From The Editor | July 29, 2019

Lupus Community Tackles Treatment & Clinical Trial Barriers

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

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Lupus is a chronic autoimmune disease that occurs when your body’s immune system attacks your own tissues and organs. Inflammation caused by the disease can impact a patient’s joints, skin, kidneys, blood cells, brain, heart, and lungs. 

Few treatments have been approved for treatment of the disease, and the industry has seen many failed clinical trials. Variations in care worldwide, as well as poor overall access to care, has also hampered efforts to bring relief to patients. For those reasons, the international lupus community has come together to conduct a study aimed at identifying clinical and treatment barriers that must be overcome. Results of the survey were recently published in Lupus Science & Medicine.

The study was titled, “Global Consensus Building and Prioritization of Fundamental Lupus Challenges: The ALPHA Project.” It brought together experts from across 20 countries to provide the first-ever global consensus on key issues in lupus. One of the researchers on the study, Dr. Karen H. Costenbader, is director of the Lupus Program at Brigham and Women’s Hospital in Boston and Professor of Medicine at Harvard Medical School. She believes that until these barriers are addressed, they will continue to hamper lupus care and research.

I spoke to Dr. Costenbader about the study and what it means for patients and researchers.

Ed Miseta: What made the international lupus community decide to come together at this time to agree on the barriers that are hampering treatment, research, and drug development?

Karen Costenbader: Historically, similar global efforts have focused largely on removing barriers to drug development. The goal of the ALPHA Project, as well as the approach to reach that goal is different. The project is working to form consensus around and then rank in order of urgency, the basic gaps and pillars that exist and major challenges that remain in both clinical care and the in the field which, until addressed, will continue to be barriers to lupus diagnosis, care, and treatment development. This is a very exciting time in the understanding and treatment of many autoimmune diseases. Years of research into the basic mechanisms of autoimmunity and drug development and trials are paying off in diseases as such as rheumatoid arthritis and psoriasis, with many new and effective medications coming on to the market and there is a sense that our time must be coming in lupus.

On the other hand, there is frustration that we are not there yet and growing recognition that there are still many barriers to having real breakthroughs for lupus care and improvement of outcomes. Lupus is unique, with its own very complex biology and challenges that are different from those in other diseases and these need to be identified, understood, broken down and surmounted to get us where we should be in really improving diagnosis, treatment, quality of life, access to medications and treatments and survival for people with lupus.

Miseta: There have been many failed clinical trials for Lupus treatments, as well as variations in care and poor access to care worldwide. Is this the result of the barriers that have existed? 

Costenbader: Yes, definitely. Negative clinical trials, as well as disparities in care and access to high quality care, are due to some of the barriers that we are recognizing in lupus. Identifying the basic gaps, or missing pillars, which are posing as the root causes for these problems was one of the driving reasons for the ALPHA project.

Little consensus evidence exists around these pillars, nor on a uniform approach for addressing these barriers. This first step creates that evidence and allows us to move forward with developing approaches that may be applied globally.

Miseta: The study, which interviewed experts from across 20 countries, was able to produce a list of the top 5 barriers impeding better lupus outcomes. One of those is flawed clinical trial design. What has been the major design flaw in trials for Lupus treatments?

Costenbader: There are many different challenges to clinical trials in lupus, and it is hard to say that one design flaw has hampered them all. These different barriers include the heterogeneity of the disease and the use of different phenotypes and definitions of lupus in different trials, the use of complex composite outcome measures that may not adequately capture improvements in single organ systems, the allowance of high levels of standard of care therapies, including glucocorticoids, as background therapies, even in the placebo arms, lack of recruitment of individuals with lupus from diverse ancestral backgrounds, including those of African descent who are more frequently affected by lupus. And lastly, maybe our understanding of the disease is still lacking, and the drugs being tested just didn’t work for reasons we were unable to foresee.

Miseta: Did the experts have any thoughts on how we can improve the design of these trials? 

Costenbader: Yes, many of the barriers identified have to do with clinical trial design, for example identification of reliable biomarkers of disease subtype and disease activity that may help to correctly define subgroups of disease likely to respond to a therapy aimed at a particular pathway or another, and biomarkers of disease activity that could be used as more accurate read-outs of disease activity in organ systems. Experts identified lupus classification and tried to start the discussion about what related conditions fall into the lupus spectrum of diseases and perhaps should be investigated in lupus clinical trials in the future (developing lupus, cutaneous only lupus, mixed connective tissue diseases, etc.)

Miseta: Another barrier was the lack of access to clinicians familiar with Lupus. Clinicians are vital to treating patients, but also vital to clinical trials. Any thoughts on how can the industry overcome that barrier?

Costenbader: Yes, lack of access to lupus-knowledgeable clinicians is a huge barrier for diagnosis and treatment of lupus. At this point, education is key- from the student to seasoned medical profession level.  Lupus also strikes women and people from lower socioeconomic status more frequently and more severely and this needs to be widely recognized in many medical fields—not only rheumatology, but also primary care, emergency medicine, obstetrics and gynecology, pediatrics, neurology, dermatology, etc. All these medical professionals need to be trained to think of lupus in their differential diagnoses and to know how to get patients to timely clinical care. Lack of knowledge about lupus on the part of the medical community in general and the need to do a better job of educating about lupus and about referral for lupus management were recognized by the expert panel. 

Miseta: Now that we have identified these barriers, any thoughts on what the future might hold for Lupus trials?

Costenbader: The ALPHA project is an important step forward. There is more interest in lupus drug development than ever before, and we have learned so much from past studies that we are in good position for change.  Identification of the barriers is the first step of the ALPHA project. The next step is for the project’s Global Advisory Committee to come together, along with industry and other stakeholders, to outline approaches to overcoming these issues. We have a better idea about what must happen – globally – for change to occur, which is having the opportunity to come together and develop a uniform approach for addressing the specific issues. 

Looking forward, one important goal is to have many more lupus patients from the sociodemographic groups most affected by the disease enrolled in trials. It would also be marvelous to have trials targeted at specific subtypes of disease based on biomarkers, with validated biomarkers or imaging as outcomes. In order to have more targeted “precision-medicine” strategies in lupus and lupus trials, however, we need to increase and expand enrollment to those who have not had access or have not wanted to be involved in the past.