Update on Clinical Trials in Systemic Lupus Erythematosus

Sonali Narain; Richard Furie

Curr Opin Rheumatol. 2016;28(5):477-487.

Targeting B Cells

B-cell targeted therapies have dominated drug development endeavors owing to the role of B lymphocytes in the pathogenesis of SLE and the regulatory approval of belimumab. Although various strategies have been conceived, the general tactic has been to affect qualitative and/or quantitative changes in B cells.^[2] Key trials are illustrated in Table 1.

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Table 1. Targeting B cells and plasma cells
Drug	Target	Study population	Route	Site	Duration	N (D/PBO)	Primary end point	Met primary end point	Significant adverse events
Belimumab (BLISSSC)	BLyS^a/BAFF^a	SLE^a	SC^a	Worldwide	52 weeks	836	SRI4^b response rate	Yes	None
Atacicept (APRIL-SLE)	BLyS/APRIL	SLE	SC	Worldwide	52 weeks	461 (304/157)	At least one flare of BILAG A or B	No	2 infection-related deaths in the 150mg arm
Blisibimod (PEARLSC)	BLyS/BAFF	SLE	SC	Worldwide	52 weeks	547 (277/270)	SRI5^c response rate	No	None
Tabalumab (ILLUMINATE 1)	BLyS/BAFF	SLE	SC	Worldwide	52 weeks	1138 (759/379)	SRI5 response rate	No	None
Tabalumab (ILLUMINATE 2)	BLyS/BAFF	SLE	SC	Worldwide	52 weeks	1124 (748/376)	SRI5 response rate	Yes (for 120 Q2W group)	More injection site reactions, hypersensitivity reactions and suicidal ideation in the drug arm
Epratuzumab (EMBLEM)	CD22	SLE	IV^a	Worldwide	12 weeks (with 12 week extension)	227 (189/38)	BICLA^d response rate	No	None
Epratuzumab (EMBODY 1&2)	CD22	SLE	IV	Worldwide	48 weeks	786 and 788	BICLA response rate	No	None
Bortezomib	Proteasome	SLE	IV	Germany	3 months after last bortezomib cycle	12	Change in baseline SLEDAI-2K^a	Yes	Infections and polyneuropathy in the drug arm

^aBAFF, B-cell activating factor; BILAG, British Isles Lupus Activity Group; BLyS, B lymphocyte stimulator; D, drug; IV, intravenous; LN, lupus nephritis; PBO, placebo; SC, subcutaneous; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.
^bSRI4, 4-point improvement in SLEDAI-2K; no clinically significant worsening (≥0.3) in PGA; and no new BILAG-2004 'A' (severe) or >1 new 'B' (moderate) organ system scores.
^cSRI5, ≥5 point improvement (reduction) in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group (BILAG) 2004 index score of A or no more than one new BILAG B score, and no worsening (increase ≥0.3 points from baseline) in physician's global assessment (PGA).
^dBICLA, British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment.

Table 2. Targeting T cells
Drug	Mechanism	Study population	Route	Site	Duration	N (D^a/PBO^a)	Primary end point	Met primary end point	Noteworthy adverse events
Edratide	Inhibits cytokine and reduces BLyS^a	SLE^a	SC^a	Worldwide	26 weeks	340 (253/87)	Reduction in SLEDAI-2K and SLEDAI adjusted mean SLEDAI (AMS)	No	None
Rigerimod	Suppresses proinflammatory cytokines	SLE	SC	Europe	26 weeks	149 (100/49)	SRI^b response at week 12	Yes (for 200 mcg q4W)	Injection site erythema in the drug arm
Tacrolimus	Inhibits development and proliferation of T cells	LN^a	Oral	China	24 weeks	368 (181/187)^d	Incidence of complete remission^c	Yes	None. However, more withdrawal in the tacrolimus arm due to infections
Tacrolimus	Inhibits development and proliferation of T cells	LN	Oral	China	6 months	150 (74/76)^π	Proportion of patients with complete response	Yes	Tremor and reversible increase in serum creatinine in tacrolimus group and Herpes zoster in mycophenolate group
Abatacept	Inhibits T-cell activation	LN	IV	Worldwide	12 months	298 (198/100)	Time to confirmed complete respons^e	No	None
Abatacept ACCESS Trial Group	Inhibits T-cell activation	LN	IV	USA and Mexico	24 weeks with extension to week 52	134 (66/68)	Frequency of complete response^f	No	None
Dapirolizumab	Prevents T–B cell interaction	SLE	IV	Europe	32 weeks	24 (16/8)	Safety and tolerability	N/A	More incidence of nasopharyngitis in the drug group

