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

Pedro L. Carreira; David A. Isenberg


Rheumatology. 2019;58(3):382-387. 

In This Article

Interferon Blockade

IFNs are a family of glycoproteins that consist of type I IFN (IFN-I) (including 12 isoforms of IFNα and one of IFNβ) and type II IFN (includes only IFNγ). IFN-I binds to the type I IFN receptor (IFNR), IFNγ binds to another receptor. IFN activates multiple signalling pathways, especially Janus kinase. IFN dysregulated activity and signalling is associated with autoimmune disease development. Rarely, when IFNα has been used, for example, in hepatitis C and cryoglobulinaemic vasculitis, autoimmune conditions, including SLE, have been reported to develop.[16,17] IFN-I levels are higher in SLE and recent studies have shown a link between IFNα levels and disease activity. In Ifnar1 gene knockout mice, reduced disease activity is seen.

Rontalizumab is a humanized IgG1 mAb against IFNα. A phase I trial proved safe but showed no clinical benefit in those with a high IFN signature.[18] A phase II trial evaluated efficacy and safety of rontalizumab in 159 patients with moderate to severe SLE. Patients were randomized to receive rontalizumab 750 mg or placebo every 4 weeks plus standard of care (SOC) (part 1) and subsequently, 300 mg rontalizumab or placebo every 2 weeks (part 2). The results did not confirm rontalizumab's general superiority, however paradoxically, in the low IFN signature group SRI response rates were superior in 31% (P = 0.0285) and the SELENA-SLEDAI flare index rate was reduced.[19] However, no further trial is ongoing.

Sifalimumab is a fully human IgG1κ mAb that binds to most subtypes of IFNα and neutralizes it. Two phase I trials showed safety and IFN signature reduction in a dose-dependent manner. A 52-week phase IIb trial followed by a 22-week safety follow-up, enrolled 431 patients randomized to receive placebo or sifalimumab (200, 600 or 1200 mg) every 28 days in addition to SOC. In all sifalimumab groups, the response rates were significantly higher than in the placebo group, however, only the group with the high IFN signature patients achieved significant improvement in SRI-4. Cutaneous Lupus Erythematosus Disease area and Severity Index (CLASI) as well as joint counts showed significant improvement. No differences in lowering anti-dsDNA antibodies or normalizing C3/C4 levels were observed. Herpes zoster was the principal AE as expected by IFN suppression.[20] Currently no phase III trial is ongoing.

Unlike the other IFN blockers, directed against IFN, anifrolumab is a fully human IgG1κ mAb that blocks subunit 1 of the IFNR and consequently both IFNα and IFNβ. A phase I trial showed safety and sustained IFN signature reduction in SSc patients. In a 52-week phase IIb lupus trial, 305 patients were randomized to receive placebo, anifrolumab 300 mg or 1000 mg every 4 weeks until week 48 as well as SOC.[21] Active LN or neuropsychiatric SLE were excluded. The primary efficacy end point was a combination of the SR-4 at weeks 24 and 52 with a sustained reduction in oral corticosteroids from weeks 12 to 24. At both weeks 24 and 52, the response was achieved in a significantly higher number of patients receiving both dosages of anifrolumab (300 mg, P = 0.014 and 1000 mg, P = 0.063). When evaluating the sub-groups by IFN signature levels, those with high levels of IFN achieved significantly better results compared with placebo at both 24 and 52 weeks. Significant improvement was also achieved using BICLA, BILAG 2004; CLASI; joint counts and other variables. Influenza and herpes zoster infections were the most frequent AE. Further studies are ongoing in active SLE patients, including in LN (NCT02547922).

IFN-α-kinoid (IFN-K) is another option in blocking IFNα. IFN-K is a vaccine composed of IFNα2b coupled to a carrier protein. It acts by inducing antibody production against all IFNα subtypes. A phase I/II trial of 28 patients with mild-to-moderate SLE showed a dose-related anti-IFNα response and improvement of C3 levels.[22] A phase II trial is ongoing to elicit IFN signature reduction and efficacy in SLE (NCT02665364).