Dr. Anca D. Askanase

For nearly two decades, Anca D. Askanase, MD, MPH, has sought answers to the many questions surrounding systemic lupus erythematosus (SLE), a rare and complex disease involving multiple organs and diverse clinical manifestations. Dr. Askanase, an internationally renowned SLE clinician, diagnostician, and researcher, is the first to admit that lupus poses unique challenges to both doctors and patients. “I have been fortunate enough to have learned a great deal about lupus, both in the lab and through years of hands-on patient care, but I find myself humbled by the fact that I am always learning something new in addressing the toll lupus can take on a patient and their family, both physically and emotionally,” says Dr. Askanase, Director of both the Lupus Center and Rheumatology Clinical Trials at NewYork-Presbyterian/Columbia University Irving Medical Center. “To continue to be schooled in SLE means that there is still more learning to be done to address all of the needs of the disease and the patients affected by it.”

“Over the past 15 years I’ve been part of both the big success story of Benlysta® [belimumab], which was the first new drug approved to treat SLE in half a century, but also the many promising drugs that failed to succeed in Phase 3 clinical trials. We’ve learned from both the successes and the failures.” — Dr. Anca D. Askanase

While the challenges of lupus are many, Dr. Askanase and her Columbia colleagues remain undaunted. “Lupus has evolved, and I do think we have made extraordinary progress,” she says. “We are certainly doing more than we did 15, 20, and 30 years ago. Today, we have a better understanding of the disease, how to treat it, and more treatment options,” continues Dr. Askanase. “In 1950, mortality from lupus was about 50 percent. We’re at a place now where the 10-year mortality is less than 10 percent but that is too much because lupus is a disease of young women.”

“Most importantly,” continues Dr. Askanase, “we have come to understand the unique insights that patients offer into managing their own disease and have developed tools that make patients active team members in most effectively treating their SLE.”

On the Road to Newer Therapeutics

The standard tools for combating lupus include an arsenal of drugs — antimalarials, nonsteroidal anti-inflammatory drugs, corticosteroids, cytotoxics, and immunosuppressants — all of which improve disease activity but put patients at risk for long-term consequences from both low-level, active SLE and from the medications themselves. “Part of the revolution in lupus care going back to the 1990s was the insight that we could use mycophenolate mofetil, an organ transplant medication with relatively tolerable side effects, instead of the old chemotherapy agent, cyclophosphamide, which could truly incapacitate patients,” says Dr. Askanase.

“Over the past 15 years I’ve been part of both the big success story of Benlysta^® [belimumab], which was the first new drug approved to treat SLE in half a century, but also the many promising drugs that failed to succeed in Phase 3 clinical trials,” says Dr. Askanase. “We’ve learned from both the successes and the failures.”

One important lesson that Dr. Askanase and the lupus community have learned is the need to create the same culture of excitement and appreciation for the research and development in SLE as exists in cancer research in order to raise SLE’s profile both among the medical and patient communities. “The potential for change is huge, and we have so many promising studies on the horizon and in the pipeline. However, there are simply not enough patients who know about these fantastic opportunities to fill all of the studies,” says Dr. Askanase. “Physicians need to discuss with their patients the advantages of participating in clinical trials — even in the placebo arm.”

Trials of new lupus drugs are often decades long and require thousands of patient participants to reach their goal: approval of a new therapy that can save the lives of patients with SLE. For example, in 2011, after a more than 60-year lag with no new medicines specially targeting lupus, the FDA approved the use of Benlysta, a monoclonal antibody, which represented a breakthrough in lupus drug development. Benlysta spent more than a decade in development and testing before it reached patients. Dr. Askanase served as a Principal Investigator in the Phase 3 clinical trial of Benlysta and several Phase 4 clinical trials designed to further understand the role and the use of the medication in special populations.

“What’s different about Benlysta is that it targets a specific lymphocyte stimulator (BLyS), or Β-cell activating factor, that is both elevated in lupus patients and correlates with SLE activity,” says Dr. Askanase. “Using novel techniques, researchers first identified an anti-ΒLyS antibody that blocks the activity of the ΒLyS. This discovery allowed scientists to take this important breakthrough from the laboratory bench to the bedside by creating a drug that would block BLyS and then offering it to patients in a clinical trial. Benlysta shined a light on lupus and now there are other promising drugs targeting different mechanisms that are currently in late phases of development and are desperately seeking lupus patients for clinical trials.”

