Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AF02

Mechanism of action

Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50 values of 5.9, 5.7, 53 and > 400 nM, respectively.

Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell.
Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.


Pharmacodynamic effects

Inhibition of IL-6 induced STAT3 phosphorylation
Administration of baricitinib resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed 2 hours after dosing which returned to near baseline by 24 hours.

Immunoglobulins
Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment, and remained stable at a lower value than baseline through at least 104 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range.

Lymphocytes
Mean absolute lymphocyte count increased by 1 week after starting treatment, returned to baseline by week 24, and then remained stable through at least 104 weeks. For most patients, changes in lymphocyte count occurred within the normal reference range.

C-reactive protein
In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as 1 week after starting treatment and were maintained throughout dosing.

Creatinine
In clinical trials, baricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, which remained stable thereafter. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules. Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse reactions. In alopecia areata, mean serum creatinine continued to increase up to week 52. In atopic dermatitis and alopecia areata, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) at week 4, with no further decreases thereafter.

In vitro skin models
In an in vitro human skin model treated with pro-inflammatory cytokines (i.e., IL-4, IL-13, IL-31), baricitinib reduced epidermal keratinocyte pSTAT3 expression, and increased the expression of filaggrin, a protein that plays a role in skin barrier function and in the pathogenesis of atopic dermatitis.

Vaccine study

The influence of baricitinib on the humoral response to non-live vaccines was evaluated in 106 rheumatoid arthritis patients under stable treatment with baricitinib 2 or 4 mg, receiving inactivated pneumococcal or tetanus vaccination. The majority of these patients (n = 94) were co-treated with methotrexate. For the total population, pneumococcal vaccination resulted in a satisfactory IgG immune response in 68 % (95 % CI: 58.4 %, 76.2 %) of the patients. In 43.1 % (95 % CI: 34 %, 52.8 %) of the patients, a satisfactory IgG immune response to tetanus vaccination was achieved.

Clinical efficacy

Rheumatoid arthritis
The efficacy and safety of baricitinib once daily were assessed in 4 Phase III randomised, double-blind, multicentre studies in adult patients with moderate to severe active rheumatoid arthritis diagnosed according to the ACR/EULAR 2010 criteria (Table 3). The presence of at least 6 tender and 6 swollen joints was required at baseline. All patients who completed these studies were eligible to enrol in a long term extension study for up to 7 years additional treatment.


Table 3. Clinical trial summary
Study name Population        Treatment arms                     Summary of key outcome measures (Duration) (Number)

RA-BEGIN MTX-naïve1          • Baricitinib 4 mg QD              •   Primary endpoint: ACR20 at week 24 (52 weeks) (584)             • Baricitinib 4 mg QD + MTX        •   Physical function (HAQ-DI) • MTX                              •   Radiographic progression (mTSS) •   Low disease activity and Remission (SDAI)
RA-BEAM      MTX-IR2         • Baricitinib 4 mg QD              •   Primary endpoint: ACR20 at week 12 (52 weeks)   (1,305)         • Adalimumab 40 mg SC Q2W          •   Physical function (HAQ-DI) • Placebo                          •   Radiographic progression (mTSS) •   Low disease activity and Remission (SDAI)
All patients on background MTX     •   Morning Joint Stiffness
RA-BUILD cDMARD-IR3 • Baricitinib 4 mg QD                       •   Primary endpoint: ACR20 at week 12 (24 weeks) (684)    • Baricitinib 2 mg QD                       •   Physical function (HAQ-DI) • Placebo                                   •   Low disease activity and remission (SDAI) •   Radiographic progression (mTSS)
On background cDMARDs5 if on       •   Morning Joint Stiffness stable cDMARD at study entry
RA-          TNF-IR4         • Baricitinib 4 mg QD              • Primary endpoint: ACR20 at week 12 BEACON       (527)           • Baricitinib 2 mg QD              • Physical function (HAQ-DI) (24 weeks)                   • Placebo                          • Low disease activity and Remission (SDAI) 
On background cDMARDs5
Abbreviations: IR = inadequate responder; QD = Once daily; Q2W = Once every 2 weeks; SC = Subcutaneously; ACR = American College of Rheumatology; SDAI = Simplified Disease Activity Index; HAQ-DI = Health Assessment Questionnaire-Disability Index; mTSS = modified Total Sharp Score
1
Patients who had received less than 3 doses of Methotrexate (MTX); naïve to other conventional or biologic DMARDs
2
Patients who had an inadequate response to MTX (+/- other cDMARDs); biologic-naïve 3
Patients who had an inadequate response or were intolerant to ≥ 1 cDMARDs; biologic- naïve 4
Patients who had an inadequate response or were intolerant to ≥ 1 bDMARDs; including at least one TNF inhibitor
5
Most common concomitant cDMARDs included MTX, hydroxychloroquine, leflunomide and sulfasalazine

