Comment on: ”Trial in Anifrolumab in Active Systemic Lupus Erythematosus” by E.F Morand, R. Furie, Y. Tanaka I.N:Bruce, A.D Askanase, C Riches, S-C Bae, P.Z Brohawn, L Pindea, A Berglind and R Tummala for the TULIP-2 Investigators. Published in NEJM 2020; 382:211-21
Commented by: Elisabet Svenungsson, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
Background: We are all aware of the great need for new and better treatments for patients with SLE. After many failed trials, belimumab is the only new approved treatment for SLE during the last 50 years.
Some investigated treatments have in clinical practice shown efficacy, e.g. rituximab, but failed in clinical trials. Many of us suspect that the lack of sensitive measures to evaluate improvements across the many manifestations in this very heterogenic disease could be the reason for some of these failures. It is in here important to mention the differences between the two composite response indices used in the anifrolumab studies. The British Isles Lupus Assessment Group (BILAG) Composite Lupus Assessment (BICLA) response index is graded and captures partial responses and improvements in different organ systems according to BILAG. The Systemic Lupus Erythematosus Responder Index (SRI) relies on Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), which register only complete responses.
The type 1 interferon (IFN) pathway has for many years been in focus of SLE research. Many SLE patients, but not all, express the type 1 IFN signature, which is based on gene expression of interferon regulated genes, measured by microarrays in peripheral-blood cells. Furthermore, genetic studies report multiple hits along the type 1 IFN pathway. These and other findings indicate that blocking type 1 IFN could be a means to treat SLE. Type 1 IFNs comprise 17 different IFN subtypes, and previous attempts to block one or several of these using specific antibodies have rendered negative or mixed results, possibly due to remaining activity in the non-blocked IFN subtypes. Anifrolumab, has another approach as it is a fully human, IgG1κ monoclonal antibody, which blocks the type I interferon receptor, the common receptor for all type-1 IFN subtypes. A large phase II trial (MUSE) showed efficacy across several endpoints (1), while the first phase III study, TULIP-1 (Treatment of Uncontrolled Lupus via the Interferon Pathway–1) (2) did not reach its primary SRI(4) endpoint. However, several secondary outcomes were reached such as the BICLA response, reduced corticosteroid dosage and improvement in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) skin score.
This study, TULIP-2 (3), is the second phase III trial of anifrolumab. The primary endpoint was changed from the SRI(4) to BICLA. This decision was made based on the results of TULIP-1, but before the unblinding of TULIP-2,.
In TULIP-2, 362 SLE patients were randomized to blindly receive 300 mg anifrolumab or placebo intravenously every 4 weeks for 48 weeks. Inclusion criteria were based on a SLEDAI score ≥ 6, with at least 4 clinical SLEDAI points. In addition, ≥ 1 severe (A), or ≥ 2 moderate (B) organ involvements by BILAG were required together with serologic positivity by ANA (≤ 1/80) or anti-dsDNA or anti-Sm antibodies. It was also a requisite that Physician’s Global Assessment (PGA) was ≥ 1 on a scale from 0 to 3. Patients should furthermore be on stable SLE treatment of prednisolone ≤ 40 mg for at least two weeks or standard lupus DMARD medication for 8 weeks. Patients with active severe lupus nephritis and/or neuropsychiatric manifestations were excluded.
The primary endpoint was response as measured by BICLA, at 52 weeks. A BICLA response was reached by 47.1 % in the anifrolumab group versus 31.5 % in the placebo group (95% CI: 6.3-26.3 %, P=0.001). Among the secondary outcomes: Lower glucocorticoid dose and ≥ 50% improvement in CLASI skin score was also reached in the anifrolumab group. Swollen/tender joint count and new flare rates did not reach significance. Reported side effects were herpes zoster and bronchitis, 7.2% and 12.2 % respectively. There was one fatality due to pneumonia in the anifrolumab treated group.
Comments: As a clinician I reflect on how representative this study is for the general lupus patient and which patients will benefit from anifrolumab, if approved for clinical use.
From the supplementary material, it is clear that a majority of the investigated patients had active involvement of skin, joints and positive serology, while few had renal, cardiovascular and hematological manifestations. Many were on glucocorticoid treatment (approx. 80 %) and almost half of them (approx. 45 %) on dosages equivalent to 10 mg prednisolone/d or higher. A high IFN score was present in a majority, 83%. These data tell me that the included patients had active disease, though efficacy for some important manifestations such as active renal, neurological (both exclusion criteria), vascular hematological and constitutional manifestations cannot be evaluated since very few had such manifestations. However, anifrolumab seems to be a good choice for patients with active skin disease, a group which is often very difficult to treat. Interestingly the response rates were similar in those with high and low type 1 IFN signature. Of note is that no patient reported outcomes have yet been presented.
Among side effects more frequent herpes zoster and upper respiratory tract infections were noted in the MUSE and TULIP-2 anifrolumab trials (1, 3). These are important observations since type 1 IFNs are important for the early innate antiviral response, and we should be cautious since we don’t know how anifrolumab will affect the clinical course of COVID-19 infections.
Overall TULIP-2 brings good news, giving hope for many patients with lupus, especially those with skin involvement. The majority of reported data point in a favorable direction for anifrolumab, but further studies are needed to address the efficacy for joint, renal hematological, vascular and neurological lupus manifestations.
- Furie R, Morand E, Bruce I, et al. A Phase 3 Randomized Controlled Trial of Anifrolumab in Patients With Moderate to Severe Systemic Lupus Erythematosus. Presented at: ACR 2019 Annual Meeting; November 8-13, 2019. Abstract ID: 1763. https://acrabstracts.org/abstract/a-phase-3-randomized-controlled-trial-of-anifrolumab-in-patients-with-moderate-to-severe-systemic-lupus-erythematosus/. Accessed: October, 2019.
- Furie R, Morand E, Bruce I, et al. Anifrolumab: Type I Interferon Inhibitor Anifrolumab in Active Systemic Lupus Erythematosus (TULIP-1): a Randomised, Controlled Phase 3 Trial, Lancet Rheumatology 2019; doi.org/10.1016/S2665-9913(19)30076-1. Accessed November 11, 2019.
- Morand E, Furie R, Tanaka Y, et al. Efficacy and Safety of Anifrolumab in Patients with Moderate to Severe Systemic Lupus Erythematosus: Results of the Second Phase 3 Randomized Controlled Trial [oral]. Presented at: ACR 2019 Annual Meeting; November 8-13, 2019. Abstract ID: L17. https://acrabstracts.org/abstract/efficacy-and-safety-of-anifrolumab-in-patients-with-moderate-to-severe-systemic-lupus-erythematosus-results-of-the-second-phase-3-randomized-controlled-trial/ Accessed: November, 2019.