Olumiant ® (baricitinib)

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What is the incidence of platelet changes in patients treated with Olumiant® (baricitinib)?

Mean increases from baseline in platelet counts were observed in patients with atopic dermatitis treated with baricitinib vs placebo. The incidence rate of thrombocytosis >600 x 109/L was 0.2 per 100 patient-years at risk.

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Platelet Evaluations in the Baricitinib Atopic Dermatitis Clinical Development Program

Integrated Safety Dataset Descriptions

The integrated datasets used to evaluate platelet changes, the incidence of abnormal platelet levels and platelet-related treatment-emergent adverse events (TEAEs) are described in Integrated Safety Datasets.

Mean Changes From Baseline in Platelets Over Time

Placebo-Controlled Datasets

Through the 16-week placebo-controlled period, the change from baseline in platelets was significantly increased with baricitinib treatment compared to placebo, and between baricitinib 2 mg vs 4 mg doses (p<.001), see Platelet Changes From Baseline to Last Observation Up to Week 16 in the Atopic Dermatitis Clinical Trials.1

Platelet Changes From Baseline to Last Observation Up to Week 16 in the Atopic Dermatitis Clinical Trials1

 

Placebo
N=743

Baricitinib 2 mg
N=576

Baricitinib 4 mg
N=489

Baseline, mean (SD)

280 (70.16)

280.9 (69.97)

285.7 (76.78)

LSM change,
LSMD (SE) [95% CI]

-4.1 (1.82)
[-7.66, -0.54]

16.7 (2.22)
[12.37, 21.10]

28.8 (2.07)
[24.72, 32.83]ab

Abbreviations: BARI = baricitinib; N = number of patients; LSM = least squares mean; LSMD = least squares mean difference. 

ap<.001 BARI 4 mg vs Placebo.

bp<.001 BARI 4 mg vs BARI 2 mg.

Extended Datasets

Mean Changes in Blood Platelets Over Time in Patients From the BREEZE-AD Clinical Program Through the Extended Time Period presents mean changes in blood platelets from the placebo-controlled dataset (week 1-16) and extension dataset (104-week extension). In patients treated with baricitinib 2 mg and baricitinib 4 mg, mean platelet counts increased at week 4 and remained increased over the 120-week period.1

Mean Changes in Blood Platelets Over Time in Patients From the BREEZE-AD Clinical Program Through the Extended Time Period1

Abbreviations: AD = atopic dermatitis; BARI = baricitinib.

Patients With Treatment-Emergent High Platelet Levels

Categorical changes in treatment-emergent (TE) abnormal laboratory values were analyzed based on

  • upper limit of normal (ULN), and
  • TE shifts by maximum count category for high platelet values.1,2

Normal reference limits of platelets were defined according to age and gender.1

Treatment-Emergent High Platelet Levels and Shift by Maximum Count Category

Overview of Treatment-Emergent High Platelets and Shifts in Maximum Platelet Count Categories From BREEZE-AD Clinical Development Program presents an overview of TE high platelets and shifts in maximum platelet count categories from the BREEZE-AD clinical development program.

Placebo-Controlled Period

As presented in Overview of Treatment-Emergent High Platelets and Shifts in Maximum Platelet Count Categories From BREEZE-AD Clinical Development Program, in the 16-week placebo-controlled period, significantly more patients reported TE high platelets when treated with

  • baricitinib 2 mg vs placebo (4.6% vs 1.4%; p≤.001), and
  • baricitinib 4 mg vs placebo (4.9% vs 1.2%; p≤.001).1

Significantly more patients also experienced a change from ≤400x109 to >400x109 cells/L when treated with

  • baricitinib 2 mg vs placebo (8.9% vs 3.1%; p≤.001), and
  • baricitinib 4 mg vs placebo (13.1% vs 3.2%; p≤.001).1

All Baricitinib-Treated Patients With Extended Data

As presented in Overview of Treatment-Emergent High Platelets and Shifts in Maximum Platelet Count Categories From BREEZE-AD Clinical Development Program, in the extended data analysis set, significantly more patients in the baricitinib 4 mg vs 2 mg groups experienced

  • TE high platelets (12.2% vs 6.1%; p<.001), and
  • a change from ≤400x109 to >400x109 cells/L (24.1% vs 13.9%; p<.001).1

In the All BARI AD analysis set, 36 (1.4%) patients experienced a change in platelet count from ≤600x109 to >600x109 cells/L (see Overview of Treatment-Emergent High Platelets and Shifts in Maximum Platelet Count Categories From BREEZE-AD Clinical Development Program).1

No patients had an adverse event (AE) at the time of the maximum platelet count that would be related to increased platelets, and no patients discontinued baricitinib due to platelet increases.1,2 There were no thrombotic events in patients with platelets greater than 600x109 cells/L, and of the 3 patients who had thrombotic events, none had platelet counts over 450x109 cells/L.1

Overview of Treatment-Emergent High Platelets and Shifts in Maximum Platelet Count Categories From BREEZE-AD Clinical Development Program1,2

Treatment-Emergent
Abnormal Higha
n/NAR (adj %)

Shift From ≤400x109 cells/L
to >400x109 cells/L
n/NAR (%)

Shift From ≤600x109 cells/L
to >600x109 cells/L
n/NAR (%)

