Summary Basis of Decision for Ebglyss

Refer to the What steps led to the approval of Ebglyss? section for more information about the review process for this submission.

Clinical Pharmacology

Lebrikizumab, the medicinal ingredient in Ebglyss, is an immunoglobulin G4 (IgG4) monoclonal antibody that binds with a high affinity and slow off-rate to interleukin (IL)-13. It 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. The blockade of IL-13 signaling may provide therapeutic benefit in diseases in which IL-13 plays a role in disease pathogenesis, such as atopic dermatitis.

The clinical pharmacology portion of the submission consisted of two Phase I studies, three Phase I comparative bioavailability studies, a single population pharmacokinetic model, and a single pharmacokinetic/pharmacodynamic model.

The observed data suggest that lebrikizumab exposure increases in an approximately dose-proportional fashion, with an observed relative bioavailability of 46%, based on maximum serum concentration (C_max), following subcutaneous dosing relative to intravenous dosing. Lebrikizumab exhibits linear elimination kinetics, with a half-life of approximately 24.5 days, irrespective of the route of administration or dose. The time to maximum serum concentration (t_max) following subcutaneous administration was approximately 8 days, and was dose independent. Lebrikizumab exposures following administration from the proposed pre-filled syringe or autoinjector presentations met pre-specified margins consistent with Health Canada Guidance for comparative bioavailability standards (2020).

The most parsimonious structural population pharmacokinetic model for lebrikizumab was a two-compartment model with first-order absorption and linear elimination from the central compartment following subcutaneous administration. Body weight was the only covariate identified as being significant in the base model and retained throughout model development.

The population pharmacokinetic model suggests that lebrikizumab exposures reach steady state after about 8 weeks of induction dosing at the to-be-marketed posology. These exposures are maintained through to Week 16, with a population pharmacokinetic predicted median minimum serum concentration (C_trough) of 86.4 mcg/mL. Lebrikizumab exposure declined after 52 weeks of maintenance dosing every 4 weeks (starting at Week 16), to a population pharmacokinetic predicted C_trough of 36.1 mcg/mL. These exposures remain above the half maximal effective concentration (EC50) for efficacy of 16.5 mcg/mL, as predicted by the pharmacokinetic/pharmacodynamic model.

Consistent with the lower body weight of the overall adolescent population, a higher predicted median C_max and C_trough was observed at Week 16 after induction phase dosing in adolescent subjects (weighing more than 40 kg) than what was observed in the adult population.

The combined immunogenicity data from the induction and maintenance phases of the Phase III studies suggest that immunogenicity is low. However, approximately 50% of samples measured were likely to have serum lebrikizumab levels above the drug tolerance limit of 100 ng/mL for the detection for anti-drug antibodies (ADAs). This ADA level is potentially clinically relevant, and therefore, the immunogenicity data presented are likely to be an underestimation of the incidence of ADAs following lebrikizumab dosing in the main Phase III studies. Based on this assay limitation, the uncertainties regarding the incidence and clinical impact of ADAs on lebrikizumab pharmacokinetics, efficacy, and safety were included in the Ebglyss Product Monograph.

Overall, the clinical pharmacology data support the use of Ebglyss for the recommended indication.

For further details, please refer to the Ebglyss Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy results supporting the use of Ebglyss (lebrikizumab) for the treatment of moderate-to-severe atopic dermatitis are primarily based on clinical data from three randomized, double-blind, placebo-controlled, pivotal Phase III studies (ADvocate 1, ADvocate 2, and ADhere). The studies enrolled a total of 1,062 adults and adolescents (aged 12 to less than 18 years and weighing at least 40 kg) with moderate-to-severe atopic dermatitis, defined by an Eczema Area and Severity Index (EASI) of at least 16; Investigator’s Global Assessment (IGA) score of at least 3; and a body surface area involvement of at least 10%. Patients enrolled into the three studies previously had an inadequate response to topical medication or a determination that topical treatments are otherwise medically inadvisable.

The 52-week monotherapy studies (ADvocate 1 and ADvocate 2) included patients treated with Ebglyss or placebo. The double-blind period of the concomitant therapy study (ADhere) was 16 weeks, and patients received treatment with Ebglyss or placebo in combination with concomitant topical corticosteroids. In all three pivotal studies, patients on Ebglyss received a 500 mg subcutaneous injection of Ebglyss (two 250 mg injections) at Weeks 0 and 2, followed by a 250 mg subcutaneous injection every other week until Week 16.

All three pivotal studies assessed the superiority of Ebglyss compared to placebo through the co-primary endpoints at Week 16, in terms of the proportion of patients with an IGA score of 0 (clear) or 1 (almost clear) and a reduction of 2 points or greater from baseline, and the proportion of patients with an improvement from baseline of at least 75% in the EASI score (EASI-75).

