Table 1.

Summary of clinical trials in non-renal systemic lupus erythematosus (SLE)

Drug	Target	Mechanism	Study and Design	Key Findings
DHEA	Unknown	Sex hormone precursor	Chang et al.12 RCT Females with mild-to-moderate SLE 1° endpoint: SLAM score at 24 weeks	1° endpoint not met Patient global assessment scores improved and fewer SLE flares in DHEA group compared to placebo
			Petri et al.11 Phase II/III RCT Females with GC-dependent SLE 1° endpoint: Sustained decrease in prednisone (≤7.5mg/day) for 2 consecutive months	1° endpoint not met Patients with active SLE (SLEDAI >2) had significant decrease in GC dose with 200mg/day of DHEA compared to placebo
			Petri et al.13 Phase III RCT Females with active SLE& 1° endpoint: Clinical response§ at 52 weeks	1° endpoint not met More responders among patients with SLEDAI >2 treated with DHEA than placebo Development program suspended, but DHEA studies guided choice of study population for subsequent trials
Rituximab	CD20	Deplete CD20+ B-cells	Merrill et al.15 (EXPLORER) Phase II/III RCT Moderate-to-severe SLE 1° endpoints: a) Major* or b) partialˆ clinical response at 52 weeks	1° endpoints not met Pre-specified subgroup analysis found better response in blacks and Hispanic group treated with rituximab vs placebo Strict definitions for major and partial clinical response Amount of background therapy mitigated differences between treatment arms
Abatacept	CD80/86	Inhibit T-cell co-stimulation	Merrill et al.17 Phase IIb RCT in mild-to-moderate SLE 1° endpoint: ≥1 BILAG A or B flare during 52 weeks	1° endpoint not met; similar flare rates with abatacept and placebo Improvements in PROs (health-related quality of life, fatigue, and sleep) with abatacept
Atacicept	BAFF/BLyS and APRIL	Neutralize BAFF/BLyS (TNFSF13B) and APRIL (TNFSF13A)	Isenberg et al.19 (APRIL-SLE) Phase II RCT Moderate-to-severe SLE 1° endpoint: ≥1 BILAG A or B flare during 52 weeks	1° endpoint not met Atacicept 75mg and placebo had similar flare rate Atacicept 150mg arm halted for adverse events, but signal of fewer flares relative to placebo
Belimumab	BAFF/BLyS	Neutralize BAFF/BLyS (TNFSF13B)	Wallace et al.20 Phase II RCT Active SLE 1° endpoints: a) Change in SELENA-SLEDAI score from baseline to 24 weeks and b) time to first flare (SFI) in 52 weeks	1° endpoints not met; guided choice of patient selection and endpoints for phase III RCTs Serologically active patients (ANA or anti-dsDNA antibody positive) had significant improvement in SELENA-SLEDAI and 2° endpoints at week 52 Led to development of SRI composite endpoint Unlimited changes in immunosuppressants and GC confounded results
			Navarra et al.27 and Furie et al.28 (BLISS-52 and BLISS-76) Phase III RCTs Moderate-to-severe seropositive SLE 1° endpoint: SRI-4 response at 52 weeks	1° endpoint met; greater SRI-4 response with belimumab vs placebo in both studies First use of SRI composite endpoint Stricter control of GC and immunosuppressants near end of study Pre-specified analyses showed improvements in HRQOL, fatigue29 Pooled post-hoc analysis suggested benefit in renal disease54
Tabalumab	BAFF/BLyS	Neutralize BAFF/BLyS (TNFSF13B)	Isenberg et al.31 and Merrill et al.32 (ILLUMINATE 1 and 2) Phase III RCTs Moderate-to-severe SLE 1° endpoint: SRI-5 response at 52 weeks	ILLUMINATE 1 did not meet 1° endpoint ILLUMINATE 2 met 1° endpoint; greater SRI-5 response with tabalumab vs placebo Neither study met key secondary endpoints (fatigue, time to flare, GC dose) Patients with any change in immunosuppression dose, including decrease, were considered non-responders Development suspended
Epratuzumab	CD22	Alter B-cell responsiveness	Wallace et al.33 (ALLEVIATE 1 and 2; SL0006 open label extension) Phase II RCTs Moderate-to-severe SLE 1° endpoint (modified): BILAG response# with no treatment failure at week 12	Enrollment suspended early for low supply of study drug; 1° endpoint evaluated at 12 weeks instead of intended 24 weeks Greater achievement of 1° endpoint with epratuzumab than placebo Improvements in HRQOL and reduced GC doses at 48 weeks34
			Wallace et al.35 (EMBLEM) Phase IIb dose-ranging study Moderate-to-severe SLE 1° endpoint: BICLA response at 12 weeks	First use of BICLA composite endpoint Not powered for significance, but suggested efficacy and safety of 2400mg combined monthly dose More homogeneous patient population than prior RCTs
			Clowse et al.37 (EMBODY 1 and 2) Phase III RCT Moderate-to-severe SLE 1° endpoint: BICLA response at 48 weeks	1° endpoint not met; no difference in BICLA response rate and secondary efficacy measures between epratuzumab and placebo
PF-04236921	IL-6	Neutralize IL-6	Wallace et al.38 Phase II RCT Moderate-to-severe SLE 1° endpoint: SRI-4 at 24 weeks	1° endpoint met for 10mg dose; also showed improvements in BICLA and HRQOL (secondary pre-specified endpoints) Reduction of flares (SFI) with 50mg dose 200mg treatment arm discontinued for serious adverse events
Edratide	Unknown	Unknown	Urowitz et al.55 Phase II RCT Mild-to-moderate SLE 1° endpoint: Reduction in SLEDAI-2K and Adjusted Mean SLEDAI (AMS) through 26 weeks	1° endpoint not met, but significant improvements in BILAG were seen (secondary pre-specified endpoint) Background GC use may have confounded results
Sifalimumab	IFN- α	Neutralize some species of IFN-α	Khamashta et al.56 Phase IIb RCT Moderate-to-severe SLE 1° endpoint: SRI-4 response at 52 weeks Statistical significance set at p<0.098	1° endpoint met; greater achievement of SRI-4 and improvements in skin disease, joint count, and fatigue with sifalimumab compared to placebo
Anifrolumab	Type 1 IFN receptor	Neutralize type 1 IFN activity	Furie et al.39 Phase II RCT Moderate-to-severe SLE 1° endpoint: SRI-4 response at 24 weeks and sustained reduction in GC dose	1° endpoint met; more SRI-4 responders and reduced GC doses with anifrolumab than placebo Effect size greater in patients with high IFN at baseline

