Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark
Pharmacotherapeutic group: Agents for dermatitis, excluding corticosteroids
ATC code: D11AH07
Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to the type 2 cytokine interleukin-13 (IL-13) and inhibits its interaction with the IL-13 receptors. Tralokinumab neutralises the biological activity of IL-13 by blocking its interaction with the IL-13Rα1/IL-4Rα receptor complex. IL-13 is a major driver of human type 2 inflammatory disease, such as atopic dermatitis and inhibiting the IL-13 pathway with tralokinumab in patients decreases many of the mediators of type 2 inflammation.
In clinical trials, treatment with tralokinumab resulted in reduced levels of type 2 inflammation biomarkers in both lesional skin (CCL17, CCL18 and CCL26) and in blood (CCL17, periostin and IgE). In lesional skin, treatment with tralokinumab led also to reductions in epidermal thickness and to increase in marker of epithelial barrier integrity (loricrin). Skin colonization with Staphylococcus aureus was reduced more than 10-fold in patients treated with tralokinumab.
The efficacy and safety of tralokinumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (ECZTRA 1, ECZTRA 2 and ECZTRA 3) in 1 976 patients 18 years of age and older with moderate to severe atopic dermatitis defined by Investigator’s Global Assessment (IGA) score of 3 or 4 (moderate or severe), an Eczema Area and Severity Index (EASI) score of ≥16 at baseline, and a minimum body surface area (BSA) involvement of ≥10%. Eligible patients enrolled into the three studies had previous inadequate response to topical medication.
In all three studies, patients received 1) an initial dose of 600 mg tralokinumab (four 150 mg injections) on day 1, followed by 300 mg every two weeks (Q2W) up to week 16 or 2) matching placebo. In ECZTRA 3, patients received concomitant topical corticosteroids on active lesions as needed. Tralokinumab was administered by subcutaneous (SC) injection in all studies.
In ECZTRA 1 and ECZTRA 2, to evaluate the maintenance of response, patients responding to the initial 16-week treatment with tralokinumab (i.e. achieved IGA 0 or 1, or EASI-75) were re-randomised to 1) tralokinumab 300 mg Q2W or 2) tralokinumab 300 mg Q4W (alternating tralokinumab 300 mg and placebo Q2W) or 3) placebo Q2W up to 52 weeks. The main endpoints for evaluating maintenance of response were IGA 0 or 1 and EASI-75 at week 52. Patients responding to the initial 16-week treatment with placebo continued on placebo. Subjects not achieving IGA 0 or 1 or EASI-75 at week 16 and subjects who did not maintain the response during the maintenance period were transferred to open-label treatment with tralokinumab 300 mg Q2W with optional use of topical corticosteroids. The studies had a treatment period of 52 weeks.
In ECZTRA 3, patients responding to the initial 16-week treatment with tralokinumab + TCS (i.e. achieved IGA 0 or 1, or EASI-75) were re-randomised to 1) tralokinumab 300 mg Q2W + TCS or 2) tralokinumab 300 mg Q4W + TCS (alternating tralokinumab 300 mg and placebo Q2W) up to 32 weeks. The main endpoints for evaluating maintenance of response were IGA 0 or 1 and EASI-75 at week 32. Patients responding to the initial 16-week treatment with placebo + TCS continued on placebo + TCS. Patients who at week 16 did not achieve IGA 0 or 1 or EASI-75 continued on tralokinumab 300 mg Q2W + TCS treatment, irrespectively of their initial treatment. The study had a treatment period of 32 weeks.
In ECZTRA 1, 802 patients were enrolled (199 to placebo, 603 to tralokinumab 300 mg Q2W).
In ECZTRA 2, 794 patients were enrolled (201 to placebo, 593 to tralokinumab 300 mg Q2W).
In ECZTRA 3, 380 patients were enrolled (127 to placebo + TCS, 253 to tralokinumab 300 mg Q2W + TCS).
In all three pivotal studies, the primary endpoints were achievement of IGA 0 or 1 (“clear” or “almost clear”) and a reduction of at least 75% in EASI (EASI-75) from baseline to week 16. Secondary endpoints included the reduction of itch as defined by at least a 4-point improvement in the Worst Daily Pruritus Numeric Rating Scale (NRS) from baseline to week 16, reduction in the SCORing Atopic Dermatitis (SCORAD) scale from baseline to week 16, and change from baseline to week 16 in the Dermatology Life Quality Index (DLQI). Additional secondary endpoints included reduction of at least 50% and 90% in EASI (EASI-50 and EASI-90, respectively) and reduction in Worst Daily Pruritus NRS (weekly average) from baseline to week 16. Other endpoints included change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM), at least 4-point improvement in POEM, and Eczema-related Sleep NRS.
