BMS-986416

We hereby examined the effects of TGFβ depletion by AVID200/BMS-986416(TGFβ-TRAP), a TGFβ ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis...Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGFβ-TRAP and anti-PD-1 combination treatment. This study suggested that TGFβ depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into anti-tumor immune agonists in PDAC, supporting the validation of such effects in human specimen.

To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1).

P1, N=134, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1, N=134, Recruiting, Bristol-Myers Squibb | Trial completion date: Nov 2023 --> Jun 2028 | Trial primary completion date: Nov 2023 --> Dec 2026

To assess the in vivo effects of AVID200, Gata1low mice, a murine model of MF, were treated with AVID200 resulting in the reduction in bone marrow (BM) fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short and long term HSCs.Collectively, these data provide the rationale for TGFβ1 blockade with AVID200 as a therapeutic strategy for MF patients.

Clinical Trial Design: Based on these findings, a phase 1 trial of AVID200 is ongoing in INT-2/high risk MF subjects resistant or intolerant to ruxolitinib; baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Furthermore, AVID200 therapy improved thrombocytopenia in MF subjects which may be due to AVID200 inhibiting the effects of TGFβ1 on normal MKpoiesis. Updated subject safety and efficacy data along with correlative data will be presented.