• Rheumatological Autoimmune Disorders
• Rheumatology Clinical Trials

In scleroderma, drug treatment of skin disease is difficult to assess due to the lack of easily measured endpoints. The modified Rodnan skin score (mRSS) is one method used to differentiate systemic sclerosis (SSc) disease subtypes, but it does not change much over short periods. Robert Lafyatis, MD, Boston University School of Medicine, Boston, Massachusetts, USA, reported results from the Fresolimumab in Systemic Sclerosis [NCT01284322] study showing that transforming growth factor-β a (TGFβ)-response genes correlate with the mRSS and may provide a means to more quickly assess drug efficacy for skin fibrosis in early phase trials. For example, TGFβ signature genes, cartilage oligomeric protein (COMP), and thrombospondin (THS1) showed decreased expression in most SSc patients after treatment with fresolimumab (GC1008), a first-in-class pan-neutralizing anti-TGFβ human antibody.

In the first part of a Phase 2, open-label study, 7 early SSc patients were administered 2 doses of fresolimumab (1 mg/kg) at Week 0 and Week 4. Skin biopsies taken on the first day prior to treatment and at 3, 7, and 24 weeks after treatment were analyzed for gene expression by reverse transcription polymerase chain reaction, microarray, and nanostring. Seven weeks after treatment, there was a significant (p<0.05) decline in the primary study outcome of expression of THS1 and COMP. The relative mRNA expression of COMP and THS1 correlated with mRSS (R²=0.44 and 0.58, respectively, for baseline skin biopsies) and with each other (R²=0.73), suggesting these mRNAs are coregulated. Microarray data also indicate decreased expression of TGFβ signature genes, which was confirmed by nanostring data.

In general, fresolimumab was tolerated with 1 severe adverse event of severe bleeding from a patient with known gastric antral vascular ectasia. There were no malignant or premalignant lesions, or apparent aggravation of interstitial lung disease.

Skin biomarkers are sensitive measures of skin disease, offering operator-blinded assessment of mRSS. Unlike mRSS, which changes slowly, the mRNA biomarker can be assessed after a short period; thus, drug efficacy for skin fibrosis in early phase clinical trials maybe assessed more quickly.

The results of this trial showed that using skin mRNA expression biomarkers for measuring therapeutic-induced changes in SSc implicates TGFβ in SSc pathogenesis.

• © 2012 MD Conference Express®