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

Pedro L. Carreira; David A. Isenberg

Disclosures

Rheumatology. 2019;58(3):382-387. 

In This Article

T Cell co-stimulation Blockade

B-cell immune stimulation follows interaction with T cells and antigen-presenting cells via co-stimulatory signals, notably CD40/40 L, CD28, cytotoxic T-lymphocyte antigen 4, and CD80/CD86.

Rigerimod is a 21-mer linear peptide derived from the small nuclear RNP U1-70 K, whose mechanism of action seems to be due to chaperone-mediated autophagy.[9] By reducing the stability of MHC molecules that present antigens to T cells, it blocks antigen presentation to autoreactive T cells, which in turn blocks B-cells maturation.

A phase II trial involved 20 patients with moderately active SLE who received three s.c. injections. Significant improvement in the SLEDAI score was reported with the 200 μg/dose.[10] A phase IIb trial showed a significant reduction of disease activity.[11] One hundred and forty-nine patients were randomized to receive rigerimod or a placebo every 2 or 4 weeks. Patients with SLEDAI-2 K≥ 6 who received rigerimod 200 μg every 4 weeks achieved a statistically higher Systemic Lupus Erythematosus Responder Index (SRI)-4 response at week 12 (67.6 vs 41.5%, P < 0.025) and week 24 (84.2 vs 45.8%, P < 0.025). A phase III trial is underway, whose primary outcome is SLEDAI-2 K reduction ≥4 (NCT02504645).

CD40 ligand (CD40L) is a protein expressed on activated T cells and a member of the TNF family. Its binding to CD40 on antigen-presenting cells and B cells induces co-stimulation and promotes B-cell maturation. Anti-CD40L mAbs block co-stimulation in experimental models. A phase II trial in 28 patients with proliferative LN showed significant reduction in circulating levels of anti-dsDNA antibodies and increased C3 levels, but was associated with thromboembolic events.[12] Another phase II trial of a different anti-CD40L mAb had no major adverse events (AE), however, efficacy was not proven.[13] The thromboembolic events were evidently caused by the functional Fc region of anti-CD40L, which triggers platelet aggregation by interacting with platelet FcγRIIA receptor. In dapirolizumab the Fc portion has been changed to a high molecular polyethylene glycol without loss of efficacy.[14] A 32-week, phase IB trial showed safety and tolerability of intravenous dapirolizumab in SLE patients. Clinical response was evident by both SRI and BILAG-based Combined Lupus Assessment (BICLA) assessments.[15] A 24-week phase II trial, followed by observational period to evaluate efficacy and safety on moderately to severely active SLE is recruiting (NCT02804763). The primary outcome is the BICLA response rate at 24 weeks.

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