In the monotherapy studies (ECZTRA 1 and ECZTRA 2), across all treatment groups, the mean age was 37.8 years, 5.0% of the patients were 65 years of age or older, the mean weight was 76.0 kg, 40.7% were female, 66.5% were white, 22.9% were Asian, and 7.5% were black. In these studies, 49.9% of patients had a baseline IGA score of 3 (moderate atopic dermatitis, 49.7% of patients had a baseline IGA of 4 (severe atopic dermatitis), and 42.5% of patients had received prior systemic immunosuppressants (cyclosporine, methotrexate, azathioprine and mycophenolate). The mean baseline EASI score was 32.3, mean baseline Worst Daily Pruritus NRS was 7.8, mean baseline DLQI was 17.3, the baseline mean SCORAD score was 70.4, the baseline mean POEM score was 22.8, and the baseline mean physical and mental components of SF-36 were 43.4 and 44.3, respectively.
In the concomitant topical corticosteroids study (ECZTRA 3), across both treatment groups, the mean age was 39.1 years, 6.3% of the patients were 65 years of age or older, the mean weight was 79.4 kg, 45.0% were female, 75.8% were white, 10.8% were Asian, and 9.2% were black. In this study, 53.2% of patients had a baseline IGA score of 3, 46.3% of patients had a baseline IGA of 4, and 39.2 % of patients received prior systemic immunosuppressants. The baseline mean EASI score was 29.4, the baseline Worst Daily Pruritus NRS was 7.7, the baseline mean DLQI was 17.5, the baseline mean SCORAD score was 67.6, the baseline mean POEM score was 22.3.
In ECZTRA 1 and ECZTRA 2, from baseline to week 16, a significantly greater proportion of patients randomised and dosed to tralokinumab achieved IGA 0 or 1, EASI-75, and/or an improvement of ≥4 points on the Worst Daily Pruritus NRS compared to placebo (see Table 2).
Table 2. Efficacy results of tralokinumab monotherapy at week 16 in ECZTRA 1 and ECZTRA 2 (FAS):
| Monotherapy | ||||
|---|---|---|---|---|
| ECZTRA 1 | ECZTRA 2 | |||
| Week 16 | Week 16 | |||
| Placebo | Tralokinumab 300 mg Q2W | Placebo | Tralokinumab 300 mg Q2W | |
| Number of patients randomised and dosed (FAS) | 197 | 601 | 201 | 591 |
| IGA 0 or 1, % respondersa,b | 7.1 | 15.8# | 10.9 | 22.2§ |
| EASI-50, % respondersa | 21.3 | 41.6§,e | 20.4 | 49.9§,e |
| EASI-75, % respondersa | 12.7 | 25.0§ | 11.4 | 33.2§ |
| SCORAD, LS mean change from baseline (± SE)c | -17.2 (± 1.98) | -24.9§ (± 1.23) | -13.8 (± 2.00) | -26.9§ (± 1.06) |
| Pruritus NRS (≥ 4-point improvement, % responders)a,d | 10.3 (20/194) | 20.0# (119/594) | 9.5 (19/200) | 25.0§ (144/575) |
| DLQI, LS mean change from baseline (± SE)c | -5.7 (± 0.63) | -7.5# (± 0.41) | -5.2 (± 0.68) | -8.6§ (± 0.36) |
LS=least squares; SE=standard error, FAS: Full Analysis Set – includes all patients randomised and dosed
If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment at the discretion of the investigator.
a Patients who received rescue treatment or had missing data were considered non-responders.
b Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear” on a 0-4 IGA scale).
c Data after initiation of rescue medication or permanent discontinuation of treatment were considered missing. Placebo based multiple imputation of missing data.
d The percentage is calculated relative to the number of subjects with a baseline value >4.
e Not adjusted for multiplicity.
* p<0.05, #p<0.01, §p<0.001
In both monotherapy studies (ECZTRA 1 and ECZTRA 2), tralokinumab reduced itch, as measured by the percent change from baseline in Worst Daily Pruritus NRS, already at Week 1 compared to placebo. The reduction in itch was observed in parallel with improvements in objective signs and symptoms of atopic dermatitis and quality of life.
In the two studies, fewer patients randomised to Adtralza 300 mg Q2W needed rescue treatment (topical corticosteroids, systemic corticosteroids, non-steroidal immunosuppressants) as compared to patients randomised to placebo (29.3% versus 45.3%, respectively, across both studies). Use of rescue treatment was higher if patients had severe atopic dermatitis at baseline (39.3% if under tralokinumab 300 mg Q2W treatment versus 56.7% in placebo group).