Clinical response

In all studies, patients treated with baricitinib 4 mg once daily had statistically significantly higher ACR20, ACR50 and ACR70 response at 12 weeks compared to placebo, methotrexate (MTX) or adalimumab (Table 4). Time to onset of efficacy was rapid across measures with significantly greater responses seen as early as week 1. Continued, durable response rates were observed, with ACR20/50/70 responses maintained for at least 2 years including the long-term extension study.

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in significant improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment and CRP, compared to placebo, MTX or adalimumab.

No relevant differences regarding efficacy and safety were observed in subgroups defined by types of concomitant DMARDs used in combination with baricitinib.


Remission and low disease activity

A statistically significantly greater proportion of patients treated with baricitinib 4 mg compared to placebo or MTX achieved remission (SDAI ≤ 3.3 and CDAI ≤ 2.8) or low disease activity or remission (DAS28-ESR or DAS28-hsCRP ≤ 3.2 and DAS28-ESR or DAS28-hsCRP < 2.6), at weeks 12 and 24 (Table 4).

Greater rates of remission compared to placebo were observed as early as week 4. Remission and low disease activity rates were maintained for at least 2 years. Data from the long-term extension study up to 6 years follow-up indicate durable low disease activity/remission rates.


Table 4: Response, remission and physical function

Study         RA-BEGIN            RA-BEAM                          RA-BUILD             RA-BEACON MTX-naïve patients    MTX-IR patients                cDMARD-IR patients      TNF-IR patients Treatment MTX BARI BARI PBO BARI              ADA               PBO BARI BARI         PBO BARI BARI group           4 mg 4 mg           4 mg     40 mg                   2 mg 4 mg              2 mg 4 mg + MTX                   Q2W
N         210    159     215  488    487      330               228    229     227     176    174      177 ACR20:
Week 12 59 % 79 %*** 77 %*** 40 % 70 %***† 61 %***             39 %   66 %*** 62 %*** 27 %   49 %*** 55 %*** Week 24 62 % 77 %** 78 %*** 37 % 74 %***† 66 %***              42 %   61 %*** 65 %*** 27 %   45 %*** 46 %*** Week 52 56 % 73 %*** 73 %***      71 %†† 62 %
ACR50:
Week 12 33 % 55 %*** 60 %*** 17 % 45 %***†† 35 %***            13 %   33 %*** 34 %*** 8 %    20 %** 28 %*** Week 24 43 % 60 %** 63 %*** 19 % 51 %*** 45 %***               21 %   41 %*** 44 %*** 13 %   23 %* 29 %*** Week 52 38 % 57 %*** 62 %***      56 %†     47 %
ACR70:
Week 12 16 % 31 %*** 34 %*** 5 % 19 %***† 13 %***              3%     18 %*** 18 %*** 2 %    13 %*** 11 %** Week 24 21 % 42 %*** 40 %*** 8 % 30 %***† 22 %***              8%     25 %*** 24 %*** 3 %    13 %*** 17 %*** Week 52 25 % 42 %*** 46 %***      37 %      31 %
DAS28-hsCRP ≤ 3.2:
Week 12 30 % 47 %*** 56 %*** 14 % 44 %***†† 35 %*** 17 %              36 %*** 39 %*** 9 %    24 %*** 32 %*** Week 24 38 % 57 %*** 60 %*** 19 % 52 %*** 48 %*** 24 %                46 %*** 52 %*** 11 %   20 %* 33 %*** Week 52 38 % 57 %*** 63 %***      56 %†     48 %
SDAI ≤ 3.3:
Week 12 6 % 14 %* 20 %*** 2 %           8 %***    7 %*** 1 %          9 %*** 9 %*** 2 %      2%     5% Week 24 10 % 22 %** 23 %*** 3 %         16 %***   14 %*** 4 %         17 %*** 15 %*** 2 %    5%     9 %** Week 52 13 % 25 %** 30 %***             23 %      18 %
CDAI ≤ 2.8:
Week 12 7 % 14 %* 19 %*** 2 %           8 %***    7 %**   2%          10 %*** 9 %*** 2 %     3%     6% Week 24 11 % 21 %** 22 %** 4 %          16 %***   12 %*** 4 %         15 %*** 15 %*** 3 %    5%     9 %* Week 52 16 % 25 %* 28 %**               22 %      18 %
HAQ-DI Minimum Clinically Important Difference (decrease in HAQ-DI score of ≥ 0.30): Week 12   60 % 81 %*** 77 %*** 46 % 68 %*** 64 %*** 44 %              60 %*** 56 %** 35 %    48 %* 54 %*** Week 24   66 % 77 %* 74 % 37 % 67 %***† 60 %*** 37 %                  58 %*** 55 %*** 24 %   41 %*** 44 %*** Week 52   53 % 65 %* 67 %**         61 %    55 %
Note: Proportions of responders at each time point based on those initially randomised to treatment (N). Patients who discontinued or received rescue therapy were considered as non-responders thereafter.
Abbreviations: ADA = adalimumab; BARI = baricitinib; IR = inadequate responder; MTX = methotrexate; PBO = Placebo
* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 vs. placebo (vs. MTX for study RA-BEGIN) † p ≤ 0.05; †† p ≤ 0.01; ††† p ≤ 0.001 vs. adalimumab 
Radiographic response

