Olumiant ® (baricitinib)

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What is the clinical trial long-term safety of Olumiant® (baricitinib) in the treatment of rheumatoid arthritis?

Data up to 9.3 years, accounting for 14,744 patient-years of exposure, show that the incidence of DVT/PE, MACE, malignancy, and deaths in patients who received baricitinib for the treatment of rheumatoid arthritis remained stable over time.

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Overview of phase 3 clinical trials

Each of the 4 phase 3 studies in the baricitinib clinical program evaluated a distinct treatment population of patients with moderate-to-severe rheumatoid arthritis.

  • RA-BEGIN compared baricitinib 4 mg monotherapy, baricitinib 4 mg plus methotrexate, and methotrexate monotherapy in patients who had limited or no prior treatment with methotrexate and were naïve to other disease-modifying antirheumatic drugs (DMARDs).1
  • RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background methotrexate, in patients with inadequate response to methotrexate.2 
  • RA-BUILD compared baricitinib 2 mg and 4 mg vs placebo, with background conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, in patients with inadequate response to csDMARDs.3
  • RA-BEACON compared baricitinib 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one tissue necrosis factor (TNF) inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.4

Patients completing the phase 3 clinical trial program were eligible to enter an ongoing extension study, also known as RA-BEYOND.5

Please refer to Study Design Features and Baseline Patient Characteristics for a summary of study design features and baseline patient characteristics in each trial.1-4

See Proportion of Patients Reporting Treatment-Emergent Adverse Events or Serious Adverse Events in Phase 3 Studies for an overview of the proportion of patients in each treatment arm of the 4 phase 3 trials who reported a treatment-emergent adverse event or a serious adverse event.

Proportion of Patients Reporting Treatment-Emergent Adverse Events or Serious Adverse Events in Phase 3 Studies1-4

Study and Treatment

TEAEs

SAEs

RA-BEGIN (through 52 weeks)

MTX Monotherapy

72%

10%

BARI Monotherapy

71%

8%

BARI Plus MTX

78%

8%

RA-BEAM (through 24 weeks)

Placebo

60%

5%

Adalimumab

68%

2%

BARI

71%

5%

RA-BUILD (through 24 weeks)

Placebo

71%

5%

BARI 2 mg

67%

3%

BARI 4 mg

71%

5%

RA-BEACON (through 24 weeks)

Placebo

64%

7%

BARI 2 mg

71%

4%

BARI 4 mg

77%

10%

Abbreviations: BARI = baricitinib; MTX = methotrexate; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 9.3 years

An integrated analysis of data from 1 phase 1 study, 3 phase 2 studies, 5 phase 3 studies, and the long-term extension study have summarized the safety profile of baricitinib for the treatment of rheumatoid arthritis in 3770 patients with a maximum exposure of 9.3 years (median exposure, 4.6 years) with data including 14,744 patient-years of exposure.6

In this analysis,

  • rates of safety events of special interest, including deaths, malignancies, major adverse cardiovascular events, and deep vein thrombosis and/or pulmonary embolism remained stable through exposures up to 9.3 years and were generally similar between the baricitinib 2-mg and 4-mg groups, and
  • the results showed a safety profile of baricitinib consistent with previous reports.6
Safety Summary of Baricitinib for the Treatment of Rheumatoid Arthritis With Data Through 9.3 Years6

Event

All-BARI-RA (N=3770; 14,744 PYE)

Treatment-emergent adverse events, n (EAIR)

Any treatment-emergent adverse event

3421 (22.6)

Serious adverse event

1117 (7.4)

Temporary study drug interruption due to adverse event

1282 (8.5)a

Permanent discontinuation of the study drug due to adverse event

704 (4.7)

Death, n (IR)

85 (0.56)

Malignancy, n (IR)

Malignancy excluding nonmelanoma skin cancer

139 (0.9)

Lymphoma

9 (0.06)

Nonmelanoma skin cancer

50 (0.3)

Infection, n (IR)

Treatment-emergent infectionsb

2590 (17.1)

Serious infection

372 (2.6)

Herpes zoster

422 (3.0)

Tuberculosisb

19 (0.1)

Opportunistic infection excluding tuberculosis

69 (0.5)

Major adverse cardiovascular event, n (IR)c

73 (0.5)

Myocardial infarction

24 (0.2)

Cardiovascular death

20 (0.1)

Stroke

38 (0.3)

