Atopic Dermatitis 

EBGLYSS is indicated for the treatment of adult and adolescent patients 12 years of age and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. EBGLYSS can be used with or without topical corticosteroids.

Vaccination Prior to Administration of EBGLYSS 

Consider completing all age-appropriate immunizations according to current immunization guidelines [see Special warnings and precautions for use (4.4)].

Recommended Dosage 

Adults and Adolescents (12 years of age and older who weigh at least 40 kg)

The recommended dosage of EBGLYSS is an initial dose of 500 mg (two 250 mg injections) injected subcutaneously at Week 0 and Week 2, followed by 250 mg every two weeks until Week 16 or later, when adequate clinical response is achieved [see Pharmacodynamic properties (5.1)]. The maintenance dose is 250 mg every four weeks [see Pharmacodynamic properties (5.1)]; some patients may maintain adequate clinical response with a dose of 250 mg every eight weeks [see Pharmacokinetic properties (5.2)].

Concomitant Topical Therapies 

Lebrikizumab can be used with or without topical corticosteroids (TCSs) or topical calcineurin inhibitors (TCIs).

Important Administration Instructions 

•     EBGLYSS is for subcutaneous administration.

•     EBGLYSS is intended for use under the guidance of a healthcare professional. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of EBGLYSS according to the “Instructions for Use”, included with the packaged product. Adult patients may self-inject, or caregivers may give EBGLYSS after training in subcutaneous injection technique. For adolescent patients, caregivers may give injections after training in subcutaneous injection technique.

•     Sites for injection include the abdomen, thigh, and back of the upper arm. Administration of EBGLYSS in the back of the upper arm may be performed by a caregiver or healthcare provider (see Instructions for Use).

•     Instruct patients not to inject in the exact same spot every time. Do not inject into areas where the skin is tender, bruised, red, hard, or in an area of skin that is affected by atopic dermatitis or skin lesions.

•     Before injection, remove EBGLYSS prefilled pen from the refrigerator and leave at room temperature for 45 minutes without removing the needle cap. Do not warm by using a heat source such as hot water or microwave.

•     Inspect EBGLYSS visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the liquid contains visible particles, is discolored or cloudy [see Pharmaceutical Form (3) and Nature and contents of container (6.5)].

•     EBGLYSS does not contain preservatives.

Missed Dose 

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

Method of administration 

injection, for subcutaneous use 

Traceability 

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 

Hypersensitivity 

Hypersensitivity reactions, including urticaria and angioedema, have been reported with use of EBGLYSS. If a serious hypersensitivity reaction occurs, discontinue EBGLYSS and institute appropriate therapy.

Conjunctivitis and Keratitis 

Conjunctivitis and keratitis adverse reactions have been reported in clinical trials.

Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received EBGLYSS compared to those who received placebo. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis or keratitis recovered during the treatment period [see Undesirable effects (4.8)].

Advise patients to report new onset or worsening eye symptoms to their healthcare provider.

Parasitic (Helminth) Infections 

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if EBGLYSS will influence the immune response against helminth infections by inhibiting IL-13 signaling.

Treat patients with pre-existing helminth infections before initiating treatment with EBGLYSS. If patients become infected while receiving EBGLYSS and do not respond to antihelminth treatment, discontinue treatment with EBGLYSS until the infection resolves.

Risk of Infection with Live Vaccines 

EBGLYSS may alter a patient’s immunity and increase the risk of infection following administration of live vaccines. Prior to initiating therapy with EBGLYSS, complete all age-appropriate vaccinations according to current immunization guidelines. Avoid use of live vaccines in patients treated with EBGLYSS. No data are available on the response to live or non-live vaccines.

Vaccinations 

Prior to initiating therapy with lebrikizumab, it is recommended that patients are brought up to date with all age-appropriate immunisations according to current immunisation guidelines. Live and live attenuated vaccines should not be given concurrently with lebrikizumab as clinical safety and efficacy has not been established. Immune responses to non-live vaccines were assessed in a combined tetanus, diphtheria and acellular pertussis vaccine (TdaP) and a meningococcal polysaccharide vaccine (see section 4.5). 

No interaction studies have been performed.

Live vaccines

The safety and efficacy of concurrent use of lebrikizumab with live and live attenuated vaccines has not been studied. Live and live attenuated vaccines should not be given concurrently with lebrikizumab.

