Safety profile of baricitinib in Japanese patients with active rheumatoid arthritis with over 1.6 years median time in treatment: An integrated analysis of Phases 2 and 3 trials

Figures & data

Table 1. Patient populations.

Study	Treatments	Prior RA treatments	Rescue (Wk)^a	Period length (Wk)	Japanese participation	All-bari-RA overall
Phase 1b
14V-MC-JADB [29], Open-label	Bari 15 mg	Back ground MTX	–	28 days		✓
	Bari 10 mg
	Bari 5 mg BID
Phase 2
NCT00902486	Placebo	csDMARD-IR prior bDMARD allowed	–	12 DB		✓
	Bari 10 mg			12 BE
	Bari 7 mg
	Bari 4 mg
NCT01185353 [13]	Placebo	MTX-IR bDMARD naive	–	12 DB		✓
	Bari 8 mg			12 BE
	Bari 4 mg			52 OE
	Bari 2 mg			52 OE
	Bari 1 mg
NCT01469013 [14] (Japan)	Placebo	MTX-IR prior bDMARD allowed^b	–	12 DB	✓	✓
	Bari 8 mg			52 BE
	Bari 4 mg
	Bari 2 mg
	Bari 1 mg
Phase 3
RA-BEAM [7];	Placebo	MTX-IR bDMARD naive	16	24 DB	✓	✓
NCT01710358	Bari 4 mg			28 DB^c
	Adalimumab			52 DB^d
RA-BEACON [8];	Placebo	TNFi-IR	16	24 DB	✓	✓
NCT01721044	Bari 4 mg
	Bari 2 mg
RA-BUILD [9];	Placebo	csDMARD-IR bDMARD naive	16	24 DB	✓	✓
NCT01721057	Bari 4 mg
	Bari 2 mg
RA-BEGIN [10];	MTX mono	DMARD naive	24	52 DB	✓	✓
NCT01711359	Bari 4 mg mono
	Bari 4 mg + MTX
LTE^e
RA-BEYOND;	Bari 4 mg	Varied	PRN	Up to 5 years^f	✓	✓
NCT01885078	Bari 2 mg

Bari: baricitinib; BID: twice-daily; DB: double-blind; bDMARD: biological DMARD; BE: blinded extension with no placebo; csDMARD: conventional DMARD; DMARD: disease-modifying antirheumatic drug; LTE: long-term extension; MTX: methotrexate; OE: open-label extension; PRN: pro re nata (as needed); TNFi: tumor necrosis factor-inhibitor; Wks: weeks.

The numbers in brackets are citation numbers.

^a First available rescue.

^b Prior bDMARDs allowable; however, patients could not have stopped treatment due to insufficient response.

^c Double-blind with no placebo.

^d Trial RA-BEAM had 24 weeks of placebo control and 52 weeks of active control.

^e Studies contributing to LTE RA-BEYOND included Ph 2 trial NCT01185353 and Ph 3 trials RA-BEAM, RA-BEACON, RA-BUILD, and RA-BEGIN. Treatment assignments and blinding in LTE RA-BEYOND vary depending on the originating study.

^f On-going trial with data as of 1 September 2016.

Table 2. Baseline demographics and measures of disease activity.

	All-bari-RA	All-bari-RA
	Japanese	Overall
Baseline characteristics	N = 514	N = 3492
Age, years, mean (SD)	53.9 (11.9)	52.9 (12.2)
Female, n (%)	392 (76.3)	2760 (79.0)
Duration of RA^a, years, mean (SD)	5.6 (7.4)	7.7 (8.2)
Corticosteroid use, n (%)
None	262 (51.0)	1738 (49.8)
0.1–4.9 mg/day	136 (26.5)	326 (9.3)
5–7.4 mg/day	87 (16.9)	326 (9.3)
7.5 + mg/day	29 (5.6)	597 (17.1)
Concomitant MTX use, yes, n (%)	410 (79.8)	2661 (76.2)
Baseline disease activity, mean (SD)	N = 514	N = 3439^b
SJC of 66	10.5 (8.8)	12.0 (9.6)
TJC of 68	13.5 (11.4)	19.6 (15.2)
CDAI	25.5 (14.5)	30.8 (16.7)
DAS28-hsCRP	4.58 (1.47)	5.05 (1.47)

Bari: baricitinib; CDAI: Clinical Disease Activity Index; DAS28-hsCRP: Disease Activity Score 28-joint count high sensitivity C-reactive protein; MTX: methotrexate; RA: rheumatoid arthritis; SD: standard deviation; SJC: swollen joint count; TJC: tender joint count.

^a Time from RA diagnosis.

^b The N is smaller for disease activity measures than for demographics because baseline disease activity measures are only available for Phase 2/3 studies.

Table 3. Safety measures of special interest.

