Get your patient on Nemluvio (Nemolizumab-Ilto)

NEMLUVIO is indicated for the treatment of adults with prurigo nodularis.

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.

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.

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.

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

• 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 ].

• 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.

Risk Summary
Available data on NEMLUVIO use in pregnant women exposed during clinical trials are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In an enhanced pre- and postnatal development study in cynomolgus monkeys, when nemolizumab-ilto was administered subcutaneously during organogenesis to parturition, an increase in early postnatal death was observed at a dose 36 times the maximum recommended human dose (MRHD) for PN and 50 times for AD (see Data). The clinical significance of this nonclinical finding is unknown.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary
There are no data on the presence of nemolizumab-ilto in human milk, the effects on the breastfed infant, or the effects on milk production. Nemolizumab-ilto was detected in breast milk of monkeys (see Data). Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to nemolizumab-ilto are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEMLUVIO and any potential adverse effects on the breastfed child from NEMLUVIO or from the underlying maternal condition.

Prurigo Nodularis
The safety and effectiveness of NEMLUVIO have not been established in pediatric patients.

Atopic Dermatitis
The safety and effectiveness of NEMLUVIO for the treatment of moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors have been established in pediatric patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies. Use of NEMLUVIO for this indication is supported by evidence from two randomized, double-blind, placebo-controlled trials [See Adverse Reactions (6.1) and Clinical Studies (14.2) ].

The safety and effectiveness of NEMLUVIO have not been established in pediatric patients younger than 12 years of age.

Prurigo Nodularis
Of the 370 subjects with prurigo nodularis exposed to NEMLUVIO in OLYMPIA 1 and OLYMPIA 2, 99 (26.8%) subjects were 65 years of age or older. The long-term safety of NEMLUVIO was assessed in 508 subjects, among which 133 (26.2%) were 65 years of age or older. Clinical trials of NEMLUVIO did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger adult subjects. [see Clinical Pharmacology (12.3) ].

Atopic Dermatitis
Of the 1192 subjects with atopic dermatitis exposed to NEMLUVIO in the primary safety population, 72 (6.0%) subjects were 65 years of age or older. The long-term safety of NEMLUVIO was assessed in 78 (4.5%) subjects 65 years of age or older. Clinical studies of NEMLUVIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects [see Clinical Pharmacology (12.3) ].

Hypersensitivity reactions, such as facial angioedema, have been reported with use of NEMLUVIO. NEMLUVIO is contraindicated in patients with a known hypersensitivity to nemolizumab-ilto or to any of the excipients in NEMLUVIO. If a clinically significant hypersensitivity reaction occurs, immediately institute appropriate therapy and discontinue NEMLUVIO [see Contraindications (4) , Adverse Reactions (6.1) ].

Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO. Avoid use of live vaccines in patients during treatment with NEMLUVIO. It is unknown if administration of live vaccines during NEMLUVIO treatment will impact the safety or effectiveness of these vaccines. No data are available on the response to non-live vaccines.

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.

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.

Pharmacodynamics of nemolizumab-ilto in the treatment of prurigo nodularis and atopic dermatitis are unknown.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of nemolizumab-ilto or other nemolizumab products.

Prurigo Nodularis:

• In the Phase 3 trials (OLYMPIA 1, OLYMPIA 2) up to 24 weeks, the incidence of treatment-emergent ADAs was 7%; neutralizing antibodies were seen in 3% of subjects.

Atopic Dermatitis:

• In the phase 3 trials (ARCADIA 1, ARCADIA 2) up to 16 weeks, the incidence of treatment-emergent ADAs was 6.1% (67/1092). Among subjects who continued treatment from week 16 through week 48 in the two studies, the ADA incidence was 13.9% (23/166) for those that received 30 mg every 4 weeks, and 10.6% (17/161) for those that received 30 mg every 8 weeks. Neutralizing antibody incidence was 4.5% (3/67) among the ADA+ subjects throughout 48 weeks in ARCADIA 1 and ARCADIA 2, respectively.

Anti-Drug Antibody Effects on Pharmacokinetics and Pharmacodynamics

• Prurigo Nodularis : In the phase 3 trials in subjects with prurigo nodularis, there was no identified clinically significant effect of anti-drug antibodies on the pharmacokinetics, safety or efficacy of nemolizumab-ilto over the treatment duration of 24 weeks.
  
