Olumiant ® (baricitinib)

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What is the incidence and risk of venous thromboembolic events in Olumiant® (baricitinib) atopic dermatitis clinical development program?

The incidence rate for VTE was 0.13 in baricitinib treated patients in the AD clinical trials. In a US claims analysis, the incidence rate for VTE was 0.31 in patients with moderate- to- severe AD vs 0.25 in non-AD patients.

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Warnings and Precautions Related to Venous Thromboembolism

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.1

Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as

  • older age,
  • obesity,
  • a medical history of DVT/PE, or
  • patients undergoing surgery and immobilisation.1

If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.1

Venous Thromboembolic Events During the Clinical Trials

In the AD clinical trials, if patients had clinical features of a VTE, study treatment was interrupted and patients were promptly evaluated. Study treatment was

  • resumed if VTE was ruled out or appropriately treated, or
  • permanently discontinued if this was a second VTE or the investigator deemed the patient was at significant risk.2

Temporary interruption of study drug was not required at times of increased risk of VTE such as

  • surgery
  • significant air travel, or
  • prolonged immobilization.2

However, following appropriate VTE prophylaxis guidelines to mitigate risk was recommended in the clinical trials.2

Incidence of Venous Thromboembolism in Atopic Dermatitis Clinical Trials

Venous thromboembolic events were identified by the investigative site or through medical review and were sent to a blinded external Clinical Event Committee for adjudication.3

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials describes in detail the integrated safety datasets that are used to evaluate VTE.

Placebo-Controlled Period

Through 16 weeks, there was 1 PE, and no DVTs, in the baricitinib 4-mg treatment group (see Incidence of Venous Thromboembolic Events in the Atopic Dermatitis Safety Datasets).3

All Baricitinib AD Dataset

In patients treated with all baricitinib doses in the All BARI AD dataset, there were no events of DVT (above the knee), 2 events of PE (IR=0.09), and 1 event of other peripheral venous thrombosis (IR=0.04) (Incidence of Venous Thromboembolic Events in the Atopic Dermatitis Safety Datasets).
 Details of Each Individual Venous Thromboembolic Case in the Atopic Dermatitis Clinical Trials presents details of the 3 events.

Incidence of Venous Thromboembolic Events in the Atopic Dermatitis Safety Datasets2,3

 

BARI 2 mg Placebo-Controlleda
n (adj %)b

BARI 4 mg Placebo-Controlleda
n (adj %)b

BARI 2 mg vs 4 mga
n (adj %)b

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

All BARI AD
n (%) [IR]


Placebo
n=840

BARI 2 mg
n=684

Placebo
n=694

BARI 4 mg
n=451

BARI 2 mg
n=539

BARI 4 mg
n=451

BARI 2 mg
n=539

BARI 4 mg
n=451

All Doses
N=2456

VTEc

0

0

0

1 (0.1)

0

1 (0.1)

1 (0.2) [0.28]

2 (0.3) [0.40]

3 (0.1) [0.13]

DVT

0

0

0

0

0

0

0

0

0

PE

0

0

0

1 (0.1)

0

1 (0.1)

0

2 (0.3) [0.40]

2 (0.1) [0.09]

Other peripheral venous thrombosis

0

0

0

0

0

0

1 (0.2) [0.28]

0

1 (0.0) [0.04]

Abbreviations: AD = atopic dermatitis; adj = adjusted; AEs = adverse events; BARI = baricitinib; DVT = deep vein thrombosis; Ext = extended; IR = incidence rate; PE = pulmonary embolism; VTE = venous thromboembolic event.

aData through 16-week placebo-controlled period.

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 (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the AEs to provide appropriate direct comparisons between treatment groups.

cPatients with ≥1 positively adjudicated VTE event, including DVT, PE, and other peripheral venous thrombosis.

Details of Each Individual Venous Thromboembolic Case in the Atopic Dermatitis Clinical Trials2,3

Patient

Age/Gender

Event

Serious

BARI Dose/Time From Start of BARI Treatment to Event

Relevant Medical History

Elevated Plateletsa

BARI Treatment
Status

AC Treatment

Outcome

1

51/F

PE

Yes

BARI 4 mg/10 weeks

Ex-smoker, concomitant oral contraceptives

No

Perm D/C

Yes

Recovered

2

61/M

PE

Yes

BARI 4 mg/19 weeks

10-hr plane trip 10 weeks prior

No

Perm D/C

Yes

Recovering

3

34/F

Other peripheral venous thrombosisb

No

BARI 2 mg/40 weeks

Factor V  Leiden mutation, contraceptive vaginal ring

No

Perm D/C

Yes

Recovering

Abbreviations: AC = anticoagulant; BARI = baricitinib; F = female; M = male; PE = pulmonary embolism; Perm D/C = permanently discontinued.

a≥400x109/L.

bDefined as such per external adjudication committee as clot was located below the knee.

Risk of Venous Thromboembolism in the Atopic Dermatitis Population

Based on publicly available literature, background risk of VTE in the AD population has not been established. Therefore, a retrospective cohort study was conducted to understand the risk of VTE in patients with AD compared to a matched general population without AD.4

Study Design

Data were pulled from IBM Watson MarketScan® Commercial Claims and Encounters, Medicare Supplemental, and Medicaid, administrative US claims databases, to include patients

  • with diagnosed AD (overall AD cohort)
  • with moderate-to-severe AD (sub-cohort), and
  • without AD (non-AD controls matched for age, gender, and calendar time).5

Both crude and adjusted hazard ratios (HRs) of VTE were calculated to compare the 2 cohorts to non-AD controls.5

Results

The Crude Incidence Rates for Venous Thromboembolism in Patients With Atopic Dermatitis Compared to a Non-atopic Dermatitis Cohort shows that compared to the non-AD control cohort, the VTE risk was similar in patients with AD, and greater in patients with moderate-to-severe AD.5

Crude Incidence Rates for Venous Thromboembolism in Patients With Atopic Dermatitis Compared to a Non-atopic Dermatitis Cohort5

 

AD Overall Cohort
n=198,685

Moderate-to severe AD Cohort
n=113,927

Non-AD Control Cohort
n=198,685

IR for VTE, per 100 person-years (95% CI)

0.24 (0.23 to 0.25)

0.31 (0.29 to 0.34)

0.25 (0.23 to 0.26)

 Abbreviations: AD = atopic dermatitis; IR = incidence rate; VTE = venous thromboembolism. 

