Olumiant ® (baricitinib)

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Does Olumiant® (baricitinib) cause creatine phosphokinase elevations or adverse musculoskeletal adverse events in patients with atopic dermatitis?

Elevations in CPK are an identified adverse reaction associated with baricitinib therapy. In the atopic dermatitis clinical trials, elevations in CPK were mostly asymptomatic and were generally not associated with muscle-related symptoms.

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Changes in Creatine Phosphokinase Levels in Atopic Dermatitis Clinical Trials

Routine monitoring of creatine phosphokinase (CPK) is not warranted during treatment with baricitinib.1

Mean Change From Baseline in Creatine Phosphokinase

The mean change from baseline CPK over time was observed in the baricitinib 2 mg and baricitinib 4 mg groups for the 16-week placebo controlled dataset, presented in Mean Change From Baseline CPK in 16-Weeks in Placebo-Controlled Atopic Dermatitis Clinical Trials, and extended baricitinib dataset (previous data cut, N=2531; patient-years of exposure [PYE]=2247; median duration 310 days), presented in Mean Changes in CPK Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials.

Mean Change From Baseline CPK in 16-Weeks in Placebo-Controlled Atopic Dermatitis Clinical Trials1

 

16-Week Placebo-Controlled Dataset

LSMD (SE) [95% CI]

Placebo
n=743

BARI 2 mg
n=576

BARI 4 mg
n=489

CPK (U/L)

1.8 (7.98) [-13.82, 17.51]

40.5 (22.24) [-3.13, 84.16]

28.9 (23.39) [-17.01, 74.77]

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = creatine phosphokinase; LSMD = least squares mean.

Mean Changes in CPK Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials1

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = creatine phosphokinase; ext = extended.

Treatment-Emergent Elevated Creatine Phosphokinase Values in the Atopic Dermatitis Clinical Trials

Dataset Description

The integrated datasets used to evaluate changes in CPK are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials.

Proportions of Patients With Elevated Creatine Phosphokinase Values in Atopic Dermatitis Clinical Trials

Increase in serum CPK to at least grade 1 was the most common laboratory change and was recorded for 19.3% and 23.8% of patients in the 2-mg and 4-mg groups, respectively, vs 10.3% in the placebo group; frequencies were also higher for baricitinib groups vs placebo for CPK increases to at least Grades 2 and 3.2 A summary of CTCAE grade increases for each dataset is provided in Overview of CTCAE Grade Increase in CPK in Atopic Dermatitis Clinical Trials.

Overview of CTCAE Grade Increase in CPK in Atopic Dermatitis Clinical Trials1,2

 

CTCAE Grade 1+
(>ULN and ≤2.5 × ULN)

n/NAR (%)a

CTCAE Grade 2+
(>2.5 × ULN and ≤5 × ULN)

n/NAR (%)a

CTCAE Grade 3+
(>5 × ULN and ≤10 × ULN)

n/NAR (%)a

CTCAE Grade 4+
(>10 × ULN)

n/NAR (%)a

16-Week Placebo-Controlled BARI AD

Placebo, n=743

69/667 (10.3)

22/717 (3.1)

14/723 (1.9)

9/727 (1.2)

BARI 2 mg, n=576

99/513 (19.3)

27/559 (4.8)

14/564 (2.5)

7/567 (1.2)

BARI 4 mg, n=489

106/446 (23.8)

31/477 (6.5)

16/487 (3.3)

7/488 (1.4)

BARI 2 mg and 4 mg Extended AD

BARI 2 mg, n=584

155/521 (29.8)

48/567 (8.5)

24/572 (4.2)

13/575 (2.3)

BARI 4 mg, n=497

179/454 (39.4)

58/485 (12.0)

32/495 (6.5)

17/496 (3.4)

All BARI AD

All doses, N=2636 

806/2288 (35.2)

269/2534 (10.6)

137/2575 (5.3)

72/2587 (2.8)

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = Creatine Phosphokinase; CTCAE = Common Terminology Criteria for Adverse Events; ULN = upper limit of normal; NAR = number of patients at risk for specified abnormality.

a% based on number of patients at risk CPK increase.

Patients With Creatine Phosphokinase Greater than 5 times the ULN

A post hoc analysis was performed in patients with a CPK >5 x ULN (grade 3 or grade 4) at any point in the All BARI AD dataset. There were initially 95 patients identified, but one patient was excluded from the post hoc analysis as this patient’s CPK was elevated on day one of the study prior to taking BARI.1

Of the 94 patients identified, baseline characteristics included

  • mean age: 31 years
  • males: 74%
  • dose received: BARI 4-mg (39%), 2-mg (45%), or 1-mg (16%), and
  • race: Caucasian (39%), Asian (32%), Caucasian-Hispanic-Latino (18%), African American (6%), Multiple (4%), and Unknown (1%).1

Of the 94 patients with a CPK >5 × ULN (grade 3 or grade 4)

  • 75.5% had a normal baseline CPK
  • a mean maximum CPK of 5556 U/L, median CPK 2779 U/L, and maximum CPK value of 28540 U/L, and
  • 82% reported strenuous exercise or work.1

The time to onset of CPK >5 x ULN (grade 3 or 4) was a mean of 125 days, a median of 82 days, and a range of 14 to 642 days.