The effect of baricitinib on progression of structural joint damage was evaluated radiographically in studies RA-BEGIN, RA-BEAM and RA-BUILD and assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

Treatment with baricitinib 4 mg resulted in a statistically significant inhibition of progression of structural joint damage (Table 5). Analyses of erosion and joint space narrowing scores were consistent with the overall scores. The proportion of patients with no radiographic progression (mTSS change ≤ 0) was significantly higher with baricitinib 4 mg compared to placebo at weeks 24 and 52.

Table 5. Radiographic changes

Study                RA-BEGIN                        RA-BEAM                    RA-BUILD MTX-naïve patients              MTX-IR patients            cDMARD-IR patients Treatment MTX          BARI4      BARI4     PBOa      BARI4    ADA        PBO    BARI2     BARI4 group                  mg         mg                  mg       40 mg             mg        mg + MTX                        Q2W
Modified Total Sharp Score, mean change from baseline:
Week 24     0.61       0.39       0.29*     0.90      0.41***  0.33***    0.70       0.33*      0.15** **                  ***
Week 52     1.02       0.80       0.40      1.80      0.71     0.60*** b
Proportion of patients with no radiographic progression :
Week 24     68 %       76 %       81 %**    70 %      81 %*** 83 %***     74 %       72 %       80 % **
Week 52     66 %       69 %       80 %      70 %      79 %**   81 %** Abbreviations: ADA = adalimumab; BARI = baricitinib; IR = inadequate responder; MTX = methotrexate; PBO = Placebo a
Placebo data at week 52 derived using linear extrapolation b
No progression defined as mTSS change ≤ 0.
* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 vs. placebo (vs. MTX for study RA-BEGIN) 
Physical function response and health-related outcomes

Treatment with baricitinib 4 mg, alone or in combination with cDMARDs, resulted in a significant improvement in physical function (HAQ-DI) and pain (0-100 visual analogue scale) compared to all comparators (placebo, MTX, adalimumab). Improvements were seen as early as week 1 and, in studies RA-BEGIN and RA-BEAM, this was maintained for up to 52 weeks.

In RA-BEAM and RA-BUILD, treatment with baricitinib 4 mg resulted in a significant improvement in the mean duration and severity of morning joint stiffness compared to placebo or adalimumab as assessed using daily electronic patient diaries.

In all studies, baricitinib-treated patients reported improvements in patient-reported quality of life, as measured by the Short Form (36) Health Survey (SF-36) Physical Component Score and fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F).

