Celiac Disease Foundation is proud to have been a funder and to participate on the Steering Committee for the FDA Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT3) workshop. Conceived by Dr. Sonia Kupfer of the University of Chicago and CDF Medical Advisory Board member Dr. Daniel Leffler of Beth Israel Deaconess Medical Center, GREAT3 served to formalize the discussion of therapeutic treatments for celiac disease. Dr. Kupfer and Dr. Leffler reflect on the experience in the article below as published in the June/July 2015 issue of AGA Perspectives.
By Sonia Kupfer, MD, and Daniel Leffler, MD, MS
On March 31, 2015, therapeutic development in celiac disease took a major step forward with a full day devoted to advancing celiac disease therapeutics.
Celiac disease has long been an outlier in the panoply of intestinal diseases. While not on par with IBS, it is significantly more common than IBD or eosinophilic disorders. While patients are not often hospitalized or in the operating room due to celiac disease, the attributed mortality is increased and burden of treatment appears to be higher than any other common luminal disease. Enteropathy is a hallmark of disease, yet, unlike ulcerative colitis, evidence does not support a strong relationship between persistent mucosal inflammation with symptoms or long-term outcomes.
These issues are all vexing but perhaps most relevant to patients and clinicians is the fact that despite the prevalence, morbidity, burden and overall highly unmet medical need, the field of celiac therapeutics has been nascent. To date, only 11 randomized controlled therapeutic trials have been published in the last 20 years, including four with larazotide acetate, one with ALV003, one with ANPEP, two with probiotics, one with rifaxamin, one with hookworm inoculation and one with pancreatic enzymes. Therapeutic development for celiac disease is hardly a thriving field, and there are multiple reasons for this current state of affairs. The major historical obstacles to drug development have been the misperceptions that celiac disease is rare and mild, and that the gluten-free diet is a near optimal therapy. Over the last decade, these premises have fallen under robust scientific scrutiny; yet one major hurdle remained, a regulatory path to approval.
On March 31, 2015, therapeutic development in celiac disease took a major step forward with a full day devoted to advancing celiac disease therapeutics during the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3) workshop sponsored by the FDA Center for Drug Evaluation and Research and co-sponsored by the American Gastroenterological Association. The meeting covered defining target populations for pharmacologic therapies, defining clinical benefit in celiac disease clinical trials, and measuring clinical benefit in celiac clinical trials to support marketing approval.
The workshop kicked off with an overview of current management of celiac disease and identification of target populations in adults and pediatrics by Joseph A. Murray, MD, Mayo Clinic, Rochester, MN, and Alessio Fasano, MD, Massachusetts General Hospital, Boston. Both speakers emphasized that the gluten-free diet, while effective, is hardly an optimal therapy. Dr. Murray noted that not all adult patients experience complete symptom relief nor complete mucosal healing, which can have consequences for quality of life and long-term complications. In pediatric populations, Dr. Fasano emphasized adherence challenges of children and adolescents, and the need for alternative therapeutic options along the age continuum. Among speakers and panelists, there was clear consensus that initial focus of drug trials should be symptomatic celiac patients with evidence of persistent mucosal damage. Additional populations to consider include screen-detected patients belonging to higher risk groups (e.g., type 1 diabetes or family members) whose symptoms may be less severe but face unique challenges in adherence to the gluten-free diet.
The second session expanded on these themes by defining clinical benefit from the perspective of patients, adult and pediatric gastroenterologists, and FDA. Alice Bast, the patient representative, shared her personal challenges living with celiac disease and explained how adjunctive therapies are needed and desired by the celiac community. Sheila E. Crowe, MD, University of California, San Diego, and Ivor Hill, MD, Nationwide Children’s Hospital, Columbus, OH, presented assessments of clinical benefit as adult and pediatric gastroenterologists. Dr. Crowe underscored that patients want to live normal lives and how drug therapies could help achieve this primary goal. Dr. Hill presented specific scenarios and expected clinical benefit in children. Finally, Jessica Lee, MD, medical team leader, FDA Division of Gastroenterology and Inborn Errors Products, outlined the FDA’s perspective on clinical benefit emphasizing use of patient reported outcomes and/or objective measures of disease activity. Speakers and panelists discussed a myriad of topics including the role of quality of life measurements in trials, challenges in dietary adherence assessments, and similarities between pediatric and adult celiac disease.
The status quo in celiac disease cannot be allowed to stand.
The final sessions addressed the difficult issue of how to best measure clinical benefit in pivotal clinical trials and covered patient-reported outcomes, histologic assessment and serologic tests. After a review of patient-reported outcomes by Elektra Papadopoulos, MD, of FDA, Benjamin Lebwohl, MD, Columbia University Department of Medicine, New York, NY, presented compelling data that quantitative histology should be used as the primary endpoint in gluten challenge studies, as the kinetics of gluten-induced inflammation are well known. Conversely, the timing and clinical significance of induced reduction in enteropathy are very poorly understood and, at this point, should not serve as a sole primary endpoint in a pivotal trial. There appeared to be good consensus that histology should be evaluated in trials of incompletely controlled celiac disease, but this could serve as either a co-primary or safety endpoint. The final session discussed the role of celiac serologic testing in clinical trials. It was noted by Julia Lathrop of the FDA Center for Devices and Radiologic Health that all celiac serologies are currently approved only as an ‘aid in diagnosis’ and therefore cannot currently be acceptable as key regulatory endpoints. While this is clearly true, I (Daniel Leffler) argued that celiac serologies are direct manifestations of celiac disease activity and have the benefits of being non-invasive and widely used in clinical practice (unlike quantitative histology). For this reason, celiac serologies should be included in all clinical trials for both cohort stratification and as an excellent safety measure in phase IV trials.
There is good reason to believe that celiac disease is entering a new phase, moving away from the now outdated concepts of the adequacy of the gluten-free diet to appreciation of celiac disease of a burdensome and morbid condition with a high, unmet medical need. While hurdles remain, not the least of which include availability of patient-reported outcomes and responder definitions, this first GREAT meeting for celiac disease was notable for a remarkable degree of collegiality and shared vision among participants from all groups. Finally, there is buy in from patients, clinicians, industry and regulatory bodies that the status quo in celiac disease cannot be allowed to stand and that we have the tools we need to improve the lives of individuals with celiac disease.