	All-bari-RA	All-bari-RA
	Japanese	Overall
Exposure
Number of patients, n	514	3492
Total patient-years	851.5	6636.7
Number of patients with ≥52 weeks, n (%)	423 (82.3)	2723 (78.0)
Number of patients with ≥104 weeks, n (%)	218 (42.4)	1867 (53.5)
Longest exposure, days	1172	2019
AEs, n (EAIR)
Any TEAE (≥1)	489 (57.4)	2941 (44.3)
SAE (≥1) including death	81 (9.3)	611 (9.0)
Temporary interruption due to ≥1 AE	192 (22.5)	864 (13.1)^a
Permanent discontinuation due to ≥1 AE	84 (9.6)	393 (5.8)
Death, n (IR)	0	22 (0.33)
Malignancy, n (IR)
Malignancy excluding NMSC	10 (1.1)	52 (0.8)
Lymphoma	2 (0.2)	6 (0.09)
NMSC	1 (0.11)	24 (0.4)
Infections, n (IR)
TE infections^b	356 (41.8)	1986 (29.9)
Serious infection	31 (3.6)	194 (2.9)
Herpes zoster (cluster)	55 (6.5)	212 (3.2)
TB	0	10 (0.15)
Infection leading to death^b	0	5 (0.07)
Adverse CV events of special interest, n (IR)
MACE^c	2 (0.3)	31 (0.5)
MI	0	14 (0.2)
CV death	0	8 (0.1)
Stroke	2 (0.3)	13 (0.2)
DVT-PE^d	4 (0.5)	31 (0.5)
DVT	4 (0.5)	20 (0.3)
PE	0	16 (0.2)
GI disorder, n (EAIR)
GI perforations	1 (0.12)	3 (0.05)
ILD/PF, n (EAIR)
ILD	4 (0.5)	11 (0.2)
PF	0	3 (0.1)

AE: adverse event; Bari: baricitinib; CV: cardiovascular; DVT: deep vein thrombosis; EAIR: exposure-adjusted incidence rate; GI: gastrointestinal; ILD: interstitial lung disease; IR: incidence rate; MACE: major adverse cardiovascular events; MI: myocardial infarction; NMSC: non-melanoma skin cancer; PE: pulmonary embolism; PF: pulmonary fibrosis; PY: patient-years; SAE: serious AE; TB: tuberculosis: TE: treatment-emergent; VTE: venous thromboembolism.

For TEAEs and AEs leading to temporary interruption, EAIRs were calculated as the number of unique patients with an event per 100 PY of overall exposure time. For AEs leading to permanent discontinuation and SAEs, EAIRs were calculated as the number of unique patients with an event per 100 PY of overall exposure time, which included any post-drug follow-up time. For AEs of pre-specified special interest including deaths, IRs were calculated as the number of unique patients with an event per 100 PY of observation time, which included any post-drug follow-up time, censored at event.

^a Some studies did not collect temporary interruption of study drug.

^b Used exposure-adjusted incidence rates events/100 patient years (patient exposure not censored at the event).

^c Potential CV adverse events from the Phase 3 trials and LTE, identified by investigators or according to a predefined list of event terms, were adjudicated by an independent, external Clinical Endpoint Committee who remained blinded to treatment assignments.

^d MedDRA preferred terms of ‘deep vein thrombosis’/‘pulmonary embolism’ were analyzed without adjudication.

After the September 2016 data cut-off, one Japanese patient experienced PE (termed pulmonary embolism) and a follow-up medical review identified an additional event of DVT (termed thrombophlebitis) in non-Japanese patient. These events are not included in this table.

Table 4. Serious adverse events (SAEs) detail.

	All-bari-RA Japanese
	N = 514
SAEs in ≥0.5% of patients from All-bari-RA set, n (EAIR)
Any SAE	81 (9.3)
Herpes zoster	13 (1.5)
Pneumonia	6 (0.7)
Interstitial lung disease	4 (0.5)
Pneumocystis jirovecii pneumonia	3 (0.3)
Fall	3 (0.3)
Hydrocele^a	1 (0.5)

Bari: baricitinib; EAIR: exposure-adjusted incidence rate; PY: patient-years; RA: rheumatoid arthritis; SAE: serious adverse event.

EAIRs were calculated as the number of unique patients with an event per 100 PY of overall exposure time including any post-drug follow-up time.

^a Denominator and patient years adjusted because event is specific to males: N = 122 (All-bari Phases 1–3).

Table 5. Case summary of malignancies (excluding NMSC) for all the cases in the All-bari-RA analysis set.

Event term	Days from first dose to event start date	Doses prior to event start date
Malignant fibrous histiocytoma	29	ADA in RA-BEAM, 4-mg in LTE
Rectal cancer	115	4-mg in parts A and B in NCT01469013
Chondrosarcoma	257	1-mg in part A and 8-mg in part B in NCT01469013
Breast cancer metastatic	261	MTX in RA-BEGIN, 4-mg in LTE
Cervix carcinoma	334	4-mg in RA-BEGIN
Gastric mucosa-associated lymphoid tissue B-cell lesion lymphoma	342	Pbo in RA-BEACON, 4-mg in LTE
Diffuse large B-cell lymphoma	399	4-mg after rescue from Pbo at week 20 in RA-BEAM, 4-mg in LTE
Gastric cancer	518	4-mg after switch from Pbo at week 24 in RA-BEAM, 4-mg in LTE
Renal cell carcinoma	717	4-mg in RA-BEAM, 4-mg in LTE
Breast cancer	841	4-mg + MTX in RA-BEGIN, 4-mg in LTE

ADA: adalimumab; Bari: baricitinib; LTE: long-term extension; MTX: methotrexate; NMSC: non-melanoma skin cancer; Pbo: placebo; RA: rheumatoid arthritis.

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