Olumiant ® (baricitinib)

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What changes in creatine phosphokinase occurred in patients taking Olumiant® (baricitinib) in the rheumatoid arthritis clinical development program?

In the RA clinical trials, mean increases in CPK were mostly observed with BARI 4 mg from 0 to 8 week and remain stable thereafter. There was no evidence that baricitinib (BARI) treatment increased the risk of serious muscle-related adverse events.

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Changes in Creatine Phosphokinase Levels Over Time in Rheumatoid Arthritis Clinical Trials

The integrated datasets used to evaluate changes in creatine phosphokinase (CPK) are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials. The exposure information, including median, maximum, and total patient-years exposure (PYE), and cut-off date described in the table are applicable to the data presented below unless otherwise specified.

Incidence rates were calculated as the number of patients with an event per 100 patient-years of exposure time, with exposure censored at time of event.1

5-Study Pooled Dataset

The 5-study pooled dataset included patients with rheumatoid arthritis (RA) randomized to baricitinib 4 mg or placebo from 1 phase 2 study and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Data include a long-term extension study (RA-BEYOND) with data through February 13, 2018.2

Baricitinib 2-mg data are pooled from 3 of these studies in which both baricitinib 2 mg and baricitinib 4 mg were options during randomization (1 phase 2 study as well as RA-BUILD and RA-BEACON).2

In 5-study pooled dataset phase 3 studies

Mean Changes in Creatine Phosphokinase Over Time From 5-Study Pooled Dataset in Rheumatoid Arthritis Studies2

Abbreviations: BARI = baricitinib; PBO = placebo.

Notes: BARI 2 mg, placebo censored at rescue or dose change, and BARI 4 mg censored at any dose change (including step=down) or rescue in RA-BEYOND. Data through February 13, 2018.

Treatment-Emergent Abnormal Creatine Phosphokinase Values in Rheumatoid Arthritis Clinical Trials

Common terminology criteria for adverse event grade shifts in elevated CPK include

  • Grade 0 (normal): ≤upper limit of normal (ULN).
  • Grade 1: >ULN and ≤2.5x ULN.
  • Grade 2: >2.5x ULN and ≤5x ULN.
  • Grade 3: >5x ULN and ≤10x ULN.
  • Grade 4: >10x ULN.2

An overview of the CPK shifts seen in the 7-study placebo-controlled dataset, 4-study extended dataset, and All-BARI-RA dataset can be seen in Overview of CTCAE Grade Shifts in Creatine Phosphokinase in Rheumatoid Arthritis Trials.

Overview of CTCAE Grade Shifts in Creatine Phosphokinase in Rheumatoid Arthritis Trials1-3

 

Shift From

Grade <1 to ≥1

n/NAR (%)

Shift From

Grade <2 to ≥2

n/NAR (%)

Shift From

Grade <3 to ≥3

n/NAR (%)

Shift From

Grade <4 to =4

n/NAR (%)

7-Study Dataset Through 24 Weeks of Assigned Treatment

Placebo (N=1184)

93/1092 (8.5)

14/1164 (1.2)

5/1171 (0.4)

2/1173 (0.2)

BARI 4 mg (N=1111)

374/1035 (36.1)a

58/1094 (5.3)a

12/1100 (1.1)

6/1100 (0.5)

4-Study Extended Datasetb

BARI 2 mg (N=479)

147/451 (32.6)

30/477 (6.3)

8/477 (1.7)

1/477 (0.2)

BARI 4 mg (N=479)

208/438 (47.5)c

63/470 (13.4)c

14/474 (3.0)

4/474 (0.8)

All-BARI-RA Datasetd

All BARI RA (N=3770)

1972/3384 (58.3)

526/3550 (14.8)

139/3560 (3.9)

32/3564 (0.9)

Abbreviations: BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality; PYE = patient years of exposure; RA = rheumatoid arthritis.

ap=.001; difference between BARI 4 mg and placebo.

bIn the 4-study extended dataset through February 13, 2018, BARI 4-mg (N=479, PYE=698.6, median exposure=342 days, maximum exposure=2520 days) and BARI 2-mg group (N=479, PYE=675.6, median exposure=257 days, maximum exposure=1805 days).

cp=.001; difference between BARI 4 mg and BARI 2 mg.

dAll-BARI-RA dataset (N=3770; PYE=14,744; median exposure=4.6 years; maximum exposure=9.3 years).

Adverse Events Related to Elevated Creatine Phosphokinase in Rheumatoid Arthritis Clinical Trials

There was no evidence that baricitinib treatment increased the risk of serious muscle-related adverse events (AEs).2,4

Evaluation of elevations in CPK in the RA development program included a review of treatment-emergent adverse events (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.2

All-BARI-RA Dataset

Treatment-Emergent Increase in Blood Creatine Phosphokinase

In the All-BARI-RA dataset, the TEAE of blood CPK increased was reported in 338 (9%) [exposure-adjusted incidence rate (EAIR)=2.2] patients.3

Of the 338 reported TEAE of blood CPK increased,

  • 4 (0.1%) were serious AEs
  • 13 (0.3%) led to temporary interruption of baricitinib, and
  • 6 (0.2%) led to permanent discontinuation of baricitinib.2

Treatment-Emergent Cases of Myopathy, Myositis, and Rhabdomyolysis

In the All-BARI-RA dataset, additional AEs reported included

  • myopathy in 7 (0.2%) patients
  • myositis in 9 (0.2%) patients (2 as serious AEs), and
  • rhabdomyolysis in 3 (0.1%) patients (2 as serious AEs).2

These events of reported rhabdomyolysis are not considered to represent confirmed rhabdomyolysis associated with baricitinib therapy as these CPK elevations were related to exercise or injury.2

In the All-BARI-RA dataset, permanent discontinuation from the study drug occurred in

  • 1 (0.0%) patient due to myopathy, and
  • 2 (0.1%) patients due to myositis.2

Information from the Label

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

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.5

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

In clinical trials, there were no confirmed cases of rhabdomyolysis.5

References

1Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):e347-e357. https://doi.org/10.1016/S2665-9913(20)30032-1

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

3Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276

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

5Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

6Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Ann Rheum Dis. 2020;79(suppl 1):642-643. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

Appendix

Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials1-3,6

Analysis Set

Descriptiona

7-Study Placebo-Controlled Dataset

Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

Compares BARI 4 mg vs placebo

Includes patients with RA from 3 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (N=1142 [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
  • placebo (N=1215 [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or
  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

  • through the 12-week placebo-controlled period in phase 2 studies
  • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
  • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

BARI 2-mg Analysis Set

BARI 2-mg data are derived from 4 studies in which both BARI 2 mg (N=479 [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or
  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through September 1, 2019 unless otherwise specified.

All-BARI-RA Dataset

Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

No between-group comparisons

Includes patients with RA (N=3770, PYE=14,744 PY exposure to BARI and 15,114 PY overall observation including time on BARI and follow up, median exposure=4.6 years, maximum exposure=9.3 years) from 1 phase 1b, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

  • BARI 4 mg (n=3401, PYE=11,872)
  • BARI 2 mg (n=1077, PYE=2678), and
  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

Evaluation time period is all exposure time points including after rescue or changes in study drug unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PY = patient-years; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

Date of Last Review: 02 December 2021


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