Deep vein thrombosis/pulmonary embolism

73 (0.5)

Deep vein thrombosisd

52 (0.4)

Pulmonary embolism

39 (0.3)

Gastrointestinal perforations, n (IR)

9 (0.06)

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rates per 100 patient-years (exposure time not censored at event); IR = incidence rates per 100 patient-years (exposure time censored at event); PYE = patient-years of exposure; RA = rheumatoid arthritis.

aSome studies did not collect temporary interruption of study drug.

bUsed EAIR per 100 PY (patient exposure not censored at the event).

cPotential cardiovascular adverse events from the phase III and long-term extension trials, identified by investigators or according to a predefined list of event terms, were adjudicated by an independent, external Clinical Endpoint Committee that remained blinded to treatment assignments.

dDeep vein thrombosis includes distal events below the knee.

Adverse Events of Special Interest in the 2-mg and 4-mg Subsets of Baricitinib for the Treatment of Rheumatoid Arthritis With Data Through 9.3 Years shows the exposure-adjusted incidence rates (EAIRs) of adverse events of special interest for the 2-mg and 4-mg subsets.

Adverse Events of Special Interest in the 2-mg and 4-mg Subsets of Baricitinib for the Treatment of Rheumatoid Arthritis With Data Through 9.3 Years6

EAIRa (95% CI)

Ever Received BARI 2 mg (N=1077)
PYE=2678

Ever Received BARI 4 mg (N=3401)
PYE=11,872

All BARI-RA (N=3770)
PYE=14,744

Death

0.56 (0.31-0.92)

0.57 (0.44-0.73)

0.56 (0.45-0.70)

Serious infections

2.13 (1.61-2.76)

2.62 (2.34-2.93)

2.58 (2.33-2.86)

Thromboembolic events

Deep vein thrombosis and/or pulmonary embolism

0.49 (0.26-0.83)

0.51 (0.39-0.66)

0.49 (0.38-0.61)

Deep vein thrombosis

0.41 (0.21-0.73)

0.35 (0.25-0.48)

0.35 (0.26-0.45)

Pulmonary embolism

0.26 (0.11-0.54)

0.27 (0.18-0.38)

0.26 (0.18-0.35)

Major adverse cardiovascular eventb

0.42 (0.21-0.74)

0.54 (0.41-0.69)

0.51 (0.40-0.64)

 Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; PYE = patient-years of exposure; RA = rheumatoid arthritis.

aExposure-adjusted incidence rates per 100 patient-years were calculated as the number of patients with an event per 100 patient-years of overall exposure time.

bPositively adjudicated events of myocardial infarction, stroke, and cardiovascular deaths.

Additional details by individual safety topics are available upon request.

Postmarketing required Studies

RA-BRIDGE and RA-BRANCH

Two randomized, controlled, open-label, phase 3b/4 studies, RA-BRIDGE (NCT03915964) and RA-BRANCH (NCT04086745), are evaluating the safety of high- and low-dose baricitinib compared to adalimumab or etanercept in patients with rheumatoid arthritis who had an inadequate response or intolerance to at least one DMARD. The outcome measures are the time from first dose of study treatment to the first

  • venous thromboembolism (primary endpoint)
  • arterial thromboembolic event
  • major adverse cerebro-cardiovascular event
  • malignancy, excluding nonmelanoma skin cancer
  • opportunistic infection, and
  • serious infection.7,8

In RA-BRIDGE and RA-BRANCH, patients had at least 1 of the following baseline characteristics:

  • documented evidence of a prior venous thromboembolism
  • aged at least 60 years
  • body mass index (BMI) ≥30 kg/m², or
  • aged 50 to less than 60 years and have a BMI 25 to <30 kg/m2.7,8

RA-BRIDGE includes an estimated enrollment of 2600 participants from sites in the United States and outside the United States. The estimated primary completion date is April 2025.8

RA-BRANCH is currently recruiting patients in the United States. The estimated enrollment will be 1300 patients and the estimated primary completion date is December 2024.7

References

1Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953

2Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345

3Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1

4Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247

5An extension study in participants with moderate to severe rheumatoid arthritis (RA-BEYOND). ClinicalTrials.gov identifier: NCT01885078. Updated February 1,2022. Accessed February 28, 2022. http://clinicaltrials.gov/ct2/show/NCT01885078.

