Ebglyss Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ........................................................................... 2

TABLE OF CONTENTS ................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ................................................... 4

1 INDICATIONS ..................................................................................................... 4

1.1 Pediatrics .................................................................................................. 4

1.2 Geriatrics .................................................................................................. 4

2 CONTRAINDICATIONS ...................................................................................... 4

4 DOSAGE AND ADMINISTRATION .................................................................... 4

4.1 Dosing Considerations .............................................................................. 4

4.2 Recommended Dose and Dosage Adjustment ......................................... 4

4.4 Administration ........................................................................................... 5

4.5 Missed Dose ............................................................................................. 5

5 OVERDOSAGE ................................................................................................... 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............ 6

7 WARNINGS AND PRECAUTIONS ..................................................................... 6

7.1 Special Populations .................................................................................. 7

7.1.1 Pregnant Women ................................................................................... 7

7.1.2 Breast-feeding ........................................................................................ 7

7.1.3 Pediatrics ............................................................................................... 8

7.1.4 Geriatrics ................................................................................................ 8

8 ADVERSE REACTIONS ..................................................................................... 8

8.1 Adverse Reaction Overview ...................................................................... 8

8.2 Clinical Trial Adverse Reactions ............................................................... 8

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ....................................... 10

8.3 Less Common Clinical Trial Adverse Reactions ..................................... 10

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ..................................................................................... 10

9 DRUG INTERACTIONS .................................................................................... 11

9.2 Drug Interactions Overview ..................................................................... 11

9.4 Drug-Drug Interactions ............................................................................ 11

9.5 Drug-Food Interactions ........................................................................... 11

9.6 Drug-Herb Interactions ............................................................................ 11

9.7 Drug-Laboratory Test Interactions .......................................................... 11

10 CLINICAL PHARMACOLOGY .......................................................................... 11

10.1 Mechanism of Action .............................................................................. 11

10.2 Pharmacodynamics ................................................................................ 12

10.3 Pharmacokinetics ................................................................................... 12

11 STORAGE, STABILITY AND DISPOSAL ........................................................ 14

12 SPECIAL HANDLING INSTRUCTIONS ........................................................... 14

PART II: SCIENTIFIC INFORMATION ........................................................................ 15

13 PHARMACEUTICAL INFORMATION .............................................................. 15

14 CLINICAL TRIALS ............................................................................................ 15

15 MICROBIOLOGY .............................................................................................. 19

16 NON-CLINICAL TOXICOLOGY ........................................................................ 19

PATIENT MEDICATION INFORMATION .................................................................... 21

INSTRUCTIONS FOR USE ......................................................................................... 25

INSTRUCTIONS FOR USE ......................................................................................... 33

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Ebglyss (lebrikizumab injection) is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years of age and older with a body weight of at least 40 kg, 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.

1.1 Pediatrics

Adolescents (12 to < 18 years of age who weigh ≥ 40 kg): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Ebglyss in adolescent patients 12 years of age and older who weigh ≥ 40 kg has been established for the treatment of moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable (see 4.2 Recommended Dose and Dosage Adjustment, 7.1.3 Pediatrics, and 10.3 Pharmacokinetics).

Pediatrics (< 12 years of age) and Adolescents (12 to < 18 years who weigh < 40 kg): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in patients < 12 years of age and in adolescents who weigh < 40 kg.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): 123 subjects ≥ 65 years of age were exposed to Ebglyss in moderate-to-severe atopic dermatitis clinical studies (see 4.2 Recommended Dose and Dosage Adjustment, 7.1.4 Geriatrics, and 10.3 Pharmacokinetics).

2 CONTRAINDICATIONS

Ebglyss is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Ebglyss can be used with or without topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI). TCI may be used but should be reserved for problem areas only, such as the face, neck, intertriginous, and genital areas.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose 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 (one injection) every two weeks until Week 16.

Once clinical response is achieved, the recommended maintenance dose is 250 mg every four weeks starting at Week 16 (see 10.3 Pharmacokinetics).

Continued therapy beyond 16 weeks should be carefully considered in a patient who does not show treatment benefit within this time period.

