Olumiant ® ▼ (baricitinib)

Olumiant® ▼ (baricitinib): Incidence of Folliculitis in Atopic Dermatitis

There was an increase in folliculitis in patients receiving topical corticosteroids in the baricitinib treatment groups.

Risk of Folliculitis in Patients With Atopic Dermatitis

Folliculitis is a common condition in the general population, as well as a frequent cutaneous comorbidity in patients with AD. In a large cross-sectional study in Germany including almost 120,000 patients, folliculitis was prevalent in

  • 16.4% of patients who presented with AD at the time of screening

  • 10.4% of patients had a medical history of AD, and

  • 8.4% of patients had no AD diagnosis at any time.1

Patients with AD have an increased risk of folliculitis due to the impaired barrier function, immunologic dysfunction, trauma from scratching, and high prevalence of Staphylococcus aureus colonization.2

Comedications With Increased Risk of Folliculitis

The commonality of folliculitis as a comorbidity in patients with AD may be due to the use of emollients and ointments.

  • Emollients provide an occlusive barrier for AD-affected skin which reduces the transepidermal water loss, but can also result in the blockage of follicles and cause occlusive folliculitis.3

  • The risk of folliculitis is more common with ointment formulations, such as the hydrocortisone ointment used in the AD studies, due to their occlusive effect.4

All patients in the atopic dermatitis clinical development program were required to use emollients daily.

In addition, TCS was used as background therapy in the BREEZE-AD phase 3 combination trials (BREEZE-AD4 and BREEZE-AD7) or as rescue therapy in the monotherapy trials (BREEZE-AD1, BREEZE-AD2, and BREEZE-AD5) through week 16.5

BREEZE-AD Phase 3 Clinical Trial Exclusion Criteria Related to Folliculitis

Folliculitis was not a specific exclusion criteria in the BREEZE-AD phase 3 clinical development program.

However, patients were excluded if they had a current or recent clinically serious viral, bacterial, or fungal infection. These infections included, but were not limited to

  • clinically serious infections requiring intravenous antibiotics within 4 weeks of randomization, and

  • any other infection the investigator believed would pose an unacceptable risk.5

Incidence of Folliculitis Treatment-Emergent Adverse Events in the Atopic Dermatitis Clinical Trials

Incidence of Folliculitis - Integrated Safety Database Analyses

The integrated datasets used to evaluate folliculitis AEs in patients with AD are described in more detail in Table 3.

During the 16-week, placebo-controlled period there was no significant difference (p>.05) between BARI 4 mg and BARI 2 mg compared to placebo in folliculitis TEAEs.

Furthermore, there was no difference in folliculitis TEAEs between BARI 2 mg and BARI 4 mg in the extended dataset (see Table 1).

Table 1. Folliculitis Treatment-Emergent Adverse Events From the Atopic Dermatitis Clinical Program5

 

 

 

 

 

 

 

 

 

 

 

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=889

BARI 2 mg
n=721

Placebo
n=743

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

All doses
N=2531

Folliculitis

11 (1.2)

15 (1.9)

11 (1.2)

10 (1.5)

14 (1.8)

10 (1.5)

19 (2.4) [4.1]

14 (2.1) [2.8]

72 (2.8) [3.2]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended 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 (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, none of the folliculitis TEAEs were considered serious and no patients discontinued treatment.

One (0%) folliculitis TEAE led to temporary interruption of treatment.5

Incidence of Folliculitis - Monotherapy vs Combination Therapy With Topical Corticosteriods

Folliculitis is a known adverse effect of TCS and the risk of folliculitis is higher with ointment formulations, such as the hydrocortisone ointment used in the AD studies, due to their occlusive effect.4

Therefore, an analysis of the incidence of follliculitis was conducted between BARI monotherapy compared to TCS combination therapy.