6Taylor 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. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

7A study of baricitinib in participants with rheumatoid arthritis (RA-BRANCH). ClinicalTrials.gov identifier: NCT04086745. Updated April 19, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04086745

8A study of baricitinib (LY3009104) in participants with rheumatoid arthritis (RA-BRIDGE). ClinicalTrials.gov identifier: NCT03915964. Updated June 10, 2021. Accessed March 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03915964

9Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Appendix

Study Design Features and Baseline Patient Characteristics1-4,9

STUDY DESIGN

RA-BEGIN
(N=584)

RA-BEAM
(N=1305)

RA-BUILD
(N=684)

RA-BEACON
(N=527)

Patient Type

DMARD-naïve

MTX-IR

csDMARD-IR

TNFi-IR

Background DMARDs

None

MTX

csDMARD(s) allowed but
not required

csDMARD(s)

TJC and SJC Entry Criteria

≥6 TJC
≥6 SJC

≥6 TJC
≥6 SJC

≥6 TJC
≥6 SJC

≥6 TJC
≥6 SJC

hsCRP Entry Criteria

≥3.6 mg/L

≥6.0 mg/L

≥3.6 mg/L

≥3 mg/L

Joint erosion/RF/ACPA entry criteria

Joint erosion (none); Either RF or ACPA+

≥3 erosions or
1-2 erosions if RF or ACPA+

None

None

Primary Endpoint

ACR20 Week 24

ACR20 Week 12

ACR20 Week 12

ACR20 Week 12

Study Duration

52 Weeks

52 Weeks

24 Weeks

24 Weeks

First opportunity for rescue therapy (as needed)

Week 24

Week 16

Week 16

Week 16

BASELINE

RA-BEGIN

RA-BEAM

RA-BUILD

RA-BEACON

Age (y), mean (SD)

49.9 (13)

53.3 (12)

51.8 (12)

55.7 (11)

Female, n (%)

425 (73)

1008 (77)

560 (82)

431 (82)

RA duration from symptom onset (y), mean (SD)

2.6 (5)

10.1 (9)

7.5 (8)

14.0 (9)

ACPA + (>10 U/ml), n (%)

RF + (>14 IU/ml), n (%)

527 (90)

562 (96)

1146 (88)

1191 (91)

504 (74)

521 (76)

368 (70)

386 (73)

≥ 1 joint erosion, n (%)

380 (65)

NRa

502 (74)

NR

Prior cDMARD, n (%)

None

533 (91)

NA

NA

NA

One

51 (9)b

600 (46)

298 (44)

212 (40)

Two

0

412 (32)

210 (31)

153 (29)

≥ Three

0

292 (22)

171 (25)

161 (31)

Corticosteroid use, n (%)

206 (35)

766 (59)

346 (51)

304 (58)

HAQ-DI (0-3), mean (SD)

1.6 (0.7)

1.6 (0.7)

1.5 (0.6)

1.7 (0.6)

TJC (68), mean (SD)

SJC (66), mean (SD)

27 (15)

16 (10)

23 (13)

15 (9)

24 (14)

13 (8)

29 (16)

17 (11)

ESR (mm/h), mean (SD)

hsCRP (mg/L), mean (SD)

52 (27)

24 (26)

49 (26)

21 (22)

43 (24)

17 (19)

47 (25)

20 (24)

DAS28-ESR, mean (SD)

DAS28-hsCRP, mean (SD)

6.6 (1.0)

5.9 (1.0)

6.4 (1.0)

5.7 (0.9)

6.2 (1.0)

5.6 (0.9)

6.6 (1.0)

5.9 (1.0)

Abbreviations: ACPA = anti-citrullinated peptide antibody; ACR20 = American College of Rheumatology 20% improvement criteria; csDMARD = conventional synthetic disease-modifying antirheumatic drug; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; DMARD = disease-modifying antirheumatic drug; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment Questionnaire Disability Index; hsCRP = high-sensitivity C-reactive protein; IR = inadequate responder; MTX = methotrexate; NA = not applicable; NR = not reported; RA = rheumatoid arthritis; RF = rheumatoid factor; SJC = swollen joint count; TJC = tender joint count; TNFi = tumor-necrosis factor inhibitors.
Note: Data in table are based on a modified intent-to-treat population.

aPer study inclusion criteria, all patients had either 1 to 2 joint erosions and seropositivity or 3+ joint erosions at baseline.

b Per protocol, patients could have had up to 3 doses of MTX prior to enrollment.

Date of Last Review: 05 October 2021


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