Current Challenges and Developments in Lupus Drug Discovery

Lupus is a chronic autoimmune disease that is characterized by systematic inflammation and dysregulation of the immune system. It has a wide range of manifestations, and can involve multiple organs in the body, including the skin, joints, kidneys and blood. This heterogeneity makes treatment difficult, and research into the development of novel therapeutics to improve patients’ quality of life is ongoing.

Xtalks and Genuity Science recently hosted a webinar where lupus experts from around the world gathered to discuss the progress and challenges of their research.

Lupus Experts Reflect on their Research

Dr. Keith Elkon, a professor of medicine and immunology and co-director of the Center for Innate Immunity and Immune Diseases at the University of Washington, has been studying the pathogenesis of lupus for more than 30 years. “The most fundamental aspect of research is that we want to know which genes and pathways are the most relevant,” Elkon says. He describes how geneticists have identified at least 100 genetic variants that are enriched in lupus patients. These genes inform researchers as to the pathways that relate to signal transduction and lymphocytes, activation of cytokines, and metabolic pathways within the cell.

The next fundamental question about lupus disease progression is, which cells are critical for orchestrating the disease? The greatest interest is in autoantibody-producing B cells, which are, in part, responsible for interferon production, and neutrophils which contribute to tissue inflammation, a major aspect of lupus pathogenesis.

Dr. Elkon explains that the treatment of lupus, as with most autoimmune diseases, often involves the use of a single biologic that reduces symptoms in the majority of patients, but he is questioning whether that is a reasonable paradigm.

“From the clinical perspective, we need safer and more effective therapies,” says Dr. Richard Furie, chief of the Division of Rheumatology at Northwell Health and professor of medicine at the Zucker School of Medicine at Hofstra/Northwell. “The name of the game is preventing damage from the disease, but also from the medicines that we use.”

Dr. Furie also conducts clinical research into lupus, with the goal of developing novel therapeutics. He explains how, at the beginning of his research in the early 1990s, there were only two drugs available to use in clinical trials for lupus, but now there is unprecedented clinical trial activity.

However, even with the large number of lupus clinical trials being conducted today, the research is not without its complications. “One of biggest challenges is clinical trial design is enrolling informative patients,” Dr. Furie explains. “We’ve had far more failures than our colleagues working on rheumatoid arthritis or psoriasis.”

He is hopeful that the future will yield more therapeutic options for lupus patients, because that ultimately translates to better outcomes for them.

Another lupus researcher, Dr. Ian N. Bruce, professor of rheumatology and director of the NIHR Manchester Biomedical Research Centre at the University of Manchester, began his work in Belfast in the early 1990s where he was focused on systemic vasculitis at the time. Dr. Bruce describes how his work on accelerated atherosclerosis as a chronic long-term outcome of lupus led him to discover several problematic factors that are always present in the disease.

“The first of these is persistent low-grade inflammation,” Dr. Bruce explains. “The other is ongoing use of, and reliance on, steroids for a large number of our patients.” He goes on to say that the extensive steroid use is a reflection of the fact that the current treatments do not fully control the disease in all patients, which drives the search for novel therapies.

Dr. Bruce is heavily involved in clinical trials for lupus drug discovery but is also trying to move beyond clinical trials. In the UK, where he works, there are a number of registries that have been set up for patients receiving biological therapies. The registries follow people in the UK who are being treated with different lupus drugs to generate real-world data with respect to the effectiveness and safety of each therapy.

A few years ago, Dr. Bruce also received funding to study stratified medicine and personalized medicine for lupus, using the registry. One of the things he says he has learned is that it is highly unlikely that a single targeted therapy will work for every patient; therefore, it’s important to match patients with the right drugs for them, which necessitates a better understanding of the subsets of lupus.

Lupus expert Dr. Michelle Petri, professor of medicine at Johns Hopkins University School of Medicine, has taken a different approach to studying the disease: longitudinal clinical research. Dr. Petri’s group diligently collected data on patients every three months, regardless of their disease activity, giving her study unprecedented completeness and consistency.

She discovered that some patients have a flare pattern, while others always have chronic activity. Following patients longitudinally allows Dr. Petri to understand what contributes to organ damage. She concluded that prednisone was extremely toxic to lupus patients, effectively poisoning them at the doses that they were being prescribed. The prednisone was found to largely be responsible for the major organ damage, especially the musculoskeletal damage.

“We have to chuck prednisone. It’s a problem. It’s never going to be a long-term solution,” concludes Dr. Petri. She explains that this is why it is so important to find new treatments for lupus. The current treatments leave 23 percent of lupus nephritis patients in renal failure after 20 years of treatment.

Lupus Therapeutics and Clinical Trials

There have been quite a few drugs developed to treat autoimmune diseases that are related to lupus, such as rheumatoid arthritis, but drug development specifically for lupus has remained a struggle. “I don’t know how many drugs we’ve studied,” describes Dr. Furie. “Probably between 75 and 100.”

Only a few of those trials have been successful. Dr. Furie suspects that trial design may be the main culprit, but he also thinks that trials may be lacking in informative patients.

It is possible that some trial participants do not truly have lupus or may be lacking in certain critical biomarkers that makes them informative for drug development. Dr. Furie explains how enrichment of clinical trials for specific types of patients is critical, which makes patient recruitment challenging.

However, there have been some recent successful Phase II and Phase III studies, which is excellent progress. “Bit by bit, we’re learning from the past,” concludes Dr. Furie.

Dr. Petri’s opinion is that it is necessary to take this approach one step further and stratify patients based on their mechanism of action. “Otherwise,” she explains, “we’ll be throwing out therapies that might help a particular subset.”

Dr. Petri explains that the approach for lupus drug development needs to be putting the right patient into the right trial. There are medications for which trials have had negative results, but which work very well in some lupus patients, such as rituximab.

Dr. Bruce agrees. He describes how clinical trials can have negative results if they include both participants who are responsive and non-responsive to a medication, because the statistical signal will be lost when the results are analyzed.

Is a high error rate in the diagnosis of lupus contributing to the failure rate of clinical trials? Dr. Petri doesn’t think this is the case, saying that there is good agreement in lupus diagnoses when it is an expert who is performing the diagnosis, which is the case in a clinical trial setting. Misdiagnoses usually happen in the clinical setting, when the evaluation is performed by a primary care physician, not a lupus expert.

The goal of lupus clinical trials is to find new methods for controlling active lupus, but also to fix the multitude of comorbidities that contribute to the long-term organ damage that is suffered by lupus patients.

Biomarkers and the Future of Lupus Clinical Trials

Dr. Petri explains how important biomarkers for lupus are, especially in the urine proteome. “We can’t keep doing renal biopsies,” she explains, even though that’s what her nephrology colleagues request. Patients don’t want to keep doing kidney biopsies, as they are invasive and not practical for real-world patient care.

She believes that it will be possible to use urine proteomics, and that this platform has massive potential for advancing the knowledge of lupus as a disease. For example, the urine proteome has shown that interleukin 16, a previously unknown contributor to lupus pathology, is a major marker for histology, and it can also be measured quite accurately in the urine.

These developments are extremely exciting for both the understanding of lupus biology and the clinical treatment of lupus patients. For more information on the latest in lupus drug discovery and development, watch this on-demand webinar.

This article was created in collaboration witht he sponsoring company and the Xtalks editorial team.