There was no difference in the risk of VTE between the overall AD cohort and non-AD controls cohort when adjusting only for the matching variables (5-year age category, sex, and calendar year). A significant (p<.001) decreased risk of VTE in overall AD cohort compared to the non-AD controls cohort was observed when adjusting HR for healthcare use and VTE risk factors (Risk of Venous Thromboembolism, Pulmonary Embolism and Deep Venous Thrombosis in Patients With Atopic Dermatitis Compared to Non-atopic Dermatitis Populations).5

In the moderate-to-severe AD cohort, the risk of VTE is 24% greater (p<.001) compared to the non-AD controls cohort when adjusting only for the matching variables. No difference in the risk of VTE between these 2 cohorts was shown when adjusting HR for healthcare use and VTE risk factors (Risk of Venous Thromboembolism, Pulmonary Embolism and Deep Venous Thrombosis in Patients With Atopic Dermatitis Compared to Non-atopic Dermatitis Populations). 5

Risk of Venous Thromboembolism, Pulmonary Embolism and Deep Venous Thrombosis in Patients With Atopic Dermatitis Compared to Non-atopic Dermatitis Populations5

Number of Events

Partially Adjusted HRa

Fully Adjusted HRb

Overall AD cohort (n=198,685), HR (95% CI), p-value

VTE

2148

1.00 (0.92 to 1.09), .95

0.77 (0.69 to 0.85), <.001 

PE

711

0.87 (0.75 to 1.01), .07

0.66 (0.56 to 0.79), <.001

DVT

1674

1.04 (0.95 to 1.15), .40

0.81 (0.72 to 0.91), <.001 

Moderate-to-severe AD cohort (n=113,927)c, HR (95% CI), p-value

VTE

1859

1.24 (1.13 to 1.36), <.001

0.95 (0.85 to 1.07), .41

PE

629

1.11 (0.95 to 1.30), .19

0.83 (0.69 to 1.01), .07

DVT

1438

1.28 (1.16 to 1.42), <.001

1.00 (0.88 to 1.14), .99

 Abbreviations: AD = atopic dermatitis; DVT = deep vein thrombosis; HR = hazard ratio; PE = pulmonary embolism; VTE = venous thromboembolism.

aAdjusted for 5-year age category, sex, and calendar year.

bAdjusted for 5-year age category, sex, calendar year, healthcare utilization, medications (hormone therapy, systemic corticosteroid, methotrexate, statins, antipsychotics, and cyclooxygenase-2 inhibitors), and comorbidities (cancer, trauma, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn’s disease, and obesity).

cPatients were selected as moderate-to-severe AD based on use of medications such as high or ultrahigh potency topical corticosteroids, systemic corticosteroids, phototherapies, or systemic immunosuppressants.

Postmarketing Spontaneous Reports

The postmarketing information provided below is based on cases reported prior to an approved indication of BARI for the treatment of atopic dermatitis.

Based on postmarketing spontaneous reports from February 2017, after the first global approval for rheumatoid arthritis, through August 2020

  • PE was rarely reported (≥0.01% and <0.1%), and
  • DVT was rarely reported (≥0.01% and <0.1%).2

Postmarketing cases of VTE were reported for both BARI 2 mg and BARI 4 mg doses and from many countries. The reporting rates were similar between BARI 2 mg and BARI 4 mg doses for VTE, DVT, and PE.2

Based on available information supplied at time of report and any follow-up, reported postmarketing cases were associated with one or more risk factors including

  • older age
  • previous history of VTE
  • post-surgical
  • lack of mobility
  • obesity
  • presence of malignancy, and/or
  • concomitant use of
    • corticosteroids
    • COX-2 inhibitor, and/or
    • estrogen.2

Postmarketing data do not necessarily represent the rate of occurrence of an AE in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an event.6

Spontaneous reporting has limited use due to

  • lack of control population
  • under-reporting or reporting bias, and
  • missing or incomplete information regarding medical history or concomitant medications.6

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,3,7

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 2 mg ADa

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

No between-group comparisons

Includes 1598 (total PYE=1434.2) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI 2 mg doses.

Includes all patients who were exposed to BARI 2 mg at any time during the 8 studies, either from randomization or switch, or rescue to BARI 2 mg.

Censoring of data at dose change in period 2 in 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.

aThe All BARI 2 mg AD analysis set uses an updated safety database with longer exposure time and with additional patients from 4 ongoing studies, compared to the All BARI AD analysis set.

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

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Bieber 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

4Meyers K, Goodloe R, Pierce E, et al. Risk of venous thromboembolism among patients with atopic dermatitis: a cohort study in a US administrative claims database [abstract]. European Academy of Dermatology 29th Congress; October 28 - November 1, 2020; Vienna, Austria.

5Meyers KJ, Silverberg JI, Rueda MJ, et al. Risk of venous thromboembolism among patients with atopic dermatitis: a cohort study in a US administrative claims database. Dermatol Ther (Heidelb). 2021;11(3):1041-1052. https://doi.org/10.1007/s13555-021-00538-4

6Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6

7King 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

Date of Last Review: 07 January 2022


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