Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors, ATC code: L04AF08

Mechanism of action

Ritlecitinib irreversibly and selectively inhibits Janus kinase (JAK) 3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family by blocking the adenosine triphosphate (ATP) binding site. In cellular settings, ritlecitinib specifically inhibits γ-common cytokines (IL-2, IL-4, IL-7, IL-15 and IL-21) signalling through JAK3-dependent common-γ chain receptors. Additionally, ritlecitinib inhibits TEC family of kinases, resulting in reduced cytolytic activity of NK cells and CD8+ T cells.

JAK3 and TEC family mediated signalling pathways are both involved in alopecia areata pathogenesis, although complete pathophysiology is still not understood.

Pharmacodynamic effects

Lymphocyte subsets
In patients with alopecia areata, treatment with ritlecitinib was associated with dose-dependent early decreases in absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8). After the initial decrease, the levels partially recovered and remained stable up to 48 weeks.
There was no change observed in B lymphocytes (CD19) in any treatment group. There was a dose-dependent early decrease in NK cells (CD16/56) which remained stable at the lower level up to Week 48.

Immunoglobulins
In patients with alopecia areata, treatment with ritlecitinib was not associated with clinically meaningful changes in Immunoglobulin (Ig)G, IgM or IgA up to Week 48, indicating a lack of systemic humoral immunosuppression.

Clinical efficacy and safety

The efficacy and safety of ritlecitinib was evaluated in a pivotal, randomised, double-blind, placebo-controlled study (study AA-I) in alopecia areata patients 12 years of age and older with ≥ 50% scalp hair loss, including alopecia totalis and alopecia universalis. The dose-response of ritlecitinib was also evaluated in this study. The study treatment period consisted of a placebo-controlled 24-week period and a 24-week extension period. Study AA-I evaluated a total of 718 patients who were randomised to one of the following treatment regimens for 48 weeks: 1) 200 mg once daily for 4 weeks followed by 50 mg once daily for 44 weeks; 2) 200 mg once daily for 4 weeks followed by 30 mg once daily for 44 weeks; 3) 50 mg once daily for 48 weeks; 4) 30 mg once daily for 48 weeks; 5) 10 mg once daily for 48 weeks; 6) placebo for 24 weeks followed by 200 mg once daily for 4 weeks and 50 mg once daily for 20 weeks; or 7) placebo for 24 weeks followed by 50 mg for 24 weeks.

This study assessed as primary outcome the proportion of subjects who achieved a SALT (Severity of Alopecia Tool) score of ≤ 10 (90% or more scalp hair coverage) at Week 24. Additionally, this study assessed as key secondary outcome the Patient’s Global Impression of Change (PGI-C) response at Week 24 and also assessed as secondary outcomes SALT score of ≤ 20 (80% or more scalp hair coverage) at Week 24 and improvements in regrowth of eyebrows and/or eyelashes at Week 24.

Baseline characteristics
Male or female patients 12 years of age and older, were assessed in study AA-I. All patients had alopecia areata with ≥ 50% scalp hair loss (SALT [Severity of Alopecia Tool] score ≥ 50) without evidence of terminal hair regrowth within the previous 6 months and with the current episode of scalp hair loss ≤ 10 years and no other known cause of hair loss (e.g., androgenetic alopecia).

Across all treatment groups 62.1% were female, 68.0% were White, 25.9% were Asian, and 3.8% were Black or African American. The mean age of patients was 33.7 years and the majority (85.4%) were adults (≥ 18 years of age). A total of 105 (14.6%) patients 12 to < 18 years of age and 20 (2.8%) patients 65 years of age and older were enrolled. The mean (SD) baseline absolute SALT score ranged from 88.3 (16.87) to 93.0 (11.50) across treatment groups; among patients without alopecia totalis/alopecia universalis at baseline, the mean SALT score ranged from 78.3 to 87.0. The majority of patients had abnormal eyebrows (83.0%) and eyelashes (74.7%) at baseline across treatment groups. The median duration since alopecia areata diagnosis was 6.9 years and the median duration of the current alopecia areata episode was 2.5 years. Randomisation was stratified by alopecia totalis/alopecia universalis status with 46% of patients classified as alopecia totalis/alopecia universalis based upon a baseline SALT score of 100.

