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

Baricitinib Prescribing Information

Hemoglobin < 8 g/dL were reported in less than 1 % of patients in clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with hemoglobin < 8 g/dL observed during routine patient management. Treatment may be initiated once values have improved above these limits.¹

Haemoglobin should be assessed before treatment initiation and thereafter according to routine patient management.¹

Hemoglobin Changes Over Time

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 2018.²

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).²

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

• increased towards baseline levels starting at week 16,

• corresponded to the timing and volume of blood draws, and 

• mean levels remained above baseline and relatively stable at a higher level thereafter through 216 weeks (Figure 1).²

Figure 1. Mean Changes in Hemoglobin Over Time From 5-Study Pooled Dataset in Rheumatoid Arthritis Studies²

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 in the placebo group 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.³

Data from BARI 2 mg (N=479, PYE=185.8) is 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).³

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.²

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, 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 01 September 2019.^4,5

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.²

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 (Table 1).

Few patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3 (Table 1).

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%).²

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%) (Table 1).²

All BARI RA Dataset

Abnormal Low Hemoglobin Values

The proportion of patients with a TE abnormal low hemoglobin value was 1073 (40.3%).²

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 ≥3.²

Table 1. Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid Arthritis Integrated Analysis Sets²

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.²

Evaluation of TEAEs of anemia included MedDRA preferred terms, anemia and iron deficiency anemia, from the Blood and Lymphatic System Disorders System Organ Class.² 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.³

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.^2,6

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.^2,6

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. ²

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.²

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.²

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.²

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).²

Anemia or iron deficiency anemia led to

• temporary interruption of study treatment in 12 patients, and

• permanently discontinuation of study treatment in 17 patients.²

Role of Janus Kinase2 in Erythropoietin Function

Erythropoietin signals through JAK2 and inhibition of the JAK/stat pathway affects erythropoiesis and hemoglobin.^7,8

References

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

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

3. Genovese MC, Smolen JS, Tsutomu 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

4. Genovese 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. http://scientific.sparx-ip.net/archiveeular/?c=a&view=4&item=2020FRI0123

5. Genovese 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.

6. Smolen 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

7. Fridman 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

8. Levine 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

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

▼ 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.