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Olumiant ® (baricitinib)

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Olumiant® (baricitinib): Changes in Haemoglobin in the Rheumatoid Arthritis Clinical Development Program

Compared with placebo, neither baricitinib dose was associated with an increased incidence of erythropenia-related treatment-emergent adverse events in the RA clinical development program.

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Hemoglobin Changes Over Time in Rheumatoid Arthritis Clinical Development Program

The 5-study pooled dataset included patients with RA randomized to BARI 4 mg or placebo from 1 phase 2 study and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with data through 13 February 2018.1

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

In 5 pooled studies including extension data through 13 February 2018, initial mean decreases in hemoglobin observed with BARI treatment

Mean Changes in Hemoglobin Over Time From 5-Study Pooled Dataset in Rheumatoid Arthritis Studies1

Abbreviations: BARI = baricitinib; PBO = placebo; RA = rheumatoid arthritis.

Notes: Baricitinib 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.

Datasets for Hemoglobin Values and Anemia TEAEs

7-Study Placebo-Controlled Dataset

The 7-study pooled dataset included patients with RA randomized to BARI 4 mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Patients could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through

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

Data from BARI 2 mg (N=479, PYE=185.8) were derived from 4 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).2

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and 2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension study (RA-BEYOND). The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.1

    All BARI RA Dataset

    The All BARI RA analysis set included 3770 patients with RA who received BARI at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with

    • 13,148 PYE
    • median exposure of 4.2 years
    • maximum exposure of 8.4 years, and
    • data through September 1, 2019.3,4

    Abnormal Low Hemoglobin Values in Rheumatoid Arthritis Clinical Trials

    Categorical changes in hemoglobin values were assessed by determining the proportion of patients who had a

    • TE value below the LLN, and
    • TE increase in CTCAE grade for low hemoglobin.1

    7-Study Placebo-Controlled Dataset

    Abnormal Low Hemoglobin Values

    No statistical difference in the proportion of patients with a TE abnormal low hemoglobin value through 24 weeks of assigned treatment or until rescue (Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid Arthritis Integrated Analysis Sets).

    Few patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3 (Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid Arthritis Integrated Analysis Sets).

    4-Study Extended Dataset

    Abnormal Low Hemoglobin Values

    The proportion of patients with a TE abnormal low hemoglobin value was not statistically significantly different between the BARI 4-mg and 2-mg groups (35.6% vs 33.2%).1

    Few patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3 in the BARI 4-mg and 2-mg groups (0.2% vs 0.6%) (Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid Arthritis Integrated Analysis Sets).1

    All BARI RA Dataset

    Abnormal Low Hemoglobin Values

    The proportion of patients with a TE abnormal low hemoglobin value was 1073 (40.3%).1

    A shift to CTCAE grade 3 indicates that hemoglobin levels have dropped below 4.9 mmol/L (8.0 g/dL). There were 31 (0.8%) BARI-treated patients in the All BARI RA dataset (N=3770) with a reported TE decrease in hemoglobin levels to CTCAE grade ≥3.1

    Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid Arthritis Integrated Analysis Sets1

     

    Treatment-Emergent Abnormal Low
    n/NAR (%)

    Shift From:
    Grade <2 to Grade ≥2
    n/NAR (%)

    Shift From:
    Grade <3 to Grade ≥3
    n/NAR (%)

    7 Study Dataset through 24 weeks of assigned treatment

    Placebo (N=1215)

    221/828 (26.7)

    78/1175 (6.6)

    2/1203 (0.2)

    BARI 2 mg (N=479)

    91/343 (26.5)

    33/462 (7.1)

    2/477 (0.4)

    BARI 4 mg (N=1142)

    237/772 (30.7)

    74/1104 (6.7)

    2/1132 (0.2)

    Extended 4 Study Dataset with data through 13 February 2018

    BARI 2 mg (N=479)

    114/343 (33.2)

    40/463 (8.6)

    3/478 (0.6)

    BARI 4 mg (N=479)

    128/360 (35.6)

    49/467 (10.5)

    1/474 (0.2)

    All BARI RA Dataset with data through 13 February 2018

    All BARI RA (N=3770)

    1073/2660 (40.3)

    376/3640 (10.3)

    31/3741 (0.8)

    Abbreviations: BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality; RA = rheumatoid arthritis.
    Note: Grade 2 is <10.0 and ≥8.0 g/dL. Grade 3 is <8.0 and ≥6.5 g/dL. Normal limits were defined according to lab methodology, age, and gender. Treatment-emergent assessments were based on postbaseline values collected at follow-up visits during the observation period defined by each integrated dataset.