At Week 16, a statistically significant higher proportion of patients achieved an IGA score of 0 or 1 in the Ebglyss group (43.1% in ADvocate 1, 33.2% in ADvocate 2, and 41.2% in ADhere) compared to the placebo group (12.7% in ADvocate 1, 10.8% in ADvocate 2, and 22.1% in ADhere). Additionally, a statistically significant higher proportion of patients achieved an EASI-75 in the Ebglyss group (58.8% in ADvocate 1, 52.1% in ADvocate 2, and 69.5% in ADhere) compared to the placebo group (16.2% in ADvocate 1, 18.1% in ADvocate 2, and 42.2% in ADhere).

Results for the key secondary efficacy endpoints from the initial treatment period (proportion of patients with a reduction of Pruritus Numerical Rating Scale of at least 4 from baseline to Week 16 and change in Dermatology Life Quality Index score from baseline to Week 16) supported the treatment benefit of Ebglyss observed for the co-primary endpoints.

Clinically meaningful efficacy results were demonstrated in adolescent subjects treated with Ebglyss as a monotherapy or in combination with topical corticosteroids. These results were consistent with the results observed in the adult population.

Overall, Ebglyss as a monotherapy or in combination with topical corticosteroids was confirmed to be superior to placebo at Week 16 in treating adults and adolescents (12 years of age and older who weigh at least 40 kg) with moderate-to-severe atopic dermatitis.

As per the information included in the Ebglyss Product Monograph, discontinuation of treatment with Ebglyss should be considered in patients who do not respond by Week 16.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Ebglyss (lebrikizumab injection) 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.	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.

For more information, refer to the Ebglyss Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 1,720 participants with atopic dermatitis were treated with Ebglyss (lebrikizumab) in controlled and uncontrolled studies. Of these, 891 participants, including 270 adolescents, were exposed to the drug for at least one year. The safety of Ebglyss was evaluated through Week 16 as a monotherapy or in combination with topical corticosteroids in the three pivotal ADvocate 1, ADvocate 2, and ADhere studies outlined in the Clinical Efficacy section above and in a Phase II dose-ranging study (KGAF).

Notable adverse drug reactions occurring in at least 1% of patients with atopic dermatitis who were treated with Ebglyss or a placebo as a monotherapy through Week 16 included (Ebglyss versus [vs.] placebo): conjunctivitis (6.8% vs. 2.1%), injection site reactions (2.6% vs. 1.5%), allergic conjunctivitis (2.2% vs. 0.9%), and dry eye (1.2% vs. 1.1%). An increase rate of adverse events relating to the eye was reported; however, these events were generally mild to moderate in severity. Increased blood eosinophil counts were also a trend observed in the Ebglyss-treated group; it was generally transient and did not result in clinical sequelae. Of the Ebglyss-treated patients, 1.3% reported at least one serious adverse event. No treatment-related deaths were reported. 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.

The safety profiles were similar whether Ebglyss was administered as a monotherapy (at Week 16 and through Week 52) or with concomitant topical corticosteroids (through Week 56). The observed safety profile of Ebglyss in adolescents (aged 12 to less than 18 years of age who weigh at least 40 kg) was similar to the observed safety profile in adults with moderate-to-severe atopic dermatitis.

Appropriate warnings and precautions are in place in the approved Ebglyss Product Monograph to address the identified safety concerns. Additional safety considerations regarding hypersensitivity reactions, helminth infections, and vaccinations, as well as important study exclusion criteria, have been included in the Ebglyss Product Monograph.

For more information, refer to the Ebglyss Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non-clinical data package was considered acceptable for the review of the pharmacodynamic, toxicokinetic, and toxicology profile of lebrikizumab (the medicinal ingredient in Ebglyss). Pharmacodynamic studies were primarily conducted in vitro and supported the use of cynomolgus monkeys as the only relevant experimental model for in vivo toxicity testing.

Lebrikizumab selectively inhibits human- and monkey-derived interleukin (IL)-13 and has demonstrated the potential to inhibit IL-13-induced proliferation, as well as production and upregulation of IL-13 receptor alpha 2 (IL-13Rα2) receptor mRNA and inflammatory markers using in vitro models. Lebrikizumab demonstrated function through inhibition of the IL-4 receptor alpha (IL4Rα)/IL-13Rα1 receptor complex, without inhibiting the function of IL-4 or direct interaction with IL-13Rα1 or IL-13Rα2.

Serum lebrikizumab concentrations in offspring of cynomolgus monkey dams dosed with lebrikizumab during gestation were higher than maternal concentrations throughout the post-dosing period ending on postnatal day 180. Although lebrikizumab was detected in the serum of offspring, this finding was not elucidated by standalone distribution studies that evaluated the distribution to milk. This finding has been appropriately described in Ebglyss Product Monograph.

Lebrikizumab was administered to sexually-immature male and female cynomolgus monkeys for 6 weeks, 13 weeks, and 9 months by intravenous or subcutaneous administration at doses of approximately 1, 5, and 25 mg/kg body weight once per week. No treatment-related and/or toxicologically significant findings, including cardiovascular effects, were reported. The no-observed-adverse-effect level (NOAEL) was estimated to be 25 mg/kg body weight in the repeat-dose studies for both intravenous or subcutaneous administration.

