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Olumiant ^® (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).

What is the incidence of MACE in Olumiant® (baricitinib) in patients with atopic dermatitis or alopecia areata?

In atopic dermatitis, the incidence of major adverse cardiovascular events (MACE) was 0.15 per 100 patients years of exposure. In alopecia areata, the incidence was below 0.1.

UK_cFAQ_BAR132_MACE_AD_AA

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Content overview

Special warnings and precautions regarding baricitinib and MACE
Incidence of major adverse cardiovascular events in placebo-controlled trials and long-term exposure
Incidence of major adverse cardiovascular events based on real-world data
References
Appendix 1: Integrated safety datasets table atopic dermatitis clinical trials
Appendix 2: Integrated safety datasets table alopecia areata clinical trials

Special warnings and precautions regarding baricitinib and MACE

In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate of MACE was observed compared to patients treated with TNF inhibitors.1

In a large randomized active‑controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, non‑fatal myocardial infarction (MI) and non‑fatal stroke ,was observed with tofacitinib (another JAK inhibitor) compared with TNF inhibitors.1

Therefore,1

in patients over 65 years of age,
patients who are current or past long‑time smokers, and
patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors,

baricitinib should only be used if no suitable treatment alternatives are available.1

Incidence of major adverse cardiovascular events in placebo-controlled trials and long-term exposure

Atopic dermatitis clinical trials

Baricitinib was evaluated for up to 4628 patient-years of exposure and up to 3.9 years to treat atopic dermatitis. Please find an overview of major adverse cardiovascular events from the atopic dermatitis (AD) clinical trials in Major Adverse Cardiovascular Events in the Baricitinib Atopic Dermatitis Clinical Trials. Appendix 1: Integrated safety datasets table atopic dermatitis clinical trials provides details about the corresponding studies.2,3

Major Adverse Cardiovascular Events in the Baricitinib Atopic Dermatitis Clinical Trials2,3
	Placebo-Controlled(to week 16) n [adj IR]a			BARI 2 mg and 4 mg Extended (up to 3.9 years) n [adj IR]^a		All BARI AD (up to 3.9 years) n [IR]
	Placebo n=743	BARI 2 mg n=576	BARI 4 mg n=489	BARI 2 mg n=584	BARI 4 mg n=497	All doses N=2636
MACE	0	0	0	1 [0.10]	1 [0.11]	7 [0.15]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate; MACE = major adverse cardiovascular 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.

In the All BARI AD dataset, 7 (IR=0.15) patients reported 8 MACE events.2

Of these 8 MACE events, there were

2 events of CV death (1 on baricitinib 2 mg and 1 on baricitinib 4 mg)
3 myocardial infarctions (2 on baricitinib 2 mg and 1 on baricitinib 4 mg), and
3 strokes (2 on baricitinib 2 mg and 1 on baricitinib 4 mg).4

One patient on baricitinib 2 mg had both stroke and CV death.4

The observed MACE IR with baricitinib of 0.15 per 100 PYE falls within the range of reported rates for the atopic dermatitis population (0.15 to 0.63 per 100 patient years).5-7

In the AD clinical trials, 1373 of the 2636 patients were considered patients at-risk, defined as ≥65 years, or with at least one of the following risk factors: atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, high-density lipoprotein cholesterol less than 40 mg/dL, body mass index at least 30, poor mobility on EuroQol-5 Dimension, and history of malignancy.8

6 of the 7 MACE events in the All-BARI-AD dataset were reported by patients at-risk with at least one cardiovascular risk factor.8

Alopecia areata clinical trials

Baricitinib was evaluated for up to 2218 patient-years of exposure for alopecia areata (AA). Please find an overview of major adverse cardiovascular events from the AA clinical trials in Major Adverse Cardiovascular Events in the Baricitinib Alopecia Areata Clinical Trials. Appendix 2: Integrated safety datasets table alopecia areata clinical trials provides details about the corresponding studies.4,9

Major Adverse Cardiovascular Events in the Baricitinib Alopecia Areata Clinical Trials4,10
	36-Week Placebo-Controlled BARI AA n (%) [IR]			Extended BARI AA n [IR]		All BARI AA n [IR]
	Placebo (n=371)	BARI 2 mg (n=365)	BARI 4 mg (n=540)	BARI 2 mg (n=383)	BARI 4 mg (n=565)	All Doses (N=1303)
MACE	0	1 (0.3) [0.4]a	0	1 [0.2]a	0	1 [<0.1]

Abbreviations: AA = alopecia areata; BARI = baricitinib; IR = incidence rate; MACE = major adverse cardiovascular event.

aSingle event of MACE was an acute myocardial infarction that was determined to be an arterial thrombotic event.