Non-live vaccines

Immune responses to non-live vaccines were assessed in a study in which adult patients with atopic dermatitis were treated with lebrikizumab 500 mg at weeks 0 and 2 followed by lebrikizumab 250 mg every other week. After 12 weeks of lebrikizumab administration, patients were vaccinated with a combined tetanus, diphtheria, and acellular pertussis vaccine TdaP vaccine (T cell-dependent) and a meningococcal polysaccharide vaccine (T cell-independent) and immune responses were assessed 4 weeks later. Antibody responses to both non-live vaccines were not negatively impacted by the concomitant lebrikizumab treatment. No adverse interactions between the non-live vaccines and lebrikizumab were noted in the study. Therefore, patients receiving lebrikizumab may receive concurrent inactivated or non-live vaccinations. For information on live vaccines see section 4.4.

Concomitant therapies

Given that lebrikizumab is a monoclonal antibody, no pharmacokinetic interactions are expected.

Pregnancy 

There are limited amount of data from the use of lebrikizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of lebrikizumab during pregnancy. 

Breast-feeding 

It is unknown whether lebrikizumab is excreted in human milk or absorbed systemically after ingestion. Maternal IgG is known to be present in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from lebrikizumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 

Fertility 

Animal studies showed no impairment of fertility (see section 5.3). 

There are no known effects on the ability to drive or use machines associated with the use of lebrikizumab.

Summary of the safety profile

The most common adverse reactions are conjunctivitis (6.9%), injection site reactions (2.6%), conjunctivitis allergic (1.8%) and dry eye (1.4%).

Tabulated list of adverse reactions

Across all clinical studies in atopic dermatitis, a total of 1720 patients were administered lebrikizumab, of which, 891 patients were exposed to lebrikizumab for at least one year. Unless otherwise stated, the frequencies are based on a pool of 4 randomised, double-blind studies in patients with moderate-to-severe atopic dermatitis where 783 patients were treated with subcutaneous lebrikizumab during the placebo-controlled period (first 16 weeks of treatment).

Listed in Table 1 are adverse reactions observed from clinical trials presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 1. List of adverse reactions

Description of selected adverse reactions

Conjunctivitis and related events

During the first 16 weeks of treatment conjunctivitis, conjunctivitis allergic and keratitis were reported more frequently in patients treated with lebrikizumab (6.9%, 1.8% and 0.6% respectively) compared to placebo (1.8%, 0.7% and 0.3%).

During maintenance treatment period (16-52 weeks) the incidence of conjunctivitis and conjunctivitis allergic with lebrikizumab was 5.0% and 5.9% respectively.

Across all clinical studies, among lebrikizumab-treated patients treatment discontinuation due to conjunctivitis and conjunctivitis allergic occurred in 0.7% and 0.3% of cases, respectively. Severe cases of conjunctivitis and conjunctivitis allergic occurred in 0.1% and 0.2% of cases, respectively. 72% of patients recovered, of those 57% recovered within 90 days.

Eosinophilia

Adverse reactions of eosinophilia were reported in 0.6% of patients treated with lebrikizumab and 0.8% of patients treated with placebo during the initial treatment period. Lebrikizumab-treated patients had a greater mean increase from baseline in eosinophil count compared to patients treated with placebo. In general, the increase in the lebrikizumab-treated patients was mild or moderate and transient. Eosinophilia >5000 cells/mcL was observed in 0.4% lebrikizumab-treated patients and none of the placebo-treated patients. Eosinophilia did not result in treatment discontinuation and no eosinophil-related disorders were reported.

Injection site reactions

Injection site reactions were reported more frequently in patients who received lebrikizumab (2.6%) compared to placebo (1.5%). The majority (95 %) of injection site reactions were mild or moderate in severity, and few patients (< 0.5%) discontinued lebrikizumab treatment.

Herpes zoster

Herpes zoster was reported in 0.6% of the patients treated with lebrikizumab and none of the patients in the placebo group. All herpes zoster events reported were mild or moderate in severity and none led to permanent discontinuation of treatment.

Long term safety

The long-term safety of lebrikizumab was assessed in 5 clinical studies. In the two monotherapy studies (ADvocate- 1, ADvocate-2) up to 52 weeks and in patients enrolled in the TCS combination therapy study (ADhere) and followed in a long-term extension study (ADjoin) for a total of 56 weeks and the monotherapy ADore study in adolescents for also up to 52 weeks. The safety profile of lebrikizumab as monotherapy through week 52 or in combination with TCS through week 56 is consistent with the safety profile observed up to week 16.