  
• Atopic Dermatitis: In the phase 3 trials in subjects with atopic dermatitis, antibodies to nemolizumab-ilto were associated with reduced serum nemolizumab-ilto concentrations beyond Week 16. NEMLUVIO treated subjects who developed ADAs had nemolizumab-ilto concentrations that were 20% to 70% lower compared to subjects who did not develop ADAs. There was no clinically significant effect of anti-drug antibodies on safety or efficacy of nemolizumab-ilto over the treatment duration of 48 weeks.

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of NEMLUVIO.

No effects on fertility parameters as reproductive organ morphology, menstrual cycle length, or sperm/testicular analysis were observed in male or female sexually mature cynomolgus monkeys that were administered nemolizumab-ilto at subcutaneous doses up to 25 mg/kg once every two weeks for 6 months (53 times the MRHD for PN and 72 times for AD, based on AUC comparison). The monkeys were not mated to evaluate fertility.

Two randomized, double-blind, placebo-controlled trials (OLYMPIA 1 [NCT04501666] and OLYMPIA 2 [NCT04501679]) enrolled a total of 560 adult subjects with prurigo nodularis (PN). Disease severity was defined using an Investigator’s Global Assessment (IGA) in the overall assessment of prurigo nodularis nodules on a severity scale of 0 to 4. Subjects enrolled in these two trials had an IGA score ≥ 3, severe pruritus as defined by a weekly average of the peak pruritus numeric rating scale (PP-NRS) score of ≥7 on a scale of 0 to 10, and greater than or equal to 20 nodular lesions. OLYMPIA 1 and OLYMPIA 2 assessed the effect of NEMLUVIO on the signs and symptoms of PN, targeting improvement in skin lesions and pruritus over 16 weeks. In OLYMPIA 1, subjects were extended up to 24 weeks of treatment.

Subjects weighing less than 90 kg in the NEMLUVIO group received subcutaneous injections of NEMLUVIO 60 mg at Week 0, followed by NEMLUVIO 30 mg injections every 4 weeks. Subjects weighing 90 kg or more in the NEMLUVIO group received subcutaneous injections of NEMLUVIO 60 mg at Week 0 and every 4 weeks.

In these trials, at baseline, 60% of subjects were female, 81% were White, 9% were Asian, 7% were Black or African American; for ethnicity, 4% of subjects identified as Hispanic or Latino. Twenty-five (25)% of subjects were older than 65 years of age. Thirty-two (32)% of subjects had a history of atopy. The baseline weekly average PP-NRS score was a mean of 8.5. Fifty-eight (58)% of subjects had a baseline IGA score of 3 (moderate PN), and 42% of subjects had a baseline IGA of 4 (severe PN).

The PP-NRS score is a weekly average of daily PP-NRS scores on an 11-point scale from 0-10 that assesses the maximal intensity of pruritus in the last 24 hours with 0 being no itch and 10 being worst itch imaginable. The IGA is a 5-category scale, including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe” indicating the investigator’s overall assessment of the pruriginous nodules.

Efficacy was assessed with the proportion of subjects with an improvement of ≥4 from baseline in PP-NRS, the proportion of subjects with an IGA of 0 (Clear) or 1 (Almost Clear) and a ≥2-point improvement from baseline, the proportion of subjects who achieved a response in both PP-NRS and IGA per the criteria described above, and the proportion of subjects with PP-NRS <2.

The efficacy results for OLYMPIA 1 and OLYMPIA 2 are presented in Table 3 and Figures 1, 2, and 3.

Figure 1:  Proportion of Adult Subjects with PN with PP-NRS Improvement ≥4 from Baseline Over Time in OLYMPIA 1 and OLYMPIA 2 ^a

^a Subjects who received rescue therapy or had missing data (fewer than 4 PP-NRS daily diary entries in a 7-day period) were considered non-responders.

Figure 2:  Proportion of Adult Subjects with PN with PP-NRS <2 Over Time in OLYMPIA 1 and OLYMPIA 2 ^a

^a Subjects who received rescue therapy or had missing data (fewer than 4 PP-NRS daily diary entries in a 7-day period) were considered non-responders.

Figure 3:  Proportion of Adult Subjects with PN with IGA Response ^a Over Time in OLYMPIA 1 and OLYMPA 2 ^b

^a Response was defined as an IGA of 0 (Clear) or 1 (Almost Clear) and a ≥2-point improvement from baseline.
^b Subjects who received rescue therapy or had missing data were considered non-responders.

