0679: Inhibition of TGFb3 in Systemic Sclerosis Patients Does Not Result in TGFb Pathway Modulation in Skin Biopsies or Circulation

Background/Purpose: There are 3 isoforms of Transforming Growth Factor Beta (TGFb), a cytokine frequently upregulated in fibrosis. Chronic targeting of TGFb1 and TGFb2 for fibrotic conditions has historically been problematic due to toxicity. Monoclonal antibodies that selectively target the TGFb3 isoform offer a potential solution, aiming to reduce fibrosis by inhibiting the TGFb pathway with a more favorable safety profile. Systemic sclerosis (SSc) is a debilitating disease where the TGFb pathway has been implicated as a disease driver. TGFb3 RNA correlated strongly with a 24-gene TGFb-responsive signature in SSc skin and also correlated with modified Rodnan skin score (Sun et al., 2024). Therefore, it was hypothesized that TGFb3 may be the main isoform involved in pathological fibrosis.

Methods: GA43360 is a Ph1b safety, tolerability, and pharmacokinetics study of SSc patients treated with 3 monthly doses of anti-TGFb3 (RO7303509). The study randomized 56 participants across three cohorts: Cohort A (75mg, n=12, and placebo, n=3), Cohort B (225mg, n=2, 360mg, n=15, and placebo, n=4), and Cohort C (1200mg, n=16, and placebo, n=4). To assess TGFb pathway modulation, we performed bulk RNAseq on patient skin biopsies collected pre- and post-anti-TGFb3 treatment and analyzed a 24-gene TGFb-responsive signature. Healthy control vendor-procured skin biopsies were also sequenced and analyzed for comparison. Indirect target engagement was assessed by measuring circulating TGFb3 protein levels in serum using the NULISA inflammation panel, and pathway modulation was evaluated by measuring serum periostin and COMP levels using immunoassays.

Results: Our drug was well tolerated at all doses, and the safety profile was acceptable. Pharmacokinetics for all doses were in agreement with model predictions and within the range of expected variability. We saw evidence of indirect target engagement through the upregulation of total TGFb3 levels in circulation post-dose with dose-dependent effects. We also observed higher levels of TGFb3 and TGFb pathway genes in SSc skin compared to healthy control skin, and elevations of periostin and COMP proteins in circulation. After 3 months of anti-TGFb3 treatment, we did not see modulation of TGFb pathway genes in the skin or circulation.

Conclusion: We demonstrated indirect target engagement but did not observe pathway modulation, suggesting that inhibition of TGFb3 alone is not sufficient for decreasing TGFb-driven pathway activation in SSc patients.