Baricitinib 4 mg vs. 2 mg

Differences in efficacy between the 4 mg and the 2 mg doses were most notable in the bDMARD-inadequate responder (IR) population (RA-BEACON), in which statistically significant improvements in the ACR components of swollen joint count, tender joint count and ESR were shown for baricitinib 4 mg compared to placebo at week 24 but not for baricitinib 2 mg compared to placebo.
In addition, for both study RA-BEACON and RA-BUILD, onset of efficacy was faster and the effect size was generally larger for the 4 mg dose groups compared to 2 mg.

In a long-term extension study, patients from Studies RA-BEAM, RA-BUILD and RA-BEACON who achieved sustained low disease activity or remission (CDAI ≤ 10) after at least 15 months of treatment with baricitinib 4 mg once daily were re-randomised 1:1 in a double-blind manner to continue 4 mg once daily or reduce dose to 2 mg once daily. The majority of patients maintained low disease activity or remission based on CDAI score:

•     At week 12: 451/498 (91 %) continuing 4 mg vs. 405/498 (81 %) reduced to 2 mg (p ≤ 0.001)
•     At week 24: 434/498 (87 %) continuing 4 mg vs. 372/498 (75 %) reduced to 2 mg (p ≤ 0.001)
•     At week 48: 400/498 (80 %) continuing 4 mg vs. 343/498 (69 %) reduced to 2 mg (p ≤ 0.001)
•     At week 96: 347/494 (70 %) continuing 4 mg vs. 297/496 (60 %) reduced to 2 mg (p ≤ 0.001) 
The majority of patients who lost their low disease activity or remission status after dose reduction could regain disease control after the dose was returned to 4 mg.

Atopic dermatitis

The efficacy and safety of baricitinib as monotherapy or in combination with topical corticosteroids (TCS) were assessed in 3 Phase III randomised, double-blind, placebo-controlled, 16 week studies (BREEZE-AD1, -AD2, and -AD7). The studies included 1,568 patients with moderate to severe atopic dermatitis defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥ 16, and a body surface area (BSA) involvement of ≥ 10 %. Eligible patients were over 18 years of age and had previous inadequate response or were intolerant to topical medicinal products. Patients were permitted to receive rescue treatment (which included topical or systemic therapy), at which time they were considered non-responders. At baseline of study BREEZE- AD7, all patients were on concomitant topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors. All patients who completed these studies were eligible to enrol in a long term extension study (BREEZE AD-3) for up to 2 years of continued treatment.

The Phase III randomised, double-blind, placebo-controlled BREEZE-AD4 study evaluated the efficacy of baricitinib in combination with topical corticosteroids over 52 weeks in 463 patients with moderate to severe atopic dermatitis with failure, intolerance, or contraindication to oral ciclosporin treatment.

Baseline characteristics

In the placebo-controlled Phase III studies (BREEZE-AD1, -AD2, -AD7, and -AD4), across all treatment groups, 37 % were female, 64 % were Caucasian, 31 % were Asian and 0.6 % were Black, and the mean age was 35.6 years. In these studies, 42 % to 51 % of patients had a baseline IGA of 4 (severe atopic dermatitis), and 54 % to 79 % of patients had received prior systemic treatment for atopic dermatitis. The baseline mean EASI score ranged from 29.6 to 33.5, the baseline weekly averaged Itch Numerical Rating Scale (NRS) ranged from 6.5 to 7.1, the baseline mean Dermatology Life Quality Index (DLQI) ranged from 13.6 to 14.9, and the baseline mean Hospital Anxiety and Depression Scale (HADS) Total score ranged from 10.9 to 12.1.

Clinical response

16-week monotherapy (BREEZE-AD1, -AD2) and TCS combination (BREEZE-AD7) studies A significantly larger proportion of patients randomised to baricitinib 4 mg achieved an IGA 0 or 1 response (primary outcome), EASI75, or an improvement of ≥ 4 points on the Itch NRS compared to placebo at week 16 (Table 6). Figure 1 shows the mean percent change from baseline in EASI up to week 16.

A significantly greater proportion of patients randomised to baricitinib 4 mg achieved a ≥ 4-point improvement in the Itch NRS compared to placebo (within the first week of treatment for BREEZE-AD1 and AD2, and as early as week 2 for BREEZE-AD7; p < 0.002).

