Olumiant® ▼ (Baricitinib): Incidence of Tuberculosis in Rheumatoid Arthritis

Short Summary

In patients with RA who received BARI in clinical trials with maximum exposure of 8.4 years, events consistent with clinically overt TB infection

• were reported in 20 out of 3770 patients, and

• occurred at an incidence rate of 0.15 per 100 PYs of exposure (total of 13,148 PYE).¹

The observed incidence rates of TB in the RA clinical trial program were consistent with the expected background rates in patients with RA from the various countries where TB was reported. Cases of TB primarily occurred in countries where TB is endemic.²

Use of Baricitinib in Patients With Active Tuberculosis

Patients should be screened for tuberculosis (TB) before starting baricitinib therapy.³

• Baricitinib should not be given to patients with active TB.³

• Anti-TB therapy should be considered prior to initiation of Baricitinib in patients with previously untreated latent TB.³

Tuberculosis in Rheumatoid Arthritis Population

The incidence of TB is estimated to be 4 to 10 times higher in patients with RA than in the general population.^4-8

Rheumatoid Arthritis Clinical Trial Exclusion Criteria Related to Tuberculosis

Patients were excluded from participation in phase 3 RA studies if they had evidence of

• active TB, documented by

  • a positive skin test or in vitro immunoassay

  • medical history

  • clinical symptoms, and

  • abnormal chest x-ray at screening, or

• latent TB, documented by

  • a positive skin test or in vitro immunoassay

  • no clinical symptoms, and

  • a normal chest x-ray at screening.^2,9

Patients could participate in the studies if they had

• latent TB with at least 4 weeks of appropriate treatment completed prior to randomization, and agreed to complete the remainder of treatment while in the study, or

• a history of active or latent TB with documented evidence of completed appropriate treatment.⁹

Across the RA phase 3 studies,

• 0.6 to 0.9% of screened patients were excluded from randomization due to active TB

• 1.1 to 4.5% of screened patients were excluded from randomization due to latent TB

• 7 to 12% of randomized patients had evidence of latent TB, and

• 2 to 13% of patients were receiving isoniazid as treatment during enrollment.^2,9

Cases of Tuberculosis in Rheumatoid Arthritis Clinical Trials  

Safety Analysis Identification of Potential Tuberculosis Infections 

Cases potentially representing TB infection were identified using a sponsor-defined list of MedDRA preferred terms from the Tuberculous Infections High Level Term and the Investigations System Organ Class.²

Description of ALL BARI RA Analysis Set

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.^1,10

Incidence of Tuberculosis Infections

In patients with RA who received BARI in clinical trials, events consistent with clinically overt TB infection

• were reported in 20 out of 3770 patients, and

• occurred at an incidence rate of 0.15 per 100 PYs of exposure.¹

Tuberculosis Case Details

Case details were analyzed from 15 cases of TB reported in the All BARI RA dataset using data from 3770 patients with up to 6.9 years of maximum exposure and 10,127 PYE.¹¹

In the majority of countries where the 15 TB cases were reported,

• there were high rates of screen failure due to detection of latent TB, and

• the observed incidence rates of TB were consistent with the expected background rates in patients with RA, see Table 1 for country details.²

Table 1. Incidence Rates of Tuberculosis by Country^2,4,12-14

Country IRa	TB in General Populationb	Estimated TB in RA Populationc	TB in BARI-Treated RA Patientsd (n/N)
Argentina	.026	.104 to .26	.134 (2/467)
Taiwan	.044e	.176 to .44	1.02 (3/92)
Russian Federation	.060	.24 to .60	.229 (1/130)
South Korea	.070	.28 to .70	.389 (1/84)
India	.204	.816 to 2.04	1.22 (3/131)
South Africa	.567	2.27 to 5.67	1.57 (3/65)
China	.063	.252 to .63	.191 (1/269)
United States	.003f	.012 to .03	.056 (1/784)

Abbreviations: BARI = baricitinib; IR = incidence rate; RA = rheumatoid arthritis; TB = tuberculosis; US = United States; WHO = World Health Organization.

^a Incidence rate per 100 people/year.

^b Source: WHO 2017 unless otherwise specified. Data converted from 100,000 to 100 people/year.

^c Incidence rate in RA population is estimated to be 4 to 10 fold higher than general population (Winthrop, 2013).

^d Includes countries where the 15 cases of TB were reported in the All BARI RA dataset using data from 3770 patients with up to 6.9 years of maximum exposure , 10,127 PYE and data through 13 February 2013.

^e Source: Centers for Disease Control, R.O.C. (Taiwan) 2016.

^f Source: Centers for Disease Control, US, 2017.

Nine of the 15 cases were associated with extra-pulmonary involvement, including

• 2 vertebral

• 3 lymph node

• 1 mediastinal

• 1 pleural, and

• 2 abdominal.^2,9

Of the 15 cases,

• 2 patients had deviations in TB screening and did not receive treatment for latent TB

• 2 patients started and completed 6 months of treatment for latent TB based on screening test results

• 1 patient had a past medical history of TB treated with isoniazid, and

• 10 patients had negative TB test results at screening.^2,9

All 15 TB cases occurred on BARI 4 mg treatment and were reported on BARI treatment day ranging from 137 to 1300, including

• 5 cases reported prior to day 500

• 7 cases reported between day 500 to 1000, and

• 3 cases reported after day 1000.²

Safety Analysis of concomitant Isoniazid Treatment for Latent Tuberculosis in RA Clinical Trials

Description of Pooled Safety Analysis From RA-BEAM, RA-BUILD and RA-BEACON

A post hoc analysis evaluated changes in ALT in patients with latent TB who were treated with isoniazid for 4 weeks prior to randomization and during the clinical trials.⁹

