11 Jun Lupus: Highly Targeted Antibody Anifrolumab Reduced Flares in Phase 3 Trials
MedicalResearch.com Interview with:
Richard Alan Furie, MD
Professor, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases
Feinstein Institutes for Medical Research
Chief, Division of Rheumatology, Northwell Health
Professor of Medicine, Donald and Barbara Zucker School of Medicine
MedicalResearch.com: What is the background for this study?
Response: It has been known for decades that type I interferons play a role in SLE pathogenesis, and therefore the burning question has been whether inhibitors of these pro-inflammatory cytokines would reduce SLE disease activity and could be used as a therapeutic. There are several strategies for inhibiting the type I interferon pathway, but a conventional approach is to create an antibody against the target protein. The first few clinical trials in SLE evaluated monoclonal antibodies to alpha interferon. Results were modest at best. Since this approach only inhibited one (alpha) of five type I interferon subtypes, there were still four subtypes unaffected that could provoke inflammation. A rather crucial piece of information is that all five subtypes bind to the same receptor. Therefore, if the receptor is blocked as opposed to a single cytokine, the entire type I interferon family of proteins would be prevented from binding the receptor. This was accomplished with anifrolumab.
The phase 2 study in SLE (known as MUSE), which yielded very robust results, was reported several years ago. It served as a foundation for the phase 3 program, which consisted of two pivotal studies known as TULIP-1 and TULIP-2. Both studies were reported at the 2019 American College of Rheumatology meeting in November, 2019. Although TULIP-1 did not achieve the primary endpoint, several secondary endpoints were met. TULIP-2 was successful. Between all three studies, approximately 1000 patients were enrolled. Taking advantage of these large numbers, additional analyses of the combined datasets afforded our ability to answer questions about the effects of anifrolumab that were not previously addressed with greater power.
In the narrative that accompanied my presentation, I stated “In lupus, disease activity begets damage, and damage begets more damage. The long-term sequelae of heightened disease activity, better known as flare, are significant. Regardless of how flare is defined or measured, a major goal is to prevent flare.
It is quite justified to think a drug that reduces lupus disease activity should also prevent flares. Well, the proof is in the pudding.
In this analysis, we evaluated the effects of anifrolumab on flares. Recall that anifrolumab targets the type I interferon receptor, blocking all 5 type I subtypes. The phase 2 MUSE study yielded robust results as did the phase 3 TULIP-2 study. While, the phase 3 TULIP-1 study did not achieve its primary endpoint, many secondary endpoints showed benefit.
In this study, we focused on flare, and examined TULIP-1 and 2 individually as well as pooled data from both studies.”
MedicalResearch.com: How does anifrolumab differ from other medications for SLE?
Response: It is a highly targeted therapy that binds the type I interferon receptor. Other medications, such as steroids, antimalarials, and immunosuppressives, used to treat SLE have far broader effects, both good and bad. The ultimate goal of treating autoimmune diseases is to focus on a single molecule with the expectation of reducing disease activity and limiting side effects through this targeted approach.
MedicalResearch.com: What are the main findings?
Response: The specifics discussed in my narrative are as follows:
- “If you look at Figure 2, compared to placebo, the annualized BILAG flare rate ratios in those who received anifrolumab were 17, 33, and 25% lower in TULIP-1, TULIP-2, and the pooled TULIP studies. Nominal p values were less than .05 for TULIP-2 and the pooled analysis.
- The assessment of annualized BILAG flares vs. baseline yielded similar numeric trends, but comparisons to placebo were not statistically significant.
- Focusing on Figure 3, fewer patients experienced 1 or more BILAG flares in the anifrolumab groups in TULIP-1 and 2, and the pooled studies.
- Figure 4 displays the Time to First BILAG Flare where we observed 24, 35, and 30% reductions in the hazard ratios.”
A highly condensed version of the above is that using conventional measures of SLE flare, we observed flare prevention in those who received anifrolumab.
MedicalResearch.com: What should readers take away from your report?
Response: We observed a reduction in flare rates in those who received anifrolumab during the studies. This is important because each time a flare occurs, the well-being of the patient is compromised. They may need more medication to treat the flare, and damage in a particular organ may have occurred either from the disease itself or from the medication used to treat the flare. The results of the TULIP trials not only support the capacity of anifrolumab to reduce disease activity but also to reduce flares, an attribute that is vital to long-term patient management.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: A number of additional analyses of the TULIP data are underway. Stay tuned for presentations at future meetings as well as publications.
I have been a recipient of research support as well as research consulting fees from AstraZeneca and Medimmune.
1)Early and Sustained Responses with Anifrolumab Treatment in Patients with Active Systemic Lupus Erythematosus (SLE) in 2 Phase 3 Trials.1
EULAR Oral Abstract Presentation Session 03 June 2020
2) Furie R, Morand E, Askanase A, et al. Flare Assessments in Patients With Active Systemic Lupus Erythematosus (SLE) Treated With Anifrolumab in 2 Phase 3 Trials . Presented at: The European League Against Rheumatism, EULAR, European E-Congress of Rheumatology 2020); 3-6 June 2020. Abstract ID: SAT0174.
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