Treatment effects in subgroups (weight, age, gender, race, disease severity, and previous treatment, including immunosuppressants) were consistent with the results in the overall study population.


Table 6. Efficacy of baricitinib at week 16 (FASa)

Monotherapy                                       TCS Combination
Study                    BREEZE- AD1            BREEZE-AD2                              BREEZE- AD7 Treatment            PBO    BARI   BARI     PBO    BARI   BARI                    PBO +     BARI    BARI Group                       2 mg   4 mg            2 mg    4 mg                    TCS     2 mg + 4 mg + TCS      TCS
N                   249      123       125        244           123      123      109      109     111 IGA 0 or 1,         4.8      11.4**    16.8**     4.5           10.6**   13.8**   14.7     23.9    30.6** % respondersb, c
EASI-75,            8.8      18.7**    24.8**     6.1           17.9**   21.1**   22.9    43.1*     47.7** % respondersc
Itch NRS            7.2      12.0      21.5**     4.7           15.1**   18.7**   20.2    38.1*     44.0** (≥ 4 point improvement),
% respondersc, d
BARI = Baricitinib; PBO = Placebo
* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo with adjustment for multiplicity.
a
Full analysis set (FAS) including all randomised patients.
b
Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on 0-4 IGA scale.
c
Non-Responder Imputation: Patients who received rescue treatment or with missing data were considered as non-responders.
d
Results shown in subset of patients eligible for assessment (patients with itch NRS ≥ 4 at baseline).

Figure 1. Mean percent change from baseline in EASI (FAS)a



LS = Least squares; * statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo with adjustment for multiplicity.
a
Full analysis set (FAS) including all patients randomised. Data collected after rescue therapy or after permanent medicinal product discontinuation were considered missing. LS means are from Mixed Model with Repeated Measures (MMRM) analyses.

Maintenance of response

To evaluate maintenance of response, 1,373 subjects treated with baricitinib for 16 weeks in BREEZE-AD1 (N = 541), BREEZE-AD2 (N = 540) and BREEZE-AD7 (N = 292) were eligible to enrol in a long term extension study BREEZE-AD3. Data are available up to 68 weeks of cumulative treatment for patients from BREEZE-AD1 and BREEZE-AD2, and up to 32 weeks of cumulative 
treatment for patients from BREEZE-AD7. Continued response was observed in patients with at least some response (IGA 0, 1 or 2) after initiating baricitinib.

Quality of life/patient-reported outcomes in atopic dermatitis

In both monotherapy studies (BREEZE-AD1 and BREEZE-AD2) and in the concomitant TCS study (BREEZE-AD7), baricitinib 4 mg significantly improved patient-reported outcomes, including itch NRS, sleep (ADSS), skin pain (skin pain NRS), quality of life (DLQI) and symptoms of anxiety and depression (HADS) that were uncorrected for multiplicity, at 16 weeks compared to placebo (See Table 7).

Table 7. Quality of life/patient-reported outcomes results of baricitinib monotherapy and baricitinib in combination with TCS at week 16 (FAS) a

Monotherapy                                    TCS Combination
Study                 BREEZE-AD1            BREEZE-AD2                           BREEZE-AD7 Treatment group    PBO BARI    BARI    PBO    BARI   BARI                  PBO +    BARI      BARI 2 mg   4 mg           2 mg   4 mg                   TCS     2 mg +   4 mg + TCS      TCS
N                 249      123      125       244     123        123       109     109      111 ADSS Item 2       12.8     11.4     32.7*     8.0     19.6       24.4*     30.6    61.5*    66.7* ≥ 2-point improvement,
% respondersc,d
Change in Skin    -0.84    -1.58    -1.93**   -0.86 -2.61**      -2.49**   -2.06     -3.22*     -3.73* Pain NRS,         (0.24)   (0.29)   (0.26)    (0.26) (0.30)      (0.28)    (0.23)    (0.22)     (0.23) mean(SE)b
Change in DLQI,   -2.46    -4.30*   -6.76*    -3.35 -7.44*       -7.56*    -5.58     -7.50*     -8.89* mean(SE)b         (0.57)   (0.68)   (0.60)    (0.62) (0.71)      (0.66)    (0.61)    (0.58)     (0.58) 
Change in         -1.22    -3.22*   -3.56*    -1.25 -2.82        -3.71*    -3.18     -4.75*     -5.12* HADS,             (0.48)   (0.58)   (0.52)    (0.57) (0.66)      (0.62)    (0.56)    (0.54)     (0.54) mean(SE)b
BARI = Baricitinib; PBO = Placebo
* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo with adjustment for multiplicity.
a
Full analysis set (FAS) including all randomised patients.
b
Results shown are LS mean change from baseline (SE). Data collected after rescue therapy or after permanent medicinal product discontinuation were considered missing. LS means are from Mixed Model with Repeated Measures (MMRM) analyses.
c
ADSS Item 2: Number of night time awakenings due to itch.
d
Nonresponder imputation: patients who received rescue treatment or with missing data were considered as nonresponders. Results shown in subset of patients eligible for assessment (patients with ADSS Item 2 ≥ 2 at baseline).