Special Populations

Renal Insufficiency

No dose adjustment is recommended in patients with renal impairment (see 10.3 Pharmacokinetics).

Hepatic Insufficiency

No dose adjustment is recommended in patients with hepatic insufficiency (see 10.3 Pharmacokinetics).

Geriatrics (≥ 65 years)

No dose adjustment is required in patients ≥ 65 years of age (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics).

Pediatrics (< 12 years of age) and Adolescents (12 to < 18 years who weigh < 40 kg):

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in patients < 12 years of age and in adolescents who weigh < 40 kg (see 1.1 INDICATIONS, Pediatrics).

Adolescents (12 to < 18 years who weigh ≥ 40 kg):

No dose adjustment is required for adolescent patients > 12 years of age and who weigh ≥ 40 kg.

4.4 Administration

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 must be performed by a caregiver or healthcare professional.

Rotation of injection sites is recommended. 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 or Ebglyss prefilled syringe 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. Do not use if the liquid contains visible particles, is discolored or cloudy.

Ebglyss is preservative-free.

4.5 Missed Dose

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing on the regularly scheduled dosing interval, starting on the new dosing day.

5 OVERDOSAGE

There is no specific treatment for Ebglyss overdose. Single intravenous doses up to 10 mg/kg and two subcutaneous doses up to 500 mg Q2W have been administered to humans in clinical trials without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Ebglyss is a sterile, preservative free, clear, colorless to slightly yellow solution, free of visible particles and is supplied as:

• 250 mg/2 mL single use prefilled pen
• 250 mg/2 mL single use prefilled syringe with needle shield

The prefilled pen contains a 2.25 mL, Type I glass syringe barrel, 27G special thin wall x 8 mm staked needle, and closed with a laminated bromobutyl elastomeric plunger and rigid needle shield.

The prefilled syringe with needle shield contains a 2.25 mL, Type I glass syringe barrel, 27 G special thin wall x 12.7 mm staked needle, and closed with a laminated bromobutyl elastomeric plunger and rigid needle shield.

Ebglyss is for single use and, therefore, contains no antimicrobial preservatives.

Ebglyss prefilled pen and prefilled syringe with needle shield are not made with natural rubber latex.

Ebglyss is available in packs containing 1 prefilled pen or 1 prefilled syringe with needle shield.

7 WARNINGS AND PRECAUTIONS

Immune

Hypersensitivity

Hypersensitivity reactions have been reported following the use of Ebglyss. If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of Ebglyss should be discontinued immediately and appropriate therapy initiated.

Helminth Infections

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if lebrikizumab will influence the immune response against helminth infections by inhibiting IL-13 signaling. Treat patients with the pre-existing helminth infections before initiating treatment with lebrikizumab. If patients become infected while receiving lebrikizumab and do not respond to antihelminth treatment, discontinue treatment with lebrikizumab until the infection resolves.

Conjunctivitis and Keratitis

Conjunctivitis and keratitis occurred more frequently in subjects with atopic dermatitis who received Ebglyss than in subjects who received placebo. Advise patients to report new onset or worsening eye symptoms to their health professional. Patients treated with Ebglyss who develop conjunctivitis that does not resolve following standard treatment should undergo ophthalmological examination, as appropriate (see 8 ADVERSE REACTIONS).

Vaccination

Prior to initiating therapy with Ebglyss, consider completion of all age-appropriate immunizations according to current immunization guidelines. Treatment with a live (attenuated) vaccine should be completed before starting the treatment. Avoid concurrent use of live vaccines in patients treated with Ebglyss. No data are available on the response to live vaccines in patients treated with Ebglyss.

Immune responses to non-live vaccines were assessed in a combined tetanus, diphtheria, and acellular pertussis (TdaP) vaccine and a meningococcal polysaccharide vaccine (see 9.4 Drug-Drug Interactions).

7.1 Special Populations

7.1.1 Pregnant Women

There are no available data on Ebglyss use in pregnant women. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, Ebglyss may be transmitted from the mother to the developing fetus. Developmental toxicity studies in pregnant monkeys at doses up to 18 times (adolescents) and 22 times (adults) the human exposure at the recommended human dose revealed no evidence of harm to the developing fetus. Lebrikizumab was detected in fetal serum at concentrations that were approximately 30% of maternal serum concentrations at all tested dose levels (see 16 NON-CLINICAL TOXICOLOGY). As a precautionary measure, it is preferable to avoid the use of Ebglyss during pregnancy. Women of reproductive potential should be advised to use effective contraception.