Patient participation in clinical trials is the primary factor in fine-tuning a new drug so that it might potentially deliver on its initial promise. For example, Dr. Askanase cites anifrolumab, a monoclonal antibody that targets interferon α receptor 1 (IFNAR1), currently in Phase 3 clinical trials. “We were part of the anifrolumab study and were enormously disappointed to learn that one of the Phase 3 trials did not meet its endpoint,” says Dr. Askanase. “Hopefully we will learn from this trial how to improve trial design and outcomes and succeed in the quest for better therapies for lupus.”

Improving Outcomes Measures in Lupus

The failure of so many promising lupus drugs after long-term trials has often confounded clinicians who depend on patient and physician reporting to gauge the efficacy of these new therapies. It underscores the need for a simple, scalable index that accurately measures disease progress and can provide reliable endpoints for international trials and quality measures for busy clinical practices. “Both physician assessments and patient experiences are important to know about, since they are complementary but not superimposable aspects of disease activity,” says Dr. Askanase. However, clinician-reported outcome (ClinRO) and patient-reported outcome (PRO) measures for SLE frequently differ, and it is unclear whether discrepancies reflect different assessments of specific symptoms or different perspectives about which symptoms are important.

“Physicians are taught to evaluate disease activity, length, severity, and medication side effects separately,” says Dr. Askanase. “Without clear instructions, patients may report mixed perceptions of what they view as key side effects — such as irreversible scarring, steroid-induced weight gain, situational anxiety or depression, fatigue, and pain — that unfortunately do not always help accurately assess the improvement or worsening of disease activity that doctors utilize in assessing outcomes.”

To address these issues, Dr. Askanase, in partnership with the Lupus Foundation of America (LFA), helped design the LFA-REAL™ (Rapid Evaluation of Activity in Lupus) tool. This simple but versatile instrument based on additive, organ-specific scales with separate and overlapping physician and patient components, accounts for this divergence of perspectives while also directing attention on symptoms responsive to immunotherapies.

The PRO part of the LFA-REAL™ was developed based on FDA guidance using in-depth patient input and cognitive debriefing to ensure it was understandable and included patients’ priorities. A similar approach invited community-wide input into the LFA-REAL™ ClinRO structure and content. In early validation studies the instrument showed great potential with low inter- and intra-rater variability, consistency among investigators, and reliability in tracking disease activity progress over time.

Patient Input: Critical to Effective Drug Development

As the LFA-REAL™ confirmed, people living with systemic lupus erythematosus are uniquely positioned to help clinicians refine their understanding of the therapeutic context for drug development and evaluation. To that end, in 2017, top decision makers at the Food and Drug Administration heard from over 550 people impacted by lupus as part of the FDA’s Patient-Focused Drug Development (PFDD) Initiative. In collaboration with the Lupus and Allied Diseases Association, Lupus Foundation of America, and Lupus Research Alliance, the two-day workshop allowed regulators to better understand the perspectives of people with lupus in order to better assess the risks and benefits of drugs under review.

Dr. Askanase was the only physician invited to address the attendees, which included patients, family members, and representatives from regulatory agencies and industry. She described the unpredictability and individuality of lupus, detailing the inadequate treatments for lupus, their varying effectiveness, and challenging side effects.

“I was honored to have a featured role in trying to present the complexity of this disease and explain why the world needs to listen to patients’ voices,” says Dr. Askanase. “We want to make sure that they are heard and are a part of the drug development process in order to provide the best improvements in their symptoms and quality of life.”

The major themes that emerged from the meeting included the substantial burden of disease in women, particularly among women of color; the considerable variability and heterogeneity of symptoms among people with lupus across their lifespan; the broad impact of the disease and treatment side effects on an individual’s work, social, and family life, self-esteem, and quality of life; and the inadequacy of currently available treatments.

Likening lupus to the “Cinderella” of diseases, unique to each patient and hidden from everyday view, Dr. Askanase says she is nevertheless encouraged that many people who once shied away from acknowledging that they had the disease are now coming forward. “Over the past decade we’ve seen a change in that regard,” she says. “I’m very grateful to all of the celebrities and public individuals who have revealed either that they have lupus or know someone with lupus. I think it sends a good, positive message to the world of patients and also to the doctors who take care of lupus patients that we are all in this together.”