16-Week Placebo-Controlled BARI ADb

Placebo, n=743

11/701 (1.2)

22/682 (3.2)

0/724 (0.0)

BARI 2 mg, n=576

28/549 (4.1)

49/528 (9.3)

7/568 (1.2)

BARI 4 mg, n=489

27/467 (4.9)c

58/444 (13.1)c

3/482 (0.6)

BARI 2 mg and 4 mg Extended ADb

BARI 2 mg, n=584

43/555 (6.1)

74/533 (13.9)

11/575 (1.9)

BARI 4 mg, n=497

68/475 (12.2)d

108/449 (24.1)d

4/490 (0.8)

All BARI ADe, n/NAR (%)

All doses, N=2636

242/2509 (9.6)

412/2393 (17.2)

36/2589 (1.4)

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate; NAR = number of patients at risk; TE = treatment emergent; ULN = upper limit of normal.

aA TE high result was defined as a change from a value ≤ULN at all baseline visits to a value >ULN at any time during the treatment period. Number at risk was defined as the number of patients with a value ≤ULN at all baseline visits. Upper limit reference of blood platelet count was different by patient according to gender and age.

bFor 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 (example 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.

cp≤.001 BAR 4-mg vs placebo.

dp<0.001 BARI 4-mg vs BARI 2-mg.

eUp to 3.9 years of data.

Treatment-Emergent Adverse Events of Thrombocytosis

As presented in Treatment-Emergent Adverse Events of Thrombocytosis, in the integrated safety datasets, no significant increases in TEAE of thrombocytosis were observed between patients treated with baricitinib vs placebo, and with baricitinib 2 mg vs 4 mg doses.1

In the All BARI AD dataset, of the 8 cases of TEAE of thrombocytosis

  • none were considered serious
  • 1 (0.0%) led to temporary interruption, and
  • none led to permanent discontinuation.1
Treatment-Emergent Adverse Events of Thrombocytosis1

Thrombocytosis TEAEs

16-Week Placebo-Controlled BARI AD, n (adj %)a


Placebo, n=743

0 (0.0)

BARI 2 mg, n=576

0 (0.0)

BARI 4 mg, n=489

1 (0.2)

BARI 2 mg and 4 mg Extended AD, n (adj %) [adj IR]a


BARI 2 mg, n=584

1 (0.1) [0.1]

BARI 4 mg, n=497

1 (0.2) [0.1]

All BARI AD, n (%) [IR]b


All doses, N=2636 

8 (0.3) [0.2]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate; TEAE = treatment-emergent adverse event.

aFor 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 (example 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.

bAll-BARI AD includes BARI 1-mg, 2-mg, and 4-mg.

Treatment-Emergent Adverse Events of Thrombocytopenia

In the All BARI AD dataset, no cases of TEAE of thrombocytopenia were reported.1

BREEZE-AD Clinical Trial Protocol Information Related to Platelets

Exclusion Criteria Related to Platelet Levels

Patients were excluded from enrollment in the BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, and BREEZE-AD7 studies if they had thrombocytopenia (platelets <100,000/µL or <100x109 cells/L) at screening.1

Patients who had a history or presence of hematological disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute an unacceptable risk when taking the investigational product or interfere with the interpretation of data were also excluded.1

Discontinuation Criteria Related to Platelet Levels

If platelet counts were <75,000 cells/μL (<75x109 cells/L), the investigational product was held. Resumption of the investigational product occurred when platelet counts were ≥100,000/μL (≥100x109 cells/L).1

Relevant Information From the Summary of Product Characteristics

Increases in mean platelet counts were observed and remained stable at a higher value than baseline over time.3

Integrated Safety Datasets

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials1,2,4,5

Analysis Set

Description

16-Week Placebo-Controlled BARI AD

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

Compares BARI 2 mg, BARI 4 mg and placebo.

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)
  • BARI 4 mg (n=489, PYE=147.1), or
  • placebo (n=743, PYE=211.8).

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

BARI 2 mg and 4 mg Extended ADa

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=584, PYE=727.1), or
  • BARI 4 mg (n=497, PYE=800.1).

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 ADb

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

No between-group comparisons

Includes 2636 (total PYE=4628.4) 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=605, PYE=441.5)
  • BARI 2 mg (n=1703, PYE=2420.9), and
  • BARI 4 mg (n=1012, PYE=1766.8).

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.

aData cut as of November 3, 2021 for BREEZE-AD3 and December 15, 2021 for BREEZE-AD4

bData cut as of November 3, 2021 for BREEZE-AD3, December 15, 2021 for BREEZE-AD4, and December 21, 2021 for BREEZE AD6

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

1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2Bieber 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

3Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

4King B, Maari C, Lain E, et al. Extended safety analysis of baricitinib 2 mg in adult patients with atopic dermatitis: an integrated analysis from eight randomized clinical trials. Am J Clin Dermatol. 2021;22(3):395-405. https://doi.org/10.1007/s40257-021-00602-x

5Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 and up to 3.9 years treatment: an updated integrated analysis of 8 clinical trials. Poster presented at: 31st Annual European Academy of Dermatology and Venereology Congress; September 7-10, 2022; Milan, Italy.

Date of Last Review: 16 August 2022


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