Increased levels of TGF-β1 were detected in serum, plasma and BM and positively correlated with both grade of BMF and extent of leukemic cell infiltration in the marrow. TGF-β likely plays a dual role in promoting myelofibrosis and myeloproliferation, both of which are the bone marrow morphologic hallmark of MF. AVID200 is a drug that targets TGF-β1 and TGF-β3. The study team hypothesizes that inhibiting the TGF-β signaling pathway in MF will decrease the fibrogenic stimuli leading to myelofibrosis and concomitantly interrupt myeloproliferation and restore normal hematopoiesis.
This is a first in human, open-label, multicenter, Phase I/Ib trial of AVID200. Patients must have intermediate-2 or higher primary myelofibrosis (PMF), post-essential thrombocythemia or polycythemia-vera related MF (Post ET/PV MF). This study will enroll up to 24 patients. AVID200 is delivered by IV infusion on day 1 of each 3 week cycle.

Start Date15 Feb 2019

Sponsor / Collaborator

Icahn School of Medicine at Mount Sinai

[+2]

NCT03834662

/ CompletedPhase 1

A Phase 1 Cohort Dose-Escalation Trial of AVID200, a Transforming Growth Factor β (TGFβ) Inhibitor, in Patients With Advanced or Metastatic Solid Tumor Malignancies

TGFβ has profound local immunosuppressive and immunoexclusion effects in the tumor microenvironment that are integrally involved in the failure of immune checkpoint inhibitors in some tumors. Preclinical data in a variety of models strongly support the study of AVID200 in patients with treatment-refractory advanced and metastatic malignancies as an approach to reducing immunosuppression/exclusion and increasing the activity of immune checkpoint inhibitors.

Start Date07 Jan 2019

Sponsor / Collaborator

Bristol Myers Squibb Co.

[+1]

NCT03831438

/ CompletedPhase 1

A Phase 1 Open-Label Study to Determine the Safety and Tolerability of AVID200: A Transforming Growth Factor β (TGFβ) Inhibitor, in Patients With Diffuse Cutaneous Systemic Sclerosis

Several lines of evidence place TGF-β, a potent pro-fibrotic cytokine, at the centre of the pathogenesis of Systemic Sclerosis (SSC). AVID200 is a novel inhibitor of TGF-β ligands. This Phase 1 trial is designed to evaluate the safety, tolerability and preliminary efficacy of AVID200 in SSc patients in order delineate doses to be further evaluated in Phase 2. Approximately 9 to 24 male and female patients with documented SSc (i.e., score ≥ 9 according to the American College of Rheumatology/European League Against Rheumatism classification criteria), and classified as having the diffuse cutaneous SSs (dcSSc) subset (i.e., according to the LeRoy and Medsger Classification), will be entered into this Phase 1a, multicentre, open-label, dose-escalation, cohort study of AVID200.

Start Date01 Jan 2019

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with AVID-200

100 Translational Medicine associated with AVID-200

100 Patents (Medical) associated with AVID-200

Literatures (Medical) associated with AVID-200

15 Sep 2023·Clinical cancer research : an official journal of the American Association for Cancer Research

A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis.

Article

Author: Arciprete, Francesca ; Kuykendall, Andrew ; Rampal, Raajit K ; Arango Ossa, Juan ; Kosiorek, Heidi ; Mascarenhas, John ; Salama, Mohamed E ; Komrokji, Rami ; Gonzalez, Agapito ; Kong, Amy ; Dougherty, Mikaela ; Bhave, Rupali ; Pettit, Kristen ; Hoffman, Ronald ; Gerds, Aaron T ; Falchi, Mario ; Vannucchi, Alessandro Maria ; Fabris, Frank ; Kremyanskaya, Marina ; Weinberg, Rona Singer ; Farnoud, Noushin ; McGovern, Erin ; Johnson, Kathryn ; Mesa, Ruben ; Mead-Harvey, Carolyn ; Dueck, Amylou ; Zingariello, Maria ; Migliaccio, Anna Rita ; Domenico, Dylan ; Yacoub, Abdulraheem ; Talpaz, Moshe ; Varricchio, Lilian ; Palmer, Jeanne ; Najfeld, Vesna

PURPOSEMyelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F.PATIENTS AND METHODSWe conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF.RESULTSNo 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.CONCLUSIONSAVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

01 May 2022·International Journal of HematologyQ4 · MEDICINE

Novel treatments for myelofibrosis: beyond JAK inhibitors

Q4 · MEDICINE

Review

Author: Tremblay, Douglas ; Mesa, Ruben

Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Given the central role of the JAK-STAT pathway in the pathobiology of myelofibrosis, JAK inhibitors are the mainstay of current pharmacologic management. Although these therapies have produced meaningful improvements in splenomegaly and symptom burden, JAK inhibitors do not significantly impact disease progression. In addition, many patients are ineligible because of disease-related cytopenias, which are exacerbated by JAK inhibitors. Therefore, there is a continued effort to identify targets outside the JAK-STAT pathway. In this review, we discuss novel therapies in development for myelofibrosis. We focus on the preclinical rationale, efficacy and safety data for non-JAK inhibitor therapies that have published or presented clinical data. 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.

22 Sep 2021·JCI InsightQ1 · MEDICINE

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

Q1 · MEDICINE

ArticleOA

Author: Rahman, Adeeb H ; Upadhyaya, Bhaskar ; Mesa, Ruben A ; Mascarenhas, John ; Denis, Jean-Francois ; Varricchio, Lilian ; Hoffman, Ronald ; Tremblay, Gilles ; Verachi, Paola ; Clementelli, Cara ; Martelli, Fabrizio ; Migliaccio, Anna Rita ; Zingariello, Maria ; O'Connor-McCourt, Maureen ; Iancu-Rubin, Camelia

Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1-induced p57Kip2 expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1lo mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF.

News (Medical) associated with AVID-200

23 Aug 2020

·www.davispolk.com

Bristol Myers Squibb acquisition of Forbius

Davis Polk is advising Bristol Myers Squibb on its acquisition of Forbius. The transaction includes an upfront payment and future success-based milestone payments. The transaction is expected to close in the fourth quarter of 2020, subject to the satisfaction of customary closing conditions. Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. Forbius is a clinical-stage protein engineering company that develops biotherapeutics to treat fibrosis and cancer. Forbius’ team of TGF-beta biology experts designed a proprietary platform of TGF-beta inhibitors with best-in-class potency and selectivity against the principal disease-driving isoforms 1 & 3. Forbius’ lead TGF-beta 1 & 3 inhibitor, AVID200, has completed Phase 1a clinical trials in one fibrotic indication as well as in solid tumors.

AcquisitionPhase 1PROTACs

100 Deals associated with AVID-200

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Primary Myelofibrosis	Phase 1	-	Bristol-Myers Squibb FCT bêta, Inc.	-
Scleroderma, Systemic	Phase 1	-	Bristol-Myers Squibb FCT bêta, Inc.	-
Mycosis Fungoides	Discovery	US	Formation Biologics Corp.	15 Feb 2019
Post-essential thrombocythemia myelofibrosis	Discovery	US	Formation Biologics Corp.	15 Feb 2019
Post-polycythemia vera myelofibrosis	Discovery	US	Formation Biologics Corp.	15 Feb 2019
Malignant Solid Neoplasm	Discovery	US	Bristol Myers Squibb Co.	07 Jan 2019
Malignant Solid Neoplasm	Discovery	CA	Bristol Myers Squibb Co.	07 Jan 2019
Solid tumor	Discovery	CA	Bristol-Myers Squibb FCT bêta, Inc.	07 Jan 2019
Solid tumor	Discovery	US	Bristol-Myers Squibb FCT bêta, Inc.	07 Jan 2019
Scleroderma, Diffuse	Discovery	US	Bristol Myers Squibb Co.	01 Jan 2019

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03831438 (EULAR 12020 \| EULAR 22020) Manual	Phase 1	Scleroderma, Diffuse	-	AVID200	(ydhexfqdve) = single cases of Grade 1 dizziness and CPK elevation, and Grade 2 anemia uwstkufepr (ipszttdefg )	Positive	04 Jun 2020

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