7.1.2 Breast-feeding

There are no data on the presence of Ebglyss in human milk, the effects on the breastfed infant, or the effects on milk production. In a pre- and post-natal developmental toxicity study in pregnant cynomolgus monkeys, lebrikizumab was detected in serum of all offspring at higher concentrations than maternal serum levels until the end of the observation period on post-natal day 180 (see 16 NON-CLINICAL TOXICOLOGY). 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.

7.1.3 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in patients < 12 years of age and in adolescents who weigh < 40 kg (see 1.1 INDICATIONS, Pediatrics).

7.1.4 Geriatrics

Evidence from 123 patients ≥ 65 years of age who were exposed to Ebglyss in moderate-to-severe atopic dermatitis clinical studies suggests that use in the geriatric population is not associated with differences in safety or efficacy between older and younger subjects (see 1.2 INDICATIONS, Geriatrics).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most commonly reported adverse reactions in adolescents weighing at least 40 kg and adults are conjunctivitis (6.5%), injection site reactions (2.6%), conjunctivitis allergic (1.8%), dry eye (1.4%), and herpes zoster (0.6%).

1.3% of Ebglyss-treated patients reported at least one serious adverse event (SAE). The proportion of patients who discontinued treatment due to adverse events was 2.3% in the Ebglyss group and 1.4% in the placebo group during the initial treatment period of up to 16 weeks.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adults and Adolescents

The safety of Ebglyss was evaluated across 4 randomized, double-blind, placebo-controlled, multicenter trials in subjects with moderate-to-severe atopic dermatitis including 3 phase 3 trials (ADvocate 1, ADvocate 2, and ADhere), and one phase 2 dose ranging trial (KGAF). In these 4 trials, all subjects (pooled across treatment groups) had a mean age of 37 years; 50% of subjects were men; 62% were White, 13% were Black, and 20% were Asian. In the phase 3 studies, 30% of the subjects had asthma, 50% had allergic rhinitis, 31% had food allergy, and 14% had allergic conjunctivitis at baseline.

ADvocate 1, ADvocate 2, and KGAF compared the safety of Ebglyss monotherapy to placebo. ADhere compared the safety of Ebglyss + TCS to placebo + TCS through 16 weeks. 783 subjects within these studies were treated with Ebglyss in the 16-week placebo-controlled period. A total of 891 subjects within the atopic dermatitis development program were treated with Ebglyss for at least 1 year.

The long-term safety of Ebglyss was assessed in the two monotherapy studies up to Week 52. The long-term safety of Ebglyss in combination with TCS was evaluated for ADhere patients who enrolled in a long-term extension study up to 56 weeks of treatment. In two monotherapy studies, 51.7% of patients treated with lebrikizumab 250 mg Q4W reported a TEAE from Week 16 to Week 52.

Table 2 summarizes the adverse reactions that were reported more frequently in the Ebglyss groups than in the placebo group during the 16-week placebo-controlled period of the clinical trials.

Table 2 – Adverse Reactions Reported by ≥ 1% Ebglyss-Treated Subjects and Higher than Placebo with Moderate-to-Severe Atopic Dermatitis Through Week 16 in Placebo-Controlled Trials

Adverse Reactions

^a Integrated analysis of the monotherapy trials: ADvocate 1 (KGAB), ADvocate 2 (KGAC), and KGAF.

^b Analysis of topical corticosteroid (TCS) combination trial: ADhere (KGAD).

^c Ebglyss 500 mg at Week 0 and Week 2, followed by 250 mg every two weeks (Q2W).

^d Injection Site Reactions includes MedDRA High-Level Term (HLT) which includes (but is not limited to) the most common terms: injection site pain, injection site erythema, and injection site reaction.