Clinical response in patients with experience with or a contra-indication to ciclosporin treatment (BREEZE-AD4 study)

A total of 463 patients were enrolled, who had either failed (n = 173), or had an intolerance (n = 75), or contraindication (n = 126) to oral ciclosporin. The primary endpoint was the proportion of patients achieving EASI-75 at week 16. The primary and some of the most important secondary endpoints at week 16 are summarised in Table 8.


Table 8: Efficacy of baricitinib in combination with TCSa at week 16 in BREEZE-AD4 (FAS)b 
Study                                                      BREEZE- AD4 Treatment                                 PBOa           BARI 2 mga               BARI 4 mga group
N                                          93                  185                    92 EASI-75,                                  17.2                 27.6                 31.5** % respondersc
IGA 0 or 1,                                9.7                 15.1                  21.7* % respondersc, e
Itch NRS (≥ 4 point                        8.2                22.9*                 38.2** improvement), % respondersc, f
Change in DLQI mean (SE)d                 -4.95                -6.57                -7.95* (0.752)              (0.494)               (0.705)

BARI = Baricitinib; PBO = Placebo
* statistically significant vs placebo without adjustment for multiplicity; ** statistically significant vs placebo with adjustment for multiplicity.
a
All patients were on concomitant topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors.
b
Full analysis set (FAS) includes all randomised patients.
c
Non-Responder Imputation: Patients who received rescue treatment or with missing data were considered as non-responders.
d
Data collected after rescue therapy or after permanent medicinal product discontinuation were considered missing. LS means are from Mixed Model with Repeated Measures (MMRM) analyses.
e
Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on 0-4 IGA scale.
f
Results shown in subset of patients eligible for assessment (patients with itch NRS ≥ 4 at baseline).

Alopecia areata
The efficacy and safety of baricitinib once daily were assessed in one adaptive Phase II/III study (BRAVE-AA1) and one Phase III study (BRAVE-AA2). The Phase III portion of BRAVE-AA1 study and the Phase III BRAVE-AA2 study were randomised, double blind, placebo-controlled, 36-week studies with extension phases up to 200 weeks. In both phase III studies, patients were randomised to placebo, 2 mg or 4 mg baricitinib in a 2:2:3 ratio. Eligible patients were adults between 18 years and 60 years of age for male patients, and between 18 years and 70 years of age for female patients, with a current episode of more than 6 months of severe alopecia areata (hair loss encompassing ≥ 50 % of the scalp). Patients with a current episode of more than 8 years were not eligible unless episodes of regrowth had been observed on the affected areas of the scalp over the past 8 years. The only permitted concomitant alopecia areata therapies were finasteride (or other 5 alpha reductase inhibitors), oral or topical minoxidil and bimatoprost ophthalmic solution for eyelashes, if at a stable dose at study entry.

Both studies assessed as primary outcome the proportion of subjects who achieved a SALT (Severity of Alopecia Tool) score of ≤ 20 (80 % or more scalp coverage with hair) at week 36. Additionally, both studies evaluated clinician assessment of eyebrow and eyelash hair loss using a 4-point scale (ClinRO Measure for Eyebrow Hair Loss™, ClinRO Measure for Eyelash Hair Loss™).

