Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: other dermatological preparations, agents for dermatitis, excluding corticosteroids , ATC code: D11AH10.

Mechanism of action

Lebrikizumab is an immunoglobulin (IgG4) monoclonal antibody that binds with high affinity 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.

Immunogenicity

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



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 achieving 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), which is a 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 patients, 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 2).

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 at 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.

Table 2. Efficacy results of lebrikizumab monotherapy at week 16 in ADvocate-1 and Advocate-2
ADvocate-1                  ADvocate-2
Week 16
Placebo         LEB 250 mg    Placebo LEB 250 mg
Q2W                      Q2W
N=141            N=283        N=146       N=281
IGA 0 or 1, %a                                               12.7            43.1***       10.8       33.2*** EASI 75, %b                                                  16.2            58.8***       18.1       52.1*** EASI 90, %b                                                   9.0            38.3***        9.5       30.7*** Pruritus NRS (≥ 4-point improvement), %c                     13.0            45.9***       11.5       39.8*** DLQI (Adults) (≥ 4-point improvement), %d                    33.8            75.6***       33.6       66.3*** LEB = lebrikizumab; N = number of patients.
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<0.001 versus placebo.


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).

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 3).



Table 3. Efficacy results of lebrikizumab monotherapy at week 52 in subjects responding to treatment at week 16 in ADvocate-1 and ADvocate-2 (pooled analysis)
ADvocate-1 and ADvocate-2 (pooled)
Week 52
Placebo d
LEB 250 mg
(LEB Withdrawal)                  Q4W
N=60                        N=118
IGA 0 or 1, %a                                                   47.9                       76.9** EASI 75, %b                                                      66.4                        81.7* EASI 90, %b                                                      41.9                       66.4** Pruritus NRS (≥ 4-point improvement), %c                         66.3                        84.7 a Subjects with IGA 0/1 with a ≥2-point improvement from baseline at week 16 who continued to exhibit IGA 0/1 with a ≥2-  point improvement at week 52.
b Subjects who achieved EASI 75 at week 16 and continued to exhibit EASI 75 at week 52, or subjects who achieved 
EASI 75 at Week 16 and exhibited EASI 90 at week 52, respectively.
c The percentage is calculated relative to the number of subjects with a baseline Pruritus NRS ≥4.
d Subjects responding to lebrikizumab 250 mg Q2W at week 16 (IGA 0 or 1 or EASI 75) and re-randomised to placebo.

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

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 4).

Table 4. Efficacy results of lebrikizumab combination therapy with TCS at week 16 in ADhere ADhere
Week 16
Placebo + TCS                             LEB
250 mg Q2W + TCS
N=66                              N=145
IGA 0 or 1, %a                                                      22.1                               41.2* EASI 75, %b                                                         42.2                              69.5*** EASI 90, %b                                                         21.7                              41.2** Pruritus NRS (≥ 4-point improvement), %c                            31.9                               50.6* DLQI (Adults) (≥ 4-point improvement), %d                           58.7                               77.4* 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.

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).

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).



Other patient-reported outcomes

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.

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 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 5.

Table 5. Efficacy results of lebrikizumab monotherapy in ADvocate-1, ADvocate-2 and lebrikizumab combination therapy with TCS in ADhere at week 16 in adolescent patients ADvocate-1                  ADvocate-2                           ADhere Week 16
Placebo         LEB        Placebo      LEB               Placebo +            LEB 250 mg                  250 mg                TCS            250 mg Q2W Q2W                     Q2W                                    + TCS
N=18          N=37         N=17       N=30                 N=14               N=32 IGA 0 or 1, %a                   22.2           48.6          5.9      44.1**               28.6               57.3 EASI 75, %a                      22.2          62.2**        12.0      61.7**               57.1               88.0* EASI 90, %a                      16.7          45.9*          6.1      34.3*                28.6               55.1 Pruritus NRS (≥ 4-point
22.8         54.3*          0.3           42.1             13.8               45.8 improvement), %b a At Week 16, subjects with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale, or a 75% or 90% reduction in EASI from baseline to week 16, respectively.
b The percentage is calculated relative to the number of subjects with a baseline Pruritus NRS ≥4.

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

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.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption

After a subcutaneous dose of 250 mg lebrikizumab, peak serum concentrations were achieved approximately 7 to 8 days post dose.

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 predicted steady-state trough concentrations (Ctrough,ss) following lebrikizumab 250 mg Q2W and Q4W subcutaneous dosing in patients with atopic dermatitis (median and 5th - 95th percentile) were 87 (46-159) µg/mL and 36 (18-68) µg/mL, respectively.

The absolute bioavailability was estimated at 86% based on a population PK analysis. Injection site location 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.
Biotransformation

Specific metabolism studies were not conducted because lebrikizumab is a protein. Lebrikizumab is expected to degrade to small peptides and individual 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 approximately 24.5 days.

Linearity/non-linearity

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.

Special populations

Gender, age, and race
Gender, age (range 12 to 93 years), and race did not have a significant effect on the pharmacokinetics of lebrikizumab.

Renal and hepatic impairment

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

Body weight

Exposure to lebrikizumab was lower in subjects with higher body weight but this had no meaningful impact on clinical efficacy.

Paediatric population

Based on population PK analysis adolescents 12 to 17 years of age with atopic dermatitis had slightly higher lebrikizumab serum trough concentrations compared to adults, which was related to their lower body weight distribution.