DHEA = dehydroepiandrosterone; RCT = randomized controlled trial; SLAM = Systemic Lupus Activity Monitor; GC = glucocorticoid; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; BAFF = B-cell activating factor; BLyS = B-lymphocyte stimulator; SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment–SLEDAI; SFI = SLE Flare Index; ANA = anti-nuclear antibody; dsDNA = double-stranded DNA; SRI = SLE Responder Index; HRQOL = health-related quality of life; BILAG = British Isles Lupus Assessment Group; BICLA = BILAG-based Combined Lupus Assessment; APRIL = a proliferation inducing ligand; PRO = patient-reported outcome; IFN = interferon.

^&Defined as SLAM score ≥7; amended to include SLEDAI >2 during enrollment

^§Composite endpoint of improvement or stabilization of two disease activity measures (SLAM and SLEDAI) and two HRQoL measures (patient global assessment and fatigue severity scale) without evidence of clinical deterioration (organ damage)

^*Defined as BILAG C or better score in all organs at week 24 without a severe flare (≥1 new BILAG A or ≥2 new BILAG B scores) from day 1 to week 24 and maintaining this response without moderate or severe flare (≥1 BILAG A or B score) to week 52

^ˆDefined as 1) BILAG C scores or better at week 24 and maintaining response without a new BILAG A or B scores for 16 weeks; 2) no more than 1 organ with BILAG B score at week 24 a new BILAG A or B score to week 52; 3) 2 BILAG B scores at week 24 without developing BILAG A or B scores in new domains until week 52 if baseline BILAG score was 1 A score plus ≥2 B scores, ≥2 A scores, or ≥4 B scores.

^#Defined as BILAG A scores decreased to B or lower OR both BILAG B scores decreased to C or lower and no new BILAG A or <2 BILAG B scores in other organ systems