Specific Adverse Drug Reactions

Injection Site Reactions

Among the subjects pooled from ADvocate 1, ADvocate 2, KGAF, and ADhere, injection site reaction was reported in 2.6% of the subjects treated with lebrikizumab and 1.5% of the subjects in the placebo group. One subject (0.1%) treated with lebrikizumab reported a severe injection site reaction, and 2 events led to permanent discontinuation of lebrikizumab treatment.

Conjunctivitis and Keratitis

Conjunctivitis was the most frequently reported eye disorder.

Among the subjects pooled from ADvocate 1, ADvocate 2, KGAF, and ADhere, conjunctivitis and conjunctivitis allergic were reported in 6.5% and 1.8% of the subjects treated with lebrikizumab and in 1.8% and 0.7% of the subjects in the placebo group. Conjunctivitis and conjunctivitis allergic events reported were mild or moderate in severity, and 2 events led to permanent discontinuation of lebrikizumab treatment.

Keratitis events occurred in 0.6% of lebrikizumab-treated patients. All were mild or moderate in severity, and 2 events led to permanent discontinuation of lebrikizumab treatment.

Herpes Zoster

Among the subjects pooled from ADvocate 1, ADvocate 2, KGAF, and ADhere, herpes zoster was reported in 0.6% of the subjects treated with lebrikizumab and none of the subjects in the placebo group. All herpes zoster events reported were mild or moderate in severity and none led to permanent discontinuation of treatment.

Immunogenicity

As with all therapeutic proteins there is a potential for immunogenicity with Ebglyss.

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.

Anti-drug antibodies were detected during the 12-month treatment period in Ebglyss studies. No definitive conclusions can be drawn regarding the impact of anti-drug antibodies on the pharmacokinetics, efficacy, or safety of lebrikizumab.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Adolescents (12 to < 18 years of age who weigh ≥ 40 kg):

The safety of lebrikizumab was assessed in 372 adolescents (age 12 to < 18 years of age who weigh ≥ 40 kg) with moderate-to-severe atopic dermatitis. This includes 270 subjects exposed for at least one year. The observed safety profile of lebrikizumab in these subjects was similar to the observed safety profile in adults with moderate-to-severe atopic dermatitis (see 1.1 INDICATIONS, Pediatrics).

Pediatrics (< 12 years of age) and Adolescents (12 to < 18 years who weigh < 40 kg):

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in patients < 12 years of age and in adolescents who weigh < 40 kg (see 1.1 INDICATIONS, Pediatrics).

8.3 Less Common Clinical Trial Adverse Reactions

Adverse drug reactions occurring in <1% of Ebglyss-treated subjects:

Blood and lymphatic system disorders: eosinophilia

Eye disorders: blepharitis, keratitis

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Eosinophilia

Lebrikizumab-treated subjects had a greater mean increase from baseline in eosinophil count compared to subjects treated with placebo. In lebrikizumab-treated subjects, 20.3% had any increase in eosinophil count compared to 11.7% with placebo. In general, the increase in the lebrikizumab-treated subjects was mild or moderate and transient. Eosinophilia >5000 cells/mcL was observed in 0.4% in the lebrikizumab-treated subjects and none of the placebo-treated subjects. Adverse reactions of eosinophilia were reported in 0.6% of subjects treated with lebrikizumab and with a similar rate in subjects treated with placebo during the initial treatment period. Eosinophilia did not result in treatment discontinuation and no eosinophil-related disorders were reported (see 8.3 Less Common Clinical Trial Adverse Reactions).

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No formal drug interaction studies were conducted. No pharmacokinetic drug interactions are expected based on the characteristics of lebrikizumab.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established. In atopic dermatitis studies, interactions between lebrikizumab and other systemic immunomodulatory agents or phototherapy have not been evaluated.

Live Vaccines

No data are available on the response to live vaccines. Avoid use of live vaccines in patients treated with Ebglyss (see 7 WARNINGS AND PRECAUTIONS, Vaccination).

