COPENHAGEN – The recent success of fresolimumab in treating early diffuse cutaneous systemic sclerosis in a proof-of-concept study signals better days ahead in the treatment of scleroderma, Dr. Thomas Krieg predicted at the annual congress of the European Academy of Dermatology and Venereology.
“There will be new and better treatments based upon our improved understanding of the pathophysiology of this complex multifaceted disease. New targeted therapies are likely,” according to Dr. Krieg, chairman of the department of dermatology and venereology and dean of the medical faculty at the University of Cologne (Germany).
Dr. Thomas Krieg
One such therapy is fresolimumab. This high-affinity neutralizing antibody targets all three isoforms of transforming growth factor–beta (TGF-beta), long believed to be a key player in the development of fibrosis. Fibrosis in patients with systemic sclerosis can affect the skin, lungs, heart, kidneys, and GI tract.
The recent U.S. open-label fresolimumab proof-of-concept study led by investigators at Boston University included 15 patients with early diffuse cutaneous systemic sclerosis. Eight patients received a single 5-mg/kg dose, while the other seven got two 1-mg/kg doses. All were then followed for 24 weeks.
The results make a strong case for TGF-beta as playing a pivotal role in the pathogenesis of systemic sclerosis, according to Dr. Krieg, who wasn’t involved in the study. The investigators characterized the rate of decline in clinical skin disease in response to fresolimumab as assessed using the modified Rodnan skin score (mRSS) as “unprecedented.” The subjects averaged mRSS reductions of 5.1 points at week 3 or 4, increasing to 6.3 points at week 7 and 8 points at week 11 (J Clin Invest. 2015;125[7]:2795-807). To put that into context, the median improvement in mRSS scores in seven previous clinical trials of other agents was an anemic 2.9 points at 6 months and 3.4 at 1 year.
Skin biopsies showed that the fresolimumab-induced rapid decline in mRSS was accompanied by a sharp drop in skin biomarkers of TGF-beta activity, including expression of the genes thrombospondin-1, cartilage oligomeric protein, and connective tissue growth factor. In addition, dermal myofibroblast infiltration dropped off.
The logical next steps in the research effort are to go larger and longer in terms of clinical trials of fresolimumab for scleroderma skin disease, and also to assess whether fresolimumab is effective in treating the fibrotic disease involving the internal organs of scleroderma patients.
Fresolimumab was well tolerated in this study. That’s also been true thus far in studies using higher doses and multiple doses for other diseases where fibrosis figures prominently. As the TGF-beta inhibitor’s side-effect profile becomes better characterized, it will be important to compare the adverse events associated with fresolimumab to the known substantial morbidity associated with current therapies.
The current treatments for the fibrotic disease in systemic sclerosis are unsatisfactory: cyclophosphamide is not terribly effective and carries the risk of malignancy, while “the jury is still out” on stem cell transplantation for systemic sclerosis, as ongoing studies attempt to establish the risk-benefit ratio of this intervention, the dermatologist said.
As for corticosteroids, Dr. Krieg believes they’re overused in systemic sclerosis.
“I have to tell you, many patients come to our center on relatively high doses of corticosteroids. Yet if you go through the literature there’s more or less no evidence for a beneficial role for corticosteroids in systemic sclerosis. And there is an increased risk of developing severe renal crisis, especially with higher doses in patients with diffuse systemic sclerosis,” the dermatologist cautioned.
More than a dozen drugs are now in clinical trials for systemic sclerosis. In addition to fresolimumab, tyrosine kinase inhibitors including imatinib (Gleevec) and nilotinib (Tasigna) are being evaluated for their antifibrotic effects. Other investigational agents target the inflammatory and vascular components of the disease.
Fresolimumab is owned by Sanofi. The fresolimumab study was supported by the National Institutes of Health. Dr. Krieg reported having no financial conflicts regarding his presentation.