Paediatric population

Adolescents 12 to 17 years of age

The safety of lebrikizumab was assessed in 372 patients 12 to 17 years of age with moderate-to-severe atopic dermatitis, including 270 patients exposed for at least one year. The safety profile of lebrikizumab in these patients was similar to the safety profile in adults with atopic dermatitis.

Pediatric Use 

The safety and effectiveness of EBGLYSS have been established in pediatric subjects aged 12 to less than 18 years who weigh at least 40 kg with moderate-to-severe atopic dermatitis. A total of 372 pediatric subjects were exposed to EBGLYSS with 270 subjects exposed to EBGLYSS for at least one year. The safety and effectiveness of EBGLYSS in pediatric subjects aged 12 years to less than 18 years who weigh less than 40 kg and pediatric subjects less than 12 years of age with moderate to severe atopic dermatitis have not been established.

Geriatric Use 

Of the 1348 adult subjects with moderate-to-severe atopic dermatitis exposed to EBGLYSS, a total of 123 were 65 years or older, and 29 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects [see Pharmacokinetic properties (5.2)].

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.

Single intravenous doses up to 10 mg/kg and multiple subcutaneous doses up to 500 mg have been administered to humans in clinical trials without dose-limiting toxicity. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. There is no known antidote to lebrikizumab overdose.

Pharmacotherapeutic group: {agents for dermatitis, excluding corticosteroids}, ATC code: D11AH10

Mechanism of action

Lebrikizumab is an immunoglubulin (IgG4) monoclonal antibody that binds with high affinity (<10 pM) to interleukin (IL)‑13 and selectively inhibits IL‑13 signalling through the IL‑4 receptor alpha (IL‑4Rα)/ IL-13 receptor alpha 1 (IL‑13Rα1) heterodimer, thereby inhibiting the downstream effects of IL‑13. Inhibition of IL-13 signalling is expected to be of benefit in diseases in which IL-13 is a key contributor to the disease pathogenesis. Lebrikizumab does not prevent the binding of IL-13 to the IL-13 receptor alpha 2 (IL-13Rα2 or decoy receptor), which allows the internalisation of IL-13 into the cell.

Pharmacodynamic effects

In lebrikizumab clinical studies, lebrikizumab reduced the levels of serum periostin, total immunoglobulin E (IgE), CC chemokine ligand (CCL)17 [thymus and activation-regulated chemokine (TARC)], CCL18 [pulmonary and activation-regulated chemokine (PARC)], and CCL13 [monocyte chemotactic protein-4 (MCP-4)]. The decreases in the type 2 inflammation mediators provide indirect evidence of inhibition of the IL-13 pathway by lebrikizumab.

Clinical efficacy and safety

Adults and adolescents with atopic dermatitis

The efficacy and safety of lebrikizumab as monotherapy (ADvocate-1, ADvocate-2) and with concomitant TCS (ADhere) were evaluated in three randomised, double-blind, placebo-controlled pivotal studies in 1062 adults and adolescents (aged 12 to 17 years and weighing ≥40 kg) with moderate-to-severe atopic dermatitis, defined by an Eczema Area and Severity Index (EASI) ≥ 16, Investigator’s Global Assessment (IGA) ≥ 3, and a body surface area (BSA) involvement of ≥ 10%. Patients enrolled into the three studies previously had an inadequate response to topical medication or determination that topical treatments are otherwise medically inadvisable.

In all three studies, patients received an initial dose of 500 mg of lebrikizumab (two 250 mg injections) at weeks 0 and 2, followed by 250 mg every other week (Q2W) until week 16, or matching placebo in a 2:1 ratio. In ADhere, study patients also received concomitant low-to-mid potency TCS or TCI on active lesions. Patients were permitted to receive rescue treatment at the discretion of the investigator to control intolerable symptoms of atopic dermatitis. Patients requiring systemic rescue treatment were discontinued from study treatment.

Patients responding to treatment at week 16 in ADvocate-1 and 2 studies (i.e., achieved IGA 0 or 1, or at least a 75% reduction in EASI (EASI 75) without having received any rescue therapy) were re-randomised in a blinded manner to (i) lebrikizumab 250 mg Q2W; (ii) lebrikizumab 250 mg every 4 weeks (Q4W); or (iii) matching placebo up to 52 weeks.