Examination of weight, age, gender, race, history of atopy, and prior treatment did not identify meaningful differences in response to NEMLUVIO among these subgroups at Week 16.

Two randomized, double-blind, placebo-controlled trials (ARCADIA 1 [NCT03985943] and ARCADIA 2 [NCT03989349]) enrolled a total of 1728 subjects 12 years of age and older with moderate-to-severe atopic dermatitis not adequately controlled by topical treatments. Disease severity was defined by an Investigator’s Global Assessment (IGA) score of 3 (moderate) and 4 (severe) in the overall assessment of atopic dermatitis, an Eczema Area and Severity Index (EASI) score of ≥16, a minimum body surface area (BSA) involvement of ≥10%, and a Peak Pruritus Numeric Rating Scale (PP-NRS) score of ≥ 4.

During the initial 16-week treatment period, subjects in the NEMLUVIO group received an initial subcutaneous injection of NEMLUVIO 60 mg (two 30 mg injections), followed by 30 mg injections every 4 weeks. Concomitant low and/or medium potency TCS and/or TCI were administered for at least 14 days prior to baseline and continued during the trial. Based on disease activity, these concomitant therapies could be tapered and/or discontinued at investigator discretion.

After 16 weeks, subjects achieving either EASI-75 or IGA success (i.e. NEMLUVIO responders) continued into the trial maintenance period for another 32 weeks to evaluate the maintenance of response achieved at Week 16. NEMLUVIO responders were re-randomized to receive either NEMLUVIO 30 mg every 4 weeks, NEMLUVIO 30 mg every 8 weeks, or placebo every 4 weeks (all groups continued background TCS/TCI). Subjects randomized to placebo in the initial treatment period who achieved the same clinical response at Week 16 continued to receive placebo every 4 weeks.

In these trials, at baseline, 51% of subjects were male, 80% were White, 13% were Asian, and 6% were Black or African American; for ethnicity, 9% of subjects identified as Hispanic or Latino. Fifteen (15)% of subjects were 12-17 years of age. Seventy (70)% of subjects had a baseline IGA score of 3 (moderate AD), and 30% of subjects had a baseline IGA score of 4 (severe AD). The baseline mean EASI score was 27.5 and the baseline mean weekly average PP-NRS was 7.1. Overall, 63% of subjects received other previous systemic treatments for AD.

The IGA is a 5-category scale, including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe” indicating the investigator’s overall assessment of the AD. EASI scores range from 0 to 72 points and reflect the severity and extent of AD. EASI-75 indicates at least a 75% improvement in EASI score from baseline. The PP-NRS score is a weekly average of daily PP NRS scores on an 11-point scale from 0-10 that assesses the maximal intensity of pruritus in the last 24 hours with 0 being no itch and 10 being worst itch imaginable.

Both ARCADIA 1 and ARCADIA 2 assessed the co-primary endpoints of:

• Proportion of subjects with an IGA success (defined as an IGA of 0 [clear] or 1 [almost clear] and a ≥2- point reduction from baseline) at Week 16
• Proportion of subjects with EASI-75 (≥75% improvement in EASI from baseline) at Week 16

PP-NRS improvement ≥ 4 from baseline at Week 16 was a key secondary outcome in both trials.

Clinical Response at Week 16 (ARCADIA 1 and ARCADIA 2)
The efficacy results for ARCADIA 1 and ARCADIA 2 evaluating the initial treatment period with NEMLUVIO administered every 4 weeks over 16 weeks are presented in Table 4.

Examination of weight, age, gender, race, and prior treatment did not identify meaningful difference in response to NEMLUVIO among these subgroups at Week 16.

Maintenance and Durability of Response (Week 16 to Week 48)
The maintenance and durability of response in NEMLUVIO responders (IGA 0/1 or EASI-75 at Week 16) was evaluated between Week 16 and Week 48 in ARCADIA 1 and ARCADIA 2 trials. For the maintenance treatment period, NEMLUVIO responders were re-randomized to NEMLUVIO 30 mg every 4 weeks, NEMLUVIO 30 mg every 8 weeks or placebo every 4 weeks (NEMLUVIO withdrawal) with concomitant TCS/TCI. The results are presented in Table 5.