Non-live Vaccines

Immune responses to non-live vaccines were assessed in a trial (ADopt-VA) in which adult subjects with moderate-to-severe atopic dermatitis were subcutaneously treated with placebo or lebrikizumab 500 mg at weeks 0 and 2 followed by lebrikizumab 250 mg every other week with the last dose administered at Week 14. At Week 12, subjects were vaccinated with two co-administered non-live vaccines, a tetanus, diphtheria, and acellular pertussis (TdaP) vaccine (T cell-dependent) and a meningococcal polysaccharide vaccine (T cell-independent). Immune responses were assessed 4 weeks later. Immune responses to both non-live vaccines were not negatively impacted by the concomitant lebrikizumab treatment. Immune responses to other non-live vaccines were not assessed. No adverse interactions between either of the non-live vaccines and lebrikizumab were noted in the study.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Lebrikizumab is an immunoglobulin G4 (IgG4) monoclonal antibody (MAb) that binds with high affinity and slow off-rate to interleukin (IL)-13 and inhibits IL-13 signaling through the IL-4 receptor alpha (IL-4Rα)/IL-13 receptor alpha 1 (IL-13Rα1) pathway, thereby blocking the downstream effects of IL-13. Lebrikizumab does not prevent the binding of IL-13 to the IL-13 receptor alpha 2 (IL13Rα2 or decoy receptor), which allows the internalization of IL-13 into the cell.

10.2 Pharmacodynamics

In a clinical study, lebrikizumab reduced the levels of the following downstream regulated molecules: serum periostin, total immunoglobulin E (IgE), CCL18 (pulmonary and activation-regulated chemokine [PARC]), and CCL13 (monocyte chemotactic protein 4 [MCP 4]).

10.3 Pharmacokinetics

Lebrikizumab exhibited linear pharmacokinetics with a dose-proportional increase in exposure over the dose range of 37.5 to 500 mg given as a subcutaneous injection in subjects with moderate-to-severe atopic dermatitis or in healthy volunteers.

Table 3 – Summary of Lebrikizumab Pharmacokinetic Parameters in Healthy Adult Participants after a Single Subcutaneous Dose with the Prefilled Pen

^a Geometric mean (geometric CV%)

^b Median (minimum-maximum)

^c Geometric mean (minimum-maximum)

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. The median (5^th - 95^th) accumulation ratio from first loading dose to steady state (Week 16) based on population pharmacokinetic (PK) predicted C_trough was 1.53 (1.04 – 2.12).

Based on a population PK analysis, the estimated steady-state maximum concentration (C_max,_ss), the steady-state average concentration (C_avg,_ss), and the steady-state trough concentration (C_trough,_ss) at Week 16 following the 250 mg Q2W subcutaneous dose in subjects with moderate-to-severe atopic dermatitis were 109 μg/mL, 100 μg/mL, and 86 μg/mL, respectively. The C_max,_ss, the C_avg,_ss, and the C_trough,_ss at Week 52 following the transition to 250 mg Q4W subcutaneous maintenance dosing in subjects with moderate-to-severe atopic dermatitis were 63 μg/mL, 51 μg/mL, and 36 μg/mL, respectively.

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 consistently 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

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

Elimination

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.

Special Populations and Conditions

• Pediatrics

  Adolescents (12 to < 18 years of age who weigh ≥ 40 kg):

  At Week 16, estimated median steady-state maximum concentration (C_max,ss), steady-state average concentration (C_avg,ss), and steady-state trough concentration (C_trough,ss) in adolescent subjects following 250 mg Q2W dosing were 121 µg/mL, 111 µg/mL, and 96 µg/mL, respectively. Corresponding estimated steady-state concentrations following 250 mg Q4W dosing were 71 µg/mL, 56 µg/mL, and 38 µg/mL, respectively.

  Pediatrics (< 12 years of age) and Adolescents (12 to < 18 years who weigh < 40 kg):

  The pharmacokinetics of lebrikizumab in these subjects have not been studied.

• Geriatrics

  Age did not have a clinically meaningful effect on the pharmacokinetics of lebrikizumab.

• Sex

  Sex did not have a clinically meaningful effect on the pharmacokinetics of lebrikizumab.

• Ethnic Origin

  Race did not have a clinically meaningful effect on the pharmacokinetics of lebrikizumab.

• Renal and Hepatic Insufficiency

  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 renal and hepatic elimination.

