Recent Developments in Biologic Therapies for SLE

B-cell Intracellular Signalling Blockade—Bruton's Tyrosine Kinase

Bruton's tyrosine kinase (BTK) is a component of B-cell receptor signalling, involved in regulating cell proliferation and survival. Its blockade results in B-cell apoptosis. B-cells overexpressing BTK in mice led to anti-dsDNA antibody production and SLE-resembling organ involvement. Many inhibitors of BTK are in development, including ibrutinib and GDC-0853.

Ibrutinib is a tyrosine kinase selective and irreversible inhibitor. It binds to BTK causing B-cell apoptosis. Pre-clinical trials showed ibrutinib reduced levels of autoantibodies (anti-nucleosome, anti-histone and anti-ssDNA but not anti-dsDNA) and renal disease.^[7] However, no current clinical trial is ongoing in SLE.

GDC-0853 is another BTK inhibitor.^[8] A phase II trial in SLE is ongoing (NCT02908100), to evaluate the safety and efficacy in patients with moderate-to-severely active SLE.

Table 1. Biologics used in SLE, mechanism of action, targeted receptors and main trials
Biologic	Immunologic action	Evidence to date in SLE	Number of patients	Inclusion criteria	Primary outcome	Therapeutic regime	Results	Future trials in SLE	Inclusion criteria	Primary outcome	Therapeutic regime	Prospects
Ofatumumab	B-cell depletion	Case reports [3–5]	1, 1 and a series of four patients	–	–	Variable	Reduction on disease activityAnti-dsDNA reduction and C3 normalization	No trials ongoing	–	–	–	Promising, needs clinical studies
Obinutuzumab	B-cell depletion	Pre-clinical [6]	–	–	–	–	B-cell depletion 2-fold the rituximab	Phase II ongoing on LN	Class III or IV LN	Complete Renal Response at week 52	1000 mg on days 1, 15, 168 and 182 plus MMF	Promising, awaiting clinical results
Ibrutinib	BTK inhibition	Pre-clinical [7]	–	–	–	–	BTK inhibition on mature B-cell and APC	No trials ongoing	–	–	–	Promising, needs clinical studies
GDC-0853	BTK inhibition	Pre-clinical and phase I [8]	111	–	–	20, 60, 150 and 250 mg BID, and 500 mg QD	BTK inhibition on mature B-cells	Phase II ongoing	Moderate to severe SLE	SRI-4 response	Low and high dose daily vsplacebo	Promising, awaits results
Rigerimod	T-cell blockade	Phase IIb [10, 11]	149	ITT SLEDAI≥6 No BILAG A	SRI-4	200 μg every 2 or 4 weeks	Improvement in subpopulation SLEDAI≥6. Best results 200 μg every 4 weeks	Phase III ongoing	SLEDAI-2K ≥6 points	SRI-4 response	200 mcg every 4 weeks	Very promising, awaits results
Dapirolizumab	T-cell co-stimulation blockade	Phase Ib [15]	24	SELENA-SLEDAI≥4	SRI-4 and BICLA	First dose 30 mg/kg then five doses of 15 mg/kg every 2 weeks	SRI-4 and BICLA response across several endpoints	Phase II ongoing	Moderate to severe disease activity	BICLA response rate at week 24	Three different doses vsplacebo	Promising, awaits results
Rontalizumab	IFNα blocker	Phase II [18, 19]	159	Moderate to severe disease activity	BILAG	750 mg every 4 weeks (part 1), 300 mg every 2 weeks (part 2)	No general superiority; in low IFN signature it had significant superiority	No trials ongoing	–	–	–	Dubious results
Sifalimumab	IFNα blocker	Phase IIb [20]	431	SLEDAI-2K≥6	SRI-4	200, 600, or 1200 mg every 28 days	Better SRI-4 response in high IFN signature group	No trials ongoing	–	–	–	Promising but not pursued
Anifrolumab	IFNα blocker	Phase IIb [21]	305	SLEDAI-2K≥6	Composite of SRI-4 and corticosteroids reduction	300 or 1000 mg every 4 weeks	Better SRI-4 response in high IFN signature group	Several phase III including LN and skin lesions	–	–	–	Very promising, awaits results
IFN-kinoid	Induction of anti-IFNα antibodies	I/II [22]	28	Mild-to-moderate	–	30, 60, 120, or 240 μmg	Dose-related response anti-IFNα.Higher C3 level	Phase II trial ongoing	SLEDAI-2K ≥ 6	BICLA response at week 36	–	Promising, awaits results
SM101	Autoimmune complexes blockade	Phase IIa [23]	51	SELENA-SLEDAI≥6 LN was included	Safety, SRI-4 and BILAG	6 and 12 mg/kg every week	Better SRI-4 response	No trials ongoing	–	–	–	Promising, needs clinical studies
SM201	Autoimmune complexes blockade	Pre-clinical [24]	–	–	–	–	B-cell inhibition	No trials ongoing	–	–	–	Very early to know