An incidence rate of MACE in the alopecia areata population is currently not available.7

In the AA clinical trials, 659 of the 1303 patients were considered patients at-risk of adverse event of special interest (AESI). 8

The major adverse cardiovascular event was reported by a patient at-risk.8

Incidence of major adverse cardiovascular events based on real-world data

Best to our knowledge, there are no systematic real-world data in baricitinib patients with atopic dermatitis or alopecia areata.

However, the absolute rates for MACE in patients with AD are low, ranging from IRs of 0.05 to 0.21 per 100 PY for myocardial infarction, 0.07 to 0.28 per 100 PY for stroke, and 0.08 to 0.44 per 100 PY for cardiovascular death.5,6

IRs of composite MACE ranged from 0.15 per 100 PY for mild AD to 0.63 per 100 PY for severe disease in real-world evidence.5

References

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

2Bieber 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.

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

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5Andersen YMF, Egeberg A, Gislason GH, et al. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(1):310-312.e3. https://doi.org/10.1016/j.jaci.2016.01.015

6Silverwood RJ, Forbes HJ, Abuabara K, et al. Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study. BMJ. 2018;361:k1786. https://doi.org/10.1136/bmj.k1786

7Bieber T, Feist E, Irvine AD, et al. A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19. Adv Ther. 2022;39(11):4910-4960. https://dx.doi.org/10.1007/s12325-022-02281-4

8Taylor, P.C., Bieber, T., Alten, R. et al. Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications. Adv Ther (2023). https://doi.org/10.1007/s12325-023-02445-w

9King 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

10King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Poster presented at: Annual Meeting of the American Academy of Dermatology Association (AAD); March 25-29, 2022; Boston, MA. Accessed April 29, 2022. https://aad-eposters.s3.amazonaws.com/AM2022/poster/33966/Integrated+safety+analysis+of+baricitinib+in+adults+with+severe+alopecia+areata+from+two+randomized+clinical+trials.pdf

11King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Br J Dermatol. Published online November 11, 2022. https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljac059/6821292

Appendix 1: Integrated safety datasets table atopic dermatitis clinical trials

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2-4,9
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 AD Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6a	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

Appendix 2: Integrated safety datasets table alopecia areata clinical trials

Integrated Analysis Datasets Used to Evaluate Safety in Alopecia Areata Clinical Trials4,11
Analysis Set	Description
36-Week placebo-controlled BARI AA	Assesses BARI 4 mg, BARI 2 mg, and placebo. Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to BARI 4 mg (n=540, PYE=363.4) BARI 2 mg (n=365, PYE=240.6), or placebo (n=371, PYE=243.2). Evaluation time period included randomization to week 36.
Extended BARI AA	Assesses BARI 4 mg and BARI 2 mg including extended evaluations. Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to BARI 4 mg (n=565, PYE=912.9), or BARI 2 mg (n=383, PYE=470.2). Evaluation time period included randomization up to data cutoff, May 10, 2022 for BRAVE-AA2 and May 24, 2022 for BRAVE-AA1. Data were censored after a patient was switched to another dose or treatment.
All BARI AA	No between-group assessments. Includes 1303 (total PYE=2217.9) patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were exposed to any BARI dose, including BARI 4 mg (n=996, PYE=1478.7) BARI 2 mg (n=595, PYE=734.4), or BARI 1 mg (n=28, PYE=14.6). Evaluation time period included any time points during the studies either from randomization or from switch or rescue from placebo.

Abbreviations: AA = alopecia areata; BARI = baricitinib; PYE = patient-years of exposure.

Date of Last Review: 05 June 2023

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Olumiant ® (baricitinib)