Baseline characteristics

The Phase III portion of BRAVE-AA1 study and the Phase III BRAVE-AA2 study included 1,200 adult patients. Across all treatment groups, the mean age was 37.5 years, 61 % of patients were female. The mean duration of alopecia areata from onset and the mean duration of current episode of hair loss were 12.2 and 3.9 years, respectively. The median SALT score across the studies was 96 (this equals 96 % scalp hair loss), and approximately 44 % of patients were reported as alopecia universalis.
Across the studies, 69 % of patients had significant or complete eyebrow hair loss at baseline and 58 % had significant or complete eyelash hair loss, as measured by ClinRO Measures for eyebrow and eyelash scores of 2 or 3. Approximately 90 % of patients had received at least one treatment for alopecia areata at some point before entering the studies, and 50 % at least one systemic immunosuppressant. The use of authorised concomitant alopecia areata treatments was reported by only 4.3 % of patients during the studies.

Clinical response

In both studies, a significantly greater proportion of patients randomised to baricitinib 4 mg once daily achieved a SALT ≤ 20 at week 36 compared to placebo, starting as early as week 8 in study BRAVE-AA1 and week 12 in study BRAVE-AA2. Consistent efficacy was seen across most of the secondary endpoints (Table 9). Figure 2 shows the proportion of patients achieving SALT ≤ 20 up to week 36.

Treatment effects in subgroups (gender, age, weight, eGFR, race, geographic region, disease severity, current alopecia areata episode duration) were consistent with the results in the overall study population at week 36.

Table 9. Efficacy of baricitinib through week 36 for pooled studies (Pooled Week 36 Efficacy Populationa)

BRAVE-AA1 (phase III part of a phase II/III study) and
BRAVE-AA2 (phase III study) Pooled Data*
Placebo      Baricitinib 2 mg        Baricitinib 4 mg
N=345             N=340                   N=515
SALT ≤ 20 at week 36           4.1 %          19.7 %**                 34.0 %** SALT ≤ 20 at week 24           3.2 %           11.2 %                  27.4 %** ClinRO Measure for             3.8 %           15.8 %                  33.0 %** Eyebrow Hair Loss of
0 or 1 at week 36 with a ≥ 2 point improvement from baselineb
ClinRO Measure for                4.3 %                12.0 %                  33.9 %** Eyelash Hair Loss of 0 or 1 at week 36 with a
≥ 2 point improvement from baselineb
Change in Skindex-16         -11.33 (1.768)        -19.89 (1.788)            -23.81 (1.488) adapted for alopecia areata emotions domain, mean (SE)c
Change in Skindex-16          -9.26 (1.605)        -13.68 (1.623)            -16.93 (1.349) adapted for alopecia areata functioning domain, mean (SE)c
ClinRO = clinician-reported outcome; SE = standard error a
Pooled Week 36 Efficacy Population: All patients enrolled in the Phase III portion of Study BRAVE-AA1 and in Study BRAVE-AA2.
* The results of the pooled analysis are in line with those of the individual studies ** Statistically significant with adjustment for multiplicity in the graphical testing scheme within each individual study.
b
Patients with ClinRO Measure for Eyebrow Hair loss score of ≥ 2 at baseline: 236 (Placebo), 240 (Baricitinib 2 mg), 349 (Baricitinib 4 mg). Patients with ClinRO Measure for Eyelash Hair loss score of ≥ 2 at baseline: 186 (Placebo), 200 (Baricitinib 2 mg), 307 (Baricitinib 4 mg). Both ClinRO 
Measures use a 4-point response scale ranging from 0 indicating no hair loss to 3 indicating no notable eyebrow/eyelashes hair.
c
Sample sizes for analysis on Skindex-16 adapted for alopecia areata at week 36 are n= 256 (Placebo), 249 (Baricitinib 2 mg), 392 (Baricitinib 4 mg).

Figure 2: Proportion of patients with SALT ≤ 20 through week 36



**p-value for baricitinib versus placebo ≤ 0.01; ***p-value for baricitinib versus placebo ≤ 0.001.
Efficacy up to week 52

The proportion of patients treated with baricitinib achieving a SALT ≤ 20 continued to increase after week 36, reaching 39.0 % of patients on baricitinib 4 mg at week 52. The results for the baseline disease severity and episode duration subpopulations at week 52 were consistent with those observed at week 36 and with the results in the overall study population.