To evaluate maintenance of response, 185 subjects from ECZTRA 1 and 227 subjects from ECZTRA 2 treated with tralokinumab 300 mg Q2W for 16 weeks who achieved IGA 0 or 1 or EASI-75 at week 16 were re-randomised to an additional 36-week treatment of 1) 300 mg tralokinumab every two weeks (Q2W) or 2) alternating tralokinumab 300 mg and placebo Q2W (tralokinumab Q4W) or 3) placebo Q2W, for a cumulative 52-week study treatment. Response rates (IGA 0/1 or EASI-75) at week 52 in the monotherapy pool were 56.2% and 50% for tralokinumab 300 mg Q2W and tralokinumab 300 mg Q4W among subjects achieving clinical response at week 16, respectively.
Table 3. Efficacy results (IGA 0 or 1 or EASI-75) at week 52 of subjects responding to tralokinumab 300 mg Q2W at week 16:
| ECZTRA 1 | ECZTRA 2 | |||||
|---|---|---|---|---|---|---|
| Treatment regimen Week 16-52e | Treatment regimen Week 16-52e | |||||
| Assessment at Week 52 | Tralokinumab 300 mg Q2W | Tralokinumab 300 mg Q4W | Placebo | Tralokinumab 300 mg Q2W | Tralokinumab 300 mg Q4W | Placebo |
| IGA 0/1a % respondersf | 51.3d (20/39) | 38.9d (14/36) | 47.4 (9/19) | 59.3c (32/54) | 44.9d (22/49) | 25.0 (7/28) |
| EASI-75a % respondersg | 59.6d (28/47) | 49.1d (28/57) | 33.3 (10/30) | 55.8b (43/77) | 51.4c (38/74) | 21.4 (9/42) |
If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment at the discretion of the investigator.
a Subjects who received rescue treatment or had missing data were treated as non-responders. The percentage is calculated relative to the number of subjects with response at week 16.
b p<0.001 compared to placebo
c p<0.05 compared to placebo
d p>0.05 compared to placebo
e All patients were initially treated with tralokinumab 300 mg Q2W week 0 to week 16.
f IGA 0/1 at week 52 was evaluated in those subjects that had IGA 0/1 at week 16.
g EASI-75 at week 52 was evaluated in those subjects that had EASI-75 at week 16.
Of the subjects randomised to tralokinumab, who did not achieve IGA 0 or 1 or EASI-75 at week 16 and were transferred to open-label tralokinumab 300 mg Q2W + optional TCS, 20.8% in ECZTRA 1 and 19.3% in ECZTRA 2 achieved IGA 0 or 1 at week 52, and 46.1% in ECZTRA 1 and 39.3% in ECZTRA 2 achieved EASI-75 at week 52. The clinical response was mainly driven by continued tralokinumab treatment rather than optional topical corticosteroids treatment.
In ECZTRA 3 from baseline to week 16, a significantly greater proportion of patients randomised to tralokinumab 300 mg Q2W + TCS achieved IGA 0 or 1, EASI-75, and/or an improvement of ≥4 points on the Worst Daily Pruritus NRS compared to placebo + TCS (see Table 4).
Table 4. Efficacy results of tralokinumab combination therapy with TCS at week 16 in ECZTRA 3 (FAS):
| Combination therapy | ||
|---|---|---|
| ECZTRA 3 | ||
| Week 16 | ||
| Placebo + TCS | Tralokinumab 300 mg Q2W + TCS | |
| Number of patients randomised and dosed (FAS) | 126 | 252 |
| IGA 0 or 1, % respondersa,b | 26.2 | 38.9* |
| EASI-50, % respondersa | 57.9 | 79.4§,e |
| EASI-75, % respondersa | 35.7 | 56.0§ |
| SCORAD, LS mean change from baseline (± SE)c | -26.7 (± 1.83) | -37.5§ (± 1.27) |
| Pruritus NRS (≥4-point improvement, % responders)a,d | 34.1 (43/126) | 45.4* (113/249) |
| DLQI, LS mean change from baseline (± SE)c | -8.8 (± 0.57) | -11.6§ (± 0.40) |
LS=least squares; SE=standard error, FAS: Full Analysis Set – includes all patients randomised and dosed
If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment at the discretion of the investigator. The supplied TCS did not constitute rescue medication.
a Subjects who received rescue treatment or had missing data were treated as non-responders.
b Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear” on a 0-4 IGA scale).
c Data after initiation of rescue medication or permanent discontinuation of treatment were considered missing. Placebo based multiple imputation of missing data.
d The percentage is calculated relative to the number of subjects with a baseline value ≥4.
e Not adjusted for multiplicity.
