AstraZeneca, Author Interviews, Rheumatology / 11.06.2020
Lupus: Highly Targeted Antibody Anifrolumab Reduced Flares in Phase 3 Trials
MedicalResearch.com Interview with:
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Dr. Furie[/caption]
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
Hofstra/Northwell
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.”
Dr. Furie[/caption]
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
Hofstra/Northwell
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.”
Prof. Dagna[/caption]
Prof. Lorenzo Dagna MD FACP
Ospedale San Raffaele and
Vita-Salute San Raffaele University
Milan, Italy
MedicalResearch.com: What is the background for this study?
Response: Upon encountering pathogens, our immune system produces pro-inflammatory mediators, called cytokines. Cytokines activate cells from the immune system. In most people, production of cytokines is an appropriate and protective response to infection. However, some individuals develop excessive and detrimental inflammatory responses, which are even more harmful than the pathogen itself to the host organism.
We hypothesized that some patients with COVID-19 might develop excessive and detrimental inflammation, and that treatment with anti-inflammatory agents might be beneficial in this population.
Anakinra is an inhibitor of the pro-inflammatory molecule interleukin 1 (IL-1). It was originally marketed for the treatment of rheumatoid arthritis, but is now mostly used to treat a variety of pediatric inflammatory diseases.
Dr. Ritch[/caption]
Robert Ritch, MD, FACS, FARVO
Shelley and Steven Einhorn Distinguished Chair
Professor of Ophthalmology, Surgeon Director Emeritus
Chief, Glaucoma Services Emeritus
The New York Eye and Ear Infirmary of Mount Sinai
New York, NY 10003
Founder, Medical Director and
Chairman, Scientific Advisory Board
The Glaucoma Foundation
MedicalResearch.com: What is the background for this study?
Response: Nailfold capillaroscopy (NFC), long used in rheumatology is a new approach to investigation of glaucoma.
Posterior to the nailbed and just anterior to the proximal nailfold is the cuticle, which has no structural elements visible to the naked eye. NFC is a non-invasive imaging modality that provides a highly magnified view of the capillaries at the nailfold of digits. It has also been used in ophthalmology to show morphological changes at the nailfold capillaries of POAG and XFG/XFS patients, helping to confirm the systemic nature of these diseases.
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