  Population PK analysis showed that markers of renal function (eGFR) had no clinically meaningful effect on lebrikizumab pharmacokinetics over a range of 27.4 to 335 mL/min/1.73 m².

  Markers of hepatic function (AST ranged from 6 to 105 IU/L, and ALT ranged from 5 to 178 IU/L) were not identified as covariates on lebrikizumab pharmacokinetics.

• Body Weight

  Lebrikizumab C_max, C_avg, and C_trough concentrations decreased with increasing body weight as determined by population PK analysis. No dose adjustments are necessary in patients with higher body weight.

11 STORAGE, STABILITY AND DISPOSAL

Ebglyss is sterile and preservative-free.

Store refrigerated at 2°C to 8°C in the original carton to protect from light.

If necessary, Ebglyss may be kept at room temperature up to 30°C 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 use prefilled pen or prefilled syringe with needle shield after use in a puncture-resistant container.

12 SPECIAL HANDLING INSTRUCTIONS

For special handling instructions on how to properly dispose of Ebglyss following an injection, refer to the PATIENT MEDICATION INFORMATION, INSTRUCTIONS FOR USE section of the product monograph.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: lebrikizumab

Molecular formula: H chain: C₂₁₇₇H₃₃₇₃N₅₆₇O₆₇₂S₁₈ L chain: C₁₀₄₀H₁₆₁₇N₂₈₃O₃₄₅S₇

Molecular mass: Approximately 145,285 Daltons for the non-glycosylated protein backbone of the molecule.

Structural formula: Lebrikizumab is a recombinant Immunoglobulin G4 (IgG4) monoclonal antibody composed of 2 identical gamma heavy chains (445 amino acid residues each) and 2 identical light chains (218 amino acid residues each) with inter- and intra-chain disulfide bonds.

Physicochemical properties: lebrikizumab solution is clear, colorless to slightly yellow, free of visible particles with a pH of 5.4 – 6.0.

Product Characteristics:

Lebrikizumab is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. Lebrikizumab drug substance manufacture begins with the thawing of the working cell bank, that is scaled-up prior to seeding a production bioreactor. The culture is harvested, clarified, and purified via a downstream purification process. Lebrikizumab drug product is formulated, sterile filtered and filled into syringes prior to final packaging.

14 CLINICAL TRIALS

Trial Design and Study Demographics

The efficacy and safety of Ebglyss were evaluated in monotherapy studies ADvocate 1 and ADvocate 2 and concomitant TCS study, ADhere. All three studies were randomized, double-blind, placebo-controlled, and involved a total of 1062 adults and adolescents (aged 12 to < 18 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) score ≥ 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.

Patients with active hepatitis, endoparasitic infections, a history of invasive opportunistic infections, history of human immunodeficiency virus (HIV) infection, severe uncontrolled asthma, and a history of malignancy, including mycosis fungoides, within 5 years before the screening visit (except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin) were excluded from clinical studies.

At baseline, the monotherapy studies ADvocate 1 and ADvocate 2 enrolled 424 and 427 patients, respectively. Across studies, the mean age was 35.8 years, the mean weight was 77.1 kg, 49.9% were female, 63.7% were white, 22.6% were Asian, 9.9% were black, and 12.0% were adolescents (12 to < 18 years). Overall, 61.5% of patients had a baseline IGA score of 3 (moderate atopic dermatitis), 38.5% of patients had a baseline IGA score of 4 (severe atopic dermatitis), and 54.8% of patients had received prior systemic treatment. The mean baseline EASI score was 29.6, the mean baseline Pruritus Numeric Rating Scale (NRS) was 7.2, the mean baseline Dermatology Life Quality Index (DLQI) was 15.5.

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

In all three studies, patients received subcutaneous injection of the initial dose of 500 mg of Ebglyss (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-mild potency TCS or TCI on active lesions on sensitive areas only, such as the face, neck, intertriginous, and genital areas.

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.

In ADvocate-1 and 2, patients achieving IGA 0 or 1 or at least a 75% reduction in EASI (EASI 75) at Week 16 without having received any rescue therapy were re-randomised in a blinded manner to (i) Ebglyss 250 mg Q2W; (ii) Ebglyss 250 mg every 4 weeks (Q4W); or (iii) matching placebo (Ebglyss withdrawal) up to 52 weeks.