* p<0.05, #p<0.01, §p<0.001.
In ECZTRA 3, subjects who received tralokinumab 300 mg Q2W from Week 0 to 16 used 50% less of the supplied topical corticosteroids at Week 16 as compared to subjects who received placebo.
In the concomitant TCS study (ECZTRA 3), tralokinumab + TCS reduced itch, as measured by the percent change from baseline in Worst Daily Pruritus NRS, already at Week 2 compared to placebo + TCS. The reduction in itch was observed in parallel with improvements in objective signs and symptoms of atopic dermatitis and quality of life.
To evaluate maintenance of response, subjects treated with tralokinumab 300 mg + TCS for 16 weeks in the ECZTRA 3 study and who achieved IGA 0 or 1 or EASI-75 at week 16 were re-randomised to an additional 16-week treatment of 1) tralokinumab 300 mg every two weeks (Q2W) + TCS or 2) alternating tralokinumab 300 mg + TCS and placebo every two weeks (tralokinumab Q4W) for a cumulative 32-week study treatment. High maintenance of clinical efficacy at week 32 were seen across tralokinumab 300 mg Q2W + TCS and tralokinumab 300 mg Q4W + TCS among subjects achieving clinical response at week 16 (see Table 5).
Table 5. Efficacy results at week 32 of subjects achieving clinical response to tralokinumab 300 mg + TCS Q2W at week 16:
| Tralokinumab 300 mg Q2W + TCS | Tralokinumab 300 mg Q4W + TCS | |
|---|---|---|
| IGA 0/1 at week 32a % respondersb | 89.6 (43/48) | 77.6 (38/49) |
| EASI-75 at week 32a % respondersc | 92.5 (62/67) | 90.8 (59/65) |
If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment at the discretion of the investigator.
a Subjects who received rescue treatment or had missing data were treated as non-responders. The percentage is calculated relative to the number of subjects with response at week 16.
b IGA 0/1 at week 32 was evaluated in those subjects that had IGA 0/1 at week 16.
c EASI-75 at week 32 was evaluated in those subjects that had EASI-75 at week 16.
Among all the subjects who achieved either IGA 0 or 1 or EASI-75 at week 16, the mean percentage improvement in EASI score from baseline was 93.5% at week 32 when maintained on tralokinumab 300 mg Q2W + TCS and 91.5% at week 32 for subjects on tralokinumab 300 mg Q4W + TCS.
Of the subjects randomised to tralokinumab 300 mg Q2W + TCS who did not achieve IGA 0 or 1 or EASI-75 at week 16, 30.5 % achieved IGA 0/1 and 55.8 % achieved EASI-75 at week 32 when treated continuously with tralokinumab 300 mg Q2W + TCS for additional 16 weeks.
The continued improvement among the subjects who did not achieve IGA 0 or 1 or EASI-75 at week 16 occurred in conjunction with the improvement of Worst Daily Pruritus NRS and objective signs of atopic dermatitis including SCORAD.
Table 6. Efficacy results of tralokinumab with concomitant TCS at weeks 16 and 32 in ECZTRA 3 in patients initially treated with tralokinumab Q2W + TCS:
| Treatment regimen Week 16-32d | ||||||
|---|---|---|---|---|---|---|
| Responders at Week 16e | Non-responders at Week 16 | |||||
| Patients randomised | Q2W + TCS | Q4W + TCS | Q2W + TCS | |||
| N=69 | N=69 | N=95 | ||||
| Week number | W16 | W32 | W16 | W32 | W16 | W32 |
| EASI-50, % respondersa | 100.0 | 98.6 | 97.1 | 91.3 | 63.2 | 76.8 |
| EASI-90, % respondersa | 58.0 | 72.5 | 60.9 | 63.8 | 1.1 | 34.7 |
| EASI, LS % mean change from baseline (SE)b | -90.5 (2.7) | -93.2 (2.3) | -89.3 (2.7) | -91.5 (2.3) | -46.9 (2.4) | -73.5 (2.0) |
| Pruritus NRS (≥ 4-point improvement, % responders)a,c | 63.2 | 70.6 | 64.2 | 61.2 | 27.4 | 38.9 |
LS: Least squares, SE: Standard error
If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment at the discretion of the investigator.
a Patients who received rescue treatment or had missing data were considered non-responders in the analyses.
b Data after initiation of rescue medication or permanent discontinuation of treatment was excluded from the analyses.
c The percentage is calculated relative to the number of subjects with a baseline value ≥4.
d All patients were initially treated with tralokinumab 300 mg Q2W + TCS from week 0 to week 16. They were subsequently treated with tralokinumab 300 mg Q2W + TCS or Q4W + TCS.
e Responders at week 16 are identified as patients achieving either IGA 0/1 and/or EASI-75.
In both monotherapy studies (ECZTRA 1 and ECZTRA 2) and in the concomitant TCS study (ECZTRA 3) tralokinumab improved patient-reported symptoms of atopic dermatitis, as measured by POEM, and the impact of atopic dermatitis on sleep, as measured by Eczema-related sleep NRS, at week 16 compared to placebo. A higher proportion of patients treated with tralokinumab had clinically meaningful reductions in POEM, (defined as at least 4 point improvement) from baseline to week 16 compared to placebo.
The licensing authority has deferred the obligation to submit the results of studies with tralokinumab in one or more subset of the paediatric population in atopic dermatitis (see section 4.2 for information on paediatric use).
After subcutaneous (SC) dose of tralokinumab median time to maximum concentration in serum (tmax) were 5-8 days. The absolute bioavailability of tralokinumab following SC dosing was estimated by population PK analysis to be 76%. In a phase 1 trial (10 subjects per arm), bioavailability was estimated to be 62% for the 150 mg dose and 60% for the 300 mg dose.
Steady-state concentrations were achieved by week 16 following a 600 mg starting dose and 300 mg every other week. Across clinical studies (ECZTRA 1, ECZTRA 2 and ECZTRA 3), the mean ±SD steady-state trough concentration ranged from 98.0±41.1 mcg/mL to 101.4±42.7 mcg/mL for 300 mg dose administered every other week.
A volume of distribution for tralokinumab of approximately 4.2 L was estimated by population PK analysis.
Specific metabolism studies were not conducted because tralokinumab is a protein. Tralokinumab is expected to degrade to small peptides and individual amino acids.
Tralokinumab is eliminated through a non-saturable proteolytic pathway. Half-life is 22 days, consistent with the typical estimate for human IgG4 monoclonal antibodies targeting soluble cytokines. In ECZTRA 1, ECZTRA 2, and ECZTRA 3, clearance was estimated by population PK analysis to be 0.149 L/day. In phase 1 trials with IV dosing, clearance was estimated to be between 0.179 and 0.211 L/day
Exposure of tralokinumab increases proportionally to the dose of tralokinumab between 150-600 mg.
Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of tralokinumab determined by population PK analysis.
Age was not found to be associated with clinically relevant impact of systemic exposure of tralokinumab determined by population PK analysis. 109 subjects above 65 years were included in the analysis.
Race was not found to be associated with any clinically meaningful impact on the systemic exposure of tralokinumab by population PK analysis.
Tralokinumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of tralokinumab. Mild hepatic impairment was not found to affect the PK of tralokinumab determined by population PK analysis. Very limited data are available in patients with moderate or severe hepatic impairment.
Tralokinumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of tralokinumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of tralokinumab. Very limited data are available in patients with severe renal impairment.
Tralokinumab trough concentrations were lower in subjects with higher body weight (see section 4.2).
Table 7. Area under the curve (AUC) by weight:
| Weight (kg) | 75 | 100 | 120 | 140 |
| AUC (mcg*day/mL) | 1532 | 1192 | 1017 | 889 |
| Ratio AUC 75 kg | 1 | 0.78 | 0.66 | 0.57 |
Calculated AUC at steady-state for the dosing interval for 300 mg Q2W for a subject of a certain weight based on the relation between Clearance and weight Clearance = 0.149 × (W/75) ^ 0.873. AUC = F × Dose Clearance, where F = 0.761.
The pharmacokinetics of tralokinumab in paediatric patients has not yet been studied.
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 tralokinumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with tralokinumab. An evaluation of the available evidence related to IL-13 inhibition and animal toxicology data with tralokinumab does not suggest an increased carcinogenic potential for tralokinumab.
Enhanced pre- and postnatal studies with tralokinumab in monkeys did not identify adverse effects in maternal animals or their offspring up to 6 months post-partum.
No effects on fertility parameters such as reproductive organs, menstrual cycle and sperm analysis were observed in sexually mature monkeys treated subcutaneously with tralokinumab up to 350 mg/animal (females) or 600 mg/animal (males) (AUC exposure up to 15-fold higher than in human patients receiving tralokinumab 300 mg every 2 weeks).
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