Roundtable on Scleroderma: Advancing Potential Drugs to Patient Care
February 27, 2015
Scleroderma is a complex disease resulting from inflammation and soft tissue fibrosis (hardening). The organ and tissue systems affected by the disease include skin, blood vessels, gastrointestinal tract, lung, heart, kidney, muscles, and joints. Scleroderma is considered an autoimmune disease, in which much of the tissue damage is thought to be caused by the patient’s own immune system. Clinically, this progressive disease is challenging to treat or prevent since there is no proven, approved therapy to alter the underlying cause. Fibrosis results in high morbidity for patients with substantial impact on their quality of life, as well as high mortality rates.
To facilitate the translation of recent discoveries in scleroderma research to clinical applications, the NIAMS held a roundtable on advancing potential drugs for scleroderma to patient care. The meeting brought together representatives from academic institutions, regulatory and funding agencies, patient organizations, and industry to exchange information, ideas, and perspectives about the current status of scleroderma research leading to drug development; opportunities and obstacles to advancing the evaluation of new therapeutic targets; and potential approaches to move candidate drugs into robust clinical trials and eventually clinical care.
The meeting focused on the following questions:
- What are the best scientifically and clinically relevant candidate targets for drug development that should be moved forward?
- What are the best animal models for translational and pre-clinical research?
- What are the best outcome measures and biomarkers for gauging and comparing the efficacy of different drugs and treatment strategies?
- What patient cohorts and stratification methods (e.g., to enable precision medicine) should be used to organize clinical trials?
- What trial designs are optimal to adequately test target hypotheses?
- What are currently acceptable clinical targets for the U.S. Food and Drug Administration (FDA) regarding scleroderma clinical trials?
- What is the role of targeting individual organs versus addressing overarching disease mechanisms?
- What is the process to create a white paper for subsequent FDA review/revision toward the creation of a draft guidance document?
These questions and written responses collected by the participants from their research communities in advance of the meeting served as the basis for the discussion. Although not all responses submitted in advance were discussed at the roundtable, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.
Targets for Drug Development
Scleroderma is characterized by immune system abnormalities, vascular injury, and pathological fibrosis. Studies of the immune defects have focused heavily on the adaptive immune system. However, recent findings suggest that the innate immune system also plays an important role in pathogenesis. Several studies have focused on fibrosis in scleroderma, including the role of myofibroblasts, the cell type primarily responsible for fibrosis, and transforming growth factor-beta (TGF-?), a profibrotic cytokine implicated in both the initiation and maintenance of the disease. Investigators have uncovered a number of genetic risk factors for scleroderma, many of which also are associated with other autoimmune diseases. At present, it is unclear why such factors give rise to scleroderma in some cases, but to different autoimmune diseases, with distinct phenotypes and outcomes, in others. The role of environmental and epigenetic factors in disease initiation and progression is another important focus of research.
Through basic studies of the molecular and genetic basis of scleroderma, scientists have identified a large number of potential biological targets for drug development that can be grouped into the three major domains of disease pathogenesis (immune/inflammatory, vascular, and fibrotic). For many of the targets, one or more candidate drugs have been identified, some of which already are being evaluated in clinical studies. Researchers also are interested in discovering additional targets, particularly those related to the vascular defects, since relatively few targets have been identified in that domain. Because many commonalities exist between scleroderma and other autoimmune, fibrotic, and vascular conditions, researchers believe that it may be possible to "re-purpose" drugs for those diseases to treat scleroderma. For example, drugs blocking lysophosphatidic acid or its receptor have been tested in idiopathic pulmonary fibrosis, and such drugs are now being evaluated in scleroderma patients with pulmonary fibrosis.
The plethora of promising biological targets for scleroderma presents a challenge for the field—how best to prioritize candidate targets and drugs for further research. At present, selection of targets for drug development is influenced by scientific considerations, such as whether the goal is to address organ-specific versus overarching disease mechanisms, as well as by practical business concerns. However, it is unclear which domain—immune/inflammatory, vascular, fibrotic, or a combination of these—should be the major focus.
Efforts to prioritize targets have been hampered by the limited availability of samples and data from completed trials. The NIH is taking steps to ensure that data and biological samples from NIH-funded research are widely available to the scientific community. One reason that data sharing has been limited is that in the past, few informed consent forms addressed data sharing. Making provisions for data and sample sharing during the planning of clinical trials should facilitate data access and foster future research.
Animal Models for Translational and Pre-clinical Research
A number of mouse models have been developed for research that recapitulates one or more of the pathological findings seen in scleroderma. However, none of the existing models produces the full spectrum of defects observed in the clinical disease, and, to date, therapies that appeared promising in pre-clinical animal studies have yielded disappointing results in humans. Although mice may not be a useful model for predicting the efficacy of drugs in humans, they can be used to dissect the pathogenic sequence of scleroderma, test specific hypotheses regarding disease processes, and assess the safety of potential therapeutic agents. However, because the various models show some, but not other features of the disease, researchers must carefully consider which model best represents the specific manifestations and stages of disease that they wish to study.
