Abstract

Systemic sclerosis (SSc) remains a challenging disease to treat with high mortality and morbidity. It represents an unmet medical need but outcomes are improving and survival overall is better than was observed in the past. This is likely a reflection of better organization of care, earlier detection of life threatening complications and also to improved management of organ based complications. For some of these such as digital ulcer disease and pulmonary arterial hypertension there are now licensed therapies that have resulted from conventional drug development pathways including pivotal phase 3 pivotal clinical trials. This is evidence that successful trial templates can be developed for individual aspects of SSc. Developing overall disease modifying treatments is more of a challenge. Nevertheless, there are positive or encouraging clinical trials emerging and these highlight different strategies that can be employed. The trials of autologous stem cell transplantation (ASCT) following high intensity immunosuppression have used a longer term event driven approach to look at overall survival and event free survival based upon the time to development of a major organ based complication. The ASSIST and ASTIS trials of immunosuppression followed by ASCT are positive and both studies were statistically significant using this approach. A limitation is that this approach requires large numbers of cases and long term studies and is only applicable to cases at high risk of progression. Other strategies include parallel group placebo controlled trials to examine effect on clinical end points such as modified Rodnan skin score or pulmonary function tests, especially FVC. There have been encouraging studies using this design and recent trials suggest that trends of benefit can be observed over 6 months in such rails although longer term studies as are likely to be needed for demonstration of clinically meaningful benefit. Two other novel approaches that are emerging are short term “biological proof of concept” studies that focus on biochemical analysis of skin biopsies at an early time point of 8 or 12 weeks to examine effect of a candidate therapeutic on targeted pathway. This can be linked to clinical assessment and later to longer term examination of clinical benefit of the early biochemical signal is promising. SSc is uniquely placed for such an approach as skin biopsies are feasible at multiple time points for matched sites of skin. Another emerging technique is the use of a composite clinical endpoint that integrates skin score, lung function and other relevant patient and physician clinical global assessments. The CRISS (composite responses index for systemic sclerosis) is being validated and offers one such approach. It is likely that these new approaches to trial design in SSc with together facilitate clinical progress and help to address the current unmet medical need, by allowing logical new treatments to be assessed in a timely manner, supported by translational science studies that identify logical new targets for therapy or treatment strategies. Thus trial design is improving although “one size” does not fit all.