FDA Approval of New Lupus Therapy Marks a Milestone
The approval of anifrolumab (Saphnelo) in 2021 by the US Food and Drug Administration marked a milestone for the treatment of people with systemic lupus erythematosus (SLE). The drug, which blocks the activity of proteins in a family called type I interferon (IFN-I), is the first approved drug of its kind to effectively do so.
IFN-I is essential for the body’s defense against viral infections — a key part of what is called the innate immune response. When a virus invades, this molecule sets off a cascade of events that rallies the immune system to fight the infection. But in autoimmune diseases like lupus, the immune system is activated in the absence of any infectious agent, resulting in endemic inflammation.
By jamming the signals sent out by IFN-I, anifrolumab significantly reduces that inflammation. Much of the groundwork for the development of this drug has been done through study of HSS patients in an HSS research laboratory over the past 20 years.
“There had been observations going back to the late 1970s suggesting that IFN-I was elevated in people with lupus and possibly other autoimmune diseases,” says Mary K. "Peggy" Crow, MD, Physician-in-Chief Emerita at HSS, Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at the HSS Research Institute. “These observations suggested a connection, but at that time the elevated interferon was viewed as just one of many immune system alterations in patients with lupus.”
What changed around the turn of the 21st century was the development of microarray platforms, which enable high-throughput analysis of broad gene expression. “This allowed our lab to study blood samples from individual patients and look at the spectrum of genes that were being transcribed in a very automated, agnostic way,” Dr. Crow says.
“We began to generate lists of gene transcripts that were significantly different between people with SLE and our control samples. I went to the literature to learn what these transcripts were doing, and IFN-I kept coming up. We interpreted our data as a clear signal that the dominant molecular alteration in patients with SLE was related to IFN-I.”
Similar efforts by two other research groups, in Texas and Minnesota, led to the same conclusion and resulted in a series of landmark publications in 2003. The gene expression data from all three groups confirmed that there was a pattern of IFN-I-induced gene expression in people with SLE.
Dr. Crow and her colleagues, including Kyriakos A. Kirou, MD, who was a member of her lab for many years and is now an associate attending physician at HSS, continued to advance the knowledge surrounding the connections between IFN-I and SLE. Among their discoveries were the identification of interferon-α as the type of IFN-1 that was most important in lupus and findings reported in a 2005 paper that took a closer look at the autoantibodies generated by patients with lupus. The data pointed to a strong association between autoantibodies that targeted RNA-containing particles and the activation of the IFN-I pathway, suggesting a role for RNA in driving production of IFN-α. These discoveries also contributed to the eventual development of anifrolumab, a monoclonal antibody that is targeted against the IFN-I receptor.
Dr. Crow has also studied the role of heritability in the development of lupus. Among her work in this area is a 2007 study, conducted with her colleague Timothy Niewold, MD, recently appointed Vice Chair for Research in the Department of Medicine at HSS, that found that in families of lupus patients, high levels of interferon-α activity were not only seen in the patients but also in their healthy first-degree relatives. Later research focused on specific inherited gene variants that were associated with lupus. The connection between heredity and the likelihood of developing lupus is now widely accepted, although the many environmental factors that also contribute to the disease are still not fully understood.
A phase II trial of anifrolumab, called MUSE, and two phase III trials, called TULIP, led to the drug’s FDA approval. In these trials, the investigators reported that about 48% of the patients who received anifrolumab had a reduction in the symptoms of SLE, compared with only 32% of those who did not get the drug. Most of those who responded had fewer disease flares, and many patients receiving anifrolumab were able to taper their steroid use.
“One of the things that makes anifrolumab so promising is that it appears to work particularly well for patients whose disease is more severe. Patients who have high levels of IFN-I responded to the drug better than patients who had lower levels of IFN-I,” says Dr. Kirou, who now leads clinical trials for lupus and was involved in the trials leading to anifrolumab’s approval. “It was especially effective against the skin rashes that are common in lupus patients.”
Although anifrolumab is an important advance, additional drugs for treating lupus are needed, especially for patients who do not respond to other treatments. Work done in Dr. Crow’s lab has contributed to other avenues of research through her study of plasmacytoid dendritic cells, the type of immune cells that secrete interferon, and T lymphocyte molecules that promote the development of autoantibody-producing cells. “It is through studying the altered immune systems of patients with SLE that we identify promising therapeutic targets and provide the rationale for new drug development,” she says.
“As an investigator working in the lab, you sometimes get narrowly focused on particular immune system mechanisms,” Dr. Crow concludes. “But what’s always on your mind is that you want your work to be useful and have a positive impact on patients. It’s very gratifying to see that this drug works. The FDA approval of this approach marks the culmination of a project that’s been ongoing for more than 20 years.”
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