Baricitinib in SLE: Results from the phase III SLE-BRAVE trials

Outcomes in patients with systemic lupus erythematosus (SLE) remain poor. Conventional therapies include antimalarials, glucocorticoids, and immunosuppressants, with trials for new drugs often producing negative results and failing to progress beyond phase III trials.¹

Baricitinib, an oral Janus kinase (JAK) 1 and 2 inhibitor, is already approved for several indications, including atopic dermatitis, alopecia, and rheumatoid arthritis; previous phase II trial of baricitinib have demonstrated improved SLE activity compared with placebo over 24 weeks. The SLE-BRAVE-I and -II trials (NCT03616912; NCT03616964) investigated the efficacy and safety of baricitinib in patients with SLE over 52 weeks.^1,2

Trial design

SLE-BRAVE-I and SLE-BRAVE-II were both multicenter, randomized, double-blind phase III trials comparing baricitinib with placebo in patients with SLE.^1,2 Eligible patients continued to receive their standard of care treatment alongside baricitinib or placebo.^1,2 The study design is shown in Figure 1.

ACR, American College of Rheumatology; BILAG, British Isles Lupus Assessment Group; CNS, central nervous system; ds, double stranded; EoT, end of treatment; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000; SRI-4, SLE Responder Index-4.
*Adapted from Morand, et al.¹ and Petri, et al.²

The primary endpoint for both trials was the proportion of patients achieving a SLE Responder Index (SRI)-4 response at Week 52 in the baricitinib 4 mg group compared with placebo group.^1,2 Secondary endpoints included:

• SRI-4 response at Week 24;
• SRI-4 response at Week 52 in patients receiving baricitinib 2 mg;
• Achievement of lupus low disease activity state at Week 52;
• 25% decrease in prednisone dose in patients receiving 7.5 mg or more at baseline;
• time to first severe flare;
• change from baseline in Worst Pain Numeric Rating Scale at Week 52; and
• change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue score at Week 52.

Adverse events were measured at each visit for both studies.

Results

In SLE-BRAVE-I, 769 patients were enrolled and 760 patients were included in the analyses.¹ In SLE-BLAVE-II, 778 patients were enrolled and 775 were included in analyses.² Key baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics in SLE-BRAVE-I and -II*

NSAID, non-steroidal anti-inflammatory drug; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000. *Adapted from Morand, et al.1 and Petri, et al.2 †Includes America Indian or Alaska Native.
Characteristic, % (unless otherwise stated)	SLE-BRAVE-I			SLE-BRAVE-II
	Placebo (n = 253)	Baricitinib 2mg (n = 255)	Baricitinib 4mg (n = 252)	Placebo (n = 256)	Baricitinib 2mg (n = 261)	Baricitinib 4mg (n = 258)
Mean age, years	42.0	42.9	41.5	43.5	42.8	42.2
Sex
Male	—	—	—	6	6	5
Female	94	93	94	94	94	95
Race
Asian	13	16	14	28	26	28
Black or African               American	14	9	12	7	9	10
White	67	69	71	58	59	55
Other†/multiple	5	7	3	6	5	5
Mean time since onset of SLE, years	9.4	9.2	8.8	9.0	8.7	8.5
Concomitant medications
Glucocorticoids	77	76	74	81	80	80
Mean               prednisone               dose, mg/day	9.8	10.4	10.1	8.8	9.6	9.8
Antimalarials	84	74	82	82	82	83
Immuno-suppressants	59	60	82	55	51	52
NSAID	25	26	27	20	25	27
Mean SLEDAI-2K score	10.1	10.3	10.0	10.1	10.1	10.1

Efficacy

The efficacy analysis was performed based on the intention-to-treat population.^1,2 SLE-BRAVE-I did not to meet any of its major secondary endpoints,¹ while SLE-BRAVE-II did not meet both its primary and major secondary endpoints.² The proportion of patients meeting the primary outcome measures is shown in Figure 2, including the primary endpoint of SRI-4 at Week 52.

BILAG, British Isles Lupus Assessment Group; PGA, Physician Global Assessment; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000; SRI-4, SLE Responder Index-4.
*Adapted from Morand, et al.¹ and Petri, et al.^2
†Defined as an increase of ≥0.3 points (10 mm) from baseline in PGA.

Safety

The incidence of adverse events and discontinuation was similar across treatment groups in both studies, as shown in Figure 3.^1,2

*Adapted from Morand, et al.¹ and Petri, et al.²

Two deaths due to COVID-19 were reported in SLE-BRAVE-I, one in a patient receiving placebo and one receiving baricitinib 2 mg.¹ In SLE-BRAVE-II, four deaths were reported in patients treated with baricitinib 4 mg, two due to myocardial infarction, one due to COVID-19 (this patient was meant to receive baricitinib 4 mg but actually received baricitinib 2 mg), and one due to sepsis; there were three deaths in placebo treated patients, all due to respiratory failure.²

Conclusion 

Despite positive results in a phase II trial in patients with SLE, baricitinib failed to meet the major secondary endpoints in both trials, with the primary endpoint not being met in SLE-BRAVE-II.^1,2 However, there were no new safety signals observed in either trial.^1,2

SLE-BRAVE-X, a phase III long-term extension in adults who completed SLE-BRAVE-II and -II, evaluated the safety and efficacy of baricitinib over three years; however, development of baricitinib for SLE has now been discontinued due to the poor efficacy outcomes seen in SLE-BRAVE-I and -II.³