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Pharmacology: Pharmacodynamics: 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 1). 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 4 years continued treatment. (See Table 1.)
Click on icon to see table/diagram/imageClinical 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, MTX or adalimumab (Table 2). 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 2).
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. (See Table 2.)
Click on icon to see table/diagram/imageRadiographic 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 3). 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. (See Table 3.)
Click on icon to see table/diagram/imagePhysical 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-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: 234/251 (93%) continuing 4 mg vs. 207/251 (82%) reduced to 2 mg (p ≤ 0.001); At week 24: 163/191 (85%) continuing 4 mg vs. 144/189 (76%) reduced to 2 mg (p ≤ 0.05); At week 48: 57/73 (78%) continuing 4 mg vs. 51/86 (59%) reduced to 2 mg (p ≤ 0.05).
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 medication. 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-AD3) 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), EASI-75, or an improvement of ≥ 4 points on the Itch NRS compared to placebo at week 16 (Table 4). 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. (See Table 4 and Figure 1.)
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Click on icon to see table/diagram/imageMaintenance 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 5.)
Click on icon to see table/diagram/imageClinical response in patients with experience with or a contraindication 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 6. (See Table 6.)
Click on icon to see table/diagram/imageAlopecia 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 7). 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. (See Table 7 and Figure 2.)
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Click on icon to see table/diagram/imageEfficacy 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.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with baricitinib in one or more subsets of the paediatric population in chronic idiopathic arthritis, atopic dermatitis and alopecia areata (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: 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 Interactions). 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 Dosage & Administration 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).
Paediatric population: The safety, efficacy and pharmacokinetics of baricitinib have not yet been established in a paediatric population (see Dosage & Administration).
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.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.
Decreases in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissues of the immune system were observed in mice, rats and dogs. Opportunistic infections related to demodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure. Decreases in red blood cell parameters were observed in mice, rats and dogs at exposures approximately 6 to 36 times the human exposure. Degeneration of the sternal growth plate was observed in some dogs, at low incidence and also in control animals, but with a dose-effect relationship regarding severity. At present it is not known whether this is clinically relevant.
In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively). No adverse foetal effects were observed at exposures 2 times the human exposure based on AUC.
In a combined male/female rat fertility study, baricitinib decreased overall mating performance (decreased fertility and conception indices). In female rats there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos. Since there were no effects on spermatogenesis (as assessed by histopathology) or semen/sperm endpoints in male rats, the decreased overall mating performance was likely the result of these female effects.
Baricitinib was detected in the milk of lactating rats. In a pre- and postnatal development study, decreased pup weights and decreased postnatal survival were observed at exposures 4 and 21 times, respectively, the human exposure.