Clinical response
A significantly greater proportion of patients achieved SALT ≤ 10 response with ritlecitinib 50 mg compared to placebo at Week 24 (Table 3). The SALT ≤ 10 response rate for ritlecitinib 50 mg increased further at Week 48 (Figure 1).

A significantly greater proportion of patients achieved Patient’s Global Impression of Change (PGI-C) response with ritlecitinib 50 mg compared to placebo at Week 24 (Table 3) with response rates continuing to increase through Week 48 (Figure 1).

A significantly greater proportion of patients achieved a SALT ≤ 20 response with ritlecitinib 50 mg compared to placebo at Week 24 (Table 3). The SALT ≤ 20 response rate increased further at Week 48.

Improvements in regrowth of eyebrows and/or eyelashes were seen at Week 24 (Table 3) with ritlecitinib 50 mg among patients with abnormal eyebrows and/or eyelashes at baseline with further increases seen at Week 48.

Treatment effects at Week 24 in subgroups (age, gender, race, region, weight, duration of disease since diagnosis, duration of current episode, prior pharmacologic treatment) were consistent with the results in the overall study population. Treatment effects at Week 24 in the alopecia totalis/alopecia universalis subgroup were lower compared to the non-alopecia totalis/non-alopecia universalis subgroup. Treatment effects at Week 24 in adolescents 12 to less than 18 years of age were consistent with the results in the overall study population.

Table 3. Efficacy results of ritlecitinib at week 24
Endpoint             Ritlecitinib 50 mg once              Placebo              Difference from daily                    (N = 131)                 placebo
(N = 130)                 % Responders               (95% CI)
% Responders
SALT ≤ 10 responsea,b                 13.4                          1.5                     11.9 (5.4, 18.3)
PGI-C responseb,c                        49.2                       9.2                     40.0 (28.9, 51.1)
SALT ≤ 20 responsed,e                    23.0                       1.6                     21.4 (13.4, 29.5)
EBA responsef                            29.0                       4.7                     24.3 (14.8, 34.5)
ELA responseg                            28.9                       5.2                     23.7 (13.6, 34.5)
Abbreviations: EBA = eyebrow assessment; ELA = eyelash assessment; CI = confidence interval; N = total number of patients; PGI-C = Patient’s Global Impression of Change; SALT = Severity of Alopecia Tool a. SALT ≤ 10 responders were patients with scalp hair loss of ≤ 10%. SALT scores range from 0 to 100 with 0 = no scalp hair loss and 100 = total scalp hair loss.
b. Statistically significant with adjustment for multiplicity.
c. PGI-C responders were patients with a score of “moderately improved” or “greatly improved” based upon a 7-point scale from “greatly improved” to “greatly worsened”.
d. SALT ≤ 20 responders were patients with scalp hair loss of ≤ 20%. SALT scores range from 0 to 100 with 0 = no scalp hair loss and 100 = total scalp hair loss.
e. Statistically significant.
f. EBA response is defined as at least a 2-grade improvement from baseline or normal EBA score on a 4-point scale in patients with abnormal eyebrows at baseline.
g. ELA response is defined as at least a 2-grade improvement from baseline or normal ELA score on a 4-point scale in patients with abnormal eyelashes at baseline.




Figure 1.      SALT ≤ 10 and PGI-C response through Week 48



Abbreviations: CI = confidence interval; N = total number of patients; PGI-C = Patient Global Impression of Change; QD = once daily; SALT = Severity of Alopecia Tool





Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

The absolute oral bioavailability of ritlecitinib is about 64%. Based on oral and intravenous administration of the labelled active substance, the relative urinary recovery (oral/intravenous) of labelled compounds was about 89%, indicating a high fraction absorbed (fa). Peak plasma concentrations are reached within 1 hour following multiple oral doses. Food does not have a clinically significant impact on the extent of ritlecitinib absorption, as a high-fat meal decreased the ritlecitinib Cmax by ~ 32% and increased AUCinf by ~11%. In placebo-controlled studies, ritlecitinib was administered without regard to meals (see section 4.2).

