Olumiant ® (baricitinib) tabletter

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Vad vet vi om Eczema Herpeticum och Olumiant® (baricitinib) i det kliniska utvecklingsprogrammet för atopisk dermatit?

Vi sammanfattar information om förekomsten och svårighetsgraden av eksem herpeticum i det kliniska utvecklingsprogrammet för atopisk dermatit med baricitinib.

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Clinical Trial Exclusion Criteria Related to Eczema Herpeticum

In the phase 3 atopic dermatitis (AD) clinical trial program, patients were excluded if they had

  • symptomatic herpes simplex at time of randomization
  • a history of eczema herpeticum within 12 months prior to screening, or 
  • a history of 2 or more episodes of eczema herpeticum in the past.1,2 

Incidence of Eczema Herpeticum in the Atopic Dermatitis Clinical Trials

In the AD clinical trials, both eczema herpeticum and Kaposi's varicelliform eruption were captured as adverse event preferred terms. For this discussion,  we combined the 2 preferred terms to eczema herpeticum.1,2

Please find the integrated datasets used to evaluate cases of eczema herpeticum in  .

Placebo-Controlled Period

Through 16 weeks, the proportion of patients with treatment-emergent eczema herpeticum was

  • significantly higher in the baricitinib (BARI) 4 mg group than the BARI 2 mg group (p≤.05), and
  • not significantly different between
    • BARI 2 mg (n=1) and placebo (n=4), or
    • BARI 4 mg (n=7) and placebo (n=4).1,2

All Baricitinib-Treated Patients With Extended Data

Of the 2531 patients treated across all BARI doses studied in AD, 43 had 50 treatment-emergent adverse events (TEAEs) of eczema herpeticum. 

Of these 50 events,

  • 41 were mild to moderate in severity
  • 9 were considered severe
  • 44 occurred while receiving concomitant topical corticosteroids therapy
  • 68% involved 10% or less body surface area 
  • 68% occurred while AD was poorly controlled (Investigator's Global Assessment  [IGA] 3 or 4)
  • 15 led to treatment interruption, and
  • 2 led to permanent discontinuation.1,2

For the severity of the TEAEs, the rating of a TEAE as mild, moderate, or severe was up to the judgement of the investigator with no objective criteria. There was no specific guidance provided on how to rate the severity of the TEAEs.1

Of the 43 patients with treatment-emergent eczema herpeticum

  • 6 were receiving BARI 1 mg (N=538)
  • 17 were receiving BARI 2 mg (N=1580), and
  • 20 were receiving BARI 4 mg (N=914).1

Additionally, of this group, events classified as serious adverse events (SAEs) were reported in 11 patients including,

  • 2 with BARI 1 mg
  • 3 with BARI 2 mg, and
  • 6 with BARI 4 mg treatment.1

By protocol definition, SAEs include any AE that resulted in

  • death
  • initial or prolonged inpatient hospitalization
  • a life-threatening experience (that is, immediate risk of dying)
  • persistent or significant disability or incapacity, and
  • congenital anomaly or birth defect.1

Eczema herpeticum infections may be correlated with the extent of AD disease severity in the BREEZE-AD clinical trial program. An increase in eczema herpeticum TEAEs in patients who initially start BARI 4mg may be offset with continued therapy as lesions improve. Additionally, no increases in eczema herpeticum cases were seen with BARI 2mg.2

Integrated Safety Analysis Datasets

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

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.

Risk of Eczema Herpeticum in Patients With Atopic Dermatitis

Patients with AD have an increased risk of bacterial and viral infections, both cutaneous and non-cutaneous, due to defective skin barrier and immunologic dysregulation.3 Eczema herpeticum (synonymous with Kaposi’s varicelliform eruption) is an acute, disseminated infection of the skin, most commonly caused by herpes simplex virus 1, and represents a typical complication of AD occurring in approximately 3% of patients with AD.4

Interferons are the first line of host defense against viral infections. There is an increased risk of recurrent and disseminated viral infections, including herpes simplex and herpes zoster, related to the insufficient production of interferons (IFNs) with down regulation of the receptor, especially in patients with AD with a history of eczema herpeticum.5,6

Relevant Information from the SmPC

Infections

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In rheumatoid arthritis clinical studies, in treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.7

The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections.7

If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.7

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex), were reported in clinical studies.7

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

3Langan SM, Abuabara K, Henrickson SE, et al. Increased risk of cutaneous and systemic infections in atopic dermatitis - a cohort study. J Invest Dermatol. 2017;137(6):1375-1377. https://doi.org/10.1016/j.jid.2017.01.030

4Ong PY, Leung DYM. Bacterial and viral infections in atopic dermatitis: a comprehensive review. Clin Rev Allergy Immunol. 2016;51(3):329-337. https://doi.org/10.1007/s12016-016-8548-5

5Kwon HJ, Bang DW, Kim EN et al. Asthma as a risk factor for zoster in adults: a population-based case-control study. J Allergy Clin Immunol. 2016;137(5):1406-1412. https://doi.org/10.1016/j.jaci.2015.10.032

6Traidl S, Kienlin P, Begemann G, et al. Patients with atopic dermatitis and history of eczema herpeticum elicit herpes simplex virus-specific type 2 immune responses. J Allergy Clin Immunol. 2018;141(3):1144-1147.e5. https://doi.org/10.1016/j.jaci.2017.09.048

7Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Datum fӧr senaste ӧversyn 2021 M01 29


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