In ADvocate-1 and 2, patients not achieving IGA 0 or 1 or EASI 75 at week 16, or who received rescue medication prior to week 16, were entered into an Escape Arm and treated with open-label lebrikizumab 250 mg Q2W through Week 52.

In ADvocate-1 and ADvocate-2, after completing the 52-week study, and in ADhere, after completing the 16-week study, patients were offered the option to continue treatment in a separate long-term extension study (ADjoin).

Endpoints

In all three studies, the co-primary endpoints were the percentage of patients with IGA 0 or 1 (“clear” or “almost clear”), with a ≥2-point reduction from baseline, and the percentage of patients achieving EASI 75 from baseline to week 16. Key secondary endpoints (adjusted for multiplicity) included the percentage of patients who achieved at least a 90% reduction in EASI (EASI 90), percentage of patients with at least 4-point improvement from baseline in Pruritus Numerical Rating Scale (Pruritus NRS), percentage of patients with at least 4-point improvement from baseline in Dermatology Life Quality Index (DLQI)  and interference of itch on sleep (Sleep-Loss Scale) patient-reported, single-item, daily scale measuring the extent of interference of itch on sleep over the last night on a 5-point Likert scale. An additional secondary endpoint (not adjusted for multiplicity) included the change from baseline in Patient Oriented Eczema Measure (POEM).

Subjects

Baseline characteristics

The monotherapy studies ADvocate-1 and ADvocate-2 enrolled 424 and 427, respectively, and across studies the mean age was 35.8, the mean weight was 77.1 kg, 49.9% were female, 63.7% were white, 22.6% were Asian, and 9.9% were black; 12.0% were adolescents (12 to 17 years). Overall, 61.5% of patients had a baseline IGA of 3 (moderate atopic dermatitis), 38.5% of patients had a baseline IGA of 4 (severe atopic dermatitis), and 54.8% of patients had received prior systemic treatment. The mean baseline EASI was 29.6, the mean baseline Pruritus NRS was 7.2 and the mean baseline DLQI was 15.5.

The concomitant TCS study ADhere enrolled 211 patients and the mean age was 37.2, the mean weight was 76.2 kg, 48.8% were female, 61.6% were white, 14.7% were Asian, and 13.3% were black; 21.8% were adolescents. In this study, 69.2% of patients had a baseline IGA of 3 (moderate atopic dermatitis), 30.8% of patients had a baseline IGA of 4 (severe atopic dermatitis), and 47.4% of patients had received prior systemic treatment. The mean baseline EASI was 27.3, the mean baseline Pruritus NRS was 7.1 and the mean baseline DLQI was 14.4.

Clinical response

Monotherapy studies (ADvocate-1 and ADvocate-2) – induction period, weeks 0-16

In ADvocate-1 and ADvocate-2, a significantly greater proportion of patients randomised to lebrikizumab 250 mg Q2W achieved IGA 0 or 1 with a ≥2-point improvement from baseline, EASI 75, EASI 90, and an improvement of ≥4 points in Pruritus NRS and DLQI compared to placebo at week 16 (see Table 3).

In both monotherapy studies, lebrikizumab reduced daily worst itch severity compared to placebo, as measured by the percent change from baseline in Pruritus NRS, already since week 1 of treatment. The improvement in Pruritus NRS occurred in conjunction with improvements in skin inflammation related to atopic dermatitis and quality of life.

Clinical Response at Week 16 (ADvocate 1, ADvocate 2, and ADhere)

The results of the EBGLYSS monotherapy trials (ADvocate 1 and ADvocate 2) and the EBGLYSS + TCS trial (ADhere) are presented in Table 2.

Table 2: Efficacy Results of EBGLYSS With or Without Concomitant TCS at Week 16^a

^a      Subjects who received rescue therapy or discontinued treatment due to lack of efficacy were analyzed as non-responders. Data after treatment discontinuation due to any other reason were considered missing. Any missing data was imputed using MCMC-MI.