    Reported Adverse Events of Anemia in Rheumatoid Arthritis Clinical Trials

    Compared to placebo, neither BARI dose was associated with an increased incidence of erythropenia-related TEAEs.1

    Evaluation of TEAEs of anemia included MedDRA preferred terms, anemia and iron deficiency anemia, from the Blood and Lymphatic System Disorders System Organ Class.1 Percentages by treatment group and EAIR are provided below.  

    Exposure-adjusted incidence rates were calculated as the number of patients with an event per 100 patient-years of exposure time, with exposure not censored at time of event.2

    7-Study Placebo-Controlled Dataset

    Through 24 weeks of assigned treatment or until rescue, the rates of anemia were

    • 3.2% (EAIR 7.8) in the BARI 4-mg group
    • 1.9% (EAIR 4.8) in the BARI 2-mg group, and
    • 3.1% (EAIR 8.4) in the placebo group.1,5

    Through 24 weeks of assigned treatment or until rescue, the rates of iron deficiency anemia were

    • 0.2% (EAIR 0.4) in the BARI 4-mg
    • 0.4% (EAIR 1.1) in the BARI 2-mg, and
    • 0.2% (EAIR 0.4) placebo group.1,5

    4-Study Extended Dataset

    In the 4-study extended dataset analysis, rates of anemia were

    • 3.8% (EAIR=2.3) in the BARI 4-mg group, and
    • 2.9% (EAIR=1.8) in the 2-mg group. 1

    Rates of iron deficiency anemia were

    • 0.4% (EAIR=0.3) in the BARI 4-mg group, and
    • 0.6% (EAIR=0.4) in the 2-mg group.1

    Temporary interruption due to anemia or iron deficiency anemia occurred in

    • 2 patients in the BARI 4-mg group, and
    • 0 patients in the BARI 2-mg group.1

    Permanent discontinuation of study treatment due to anemia or iron deficiency anemia occurred in

    • 2 patients in the BARI 4-mg group, and
    • 3 patients in the BARI 2-mg group.1

    All BARI RA Dataset

    In the All BARI RA analysis

    • rates of anemia were 6.1% (EAIR=1.7), and
    • rates of iron deficiency anemia were 0.9% (EAIR=0.3).1

    Anemia or iron deficiency anemia led to

    • temporary interruption of study treatment in 12 patients, and
    • permanently discontinuation of study treatment in 17 patients.1

    Role of Janus Kinase2 in Erythropoietin Function

    Erythropoietin signals through JAK2 and inhibition of the JAK/stat pathway affects erythropoiesis and hemoglobin.6,7

    Information From the Label

    Haemoglobin < 8 g/dL was reported in less than 1 % of patients in rheumatoid arthritis clinical trials.8

    Treatment should not be initiated, or should be temporarily interrupted, in patients with a haemoglobin value < 8 g/dL observed during routine patient management. Treatment may be initiated once values have improved above these limits.8

    Haemoglobin should be assessed before treatment initiation and thereafter according to routine patient management.8

    References

    1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    2Genovese 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

    3Genovese 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 [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. https://ard.bmj.com/content/79/Suppl_1/642.1

    4Genovese 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. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

    5Smolen 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

    6Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

    7Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature Rev Cancer. 2007;7(9):673-683. http://dx.doi.org/10.1038/nrc2210

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

    Glossary

    BARI = baricitinib

    CTCAE = Common Terminology Criteria for Adverse Events

    EAIR = exposure-adjusted incidence rate

    JAK = Janus kinase

    LLN = lower limit of normal

    MedDRA = Medical Dictionary for Regulatory Activities

    PYE = patient-years of exposure

    RA = rheumatoid arthritis

    TE = treatment-emergent

    TEAE = treatment-emergent adverse event

    Date of Last Review: 14 March 2021

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