Dataset Descriptions

Combination therapy with TCS studies included patients with AD from 1 phase 2 and 2 phase 3 studies, BREEZE-AD4 and BREEZE-AD7, who were randomized to

  • BARI 4 mg (n=241, PYE=71.6)

  • BARI 2 mg (n=330, PYE=96.9), or

  • placebo (n=250, PYE=68.9).5

Monotherapy studies included patients with AD from the 3 phase 3 studies, BREEZE-AD1, BREEZE-AD2, and BREEZE-AD5 randomized to

  • BARI 2 mg (n=391, PYE=183.8), or

  • placebo (n=639, PYE=113.7).5

The monotherapy dataset describing BARI 4 mg compared to placebo were from BREEZE-AD1 and BREEZE-AD2. This dataset included patients randomized to

  • BARI 4 mg (n=248, PYE=75.50), or

  • placebo (n=493, PYE=142.88).5

Incidence of Folliculitis

A significant difference (p≤.10) in treatment effect was seen for folliculitis between monotherapy studies vs TCS combination studies. In the TCS combination studies, folliculitis was reported numerically more frequently in the BARI 4 mg and 2 mg groups, whereas patients in the monotherapy studies reported folliculitis numerically more frequently in the placebo group (see Table 2).5

In the BREEZE-AD program, the frequencies of folliculitis in patients with use of TCS varied from 2.3% to 2.9% in the extended period, compared with 1.2% to 1.9% in patients in monotherapy, which is less than expected based on the epidemiological data. This could be explained by the reduced need for TCS use in patients treated with BARI.5

Table 2. Folliculitis Treatment-Emergent Adverse Events in Monotherapy vs. Combination Clinical Trials5

 

 

 

 

 

 

 

 

 


Monotherapy Clinical Trials

Combination TCS Clinical Trialsa

 

BARI 2 mg Placebo-Controlledb
n (adj %)
c

BARI 4 mg Placebo-Controlledb
n (%)
d

BARI 2 mg Placebo-Controlledb
n (adj %)
c

BARI 4 mg Placebo-Controlledb
n (adj %)
c


Placebo
n=639

BARI 2 mg
n=391

Placebo
n=493

BARI 4 mg
n=248

Placebo
n=250

BARI 2 mg
n=330

Placebo
n=250

BARI 4 mg
n=241

Folliculitis

10 (1.5)

5 (1.4)

10 (2.0)

4 (1.6)

1 (0.5)

10 (3.0)e

1 (0.5)

6 (1.9)

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; TCS = topical corticosteroids.

a Combination trials included phase 2 and BREEZE-AD4 and BREEZE-AD7.

b Data through 16-week placebo-controlled period.

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 (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. 

d Monotherapy trials BREEZE-AD1 and BREEZE-AD2 included BARI 4 mg dose.

e p<.05 BARI 2 mg compared to placebo.

Integrated Safety Dataset Table

Table 3. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials5

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 is 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 is 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).

Treatment is 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).

Treatment period is 0 to 16 weeks.

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. Zander N, Augustin M, Reinert R, et al. Atopic dermatitis shows significant cutaneous comorbidity: results from large-scale investigations in the working population. J Eur Acad Dermatol Venereol. 2020;34(1):135-141. https://doi.org/10.1111/jdv.15792

2. Alexander H, Paller AS, Traidl-Hoffmann C, et al. The role of bacterial skin infections in atopic dermatitis: expert statement and review from the Internal eczema council skin infection group. Br J Dermatol. 2020;182(6):1331-1342. https://doi.org/10.1111/bjd.18643

3. Lynde CW. Moisturizers: what they are and how they work. Skin Therapy Lett. 2001;6(13):3-5. https://www.skintherapyletter.com/eczema/how-moisturizers-work/

4. Rathi SK, D'Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57(4):251‐259. https://doi.org/10.4103/0019-5154.97655

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

Glossary

AD = atopic dermatitis

AE = adverse event

BARI = baricitinib

TCS = topical corticosteroids

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: August 05, 2020


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