Creatine phosphokinase values returned to baseline in 73% patients, the mean time to return to baseline was 37 days (range of 4 to 126 days).1

Adverse events were reported in 24 patients, and of these

  • 12 were mild
  • 7 were moderate
  • 2 were severe, and
  • 3 cases did not have a severity provided.1

Grade 3 or grade 4 CPK (>5 x ULN) elevation led to

  • interruption of treatment in 2 (2.1%) patients, and
  • discontinuation of treatment in 2 (2.1%) patients.1

Incidence of Muscle-Related Adverse Events in Patients With Creatine Phosphokinase >5 ULN

In patients with a CPK >5 × ULN (grade 3 or grade 4), 5 patients had muscular symptoms including

  • mild myalgia (n=2)
  • diffuse leg pain (n=1)
  • muscular pain (n=1), and
  • sore muscles (n=1).1

In these 5 patients, the muscle symptoms were not associated with rhabdomyolysis.1
A dose related response was not observed.1

Adverse Events Related to Elevated Creatine Phosphokinase in the Atopic Dermatitis Clinical Trials

In the All BARI AD dataset, none of the CPK-related treatment-emergent adverse events (TEAEs) were considered serious. The TEAEs led to

  • interruption of treatment in 6 (0.2%) patients, and
  • discontinuation of treatment in 6 (0.2%) patients.1

Evaluation of elevations in CPK in the AD clinical program included a review of TEAEs using a query for “muscle symptoms.” The muscle symptoms query used a sponsor-defined Medical Dictionary for Regulatory Activities (MedDRA) search criteria list that contained narrow scope terms from the rhabdomyolysis and myopathy standardized MedDRA query plus selected terms from the Musculoskeletal System Organ Class.1

Treatment Emergent Muscle Symptoms in the All BARI AD Dataset

In patients with AD who received baricitinib in clinical trials, treatment-emergent (TE) muscle symptoms

  • were reported in 43 out of 2636 patients, and
  • occurred in 1.6% of patients with an incidence rate of 0.9 per 100 PYE.1

In the All BARI AD dataset, treatment emergent muscle symptoms observed included

  • myalgia in 32 (1.2%) patients
  • muscle spasms in 10 (0.4%) patients
  • muscle tightness in 2 (0.1%) patients
  • myofascial pain syndrome in 1 (<0.1%) patient, and
  • myositis in 1 (<0.1%) patient.1

There were no confirmed cases of rhabdomyolysis.1,3

Potential Role of Janus Kinase Inhibition In Muscle Metabolism

Increases in CPK have been described in association with janus kinase (JAK) inhibitors.4-6

The mechanism of CPK increase with JAK inhibitors is not known.7

Baricitinib Label Information Related to Creatine Phosphokinase

The frequency of creatine phosphokinase increased > 5 x ULN was common (≥ 1/100 to < 1/10).

This frequency is based on integrated data from8

  • clinical trials and/or
  • postmarketing setting

across

  • rheumatoid arthritis, 
  • atopic dermatitis, and
  • alopecia areata

indications unless stated otherwise.8 

In rheumatoid arthritis clinical trials, the frequency of creatine phosphokinase increased > 5 x ULN was uncommon (≥ 1/1 000 to < 1/100).8

Baricitinib treatment was associated with dose-dependent increases in CPK. Elevations of mean CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter.8

Across indications, most cases of CPK elevations ≥ 5 x ULN were transient and did not require treatment discontinuation.8

In clinical trials, there were no confirmed cases of rhabdomyolysis.8

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials1-3,9

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

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

3Bieber 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.

4Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol. 2019;46(1):7-18. http://dx.doi.org/10.3899/jrheum.171361

5Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open‑label, longterm extension studies. J Rheumatol 2014;41(5):837-852. https://doi.org/10.3899/jrheum.130683

6Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234-243.  https://doi.org/10.1038/nrrheum.2017.23

7Queeney K, Housley W, Sokolov J, Long A. Fri0131 elucidating the mechanism underlying creatine phosphokinase upregulation with upadacitinib. Annals of the Rheumatic Diseases. 2019;78(suppl 2):734-735. http://dx.doi.org/10.1136/annrheumdis-2019-eular.7509

8Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

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

Date of Last Review: 02 August 2022


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