BMS-986416 / BMS, Ono Pharma - LARVOL DELTA

Safety and Tolerability Study of AVID200 in Pts With Diffuse Cutaneous Systemic Sclerosis (clinicaltrials.gov) - P1 | N=9 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=24 ➔ 9

Enrollment change • Trial completion • Immunology • Scleroderma • Systemic Sclerosis

A Trial of AVID200, a Transforming Growth Factor β (TGFβ) Inhibitor, in Patients Malignancies (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed

Metastases • Trial completion • Oncology • Solid Tumor

Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGFβ depletion. (PubMed, JCI Insight) - "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."

Heterogeneity • Journal • Preclinical • Tumor microenvironment • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • CCL8 • CD4 • TGFB1

The Variation in the Traits Ameliorated by Inhibitors of JAK1/2, TGF-β, P-Selectin, and CXCR1/CXCR2 in the Gata1low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination. (PubMed, Int J Mol Sci) - "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)."

Journal • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CXCL1 • CXCR1 • CXCR2 • JAK1 • TGFB1 • TGFBR1

A Study of BMS-986416 With and Without Nivolumab in Select Solid Tumors (clinicaltrials.gov) - P1 | N=134 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Study of BMS-986416 With and Without Nivolumab in Select Solid Tumors (clinicaltrials.gov) - P1 | N=134 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Nov 2023 ➔ Jun 2028 | Trial primary completion date: Nov 2023 ➔ Dec 2026

Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis (Clin Cancer Res) - P1 | N=21 | NCT03895112 | "No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells."

P1 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

A Phase 1b trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis. (PubMed, Clin Cancer Res) - "AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of MF patients and should be evaluated further in thrombocytopenic MF patients in combination with agents that target aberrant MF intracellular signaling pathways."

Journal • P1 data • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • TGFB1

A Phase 1b trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis (Clin Cancer Res) - P1b | N=21 | NCT03895112 | "No dose limiting toxicity was identified at the three dose levels tested and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGF-β1 levels, and pSMAD2 in MF cells."

P1 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Treatment of Myelofibrosis Patients with the TGF-β 1/3 Inhibitor AVID200 (MPN-RC 118) Induces a Profound Effect on Platelet Production (ASH 2021) - P1 | "A phase 1b trial of AVID200 (NCT03895112) was performed and completed in INT-2/high risk MF patients resistant/intolerant to ruxolitinib (rux); baseline platelet count of ≥ 25 x 10 9 /L, and grade 2/3 BMF. However, AVID200 therapy resulted in significant reduction in serum TGFβ levels and improvements in platelet counts indicating that TGF β1 plays a pivotal role in MF leading to thrombocytopenia which can be reversed with AVID200 therapy. We conclude that AVID200 may best be employed in combination therapy approaches in thrombocytopenic MF patients."

Clinical • Anemia • Fatigue • Immunology • Infectious Disease • Mucositis • Myelofibrosis • Nephrology • Thrombocytopenia • ASXL1 • CALR • JAK2 • TET2 • TGFB1 • TGFB2

A Study of BMS-986416 With and Without Nivolumab in Select Solid Tumors (clinicaltrials.gov) - P1 | N=134 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

GCO 07-0548-01401: MPN-RC 118 AVID200 in Myelofibrosis (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: John Mascarenhas | Active, not recruiting ➔ Completed | Trial completion date: Mar 2023 ➔ May 2022 | Trial primary completion date: Aug 2021 ➔ May 2022

Trial completion • Trial completion date • Trial primary completion date • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis

Novel treatments for myelofibrosis: beyond JAK inhibitors. (PubMed, Int J Hematol) - "Specifically, we discuss agents that target epigenetic modification (pelabresib, bomedemstat), apoptosis (navitoclax, navtemdalin), signaling pathways (parsaclisib), bone marrow fibrosis (AVID200, PRM-151), in addition to other targets including telomerase (imetelstat), selective inhibitor of nuclear transport (selinexor), CD123 (tagraxofusp) and erythroid maturation (luspatercept). We end by providing commentary on the ongoing and future therapeutic development in myelofibrosis."

