This week at the Scleroderma Foundation of Southern California’s 17th annual “Key to a Cure” gala, Genentech‘s Senior Group Medical Director of Immunology, Dr. Jeffrey Siegel, will receive the honor of the Spirit of Leadership Award. The award is given to prominent individuals who have contributed to the scientific and clinical communities’ progress in the realm of developing treatments for scleroderma. With more than 20 years of experience working in the field of scleroderma research at the Food and Drug Administration (FDA) and Genentech, Dr. Siegel has helped with the review and approval processes behind multiple rheumatic disease therapies.
“I have devoted my whole career to unmet clinical needs,” stated Dr. Siegel in an exclusive interview with Scleroderma News. “I am deeply honored to be recognized by the Scleroderma Foundation for my devotion to researching treatments for scleroderma.”
In 1996, Dr. Siegel became a reviewer at the FDA involved in rheumatology research and later became Clinical Team Leader in Rheumatology. He had the opportunity to help design the first Phase 3 clinical trial testing a treatment in patients with scleroderma to maximize the chance of seeing if there was a clinical benefit of treatment. Although ultimately the treatment was not approved, Dr. Siegel learned a vast amount about conducting clinical trials and how best to design trials to see clinical benefits of therapy.
Following his departure from the FDA in 2010, Dr. Siegel joined Genentech, where he was involved in a project investigating the role of interleukin 6 (IL-6) pathway in the pathophysiology of scleroderma. Dr. Siegel was a part of the Phase 2 clinical trial evaluating Actemra® (tocilizumab) in patients with scleroderma. The trial, faSScinate, showed positive benefits of Actemra on scleroderma patients. Treatment with Actemra resulted in clinically meaningful improvements in skin thickening, which patients experience as softening of the skin. In addition, an exploratory endpoint indicated stabilization of lung function as measured by forced vital capacity (FVC). These results led to breakthrough therapy designation status for Actemra from the FDA, a designation designed to recognize treatments that show promising results in areas of unmet clinical needs. This will expedite the review process by the FDA if the results of the upcoming Phase 3 trial are positive and potentially allow physicians to prescribe Actemra for the treatment of patients with scleroderma earlier.
During the faSScinate trial, patients also gave skin biopsy and blood samples for subsequent analysis of protein levels and gene expression related to scleroderma and the changes induced by IL-6 blockade in patients who were treated with Actemra. Researchers analyzing the samples discovered a significant reduction in a chemokine known as CCL-18 following treatment with Actemra. Whereas scleroderma patients had significantly increased levels of CCL-18 at the beginning of the study, Actemra treatment seemed to reduce CCL-18 to near-normal levels. Since CCL-18 is part of the immune system and not necessarily directly involved in fibrosis, it seems that Actemra may not directly prevent fibrosis but instead acts as a negative regulator of a system that promotes fibrosis.
The follow-up Phase 3 trial of Actemra in scleroderma is in the works and will be called focuSSced. The clinical research team at Genentech has been busy writing protocols for the trial and is awaiting patient enrollment and initiation of treatment. “I am looking forward to the Phase 3 clinical trial and potentially bringing a much-needed therapy to people with scleroderma,” said Dr. Siegel in a press release submitted to Scleroderma News. One highlight of the focuSSced trial will be an analysis of the effects of Actemra on lung physiology in order to confirm the reduced risk of developing lung disease and progressive interstitial fibrosis.
According to Dr. Siegel, clinical trial design is essential to the development of a therapeutic intervention. “To be able to demonstrate a benefit of a product, you need to focus on an area that may have a benefit from treatment,” said Dr. Siegel. For example, in the faSScinate trial, the primary outcome was skin thickening, but the team also explored the effects of Actemra on lung physiology. Since they identified a benefit of less progressive lung disease in treated patients, they will therefore include change in FVC as one of the secondary outcome measures in the follow-up focuSSced trial. If the team were to also look at the effects of Actemra on patient pulmonary arterial hypertension or Raynaud’s phenomenon (two additional common comorbidities of scleroderma), the number of variables that must be analyzed by statistics would increase and consequently reduce the likelihood of identifying any difference.
Identifying effective treatments and investigating how and why the treatments work may be part of the overarching goal of finding a cure to scleroderma. Dr. Siegel cautions that understanding, treating, and curing scleroderma are remarkably different aspects of disease. “I think we are on the verge of understanding enough about what causes scleroderma to develop effective therapies,” said Dr. Siegel. Already, scientific and clinical researchers and physicians have developed sensitive outcomes and measures (such as the Rodnan skin score) to detect differences in treatments during clinical trials. However, even better endpoints and biomarkers of disease are necessary to understand which patients are likely to benefit from therapies and which are more likely to experience progressive disease. Once researchers have a better understanding of the disease and the effects of different treatments, the field may very well be on the way to finding a “Key to a Cure.”