In all the three studies, the co-primary endpoints were the proportion of patients with IGA 0 or 1 with at least a 2-point reduction in IGA score from baseline and EASI 75 from baseline to Week 16. Key secondary endpoints included the proportion of patients achieving EASI 90, reduction in itch as defined by at least 4-point improvement in Pruritus NRS, and change in DLQI from baseline to Week 16.

Table 4 – Summary of Patient Demographics for Clinical Trials in Moderate-to-Severe Atopic Dermatitis

^a Participants randomly assigned to Ebglyss 250 mg Q2W at Baseline received 500 mg loading doses at Week 0 and Week 2.

^b Participants who received PBO during the first 16 weeks of the study and who were re-randomized to Ebglyss treatment received a loading dose of either 500 mg at Weeks 16 and 18 if randomized to Ebglyss 250 mg Q2W or 500 mg at Week 16 if randomized to Ebglyss 250 mg Q4W.

Study Results

Clinical Response at Week 16 (ADvocate 1, ADvocate 2, and ADhere) in Moderate-to-Severe Atopic Dermatitis Patients

The results of the Ebglyss monotherapy trials (ADvocate 1 and ADvocate 2) and the Ebglyss + TCS trial (ADhere) are presented in Table 5.

Table 5 – Efficacy Results of Ebglyss at Week 16^a In ADvocate 1 (monotherapy), ADvocate 2 (monotherapy), and ADhere (combination therapy with TCS)

^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. The categorical primary and key secondary endpoints were analyzed using the Cochran-Mantel-Haenszel test.

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

^c 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, or a 75% reduction in EASI from Baseline to Week 16, respectively.

^d A prespecified graphical multiple testing procedure was used to control the overall Type I error rate at a 2-sided alpha of 0.05 for all primary and key secondary endpoints.

A greater proportion of patients randomized to Ebglyss achieved improvement in Pruritus NRS (p < 0.01) or in EASI 90 (p < 0.05) as early as Week 4 compared to placebo. The proportion of patients responding on Pruritus NRS or EASI 90 continued to increase through the treatment period.

In the monotherapy trials ADvocate 1 and ADvocate 2 (pooled), 291 Ebglyss-treated patients who were responders at Week 16 were re-randomized to 36 weeks of treatment, with 118 patients re-randomized to treatment with Ebglyss 250 mg Q4W dose regimen. 59/77 (76.9%) patients who were IGA 0,1 responders at Week 16 and 94/115 (81.7%) patients who were EASI 75 responders at Week 16 maintained their response through Week 52.

Quality of Life/Patient-Reported Outcomes

In both monotherapy studies (ADvocate 1 and ADvocate 2) and in the TCS combination study (ADhere), improvements in patient reported outcomes were associated with Ebglyss 250 mg Q2W.

In ADvocate 1, the proportion of Ebglyss-treated responders for Sleep-Loss Scale (with baseline Sleep-Loss Scale ≥ 2) and DLQI (with baseline DLQI ≥ 4) was 39% and 76%, respectively, compared to 5% and 34% for placebo at Week 16.

In ADvocate 2, the proportion of Ebglyss-treated responders for Sleep-Loss Scale (with baseline Sleep-Loss Scale ≥ 2) and DLQI (with baseline DLQI ≥ 4) was 28% and 66%, respectively, compared to 8% and 34% for placebo at Week 16.

In ADhere, the proportion of Ebglyss-treated responders for Sleep-Loss Scale (with baseline Sleep-Loss Scale ≥ 2) and DLQI (with baseline DLQI ≥ 4) was 35% and 77%, respectively, compared to 18% and 59% for placebo at Week 16.

Adolescents (12 to < 18 years of age)

In the monotherapy studies ADvocate 1 and ADvocate 2, the mean age of adolescent subjects 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 study with TCS ADhere, the mean age of adolescent subjects 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.