Journal • Review • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • CD123

Update on Phase Ib trial of AVID200 in myelofibrosis (YouTube) - "Ronald Hoffman...explains the rationale and gives an update on the safety and efficacy results of a Phase Ib trial evaluating AVID200, a TGFβ1/3 protein trap, in patients with intermediate-2/high-risk myelofibrosis (MF)."

Interview • P1 data • Video

Post-ASH 2021 International Workshop on Myeloproliferative Neoplasms (iwMPNs) (VJHemOnc) - "1:12 PM - 1:55 PM, Treatment of Myelofibrosis Patients with the TGF-β 1/3 Inhibitor AVID200 (MPN-RC 118) Induces a Profound Effect on Platelet Production; Discussion - panellist: John Mascarenhas; 2:33 PM - 3:33 PM, A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 (Int-2) or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase Inhibitor (JAKi); Discussion - panellist: John Mascarenas."

Live event

Mount Sinai Researchers Present Encouraging Clinical Trial Results on Novel Therapy for Bone Marrow Cancer (Icahn School of Medicine at Mount Sinai) - "This is a real testament to cutting-edge translational research at The Tisch Cancer Institute,' said John Mascarenhas, MD...The most interesting finding in this trial was that a subset of patients had a lasting improvement in their platelet counts-including three whose counts were normalized-supporting the preclinical studies conducted by Mount Sinai researchers Ronald Hoffman, MD..."

Media quote

Phase Ib trial of AVID200 in refractory myelofibrosis (YouTube) - PIb, N=21; MPN-RC 118 (NCT03895112); Sponsor: Formation Biologics; "AVID200 was well tolerated, with no DLTs. No significant changes in bone marrow fibrosis scores were seen but the results showed a significant reduction in serum TGFβ levels and improvements in platelet counts."

Interview • P1 data • Video

"Avid-200 targeting TGFb in MF, a key pathway in fibrosis formation. MPN-RC 118 study. SVR/TSS and Platelet responses noted. Sadly no reduction in fibrosis. @mpdrc #ASH21 #mpnsm" (@AaronGerds)

Fibrosis • Hematological Malignancies • Immunology

[VIRTUAL] AVID200, first-in-class TGF-beta 1 and 3 selective and potent inhibitor: Safety and biomarker results of a phase I monotherapy dose-escalation study in patients with advanced solid tumors. (ASCO 2020) - P1 | "AVID200 was safe and well tolerated at dose levels of 5-30 mg/kg, with peripheral target engagement across the entire dosing period. AVID200 led to TGF-beta target modulation and immune activation. These data provide proof-of-principle that AVID200-mediated selective and potent inhibition of TGF-beta 1 & 3 is feasible in the clinic."

Biomarker • Clinical • IO Biomarker • Monotherapy • P1 data • Breast Cancer • Hematological Disorders • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor

AVID200, first-in-class TGF-beta1 and beta3 selective inhibitor: Results of a Phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients (SITC 2019) - "AVID200 was well tolerated as monotherapy and provided novel proof-of-principle data for the feasibility of selectively and potently inhibiting TGF-beta 1 and 3 in the clinic. A dose-escalation study of AVID200 in combination with anti-PD(L)1 therapy is ongoing."

Clinical • IO Biomarker • Late-breaking abstract • Monotherapy • P1 data

TGFβ1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis. (PubMed, JCI Insight) - "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."

Journal • Chronic Eosinophilic Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CDKN1C • GATA1 • JAK2 • TGFB1 • TGFB2

Next Generation Therapeutics for the Treatment of Myelofibrosis. (PubMed, Cells) - "We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis."

Journal • Review • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

MPN-RC 118 AVID200 in Myelofibrosis (clinicaltrials.gov) - P1; N=22; Active, not recruiting; Sponsor: John Mascarenhas; Recruiting ➔ Active, not recruiting; Trial primary completion date: Mar 2021 ➔ Aug 2021

Clinical • Enrollment closed • Trial primary completion date • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis

Novel therapies emerging in oncology to target the TGF-β pathway. (PubMed, J Hematol Oncol) - "We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers...Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the..."

IO biomarker • Journal • Review • Oncology • PD-L1 • TGFB1

[VIRTUAL] Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial (ASH 2020) - "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."

Clinical • P1 data • Chronic Eosinophilic Leukemia • Fatigue • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Transplantation • JAK2 • TGFB1