Olumiant ® ▼ (baricitinib)

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Olumiant® ▼ (baricitinib): Changes in Eosinophils in the Atopic Dermatitis Trials

The proportion of patients with treatment-emergent high blood eosinophils was significantly lower in atopic dermatitis patients treated with baricitinib compared to placebo.

Eosinophil Count in Patients With Atopic Dermatitis

Elevated eosinophils are very common in patients with AD and appear to correlate with disease activity.1,2

BREEZE-AD Phase 3 Clinical Trial Exclusion Criteria Related to Eosinophil Count

No limit range for eosinophils was specified in the protocol exclusion criteria.3 However, patients were excluded from the studies if they had screening laboratory test values outside the reference range for the population or investigative site that, in the opinion of the investigator, could pose an unacceptable risk for the patient’s participation in the study.3

Eosinophil Count in the Atopic Dermatitis Clinical Trial Program

Absolute count of eosinophils was part of the planned clinical laboratory tests in all the BREEZE-AD studies.3

Integrated Safety Dataset Descriptions

Table 4 describes the integrated datasets used to evaluate

  • mean changes from baseline in eosinophil count

  • TE high eosinophil count, and

  • eosinophilia TEAE.3,4

Mean Change From Baseline Eosinophil Count

Placebo-Controlled Dataset

Through the 16-week placebo-control period, the change from baseline to last postbaseline observation in blood eosinophils was significantly decreased in the

  • BARI 4 mg vs placebo groups (p<.01), and

  • BARI 4 mg vs BARI 2 mg groups (p<.05).3

No significant change from baseline was observed in the BARI 2 mg vs placebo groups (see Table 1).3

Table 1. Change From Baseline to Last Postbaseline Observation in Blood Eosinophils During the Placebo-Controlled Period Up to 16 Weeks3

Placebo-Controlled Dataset

Change From Baseline in Blood Eosinophils
LSMD (SE) [95% CI]

BARI 2 mg AD placebo-controlled

Placebo, n=889

-0.1 (0.01) (-0.14, -0.09)

BARI 2 mg, n=721

-0.1 (0.01) (-0.17, -0.12)

BARI 4 mg AD placebo-controlled

Placebo, n=743

-0.2 (0.01) (-0.18, -0.12)

BARI 4 mg, n=489

-0.2 (0.02) (-0.24, -0.18)a

BARI 2 vs 4 mg AD placebo-controlled

BARI 2 mg, n=576

-0.2 (0.02) (-0.21, -0.15)

BARI 4 mg, n=489

-0.2 (0.02) (-0.26, -0.20)b

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; LSMD = least squares mean difference.

a p<.01 BARI 4 mg vs placebo.

b p<.05 BARI 4 mg vs BARI 2 mg.

Extended Dataset

Decreases in blood eosinophils were noted after 4 weeks of treatment with BARI (see Figure 1).3

Decreased blood eosinophil levels were maintained throughout the duration of the extended time period, and no significant change from baseline to last observation was observed between the BARI 4 mg vs BARI 2 mg groups.3 

Figure 1. Mean Changes in Blood Eosinophils Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials3

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; ext = extended.

Treatment-Emergent High Blood Eosinophil Count

The number and percentage of patients with TE high blood eosinophil counts at anytime during the AD clinical trials are summarized for the BARI-treated and placebo-treated patients in Table 2.

In the placebo-controlled analysis sets, the proportion of patients with TE high blood eosinophils (adjusted percentages) was significantly lower in the

  • BARI 2 mg vs placebo groups (14.5% vs 21.0%; p<.01), and

  • BARI 4 mg vs placebo groups (13.0% vs 17.7%; p<.05).3

No significant difference was observed between the BARI 2 mg vs 4 mg groups in the 16-week placebo-controlled period and the extended time period.3

Table 2. Treatment-Emergent High Blood Eosinophil Counts at Any Time During the Atopic Dermatitis Clinical Trials3


Treatment-Emergent Higha
n/NAR
b (adj %c)

BARI 2 mg placebo-controlledd

Placebo, N=889

109/505 (21.0)

BARI 2 mg, N=721

54/395 (14.5)e

BARI 4 mg placebo-controlledd

Placebo, N=743

91/412 (17.7)

BARI 4 mg, N=489

36/246 (13.0)f

BARI 2 mg vs 4 mgd

BARI 2 mg, N=576

45/308 (12.7)

BARI 4 mg, N=489

36/246 (13.0)

BARI 2 mg vs 4 mg extended

BARI 2 mg, N=576

72/308 (20.1)

BARI 4 mg, N=489

55/246 (20.4)

All BARI AD

All doses, N=2531

285/1310 (21.8)

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; n = number of patients with the specified abnormality; NAR = number of patients at risk for the abnormality in each treatment group.

a A TE high result was defined as a change from a value less than or equal to the upper limit at all baseline visits to a value greater than the upper limit at any time during the treatment phase. Upper limit reference of blood eosinophil count was different by patient according to gender and age.

b The NAR for the TE high result is defined as the number of patients with a value less than or equal to the high limit at all baseline visits.

c For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.

d Data through 16-week placebo-controlled period.

e p<.01 BARI 2 mg vs placebo.

f p<.05 BARI 4 mg vs placebo.

Eosinophilia Treatment-Emergent Adverse Event

Evaluation of TEAEs included the MedDRA preferred term eosinophilia from the Blood and Lymphatic System Disorders SOC.3

As presented in Table 3, no significant differences were observed in eosinophilia TEAE between the BARI and placebo treatment groups and the BARI 2 mg vs 4 mg groups in all of the integrated analysis datasets.3

Table 3. Treatment-Emergent Eosinophilia in the Atopic Dermatitis Clinical Trials3


Treatment-Emergent Eosinophilia

BARI 2 mg placebo-controlleda, n (adj %)b

Placebo, n=889

1 (0.1)

BARI 2 mg, n=721

0

BARI 4 mg placebo-controlleda, n (adj %)b

Placebo, n=743

0

BARI 4 mg, n=489

1 (0.2)

BARI 2 mg vs 4 mga, n (adj %)b

BARI 2 mg, n=576

0

BARI 4 mg, n=489

1 (0.2)

BARI 2 mg vs 4 mg extended, n (adj %)b [adj IR]

BARI 2 mg, n=576

0 [0.0]

BARI 4 mg, n=489

1 (0.2) [0.3]

All BARI AD, n (%) [IR]

All doses, N=2531

3 (0.1) [0.1]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate.

a Data through 16-week placebo-controlled period.

b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.

In the All BARI AD dataset, none of the eosinophilia TEAEs were considered serious. There was no patient discontinuation or temporary interruption to treatment due to eosinophilia.3

Integrated Analysis Datasets

Table 4. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials3,4

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1. Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy. 2004;59(6):561-570. https://doi.org/10.1111/j.1398-9995.2004.00476.x

2. Kägi MK, Joller-Jemelka H, Wüthrich B. Correlation of eosinophils, eosinophil cationic protein and soluble interleukin-2 receptor with the clinical activity of atopic dermatitis. Dermatology. 1992;185(2):88-92. https://doi.org/10.1159/000247419

3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4. Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

Glossary

AD = atopic dermatitis

BARI = baricitinib

MedDRA = Medical Dictionary for Regulatory Activities

SOC = system organ class

TE = treatment-emergent

TEAE = treatment-emergent adverse event

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: February 19, 2021


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