By week 16, clinically meaningful efficacy results were demonstrated in adolescent subjects treated with Ebglyss and Ebglyss + TCS and were consistent with the results observed in the adult population.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: Repeat dose studies and safety pharmacology evaluations administering lebrikizumab to primarily sexually-immature cynomolgus monkeys did not reveal lebrikizumab-related adverse effects. Lebrikizumab was administered once weekly to male and female cynomolgus monkeys (3/sex/group; 2.4-3.4 years of age) at dose levels of 0, 5, and 25 mg/kg by subcutaneous (SC) injection for 3 months (13 doses) or once weekly by intravenous (IV) injection to male and female monkeys (4/sex/group; 2.5-4.5 years of age) for up to 9 months (39 doses) at dose levels of 0, 1, 5, and 25 mg/kg. There were no deaths or treatment-related adverse clinical signs or findings noted during physical or ophthalmic examinations. There were no adverse effects on ECG parameters, body weight, food consumption, clinical chemistry, hematology, coagulation or urinalysis parameters, peripheral blood immunophenotype, organ weights, or tissue morphology attributed to lebrikizumab. The NOAEL was the high dose of 25 mg/kg/week IV. Margins of exposure were not calculated based on a lack of toxicokinetic data from the pivotal 9-month study. However, C_avg,ss at the NOAEL is expected to approximate the C_avg,ss observed in a 9-month female monkey fertility study on the basis of similar peak serum concentrations in both males and females. At the NOAEL of 25 mg/kg administered once a week, systemic exposure is approximately 15 to 18 times higher than adolescents and adults at the recommended human dose (500 mg SC W0 and W2, then 250 mg SC Q2W), based on C_avg,ss.

Carcinogenicity: Nonclinical studies have not been conducted to evaluate the carcinogenic potential of lebrikizumab.

Genotoxicity: Nonclinical studies have not been conducted to evaluate the mutagenic or genotoxic potential of lebrikizumab.

Reproductive and Developmental Toxicology: No lebrikizumab-related adverse effects on reproductive organs, reproductive hormones, menstrual cycles, spermatogenesis or sperm were observed in sexually mature cynomolgus monkeys that received lebrikizumab at a dose of 25 mg/kg weekly for 37 weeks (females; intravenous route) or 13 weeks (males; subcutaneous route). Exposure at 25 mg/kg once a week in male and female cynomolgus monkeys is 11 to 14 or 15 to 18 times the adolescent and adult exposure at the recommended human dose (500 mg SC W0 and W2, then 250 mg SC Q2W), respectively, based on C_avg,ss.

In an embryofetal development study, no malformations or embryofetal toxicity were observed in fetuses from pregnant cynomolgus monkeys administered lebrikizumab during organogenesis (GD 20 to GD 48) at an initial dose of 150 mg/kg followed by 50 mg/kg per week by subcutaneous injection, 22 times (adults) the human exposure (C_avg,_ss) at the recommended dose (500 mg/kg SC W0 and W2, then 250 mg SC Q2W) based on C_avg,ss. Lebrikizumab was detected in fetal serum at concentrations that were approximately 30% of maternal serum concentrations at all tested dose levels indicating that lebrikizumab crossed the placenta in monkeys.

In a pre- and post-natal development study, pregnant cynomolgus monkeys were administered lebrikizumab from GD 35 to parturition at 150 mg/kg initial followed by 50 mg/kg per week by subcutaneous injection. No embryofetal toxicity or malformations, or effects on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age. Serum lebrikizumab concentrations in all offspring were higher than maternal serum concentrations until the end of the observation period on post-natal day (PND) or lactation day (LD) 180. The NOAEL was 150 mg/kg followed by 50 mg/kg/week (leading dose followed by maintenance dose). Margins of exposure were not calculated based on a lack of toxicokinetic data. However, C_avg,ss at the NOAEL is expected to approximate the C_avg,ss observed in the embryofetal development study on the basis of similar trough serum concentrations in females. At the NOAEL of 150 mg/kg followed by 50 mg/kg/week, systemic exposure is approximately 22 times (adults) the human exposure (C_avg,_ss) at the recommended human dose (500 mg SC W0 and W2, then 250 mg SC Q2W) based on C_avg,ss

Juvenile Toxicity: Juvenile toxicity studies were not conducted with lebrikizumab.