^b     Subjects received 500 mg of EBGLYSS at Week 0 and Week 2, and 250 mg Q2W up to Week 16

^c      Primary endpoint. Responder was defined as a subject with an IGA 0 or 1 (“clear” or “almost clear”) and a reduction of ≥2 points on a 0-4 IGA scale

In the two studies, fewer patients randomised to lebrikizumab needed rescue treatment (topical corticosteroids, systemic corticosteroids, immunosuppressants) as compared to patients randomised to placebo (14.7% versus 36.6%, respectively, across both studies).

Figure 1 and Figure 2 show the mean percent change from baseline in EASI and Pruritus NRS up to week 16.

***p<0.001 versus placebo

Treatment effects in subgroups (weight, age, gender, race, severity, and prior use of systemic treatments) in ADvocate-1 and ADvocate-2 were consistent with the results in the overall study population during the induction phase.

Monotherapy Studies (ADvocate-1 and ADvocate-2) – maintenance period, weeks 16-52

To evaluate maintenance of response, 157 subjects from ADvocate-1 and 134 subjects from ADvocate-2 treated with lebrikizumab 250 mg Q2W, who achieved IGA 0 or 1 or EASI 75 at week 16 without topical or systemic rescue treatment, were re-randomised in a blinded manner 2:2:1 to an additional 36-week treatment of (i) lebrikizumab 250 mg Q2W, or (ii) lebrikizumab 250 mg Q4W, or (iii) matching placebo for a cumulative 52-week study treatment (see Table 4).

Maintenance and Durability of Response (Week 16 to Week 52)

Monotherapy Trials

The results of EBGLYSS-treated subjects achieving IGA 0 or 1 or EASI-75, and did not receive rescue therapy at Week 16 who were re-randomized to 36 weeks of maintenance treatment with EBGLYSS 250 mg Q2W, EBGLYSS 250 mg Q4W, or placebo in ADvocate 1 and Advocate 2 are presented in Table 3.

Table 3: Efficacy Results of EBGLYSS at Week 52 in ADvocate 1 and ADvocate 2^a

^a      Subjects who received systemic rescue therapy, discontinued treatment due to lack of efficacy were analyzed as non-responders. Data after topical rescue medication or treatment discontinuation due to any other reason were considered missing. Any missing data were imputed using MCMC-MI.

^b     Responder was defined as a subject with an IGA 0 or 1 (“clear” or “almost clear”) and a reduction of ≥2 points on a 0-4 IGA scale

Among subjects who received lebrikizumab during the induction period and continued lebrikizumab 250 mg Q2W open-label treatment up to week 52 in the Escape Arm, 58% achieved EASI 75 and 28% achieved IGA 0 or 1 with a ≥2-point improvement from baseline at week 52 in ADvocate-1 and ADvocate-2 (pooled).

Concomitant TCS Study (ADhere)

In ADhere, from baseline to week 16, a significantly greater proportion of patients randomised to and dosed with lebrikizumab 250 mg Q2W + TCS achieved IGA 0 or 1, EASI 75, and improvements of ≥ 4 points in the Pruritus NRS and DLQI compared to placebo + TCS (see Table 6).

Table 4. Efficacy results of lebrikizumab combination therapy with TCS at week 16 in ADhere

^a Subjects with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale.

^b Subjects with a 75% or 90% reduction in EASI from Baseline to week 16, respectively.

^c The percentage is calculated relative to the number of subjects with a baseline Pruritus NRS ≥ 4.

^d The percentage is calculated relative to the number of subjects with a baseline DLQI ≥4.

^* p<0.05; **p<0.01; *** p<0.001 versus placebo versus placebo.

In ADhere, subjects who received lebrikizumab 250 mg Q2W+TCS from week 0 to 16 used high potency TCS as rescue medication less often as compared to subjects who received placebo + TCS (1.4% and 4.5%, respectively).

In the concomitant TCS study (ADhere) lebrikizumab 250 mg Q2W significantly improved the EASI and Pruritus NRS mean percent change from baseline to week 16 (76.76% and 50.7%) compared to TCS + placebo (53.12% and 35.5%).

Treatment effects in subgroups (weight, age, gender, race, severity or prior use of systemic treatment) in ADhere were consistent with the results in the overall study population.

Subjects who responded at week 16 in ADhere and entered ADjoin were treated with lebrikizumab 250 mg Q4W maintained their responses up to 56 weeks (86.8% for IGA 0 or 1 and 81.2% for EASI 75).