Scientists continue to pursue new approaches to develop better models. The recently described stiff skin mouse was genetically engineered to carry an exact equivalent of a human mutation that causes stiff skin syndrome (SSS), a rare, severe inherited scleroderma-like disease. Researchers also are exploring the use of "humanized" mice for scleroderma research and the utility of various non-murine models of the disease (e.g., zebrafish to study vascular defects).
Scleroderma Clinical Trials
Outcome Measures and Biomarkers for Assessing the Efficacy of Interventions
Currently, the most widely accepted outcome measures for scleroderma clinical trials focus primarily on aspects of the disease that are considered amenable to intervention, such as skin manifestations, pulmonary complications, Raynaud’s phenomenon, and digital ulcers. For example, the modified Rodnan skin score (MRSS) is a validated measure that has been used to assess therapeutic skin response in patients with early diffuse disease; and pulmonary function testing allows for reproducible quantitative assessment of interstitial lung disease. However, there is an unmet need for outcome measures for other disease manifestations, such as gastrointestinal issues and a condition called calcinosis in which small white calcium lumps form under the skin.
In addition to clinical measures, investigators also use patient-reported outcomes (PROs) to assess scleroderma treatment. PROs incorporate patients’ feedback and, in some cases, can provide an indication of whether a patient’s condition is improving or worsening even before clinicians see a change in a clinical score. For example, researchers have developed and initially validated a combined response index for systemic sclerosis (CRISS) that incorporates both clinical and patient-reported outcomes, demonstrating how PROs and clinical information can be combined to enhance clinical research and care.
Many of the most commonly used clinical outcome measures for scleroderma require multiple months to yield results. This presents a major challenge for moving clinical research forward and developing drugs for scleroderma due to the significant investment required to conduct lengthy clinical trials. Although surrogate measures and biomarkers could help to reduce the time needed to assess the potential of new therapies, to date relatively few biomarkers have been reported that are sensitive to change over time and correlated with a clinical endpoint. One barrier to development of robust biomarkers has been the lack of a widely accepted effective therapy for the disease that would allow for full validation of new markers.
Stratification of Cohorts for Clinical Trials
Scleroderma is an extremely heterogeneous disease in terms of both clinical manifestations and molecular phenotypes. This presents a challenge for selecting cohorts for scleroderma clinical trials, since in some cases only a subset of the cohort may respond to therapy. To address this issue, researchers have begun to explore strategies for grouping research participants into more homogeneous cohorts based on shared clinical and molecular phenotypes. Such strategies could help to enhance clinical trials and set the stage for precision medicine in scleroderma—the tailoring of treatment to an individual patient based on their unique biology and environment.
To date, patient stratification for scleroderma studies has been based primarily on the natural history of the disease. Recent findings suggest that data-driven approaches for patient stratification would improve trial design and outcomes. Researchers are investigating the use of molecular genetic measures, including gene expression and genetic polymorphisms, to assemble research cohorts. Researchers also are using clinical and serological measures of disease activity to stratify patients. For example, some investigators have grouped participants according to the autoantibodies they express or by using combinatorial and multivariate analysis of other clinical parameters.
While there are many potential benefits of conducting clinical trials in more homogenous groups of patients, this strategy is likely to make patient accrual more challenging. As the number of scleroderma clinical trials grows, assembling homogenous cohorts will become increasingly difficult, and recruitment issues could prevent important studies from going forward. In addition to designing state-of-the science clinical trials, an important goal for the field should be to increase participation in clinical research by improving access to and information about clinical trials, particularly for patients being treated outside of a major medical center. Outreach to patient advocacy groups could also help to boost participation in research studies. Scleroderma researchers also should investigate the strategies used by other research communities that have successfully recruited for studies of rare diseases, e.g., pediatric rheumatologists.
Additional Considerations for the Design and Conduct of Scleroderma Clinical Trials
Use of Placebo/Standard of Care Controls and Open Label Studies
An important current question regarding the design of randomized controlled trials in scleroderma is whether to include a placebo/standard of care control group. Although having some sort of comparator, placebo or active, allows more meaningful statistical and clinical inferences, at present, not all studies include a control group. This is particularly problematic for open-label studies—in which both the participants and researchers know what treatment is being administered. Although numerous open-label trials have been conducted in scleroderma, for the most part these have yielded negative results or results that are difficult to interpret, particularly when a placebo/standard of care control was not included. Open-label designs might be useful and appropriate for some biomarker studies, such as those with objective endpoints (e.g., lab-imaging tests). Although open-label studies looking at one treatment (i.e., lacking a placebo/standard of care control) are unlikely to provide useful information, multiple-arm open-label studies comparing different treatments could be informative. The roundtable participants agreed that ideally, scleroderma clinical trials should be randomized, should include a placebo control or active comparator group, and should be blinded.
An example of the difficulty in defining an appropriate control group was provided for the scleroderma-related lung disease (SSc-ILD) study. Many in the community believe that mycophenolate mofetil (MMF), an oral drug already commonly used to treat SSc-ILD, is a more effective treatment than the established oral cyclophosphamide, and, since lung function lost while on placebo is not likely to be recovered, many feel that MMF should be given to all patients in clinical trials for SSc-ILD. Results from the NIH-funded Scleroderma Lung Study II, which is comparing the effectiveness of MMF and oral cyclophosphamide, should shed light on the selection of the most appropriate control for future SSc-ILD studies.