A total of 2516 patients were pooled from 3 phase 3 studies and included

• 891 in the BARI 4-mg group

• 403 in the BARI 2-mg group

• 330 in the ADA group, and

• 892 in the placebo group.^9,15

Changes in ALT levels were measured from baseline up to week 24 for all patients analyzed. The proportions of patients with ALT levels ≥1X, ≥3X, ≥5X, and ≥10X ULN were calculated for each treatment group by concomitant isoniazid treatment or no isoniazid treatment.⁹

Alanine Aminotransferase Results in Isoniazid-Treated Patients

Of the 2516 patients analyzed, 246 were positive for latent TB, and 169 received isoniazid treatment. Isoniazid- treated patients with ALT levels ≥1X ULN included

• 24/58 (41.4%) patients from the BARI 4-mg group

• 9/27 (33.3%) patients from the BARI 2-mg group

• 12/27 (44.4%) patients from the ADA group, and

• 21/57 (36.8%) patients from the placebo group.^9,15

Across all treatment groups, a higher number of isoniazid-treated patients had ALT levels ≥1X ULN than patients not taking isoniazid. However, there were no treatment interruptions or discontinuations due to abnormal hepatic laboratory results in patients taking concomitant isoniazid and BARI or ADA treatment.^9,15

There were no reports of ALT levels ≥3X, ≥5X, and ≥10X ULN in patients treated with BARI 4 mg and isoniazid.⁹ Additional results on the proportion of patients with ALT levels ≥3X, ≥5X, and ≥10X ULN are provided in Table 2.

Table 2. Alanine Tramsaminase Levels in Patients With and Without Isoniazid Treatment in RA Clinical Trials^a9,15

Changes from baseline to 24 weeks n (%)	BARI 4 mgb N=891	BARI 4 mg c N=891	BARI 2 mgd N=403	BARI 2 mge N=403	Adalimumabf N=330	Adalimumabg N=330	Placebob N=892	Placebo h N=892
	INH n=58	No INH n=833	INH n=27	No INH n=376	INH n=27	No INH n=303	INH n=57	No INH n=835
ALT ≥1X ULN	24 (41.4)	260 (31.2)	9 (33.3)	82 (21.8)	12 (44.4)	91 (30.0)	21 (36.8)	183 (21.9)
ALT ≥3X ULN	0	13 (1.6)	2 (7.4)	6 (1.6)	2 (7.4)	9 (3.0)	2 (3.5)	13(1.6)
ALT ≥5X ULN	0	5 (0.6)	1 (3.7)	1 (0.3)	1 (3.7)	3 (1.0)	2 (3.5)	3 (0.4)
ALT ≥10X ULN	0	2 (0.2)	1 (3.7)	0	0	1 (0.3)	0	0

Abbreviations: ALT = alanine transaminase; BARI = baricitinib; INH = isoniazid; RA = rheumatoid arthritis; ULN = upper limit of normal.

^a All patients were on background conventional disease-modifying antirheumatic drugs, mainly methotrexate.

^b Patient population from RA-BEAM, RA-BUILD, and RA-BEACON.

^c Patient population from RA-BEAM, RA-BUILD, and RA-BEACON.

^d Patient population from RA-BUILD and RA-BEACON.

^e Patient population from RA-BUILD and RA-BEACON.

^f Patient population from RA-BEAM.

^g Patient population from RA-BEAM.

^h Patient population from RA-BEAM, RA-BUILD, and RA-BEACON.

References

1. 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. https://ard.bmj.com/content/79/Suppl_1/642.1

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

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

4. Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumor necrosis factor therapy in USA. Ann Rheum Dis. 2013;72(1):37-42. https://dx.doi.org/10.1136/annrheumdis-2011-200690

5. Brassard P, Lowe AM, Bernatsky S, et al. Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebex, Canada. Arthritis Rheum. 2009;61(3):300-304. https://dx.doi.org/10.1002/art.24476

6. Carmona L, Hernandez-Garcia C, Vadillo C, et al. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol. 2003;30(7):1436-1439. http://www.jrheum.org/content/30/7/1436.long

7. Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52(7):1986-1992. https://dx.doi.org/10.1002/art.21137

8. Seong SS, Choi CB, Woo JH, et al. Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers. J Rheumatol. 2007;34(4):706-711. http://www.jrheum.org/content/34/4/706.long

9. Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. Published online August 11, 2020. http://dx.doi.org/10.1136/annrheumdis-2019-216852

10. 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.

11. Genovese 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

12. World Health Organization. Global tuberculosis report 2017. World Health Organization website. https://www.who.int/tb/publications/global_report/gtbr2017_main_text.pdf. Accessed May 9, 2019.

13. Centers for Disease Control and Prevention: Tuberculosis Data and Statistics 2017. CDC.gov website. https://www.cdc.gov/tb/statistics/default.htm. Accessed May 9, 2019.

14. Taiwan Centers for Disease Control. CDC.gov.tw website. https://nidss.cdc.gov.tw/en/. Accessed May 9, 2019.

15. Hsieh TY, Huang WN, Tony HP, et al. Hepatic safety in patients with rheumatoid arthritis who received isoniazid for latent tuberculosis: post-hoc analysis from phase 3 baricitinib studies [abstract]. Ann Rheum Dis. 2018;77(suppl 2):098. https://ard.bmj.com/content/77/Suppl_2/593.1.abstract

Glossary

ADA = adalimumab

ALT = alanine aminotransferase

BARI = baricitinib

MedDRA = Medical Dictionary for Regulatory Activities

PYE = patient-years of exposure

RA = rheumatoid arthritis

TB = tuberculosis

ULN = upper limit of normal

▼ 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.