Table 1. Biologics used in SLE, mechanism of action, targeted receptors and main trials

Biologic

Immunologic action

Evidence to date in SLE

Number of patients

Inclusion criteria

Primary outcome

Therapeutic regime

Results

Future trials in SLE

Inclusion criteria

Primary outcome

Therapeutic regime

Prospects

Ofatumumab

B-cell depletion

Case reports [3–5]

1, 1 and a series of four patients

–

Variable

Reduction on disease activityAnti-dsDNA reduction and C3 normalization

No trials ongoing

–

Promising, needs clinical studies

Obinutuzumab

B-cell depletion

Pre-clinical [6]

–

B-cell depletion 2-fold the rituximab

Phase II ongoing on LN

Class III or IV LN

Complete Renal Response at week 52

1000 mg on days 1, 15, 168 and 182 plus MMF

Promising, awaiting clinical results

Ibrutinib

BTK inhibition

Pre-clinical [7]

–

BTK inhibition on mature B-cell and APC

No trials ongoing

–

Promising, needs clinical studies

GDC-0853

BTK inhibition

Pre-clinical and phase I [8]

111

–

20, 60, 150 and 250 mg BID, and 500 mg QD

BTK inhibition on mature B-cells

Phase II ongoing

Moderate to severe SLE

SRI-4 response

Low and high dose daily vsplacebo

Promising, awaits results

Rigerimod

T-cell blockade

Phase IIb [10, 11]

149

ITT SLEDAI≥6 No BILAG A

SRI-4

200 μg every 2 or 4 weeks

Improvement in subpopulation SLEDAI≥6. Best results 200 μg every 4 weeks

Phase III ongoing

SLEDAI-2K ≥6 points

SRI-4 response

200 mcg every 4 weeks

Very promising, awaits results

Dapirolizumab

T-cell co-stimulation blockade

Phase Ib [15]

SELENA-SLEDAI≥4

SRI-4 and BICLA

First dose 30 mg/kg then five doses of 15 mg/kg every 2 weeks

SRI-4 and BICLA response across several endpoints

Phase II ongoing

Moderate to severe disease activity

BICLA response rate at week 24

Three different doses vsplacebo

Promising, awaits results

Rontalizumab

IFNα blocker

Phase II [18, 19]

159

Moderate to severe disease activity

BILAG

750 mg every 4 weeks (part 1), 300 mg every 2 weeks (part 2)

No general superiority; in low IFN signature it had significant superiority

No trials ongoing

–

Dubious results

Sifalimumab

IFNα blocker

Phase IIb [20]

431

SLEDAI-2K≥6

SRI-4

200, 600, or 1200 mg every 28 days

Better SRI-4 response in high IFN signature group

No trials ongoing

–

Promising but not pursued

Anifrolumab

IFNα blocker

Phase IIb [21]

305

SLEDAI-2K≥6

Composite of SRI-4 and corticosteroids reduction

300 or 1000 mg every 4 weeks

Better SRI-4 response in high IFN signature group

Several phase III including LN and skin lesions

–

Very promising, awaits results

IFN-kinoid

Induction of anti-IFNα antibodies

I/II [22]

Mild-to-moderate

–

30, 60, 120, or 240 μmg

Dose-related response anti-IFNα.Higher C3 level

Phase II trial ongoing

SLEDAI-2K ≥ 6

BICLA response at week 36

–

Promising, awaits results

SM101

Autoimmune complexes blockade

Phase IIa [23]

SELENA-SLEDAI≥6 LN was included

Safety, SRI-4 and BILAG

6 and 12 mg/kg every week

Better SRI-4 response

No trials ongoing

–

Promising, needs clinical studies

SM201

Autoimmune complexes blockade

Pre-clinical [24]

–

B-cell inhibition

No trials ongoing

–

Very early to know

Recent Developments in Biologic Therapies for the Treatment of Patients With Systemic Lupus Erythematosus

B-cell Intracellular Signalling Blockade—Bruton's Tyrosine Kinase

Comments

Most Popular Articles

What to Read Next on Medscape

About

Membership

Apps

WebMD Network

Editions

Recent Developments in Biologic Therapies for the Treatment of Patients With Systemic Lupus Erythematosus

B-cell Intracellular Signalling Blockade—Bruton's Tyrosine Kinase

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Rheumatology key Messages

Comments

Most Popular Articles

What to Read Next on Medscape

Latest News & Perspective

Recommended Reading

Drugs Related to Systemic Lupus Erythematosus (SLE)

Most Popular Articles

Recommendations

Email This

Find Us On

About

Membership

Apps

WebMD Network

Editions