In vitro, ritlecitinib is a substrate of P-glycoprotein (P-gp) and BCRP. However, as ritlecitinib has a high fraction absorbed (fa) with both Cmax and AUC increases in a dose proportional manner (20 – 200 mg single dose range), P-gp and BCRP are not expected to have a meaningful impact on the absorption of ritlecitinib.

Distribution

After intravenous administration, the volume of distribution of ritlecitinib is about 74 L.
Approximately 14% of circulating ritlecitinib is bound to plasma proteins, primarily albumin. The blood/plasma distribution ratio of ritlecitinib is 1.62. Ritlecitinib is a covalent inhibitor that has been shown to bind to off-target proteins such as MAP2K7, DOCK10, albumin, CYP1A2, CYP3A, UGT1A1, and UGT1A4, some of which may have clinical relevance in drug interactions (see section 4.5).

Biotransformation

The metabolism of ritlecitinib is mediated by multiple isoforms of Glutathione S-transferase (GST: cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1, and microsomal Membrane Associated Proteins involved in Eicosanoid and Glutathione metabolism [MAPEG]1/2/3) and CYP enzymes (CYP3A, CYP2C8, CYP1A2, and CYP2C9), with no single clearance route contributing more than 25%. Hence, medicinal products inhibiting a selective metabolic pathway are unlikely to impact the systemic exposures of ritlecitinib. Specific inhibitors of transporters are unlikely to result in clinically relevant changes in the bioavailability of ritlecitinib.

In a human radiolabeled study, ritlecitinib was the most prevalent circulating species (30.4% of circulating radioactivity) after oral administration, with a major cysteine conjugate metabolite M2 (16.5%), which is pharmacologically inactive.

Elimination

Ritlecitinib is eliminated primarily by metabolic clearance mechanisms, with approximately 4% of the dose excreted as unchanged active substance in urine. Approximately 66% of radiolabeled ritlecitinib dose is excreted in the urine and 20% in the faeces. Following multiple oral doses, steady state was reached approximately by Day 4 due to non-stationary PK. The steady state PK parameters of AUCtau and Cmax appeared to increase in an approximately dose-proportional manner up to 200 mg with the mean terminal half-life ranging from 1.3 to 2.3 hours.

Special populations

Body weight, gender, genotype, race and age
Body weight, gender, GST P1, M1, and T1 genotype, race and age did not have a clinically meaningful effect on ritlecitinib exposure.


Adolescents (≥ 12 to < 18 years)
Based on population PK analysis, there was no clinically relevant difference in ritlecitinib exposures in adolescent patients compared to adults.

Paediatric (< 12 years)
The PK of ritlecitinib in children under 12 years of age have not yet been established.

Renal impairment
The AUC24 and Cmax in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min) was about 55% and 44% higher, respectively, compared with matched participants with normal renal functions. This was confirmed by popPK analysis. These differences are not considered clinically significant. Ritlecitinib was not studied in patients with mild (eGFR 60 to < 90 mL/min) or moderate (eGFR 30 to < 60 mL/min) renal impairment. However, based on the results obtained in patients with severe renal impairment, a clinically significant increase in ritlecitinib exposure is not expected in these patients. The eGFR and classification of renal function status of participants was done using the Modification of Diet in Renal Disease (MDRD) formula.

Based on the above considerations, no dose adjustment is required in patients with mild, moderate or severe renal impairment. Ritlecitinib has not been studied in patients with ESRD or in renal transplant recipients (see section 4.2).

Hepatic impairment

Patients with moderate (Child Pugh B) hepatic impairment had an 18.5% increase in ritlecitinib AUC24 compared to participants with normal hepatic function. Ritlecitinib was not studied in patients with mild (Child Pugh A) hepatic impairment. However, based on the results obtained in patients with moderate hepatic impairment, a clinically significant increase in ritlecitinib exposure is not expected in these patients. No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 4.2). Ritlecitinib has not been studied in patients with severe (Child Pugh C) hepatic impairment (see section 4.3).