Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with an estimated prevalence as high as 75 per 100,000. Pulmonary fibrosis occurs in ~40% of patients and is the leading cause of death while skin fibrosis is a significant cause of morbidity. There are no therapies that have shown a sustained effect in SSc associated pulmonary and skin fibrosis. Nevertheless, mycophenoalate mofetil (MMF) has become 1st line therapy at many SSc centers. Our published data shows that bortezomib, an FDA approved proteasomal inhibitor for the treatment of multiple myeloma, administered 7 or 14 days after the induction of lung injury by bleomycin prevented lung and skin fibrosis. Bortezomib has been used in more than 350,000 multiple myeloma patients worldwide with acceptable toxicity and tolerability. There is, however, no such data for bortezomib in SSc patients. Our in vitro and animal data provide a compelling pathophysiologic rationale for testing bortezomib for pulmonary and skin fibrosis. Thus in this grant we propose a pilot clinical trial of adding bortezomib to mycophenolate mofeteil (MMF) in patients with SSc Pulmonary Fibrosis. The objective of the trial is to assess safety, tolerability & efficacy of bortezomib in combination wih MMF in SSc patients at high risk of pulmonary disease progression.
SSc is an orphan disease and treatment approaches for SSc associated fibrosis or tissue fibrosis in general represent a significant unmet need in medicine. The proposed study by very experienced investigators would provide a rationale for a pivotal multi-center phase 3 trial to test bortezomib alone or in combination with mycophenolate as novel therapy for SSc. The proposed study may have implications for idiopathic pulmonary fibrosis, pulmonary hypertension and other diseases marked by tissue fibrosis as well.
