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Greater Flexibility in Clinical Trial Design Needed for Lupus

An editorial published in NEJM by Jane E. Salmon, MD, suggests regulators should require that only one of two outcomes should be met

A successful phase III trial of anifrolumab in systemic lupus erythematosus (SLE), called TULIP-2 (Treatment of Uncontrolled Lupus via the Interferon Pathway–2), reported positive results in this week’s New England Journal of Medicine (NEJM).

At present, only one drug is approved for SLE based on a successful randomized, placebo-controlled trial. Numerous immunomodulatory treatments have failed in phase III trials, and patients continue to be burdened with complications from their disease.

While the positive results from the TULIP-2 trial were met with great excitement, there is concern because TULIP-1, a simultaneous trial of anifrolumab, an antibody that inhibits all signaling through the type I interferon receptor — failed to meet its primary endpoint. In an editorial also published in this week’s NEJM, ahead of print, Jane E. Salmon, MD, the Collette Kean Research Chair at Hospital for Special Surgery (HSS), makes the case that future study designs should allow greater flexibility in defining success. Dr. Salmon was asked to discuss the differences between TULIP-1 and TULIP-2 along with Timothy Niewold, MD, the Judith and Stewart Colton Professor of Medicine and Pathology at the Colton Center for Autoimmunity at NYU School of Medicine.

Multiple investigators, including Mary K. Crow, MD, physician-in-chief and chief of the Division of Rheumatology at HSS and NewYork-Presbyterian/Weill Cornell Medical Center, have shown that activation of type I interferon is a central pathogenic mediator of SLE. While TULIP-2 delivered positive results using both instruments for assessing drug efficacy, the BILAG-Based Composite Lupus Assessment (BICLA) and Systemic Lupus Erythematosus Responder Index (SRI), TULIP-1 was positive only on BICLA (a secondary outcome) and did not show a significant response in SRI, the predetermined primary outcome.

SRI and BICLA used in TULIP-1 and -2 are rigorous composite responder indices used to test drugs for SLE. “To have successful lupus trials, we need to be more flexible in how to define success. Our goal is to prevent organ damage and help patients live with lupus. It is not clear that a BICLA response differs from an SRI response in this regard,” said Dr. Salmon, who is also professor of medicine and professor of and associate dean, faculty affairs, at Weill Cornell College of Medicine.

Lupus is clinically very heterogeneous. Disease activity in SLE is manifest in up to eight organ systems, and response is difficult to assess without the use of complex outcomes measures. The BICLA and SRI instruments incorporate several dichotomous endpoints that classify patients as responders based on discrete components of subsidiary scales. Both composite indices require that responders demonstrate global improvement, that they cannot significantly worsen in individual domains (mainly organ dysfunction), and that they do not require use of restricted medications. Efficacy in SRI is determined by a reduction in the SLE Disease Activity Index (SLEDAI) total score, whereas improvement in British Isles Lupus Assessment Group (BILAG) is defined by efficacy in the BICLA.

Since concordance between SRI and BICLA has been demonstrated, it would be expected that these indices should provide comparable results, but this has not been true in all lupus clinical trials. Dr. Salmon noted the selection of outcomes instruments is a challenge in designing clinical trials for lupus. Because TULIP-1 showed a BICLA response, the primary end point for TULIP-2 was changed from SRI to BICLA response before the trial was unblinded. During the design of both phase III TULIP trials, SRI and BICLA response were candidates for primary end points; SRI was selected on the basis of precedence from phase III trials of belimumab.

“If one considers the BICLA and SRI response rates used in the three anifrolumab trials, the phase II trial and two TULIP trials, five of six primary and key secondary outcomes favored the drug compared with placebo,” cited Dr. Salmon. She suggested that regulators should require that only one of two outcomes need to be met — SRI or BICLA — to declare a drug effective in a disease as complex as lupus. “Such strategies might accelerate drug development in lupus until we have universally accepted response measures and biomarkers that allow grouping of SLE patients by biological pathways that drive their disease,” said Dr. Salmon.

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 14th consecutive year), No. 2 in rheumatology by U.S. News & World Report (2023-2024), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2023-2024). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a fourth consecutive year (2023). Founded in 1863, the Hospital has the lowest readmission rates in the nation for orthopedics, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.