Innovative trial designs
Innovative alternatives to the traditional randomized controlled trial design are needed to facilitate clinical research in scleroderma. In light of the large number of candidate targets and drugs, a novel design ideally would allow for rapid and efficient testing of many drugs at once and shorten the time needed to obtain meaningful results. Recent innovations in trial design in other diseases (e.g., cancer and Ebola) provide examples of novel approaches that could be adapted for scleroderma. One strategy, based on a recent example, would begin with all patients receiving the optimal standard of care. Investigators would add a new drug to this standard therapy to create an experimental arm while keeping standard therapy as a control arm. Those therapies found effective would then be added to an improved standard therapy, allowing subsequent testing of another novel therapy. Researchers also could consider observational comparative effectiveness research trials and adaptive trial designs.
Many of the centers conducting clinical research in scleroderma collect similar data and biological samples. Scleroderma researchers collaborate in a number of areas and have discussed the possibility of developing a common clinical repository. However, most centers maintain their own sample repositories and databases, creating barriers to shared data management and analysis. Additional efforts are needed to promote sharing of data and samples and to harmonize trial designs.
Next Steps to Advance Drug Development
Substantial progress has been made over the last two to three decades in scleroderma basic, translational, and clinical research. The field has a number of outcome measures for clinical trials. Efforts to develop biomarkers are encouraging, and there have been many promising findings from pre-clinical and early-stage clinical studies. Despite these successes, experts agree that there is an urgent need to develop more effective therapies to treat individual organs and the underlying disease process. Translating findings from academic research settings into late-stage clinical trials and drug development has been challenging. One possible way to move forward would be to establish public-private partnerships. The NIH can play an important role in supporting small, early-phase trials to advance drug candidates to the point that they can be further developed by industry. Industry could support such NIH-funded efforts by providing access to drugs for testing.
Another consideration for companies interested in developing drugs for scleroderma is the absence of guidance from the FDA regarding appropriate outcomes for scleroderma research. Because there is no recognized treatment for SSc, developing an FDA guidance document may be challenging and any guidance developed at this point may be vague—potentially reducing flexibility and discouraging industry from pursuing innovative ideas. A more productive next step to move the field forward may be to develop a white paper that lays out the current state of the science. The document initially could be drafted by a small group (e.g., academic and industry researchers, professional and patient societies, Federal partners), then distributed to gain the endorsement of the wider research community. The document could help to harmonize research efforts and serve as a starting point for future FDA guidance.
BEGG, Lisa, Dr.P.H., R.N., Office of Research on Women’s Health, National Institutes of Health
BOWDISH, Kate, Patient Advocate
DIETZ, Harry, M.D., Johns Hopkins University School of Medicine
DOMSIC, Robyn, M.D., M.P.H., University of Pittsburgh Medical Center
EU, Jerry, M.D., National Heart, Lung, and Blood Institute, National Institutes of Health
EVNIN, Luke, Ph.D., Scleroderma Research Foundation/MPM Capital
GOLDMUNTZ, Ellen, M.D., Ph.D., National Institute of Allergy and Infectious Diseases, National Institutes of Health
GOURH, Pravitt, M.D., NIAMS & National Human Genome Research Institute, National Institutes of Health
HUMMERS, Laura K., M.D., Sc.M., Johns Hopkins Scleroderma Center
KHANNA, Dinesh, M.D., M.Sc., University of Michigan Scleroderma Program
LAFYATIS, Robert, M.D., Boston University School of Medicine
MAYES, Maureen D., M.D., M.P.H., University of Texas — Houston Medical School
MERKEL, Peter A., M.D., M.P.H., University of Pennsylvania
POLISSON, Richard P., M.D., M.HSc., Sanofi-Genzyme
ROTHERMEL, Annette, Ph.D., National Institute of Allergy and Infectious Diseases, National Institutes of Health
SEIBOLD, James R., M.D., Scleroderma Research Consultants, LLC
STEEN, Virginia, M.D., Georgetown University Medical Center
VARGA, John, M.D., Feinberg School of Medicine, Northwestern University (co-chair)
WEINMANN, Gail, M.D., National Heart, Lung, and Blood Institute, National Institutes of Health
WHITFIELD, Michael, Ph.D., Dartmouth Medical School
YIM, Sarah, M.D., Division of Pulmonary, Allergy, and Rheumatology Products, U.S. Food and Drug Administration
BURROWS, Stephanie, Ph.D.
CARTER, Robert H., M.D.
KATZ, Stephen I., M.D., Ph.D. (co-chair)
KESTER, Mary Beth, M.S.
LINDE, Anita M., M.P.P.
MANCINI, Marie, Ph.D.
McGOWAN, Joan A., Ph.D.
MOEN, Laura K., Ph.D.
REUSS, Reaya, M.S.
SERRATE-SZTEIN, Susana A., M.D.
TSENG, Hung, Ph.D.
WITTER, James, M.D., Ph.D. (co-chair)