In an embryofetal developmental study, no maternal toxicity or effect on gestational parameters were observed in cynomolgus monkeys following exposure during gestational day 20 to 48, and no statistically significant or toxicologically meaningful findings were noted in the offspring. Lebrikizumab was detected in fetal serum on gestational day 100 with mean fetal to maternal concentration ratios of approximately 0.3. In the pre- and post-natal developmental study, the incidence of abortion, fetal deaths, or stillbirth were not increased at any dose, and the development and behaviour of the offspring were unaffected when compared to the control group. A NOAEL of 50 mg/kg body weight was estimated, which is based on the highest dose tested in both studies. Fertility parameters in males and females were unaffected by the weekly administration of lebrikizumab for 13 weeks and 9 months, respectively. Effects on mating indices were not evaluated.

In alignment with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and based on an acceptable scientific rationale, carcinogenicity and juvenile toxicity studies were not conducted.

A margin of exposure of 11 or greater was estimated for all repeat-dose and reproductive and developmental toxicity studies when compared to adult or adolescent exposure.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Ebglyss Product Monograph. Appropriate warnings and precautionary measures are in place in the Ebglyss Product Monograph to address the identified safety concerns.

In view of the intended use of Ebglyss, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Ebglyss Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Ebglyss drug substance (lebrikizumab) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody produced in Chinese hamster ovary cells. It is composed of two kappa light chains and two identical heavy chains. Each heavy chain contains a substitution to increase the stability of the antibody. Lebrikizumab binds with high affinity to interleukin (IL)-13 and inhibits IL-13 signaling through the IL-4 receptor alpha/IL-13 receptor alpha 1 pathway. This interaction selectively blocks downstream effects of IL-13, which is expected to provide therapeutic benefit in diseases in which IL-13 is a key contributor to the disease pathogenesis.

Detailed characterization studies were performed to provide assurance that lebrikizumab consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The drug substance (lebrikizumab) upstream manufacturing process begins with the thawing of the working cell bank, followed by a series of cell expansion steps. Fed-batch production fermentation of lebrikizumab occurs in a production bioreactor. The culture is harvested, clarified, and then transferred for downstream processing. The downstream process consists of Protein A capture chromatography, low-pH viral inactivation, anion exchange chromatography, hydrophobic interaction chromatography, viral filtration, and ultrafiltration and diafiltration. Finally, the purified bulk drug substance is filtered and dispensed into either 120 L cryovessel tanks and stored at ≤ -20 °C or in 5 L polycarbonate bottles and stored at ≤ -65 C.

The Ebglyss drug product is manufactured as a sterile, non-pyrogenic, aseptically filled liquid at a target concentration of 125 mg/mL and filled as a 2-mL semi-finished syringe. Ebglyss is supplied in the following presentations: a semi-finished syringe in a prefilled syringe needle safety device (PFS-NSD) and a semi-finished syringe in an autoinjector. The semi-finished syringe manufacturing process is largely the same for both presentations, and consists of thawing of the drug substance in cryovessels followed by drug product compounding, bioburden reduction filtration, sterilizing filtration, filling, and inspection. The semi-finished syringe is then assembled with syringe accessories to form either the PFS-NSD or autoinjector.

Process validation was performed on the semi-finished syringes for the PFS-NSD and autoinjector presentations. In these studies, all process parameters were within operating ranges and met the protocol acceptance criteria. As well, all in-process test results met their acceptance criteria and all batch release results met the proposed commercial specifications. The data demonstrate that the commercial manufacturing and assembly processes are capable of consistently producing the drug product with the desired product quality. The proposed commercial manufacturing process has been successfully validated at a scale of 50 to 150 liters for the PFS-NSD presentation and at a scale of 60 to 200 liters for the autoinjector presentation.

The semi-finished syringe manufacturing process steps remained virtually the same and the commercial formulation remained unchanged throughout its development. Comparability studies were conducted to support changes made to the drug substance primary container closure system, the drug product manufacturing process, and the inclusion of an additional drug product manufacturing site. The comparability of the drug product throughout development and between manufacturing sites has been appropriately demonstrated.

Control of the Drug Substance and Drug Product

An integrated control strategy for Ebglyss was developed based on critical quality attributes, risk assessments, process characterization studies, and overall experience gained throughout development. The control strategy includes control of the materials, the critical steps within the manufacturing processes, and the product through release and stability testing.

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Each lot of Ebglyss drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Ebglyss is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life for the PFS-NSD presentation and 24-month shelf life for the autoinjector presentation is acceptable when Ebglyss is stored at 2 °C to 8 °C and protected from light. In addition, the data provided support an in-use shelf-life of up to 7 days at 30 °C for both drug product presentations.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug product and drug substance facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The master cell bank, working cell bank, unprocessed bulk, and pre-harvest culture fluid are tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

None of the materials used in the drug substance manufacturing process are of animal or human origin. Raw materials of recombinant deoxyribonucleic acid (DNA) origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents.