Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC17

Mechanism of action
Tildrakizumab is a humanised IgG1/k monoclonal antibody that specifically binds to the p19 protein subunit of the interleukin-23 (IL-23) cytokine without binding to IL-12 and inhibits its interaction with the IL-23 receptor.
IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

Clinical efficacy and safety
The multicentre, randomised, double-blind, placebo-controlled trials reSURFACE 1 and reSURFACE 2 studies enrolled a total of 1,862 patients 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a Physician Global Assessment (PGA) score of ≥3 in the overall assessment (plaque thickness, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy.
In these studies, patients were randomised to either placebo or tildrakizumab (including 200 mg and 100 mg at 0, 4 and every twelve weeks thereafter [Q12W]), up to 52 or 64 weeks. In the active comparator study (reSURFACE 2), patients were also randomised to receive etanercept 50 mg twice weekly for 12 weeks, and weekly thereafter up to 28 weeks. Patients who did not respond to etanercept treatment (˂75% reduction in PASI from baseline) were switched to tildrakizumab 200 mg Q12W up to 52 weeks, while patients who responded to etanercept were discontinued from the study.

Eligible patients who completed the double-blind periods of reSURFACE 1 and reSURFACE 2 with ≥ 50% improvement in PASI from baseline could participate in open-label extension phases of these studies in order to evaluate the long-term safety and maintenance of efficacy of continuous tildrakizumab treatment. Patients entering the extension periods of reSURFACE 1 and reSURFACE 2 continued treatment at the same 
dose of tildrakizumab, 100 mg or 200 mg, that they were receiving at week 64 or 52, respectively. Up to 6 years of follow-up data are available.
Overall demographic and baseline characteristics in reSURFACE1 and reSURFACE2 studies were consistent across individual trials. Patients were 18 to 82 years old, with a mean age of 45.9 years old. The median baseline PASI score ranged from 17.7 to 18.4 across treatment groups. Baseline PGA score was marked or severe in 33.4% of patients.
Of all patients, 35.8% had received prior phototherapy, 41.1% had received prior conventional systemic therapy, 16.7% had received prior biologic therapy for the treatment of plaque psoriasis. A total of 15.4% of study patients had a history of psoriatic arthritis. Mean baseline Dermatology Life Quality Index (DLQI) ranged from 13.0 to 14.8.
Studies reSURFACE 1 and reSURFACE 2 assessed the changes from baseline at Week 12 in the two co-primary endpoints: 1) PASI 75 and 2) PGA of “0” (cleared) or “1” (minimal), with at least a 2-point improvement from baseline. Other evaluated outcomes included the proportion of patients who achieved PASI 90, PASI 100, the proportion of patients with DLQI 0 or 1, and maintenance of efficacy up to 52/64 weeks.

Results obtained at weeks 12, 28 and beyond (up to week 64 in reSURFACE 1 and up to week 52 in reSURFACE 2) are presented in Table 2 and Table 3.

Table 2. Summary of response rates in studies reSURFACE 1 and reSURFACE 2 Week 12 (2 doses)*                                  Week 28 (3 doses)* 200 mg       100 mg     Placebo          Etanercept                           Etanercept 200 mg   100 mg
 reSURFACE1
Number of patients                       308           309           154              -             298         299          - PASI 75a (%)                            62.3†b        63.8†b         5.8b             -           81.9c        80.4c         - PGA of “clear” or
“minimal” with ≥2 grade
59.1†b        57.9†b         7.1b             -           69.1c        66.0c         - improvement from
Baselinea (%)
PASI 90 (%)                             35.4†b        34.6†b         2.6b             -           59.0c        51.6c         - PASI 100 (%)                            14.0†b        13.9†b         1.3b             -           31.5c        23.5c         - DLQI Score 0 or 1 (%)                   44.2†        41.5 †          5.3              -           56.7c        52.4c         - reSURFACE2
Number of patients                       314           307           156             313            299         294       289 a                                   †‡b           †‡b           b                 b            ‡b            ‡b   53.6b PASI 75 (%)                             65.6         61.2            5.8           48.2           72.6         73.5 PGA of “clear” or “minimal” with ≥2 grade improvement
59.2†¥b       54.7†b         4.5b          47.6b          69.2‡b       64.6‡b     45.3b from
Baselinea (%)
PASI 90 (%)                             36.6†‡b      38.8†‡b         1.3b          21.4b          57.7‡c       55.5‡c     29.4 c PASI 100 (%)                            11.8†‡b      12.4†‡b          0             4.8b          27.0‡c       22.8‡c     10.7c DLQI Score 0 or 1 (%)                   47.4†¥        40.2†          8.0            35.5          65.0‡c       54.1‡c     39.4c a Co-primary efficacy endpoint at week 12.
b Non responder imputation for missing data.
c No imputation for missing data.

*The number of doses administered refers only to tildrakizumab groups.
n = number of patients in the full analysis set for which data was available, after imputation when applicable.
p-values calculated using the Cochran-Mantel-Haenszel (CMH) test stratified by body weight (≤90 kg, >90 kg) and prior exposure to biologic therapy for psoriasis (yes/no).
† p≤0.001 versus placebo; ‡ p≤0.001 versus etanercept; ¥ p≤0.05 versus etanercept.


Maintenance of response
The maintenance of response in studies reSURFACE1 and reSURFACE2 are presented in Table 3. Maintenance and durability of PASI 90 response over time is presented in Figure 1.

Table 3. Maintenance of response in studies reSURFACE 1 and reSURFACE 2 Long term responsea,b
200 mg                     100 mg reSURFACE 1                                            Week 28      Week 64      Week 28      Week 64 Number of patients                                      116          114           115          112 PGA of “clear” or “minimal” with ≥2
80.2               76.3              80.9              61.6 grade improvement from Baseline (%)
PASI 90 (%)                                             70.7               74.6              65.2             58.0 PASI 100 (%)                                            38.8               40.4              25.2             32.1 reSURFACE 2                                            Week 28            Week 52           Week 28          Week 52 Number of patients                                      108                105               213              204 PGA of “clear” or “minimal” with ≥2                                                                           79.4 grade improvement from Baseline (%)                       88.0               84.8              84.0 PASI 90 (%)                                               75.0               81.9              74.2              78.4 PASI 100 (%)                                              34.3               46.7              30.2              35.3 a   Long-term response in patients who were responders (had achieved at least PASI 75) to tildrakizumab at week 28.
b No   imputation for missing data.


Figure 1. Maintenance and durability of PASI 90 response. Proportion of patients with PASI 90 response over time up to week 64 (full analysis set part 3*) 


Of the patients who completed the double-blind period, 506 (79%) in reSURFACE 1 and 730 (97%) in reSURFACE 2 entered the extension period. Across studies, at least 76% of patients who had a PASI 90 response at the end of double-blind period, maintained a PASI 90 response during the extension period, when tildrakizumab 100 mg or 200 mg treatment was continued during a period of 192 weeks (Figure 2 and Figure 3).

Figure 2. Percentage of patients who maintained a PASI 90 response by visit in the openlabel extension of reSURFACE 1 (Full Analysis Set,
Extension Period*)



*Among PASI 90 responders at the end of the double-blind study period. No imputation of missing data.
Note: Visit week is nominal, as study participants had a window of up to approximately 12 weeks from week 64 to begin the extension.

Figure 3. Percentage of patients who maintained a PASI 90 response by visit in the openlabel extension of reSURFACE 2 (Full Analysis Set,
Extension Period*)



*Among PASI 90 responders at the end of the double-blind study period. No imputation of missing data.

Quality of life/patient-reported outcomes
At week 12 and across studies, tildrakizumab was associated with statistically significant improvement in health-related quality of life as assessed by the DLQI (Table 2).
Improvements were maintained over time with at week 52, 63.7% (100 mg) and 73.3% (200 mg) in reSURFACE 1, and 68.8% (100 mg) and 72.4% (200 mg) in reSURFACE 2 of patients who were PASI 75 responders at week 28 having a DLQI of 0 or 1.

Immunogenicity

In pooled Phase 2b and Phase 3 analyses, 7.3% of tildrakizumab-treated patients developed antibodies to tildrakizumab up to week 64. Of the subjects who developed antibodies to tildrakizumab, 38% (22/57 patients) had neutralizing antibodies. This represents 2.8% of all subjects receiving tildrakizumab.

In pooled phase 3 analyses, 8.3% of tildrakizumab-treated patients developed antibodies to tildrakizumab up to 420 weeks of treatment. Of the tildrakizumab-treated patients who developed antibodies to tildrakizumab, 35% (36/102 patients) had antibodies that were classified as neutralizing, which represents 2.9% of all tildrakizumab-treated patients.

The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
The subcutaneous formulation of tildrakizumab showed an absolute bioavailability ranging from 73% (90% CI: 46% - 115%, 200 mg subcutaneous vs. 3 mg/kg intravenous) to 80% (90% CI: 62% - 103%, 50 mg subcutaneous vs. 0.5 mg/kg intravenous) in healthy subjects, as a result of cross study single dose comparison.
Maximum concentration was reached at 6.2 days after injection. Population pharmacokinetic analysis indicated a 31% higher bioavailability in healthy subjects compared to patients.
At steady state, following administration of 100 mg of tildrakizumab in subjects with moderate to severe plaque psoriasis geometric means (% coefficient of variation [%CV]) of AUC0-τ and Cmax values were respectively 305 μg·day/mL (41%) and 8.1 μg/mL (34%), whereas they were 612 μg·day/mL (40%) and 16.3 μg/mL (33%) following administration of 200 mg.

Distribution
Tildrakizumab has limited extravascular distribution with volume of distribution (Vd) values ranging from 76.9 to 106 mL/kg.

Biotransformation
Tildrakizumab is catabolised into component amino acids by general protein degradation processes. Small-molecule metabolic pathways (e.g., CYP450 enzymes,
glucuronosyltransferases) do not contribute to its clearance.

Elimination
Clearance values range from 2.04 to 2.52 mL/day/kg and the half-life was 23.4 days (23% CV) in subjects with plaque psoriasis.

Linearity/non-linearity
Tildrakizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 50 mg to 400 mg following subcutaneous administration, with clearance being independent of dose.
Steady-state is achieved by 16 weeks with the clinical regimen of 0, 4, and every 12 weeks thereafter, with 1.1-fold accumulation in exposure between week-1 and week-12 independent of dose.
Pharmacokinetics in special populations
Elderly
Population pharmacokinetic analysis indicated that age did not have a clinically significant influence on the clearance of tildrakizumab in adult subjects with plaque psoriasis. Following administration of 100 mg or 200 mg of tildrakizumab, subjects who are 65 years or older (n=81 and n=82, respectively) had a similar tildrakizumab clearance as compared to subjects less than 65 years old (n=884).
Renal and hepatic impairment
No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of tildrakizumab was conducted. Tildrakizumab is catabolised into component amino acids by general protein degradation processes and is not eliminated by renal or hepatic pathways.

Body weight
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. The geometric mean exposure (AUC0-τ at steady state) in adult patients weighing >90 kg following a 100 mg or 200 mg subcutaneous dose was predicted to be about 30% lower than in an adult patient weighing ≤90 kg (see section 4.2).

Drug interactions
Results from a drug-drug interaction study conducted in plaque psoriasis subjects suggest that tildrakizumab had no clinically relevant effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Therefore, tildrakizumab does not impact the pharmacokinetics of concomitant medicines metabolised by CYP enzyme (see section 4.5).