Written By: Sarah Compton, Sam Minkin, Whitney Elg-Salsman, Ana Tucker, and Jen Schmidt; MUSC Rheumatology Fellowship

Based on: TULIP-1 and TULIP-2 trials of anifrolumab

Topic Overview

Type I interferons are cytokines that link innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus (SLE) with increased interferon-stimulated gene expression seen in most patients with SLE. Anifrolumab is a fully human IgG1K monoclonal antibody to type 1 interferon receptor subunit 1, and inhibits signaling by all type I interferons, which results in enhanced blockage of the type I interferon pathway. Anifrolumab has undergone two phase 3 trials- TULIP 1 and TULIP 2. TULIP 1 was a double-blind, randomized, controlled phase 3 trial performed internationally in multiple centers. The trial was designed to assess the efficacy and safety of IV anifrolumab versus placebo in adults with SLE who are receiving standard of care treatment. Patients were randomly assigned to high or low dose anifrolumab or placebo. Patients were also randomized according to their interferon gene signature. Patients had to have moderate to severe SLE and be on stable doses of medication. Patients with lupus nephritis and neuropsychiatric manifestations were excluded. Primary endpoint of SLE-Responder index-4 (SRI-(4)) was not reached. Secondary endpoints were not formally statistically assessed but there were improvements in oral corticosteroid dose, cutaneous lupus erythematosus disease area and severity index (CLASI) responses, and the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA) responses. TULIP 2 used only high dose anifrolumab against placebo which did meet its primary endpoint of the BICLA response after changing from the SRI-(4). SRI-(4) was enticing given its promise shown in the phase 2 MUSE trial as well as its use in the belimumab phase 3 trial. Adverse effects were shown in a high proportion in both groups, but a higher incidence of herpes zoster was shown in the anifrolumab group.

Implications for Patients, Providers, & Researchers

Current implications: Limited application at this time pending additional studies, but in patients with active cutaneous manifestations of SLE who have failed or have contraindications or intolerance to multiple therapies and remain on glucocorticoids could consider for off label use.

Future implications: We hope for this team FDA approval of anifrolumab in the coming future. We also envision this medication will be used for those patients that are steroid dependent and those with cutaneous manifestations. We would like to see anifrolumab be put up against lupus nephritis and neuropsychiatric manifestations to help us better understand how it will work in our patients with these manifestations. Those patients that are unable to have control of their disease despite standard medications will benefit from this medication.

Will Anifrolumab Win its First Round Match-up?

This team is definitely the underdog against FDA-approved belimumab. Breaking way as the first FDA approved drug for SLE in 60 years, some may say belimumab is already the champion. This team has promise though as it too was able to meet its primary endpoint in BICLA response after some trial and error. This team was also able to improve oral corticosteroid dose and skin manifestations.

Could Anifrolumab Win it All?

Chances are somewhat slim for anifrolumab to win it all in the tournament, but anifrolumab did make a comeback in the TULIP 2 trial using the secondary endpoint, BICLA response, from the first trial by proving significance. The primary endpoint was changed prior to unblinding the study to BICLA response from SRI-(4) which some may say is sneaky or others genius. Who knows?- anifrolumab may have the fairytale ending it deserves. With the demonstration of inhibition of interferon type 1 in those with a high interferon signature its unique mechanism of action, steriod sparing effects and improvement in cutaneous manifestations of SLE make this distinctive player one to watch in the armamentarium to treat the cruel mystery that is lupus.

Reference(s)

1. Furie, R. A., Morand, E. F., Bruce, I. N., Manzi, S., Kalunian, K. C., Vital, E. M., Lawrence Ford, T., Gupta, R., Hiepe, F., Santiago, M., Brohawn, P. Z., Berglind, A., & Tummala, R. (2019). Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomized, controlled, phase 3 trial. The Lancet Rheumatology. doi:10.1016/S2665-9913(19)30076-1
2. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 01 2020;382(3):211-221. doi:10.1056/NEJMoa1912196

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