Dose tapering substudy

In the study BRAVE-AA2, patients who had received baricitinib 4 mg once daily since the initial randomization and achieved SALT ≤ 20 at week 52 were re-randomised in a double-blind manner to continue 4 mg once daily or reduce dose to 2 mg once daily. The results show that 96 % of the patients who remained on baricitinib 4 mg and 74 % of the patients who were re-randomised to baricitinib 2 mg maintained their response at week 76.

Pediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with baricitinib in one or more subsets of the pediatric population in chronic idiopathic arthritis, atopic dermatitis and alopecia areata (see section 4.2 for information on pediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Following oral administration of baricitinib, a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The PK of baricitinib is linear with respect to time.

Absorption

Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour (range 0.5 - 3.0 h) and an absolute bioavailability of approximately 79 % (CV = 3.94 %). Food 

intake led to a decreased exposure by up to 14 %, a decrease in Cmax by up to 18 % and delayed tmax by 0.5 hours. Administration with meals was not associated with a clinically relevant effect on exposure.

Distribution

Mean volume of distribution following intravenous infusion administration was 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50 % bound to plasma proteins.

Biotransformation

Baricitinib metabolism is mediated by CYP3A4, with less than 10 % of the dose identified as undergoing biotransformation. No metabolites were quantifiable in plasma. In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and faeces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in faeces) constituting approximately 5 % and 1 % of the dose, respectively. In vitro, baricitinib is a substrate for CYP3A4, OAT3, Pgp, BCRP and MATE2-K, and may be a clinically relevant inhibitor of the transporter OCT1 (see section 4.5). Baricitinib is not an inhibitor of the transporters OAT1, OAT2, OAT3, OCT2, OATP1B1, OATP1B3, BCRP, MATE1 and MATE2-K at clinically relevant concentrations.

Elimination

Renal elimination is the principal mechanism for baricitinib’s clearance through glomerular filtration and active secretion via OAT3, Pgp, BCRP and MATE2-K. In a clinical pharmacology study, approximately 75 % of the administered dose was eliminated in the urine, while about 20 % of the dose was eliminated in the faeces.

Mean apparent clearance (CL/F) and half-life in patients with rheumatoid arthritis was 9.42 L/hr (CV = 34.3 %) and 12.5 hrs (CV = 27.4 %), respectively. Cmax and AUC at steady state are 1.4- and 2.0-fold higher, respectively, in subjects with rheumatoid arthritis compared to healthy subjects.

Mean apparent clearance (CL/F) and half-life in patients with atopic dermatitis was 11.2 L/hr (CV = 33.0 %) and 12.9 hrs (CV = 36.0 %), respectively. Cmax and AUC at steady state in patients with atopic dermatitis are 0.8-fold those seen in rheumatoid arthritis.

Mean apparent clearance (CL/F) and half-life in patients with alopecia areata was 11.0 L/hr (CV = 36.0 %) and 15.8 hrs (CV = 35.0 %), respectively. Cmax and AUC at steady state in patients with alopecia areata are 0.9-fold those seen in rheumatoid arthritis.

Renal impairment

Renal function was found to significantly affect baricitinib exposure. The mean ratios of AUC in patients with mild and moderate renal impairment to patients with normal renal function are 1.41 (90 % CI: 1.15-1.74) and 2.22 (90 % CI: 1.81-2.73), respectively. The mean ratios of Cmax in patients with mild and moderate renal impairment to patients with normal renal function are 1.16 (90 %CI: 0.92-1.45) and 1.46 (90 %CI: 1.17-1.83), respectively. See section 4.2 for dose recommendations.

Hepatic impairment

There was no clinically relevant effect on the PK of baricitinib in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment.


Elderly

Age ≥ 65 years or ≥ 75 years has no effect on baricitinib exposure (Cmax and AUC).

Pediatric population
The safety, efficacy and pharmacokinetics of baricitinib have not yet been established in a pediatric population (see section 4.2).

Other intrinsic factors

Body weight, sex, race, and ethnicity did not have a clinically relevant effect on the PK of baricitinib.
The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. Therefore, no dose adjustment is needed based on these patient factors.