Interferon, Lupus Research, & More: An Interview with Dr. Mary Crow
Dr. Mary Crow
- Current Physician-in-Chief and Chair of the Department of Medicine at the Hospital for Special Surgery (HSS) in New York
- Chief of the Division of Rheumatology at HSS and New York-Presbyterian/Weill Cornell Medical Center
- Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at HSS
- Co-Chair of the Lupus Research Alliance Scientific Advisory Board
- Served as the President of the American College of Rheumatology
- A past President of the Henry Kunkel Society
- Honored as an “Arthritis Hero” of the Arthritis Foundation, and in 2010 she received the Margaret D. Smith Lifetime Achievement Award of the Arthritis Foundation, New York Chapter
Dr. Crow was one of the first scientists to be interested in the role of alpha interferon as a driver of lupus. As a recipient of a grant from the Lupus Research Alliance (LRA), her work contributed to the development of anifrolumab.
A conversation with Dr. Mary Crow
Dr. Crow spoke on the phone with LupusCorner earlier this month to share insight into the drug development process, the mechanisms involved with interferon, and more. Dr. Crow’s responses have been edited with her permission for brevity and clarity.
Thank you very much to Dr. Crow for sharing her expertise!
Q1 | Anifrolumab, a potential new medication to treat lupus, has been in the news recently. What do we know about the clinical trial?
DR. CROW: Really all we know at this point is that, according to a press release, the trial called TULIP II (which is just the name of the phase III trial) had a successful result. This means that it met the clinical endpoint that the company [AstraZeneca] had determined as the goal of the study. We have no information on the details of the trial of the outcome.
Still, it is certainly very encouraging. It is great to hear about a success in a phase III trial in lupus. As a drug that targets the type I interferon pathway, the development of anifrolumab has been closely followed by lupus investigators and patients. Some of the most important scientific advances that have defined type I interferon as an important mediator in lupus have come out of research studies funded by the Lupus Research Alliance. In fact more than 15 research projects have focused on the role of interferon in lupus.
Q2 | What does the anifrolumab clinical trial result mean for patients?
DR. CROW: Drug development programs go through several phases, testing not only “does it work?” but also for safety. The fact that the anifrolumab study met its endpoint is certainly a good thing. It’s a little difficult to discuss at this point what it will mean for patients or what it will mean for approval by the FDA.
The next challenge for the company is to ensure that they thoroughly explore the data. There is still more work to be done. At an upcoming meeting, perhaps the ACR (American College of Rheumatology) meeting in November, they [the company and/or researchers] could present details of the study.
Currently, I don’t think we really know what the next step will be. Often, for drug trials, the FDA requires 2 successful phase III studies.
An important question will be: Does the FDA want the company to do another phase III study, or will they accept the data as it is now?
Q3 | An earlier phase III trial on anifrolumab, TULIP I, failed to meet the clinical endpoint. For the TULIP II trial, a different endpoint was used. How do researchers select clinical endpoints for lupus trials?
DR. CROW: Identifying the most informative end point for lupus clinical trials has been very challenging over the years and is still a moving target. Some of these challenges relate to lupus as a disease. Many organ systems are involved and any given patient with lupus is going to look a little different from other patients. Experienced rheumatologists who treat lupus are excellent at saying “yes this person has lupus. Today the patient is more active than they were last month.” We understand a lot about this disease, but it can still be difficult to measure objectively.
Likely, AstraZeneca looked at the data from the TULIP I trial which used the SRI4 endpoint and saw that the data were not significant. But, they also had the information on a different endpoint, BICLA, and saw promise in use of that measure.
There are lots of ideas about molecules and pathways that suggest therapeutic targets for lupus. It’s not hard to come up with ideas for potential therapies. But it’s hard to design successful clinical trials. It’s hard to have informative outcome measures that will really pick up the signal when a drug works.
Clinical trial design has been in evolution. We learn from situations where we don’t succeed. There has been a lot of progress in understanding trial design. Important progress has been made in answering questions like:
- What are the criteria that should be used to enroll patients?
- How should steroids be used so that they don’t blunt the effects of the study drug?
Q4 | Let’s shift gears to the biology of the immune system. How is interferon connected to lupus?
DR. CROW: Interferon comes in different types. Type I interferon has different “family members” so you might hear about interferon-alpha, interferon-beta, or a few others. Interferon-alpha is the main family member for lupus, but others might play some role in the disease.
Putting together a lot of information from patients, mouse models, gene expression studies, the impact of type I interferon on the activation of molecular pathways and mechanisms related to the immune system, it is very likely that type I interferon plays an important role in lupus.
Interferon-alpha is best studied in the context of immune responses to virus infection. It can be a very good thing in battling viruses because it rallies cells of the immune system to eliminate the virus. In most healthy people, very little interferon is detectable. When one is infected with a virus, the interferon is produced for only several days. In contrast, in lupus, interferon can be detected over many months and years. The sustained production of interferon promotes autoimmunity and inflammation in tissues.
There should be great value in inhibiting the interferon pathway in lupus. This can be done in many ways. A compound could act upon:
- the cells that make interferon
- the pathways involved in inducing production of interferon
- interferon itself or its receptor
- the signaling pathways triggered by the interferon receptor
Q5 | What is the mechanism of action for anifrolumab?
DR. CROW: Anifrolumab is a molecule, a biologic therapy, that is targeting the type I interferon receptor. Receptors are specific molecules on many cells that interferon can bind to. When interferon binds, it activates the cell.
Anifrolumab blocks the various interferon receptors. There is a lot of support for this concept and the idea seems like a very good one. Block the effect of all interferon types by blocking the receptor.
Q6 | What is the role of the Lupus Research Alliance in developing new treatments?
DR. CROW: The goal of the Lupus Research Alliance is to ultimately make patients better. How do we do that? Through research.
The LRA was founded about 20 years ago and has focused on supporting research. By understanding the lupus disease mechanisms, we have more information that helps us to design approaches to treat it. LRA has had a significant role in identifying investigators and supporting the research projects that have informed our understanding of lupus. That new knowledge provides the essential framework for developing new and effective treatments.
Over the last 5-6 years, the scope of the organization has grown beyond support for laboratory research. There had been a lot of frustration because of failed clinical trials. This led the LRA to form LuCIN (Lupus Clinical Investigators Network), a group of institutions and people around the country who can do lupus trials well. LuCIN falls under the umbrella of the LRA’s affiliate Lupus Therapeutics.
LRA-funded research has made an essential and significant contribution to defining biomarkers of disease, immune mechanisms of lupus, and therapeutic targets. We have an excellent foundation for moving forward toward new and improved therapies for patients.
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