEMLUVIO visually prior to reconstitution. NEMLUVIO is supplied in a single-dose, prefilled, dual-chamber pen with white powder in one chamber and a clear diluent in the other chamber. Do not use if powder is not white, or if diluent is cloudy or contains visible particles. NEMLUVIO must be reconstituted prior to administration. Refer to the Instructions for Use for complete preparation instructions with illustrations [ see Instructions for Use ]. Following reconstitution, each prefilled pen delivers 30 mg/0.49 mL as a clear and colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the reconstituted solution has discoloration or contains particles. Use NEMLUVIO pens within 4 hours after reconstitution. Discard unused reconstituted NEMLUVIO pens after 4 hours. Discard any unused portions after administration.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater details elsewhere in the labeling: Hypersensitivity [ see Warnings and Precautions (5.1) ] Most common adverse reactions are: Prurigo Nodularis (incidence ≥1%): headache, dermatitis atopic, eczema, and eczema nummular. ( 6.1 ) Atopic Dermatitis (incidence ≥1%): headache (including migraine), arthralgia, urticaria, and myalgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Prurigo Nodularis A total of 508 adult subjects with prurigo nodularis were treated with NEMLUVIO in two placebo-controlled trials and an open label long-term extension trial. Of these, 375 subjects were exposed for at least 1 year in the drug development program for prurigo nodularis. The safety of NEMLUVIO in adult subjects with prurigo nodularis was evaluated in two randomized, doubleblind, placebo-controlled, multicenter trials (OLYMPIA 1 and OLYMPIA 2). Subjects were treated for up to 24 weeks in OLYMPIA 1 and up to 16 weeks in OLYMPIA 2. In these 2 trials, 370 subjects were treated with subcutaneous injections of NEMLUVIO, and 186 subjects received placebo [ see Clinical Studies (14.1 )]. Subjects weighing less than 90 kg in the NEMLUVIO group received an initial NEMLUVIO dose of 60 mg or placebo at Week 0, followed by a NEMLUVIO dose of 30 mg or placebo every 4 weeks. Subjects weighing 90 kg or more in the NEMLUVIO group received an initial NEMLUVIO dose of 60 mg or placebo at Week 0 followed by a NEMLUVIO dose of 60 mg or placebo every 4 weeks. During the treatment period in Trials OLYMPIA 1 and OLYMPIA 2, the proportion of subjects who discontinued treatment because of adverse reactions was 4% in the NEMLUVIO group versus 3% in the placebo group. Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% in the NEMLUVIO group, and for which the rate exceeds the rate in the placebo group through Week 16. Table 1: Adverse Reactions Occurring in ≥1% of Adult Subjects with Prurigo Nodularis in the NEMLUVIO Group and Greater than Placebo in the OLYMPIA 1 and OLYMPIA 2 Trials through Week 16. *includes: headache and tension headache Adverse Reaction NEMLUVIO N= 370 n (%) Placebo (N= 186) n (%) Headache* 23 (6) 6 (3) Dermatitis atopic 16 (4) 1 (0.5) Eczema 14 (4) 3 (2) Eczema nummular 11 (3) 0 Specific Adverse Reactions Hypersensitivity reactions Type 1 hypersensitivity reactions (Ig-E mediated reactions), including one report of discrete facial (peri-ocular) angioedema, were reported in subjects treated with NEMLUVIO [ see Contraindications (4) ]. Atopic Dermatitis Adults and Pediatric Subjects 12 Years of Age and Older A total of 1148 subjects, including 180 subjects 12 to 17 years of age, with moderate-to-severe atopic dermatitis were treated with NEMLUVIO for at least 1 year during the drug development program. The safety of NEMLUVIO was evaluated in a pool of two randomized, double-blind, placebo-controlled, multicenter phase 3 trials (ARCADIA 1, ARCADIA 2). In these two trials, 1135 adult and pediatric subjects 12 years of age and older with moderate-to-severe AD were treated with subcutaneous injections of NEMLUVIO (initial dose of 60 mg, followed by 30 mg every 4 weeks), with concomitant topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) for up to 16 weeks (Initial Treatment Period) [ see Clinical Studies (14.2 )]. After the Initial Treatment Period, subjects who responded to NEMLUVIO were re-randomized to receive NEMLUVIO 30 mg every 4 weeks, NEMLUVIO 30 mg every 8 weeks, or placebo every 4 weeks for the Maintenance Treatment Period (Week 16 through Week 48) [see Clinical Studies (14.2)] . The safety population during the Maintenance Treatment Period had a mean age of 31 to 33 years (median age of 26 to 29 years) for the NEMLUVIO cohorts. Week 0 to Week 16 In ARCADIA 1 and ARCADIA 2 trials through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 2.3% in the NEMLUVIO every 4 weeks group and 2.2% in the placebo groups. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% in the NEMLUVIO group, and for which the rate exceeds the rate in the placebo group during the first 16 weeks of treatment. Table 2: Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 12 Years of Age and Older with Atopic Dermatitis in the NEMLUVIO Group and Greater than in the Placebo Group in ARCADIA 1 and ARCADIA 2 Trials through Week 16 Adverse reactions NEMLUVIO N = 1135 n (%) Placebo N=584 n (%) Headache (incl. migraine) 52 (5) 22 (4) Art