^aBILAG, British Isles Lupus Activity Group; BLyS, B lymphocyte stimulator; D, drug; IV, intravenous; LN, lupus nephritis; PBO, placebo; SC, subcutaneous; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.
^bSRI response, SLEDAI-2K score of ≥4 points, no increase in the PGA score of >0.3 point on a visual analogue scale of 0–3, no new A score on the BILAG-2004 and ≤1 new B score were considered to be SRI responders.
^cComplete remission, 24-h urinary protein excretion of 0.4 g or less, the absence of active urine sediments, serum albumin level of 35 g/l or greater, and normal serum creatinine levels.
^dPatients were randomized to get oral tacrolimus + mycophenolate mofetil versus IV cyclophosphamide ^πPatients were randomized to get oral tacrolimus versus oral mycophenolate mofetil.
^eComplete response, 1) Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) ≥90% of screening level if normal at screening visit, or eGFR ≥90% of 6-month, preflare value if abnormal at screening, 2) urinary protein-to-creatinine ratio<0.26 g/g (30 mg/mmol), and 3) inactive urinary sediment (RBCs and WBCs per high-power field within normal limits of central laboratory assessments; no RBC or WBC casts); reconfirmed at 4 week follow-up.
^fComplete response: (i) Urine protein-to-creatinine ratio <0.5 based on a 24-h urine collection; (ii) serum creatinine ≤1.2 mg/dl or ≤125% of baseline; and (iii) adherence to the prednisone taper to 10 mg/day by week 12.

Table 3. Targeting interferons
Drug	Target	Study population	Route	Site	Duration	N (D^a/PBO^a)	Primary end point	Met primary end point	Noteworthy adverse events
Rontalizumab (ROSE)	IFNα	SLE^a	IV^a and SC^a	Worldwide	24 weeks (with 144 week extension)	238 (159/79)	Step-down improvement in the BILAG^a score at week 24 without a new A or >1 new B scores, or off-protocol rescue therapies	No	None
Sifalimumab	IFNα	SLE	IV	Worldwide	52 weeks (with 22 week extension)	432 (324/108)	Patients achieving SRI4^b response	Yes	Herpes zoster in the drug arm
Anifrolumab	Type I IFN receptor	SLE	IV	Worldwide	48 weeks	305 (203/102)	SRI4 response at day 169 with sustained reduction of OCS^a,c	Yes	Herpes zoster
IFNα kinoid	IFNα	SLE	IM^a	Europe	24 weeks	28 (21/7)	N/A	N/A	None
AMG811	IFNγ	LN^a	SC	Worldwide	12 weeks	28 (21/7)	Safety, tolerability and antidrug antibodies	N/A	No SAEs^a; more infections in drug group

^aBILAG, British Isles Lupus Activity Group; D, drug; IM, intramuscular; IV, intravenous; LN, lupus nephritis; OCS, oral corticosteroids; PBO, placebo; SAEs, serious adverse events; SC, subcutaneous; SLE, systemic lupus erythematosus.
^bSRI4, 4-point improvement in SLEDAI-2K; no clinically significant worsening (≥0.3) in PGA; and no new BILAG-2004 'A' (severe) or >1 new 'B' (moderate) organ system scores.
^cSustained reduction of OCS defined as: <10 mg/day and ≤day 1 dose maintained between days 85 and 169.

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Update on Clinical Trials in Systemic Lupus Erythematosus

Targeting B Cells

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