Patient-reported outcomes and health-related quality of life

In both monotherapy studies (ADvocate-1 and ADvocate-2) and in the concomitant TCS study (ADhere) lebrikizumab 250 mg Q2W significantly improved POEM and interference of itch on sleep (Sleep-Loss Scale) at week 16 compared to placebo.

The efficacy of lebrikizumab 250 mg Q2W, both as monotherapy and in combination with TCS, compared with placebo was evaluated across 3 pivotal Phase 3 studies. In the first 16 weeks of all 3 studies, participants who were given lebrikizumab 250 mg Q2W demonstrated statistically significant and clinically meaningful improvement across multiple investigator-assessed clinical outcomes (IGA 0 or 1, EASI 75, and EASI 90) and PROs related to itch (Pruritus NRS), interference of itch on sleep, QoL (DLQI), and disease severity (POEM).

Table 5: Proportion of Participants with a 4-Point or Greater Improvement in DLQI and DLQI Mean Change from Baseline at Week 16 Primary Estimand (Hybrid) with MCMC-MI

Abbreviations: ANCOVA = analysis of covariance; BL = baseline; CI = confidence interval; CSR = clinical study report; Diff = difference; DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; LEB = lebrikizumab; LSM = least standard mean; MCMC-MI = Markov Chain Monte Carlo multiple imputation; N = number of participants in the analysis population; n = number of participants in the specified category; PBO = placebo; Q2W = every 2 weeks; SD = standard deviation; SE = standard error; TCS = topical corticosteroids.

^a DLQI 4-point improvement response was analyzed in participants with a Baseline DLQI score of 4 or more.

^b Cochran-Mantel-Haenszel test adjusted by geographic region (US versus EU versus rest of world), age

(adolescent versus adult), and disease severity (IGA 3 versus 4).

^c Change from Baseline in DLQI analyzed in participants with nonmissing DLQI baseline values.

^d The ANCOVA model includes treatment, geographic region (US versus EU versus rest of the world), age group (adolescent participants 12 to <18 versus adults ≥18 years) and baseline IGA score (3,4) as fixed factors and baseline value as covariate.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.

Adolescents (12 to 17 years of age)

In the monotherapy studies ADvocate 1 and ADvocate 2, the mean age of adolescent patients was 14.6 years, the mean weight was 68.2 kg, and 56.9% were female. In these studies, 63.7% had a baseline IGA of 3 (moderate atopic dermatitis), 36.3% had a baseline IGA of 4 (severe atopic dermatitis), and 47.1% had received prior systemic treatment. In the concomitant combination study with TCS ADhere, the mean age of adolescent patients was 14.6 years, mean weight was 62.2 kg, and 50.0% were female. In this study, 76.1% had a baseline IGA of 3 (moderate atopic dermatitis), 23.9% had a baseline IGA of 4 (severe atopic dermatitis), and 23.9% had received prior systemic treatment.

The efficacy results at week 16 in adolescent patients are presented in Table 7.

Table 6. Efficacy results of lebrikizumab monotherapy in ADvocate-1, ADvocate‑2 and lebrikizumab combination therapy with TCS in ADhere at week 16 in adolescent patients 

Adolescent patients treated with lebrikizumab and lebrikizumab + TCS achieved clinically meaningful improvements in disease severity and maintained response up to week 52. Additional data from the single-arm ADore study with lebrikizumab in 206 adolescents support the efficacy of lebrikizumab in adolescent patients up to 52 weeks of treatment.

Pharmacokinetics 

Following the 500 mg loading doses at Week 0 and Week 2, steady-state serum concentrations were achieved with the first 250 mg Q2W dose at Week 4.

Based on a population pharmacokinetic (PK) analysis, the steady-state maximum concentration (C_max,ss), the steady-state average concentration (C_avg,ss), and the steady-state trough concentration (C_trough,ss) following the 250 mg Q2W subcutaneous dose in patients with atopic dermatitis (AD) were 108 µg/mL, 100 µg/mL, and 87 µg/mL, respectively. The C_max,ss, the C_avg,ss, and the C_trough,ss following the 250 mg Q4W subcutaneous dose in patients with AD were 63 µg/mL, 51 µg/mL, and 36 µg/mL, respectively.

A longitudinal exposure-response model describing the PK and EASI relationship predicted EASI 75 response rates of 80% and 73% for 250 mg Q4W and Q8W, respectively, at Week 52 for subjects who initially received 250 mg Q2W and achieved EASI response criteria at Week 16.

Absorption

Following a single subcutaneous 250 mg dose of lebrikizumab, peak serum concentrations were achieved approximately 7 to 8 days post dose. The absolute bioavailability for a subcutaneous dose was estimated as 86%.

Injection site locations did not significantly influence the absorption of lebrikizumab.

Distribution

Based on a population PK analysis, the total volume of distribution at steady-state was 5.14 L.

Metabolism/Elimination

Lebrikizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

In the population PK analysis, clearance was 0.154 L/day and was independent of dose. The mean elimination half-life was 24.5 days.

Dose Proportionality

Lebrikizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 37.5 to 500 mg given as a subcutaneous injection in patients with AD or in healthy volunteers.

Specific Populations

Age, Sex, Race

Age, sex, or race did not have a significant effect on the pharmacokinetics of lebrikizumab.

Weight

Lebrikizumab trough concentrations were lower in subjects with higher body weight.

Patients with Renal or Hepatic Impairment

Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the pharmacokinetics of lebrikizumab have not been conducted. Lebrikizumab, as a monoclonal antibody, is not expected to undergo significant hepatic or renal elimination. Population pharmacokinetic analysis showed that markers of renal and hepatic function did not affect the pharmacokinetics of lebrikizumab.

Drug Interaction Studies

An effect of lebrikizumab on the PK of co-administered medications is not expected.

Immunogenicity 

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 EBGLYSS or of other drug products.

During the 12-month treatment period in EBGLYSS studies, 4/145 (2.8%) of subjects treated with 250 mg EBGLYSS every 2 weeks followed by 250 mg every four weeks developed antibodies to lebrikizumab, most of which were neutralizing and of low titer. Similar results were observed in adolescent subjects who received EBGLYSS up to 12 months. The presence of anti-drug antibodies was not associated with changes to pharmacokinetics, efficacy, or safety of lebrikizumab. Because of the low occurrence of ADA, the clinical relevance of these findings is unknown.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.

The mutagenic potential of lebrikizumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.

Carcinogenicity studies have not been conducted with lebrikizumab. Evaluation of the available evidence related to IL-13 inhibition and animal toxicology data with lebrikizumab does not suggest carcinogenic potential for lebrikizumab.

No effects on fertility parameters were observed in sexually mature monkeys after a long-term intravenous (females) or subcutaneous (males) treatment with lebrikizumab. Lebrikizumab had no effects on embryo-fetal or postnatal development.

·       glacial acetic acid

·       L-histidine

·       polysorbate 20

·       sucrose

·       Water for Injection, USP.

Not applicable for subcutaneous single-dose product. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Storage and Handling

·       EBGLYSS is sterile and preservative-free.

·       Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

·       If necessary, EBGLYSS may be kept at room temperature below 30°C (86°F) for up to 7 days in the original carton. Throw away EBGLYSS if not used within 7 days at room temperature.

·       Do not freeze. Do not use EBGLYSS if it has been frozen.

·       Do not shake.

·       Discard the EBGLYSS single-dose prefilled pen after use in a puncture-resistant container.

EBGLYSS (lebrikizumab) injection is a sterile, preservative free, clear, colorless to slightly yellow solution, free of visible particles, available in a single-dose prefilled pen. Each prefilled pen is designed to deliver 250 mg of EBGLYSS in 2 mL.

EBGLYSS is supplied as:

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the approved patient labeling (Package leaflet and Instructions for Use).

Administration Instructions: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the prefilled pen correctly [see Posology and method of administration (4.2) and Instructions for Use].

Hypersensitivity: Advise patients to discontinue EBGLYSS and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions [see Special warnings and precautions for use (4.4)].

Conjunctivitis and Keratitis: Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop [see Special warnings and precautions for use (4.4)].

Parasitic (Helminth) Infections: Advise patients to notify their healthcare provider if they present with clinical features consistent with helminthic infection [see Special warnings and precautions for use (4.4)].

Risk of Infection with Live Vaccines: Advise patients that EBGLYSS may increase the risk of infection following administration of live vaccines and that vaccination with live vaccines is not recommended during EBGLYSS treatment. Instruct patients to inform the healthcare provider that they are taking EBGLYSS prior to a potential vaccination [see Warnings and Precautions (5.4)].