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ASH 2021 | Update on Phase Ib trial of AVID200 in myelofibrosis

Ronald Hoffman, MD, Icahn School of Medicine at Mount Sinai, New York, NY, 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). TGFβ is known to play an important role in MF by promoting bone marrow fibrosis, increasing the dormancy of normal hematopoietic stem cells (HSCs), and inhibiting megakaryocyte production. Previous pre-clinical studies showed that AVID200 leads to a reduction in mesenchymal stromal cell proliferation and mutated colonies and an increase in the number of megakaryocytes and wild-type JAK2 cells. A dose-escalation study conducted in patients resistant or intolerant to ruxolitinib showed that this drug was well tolerated, without dose-limiting toxicities. The phase Ib dose-expansion study reported Grade 3/4 adverse events in 16 out of 22 subjects and clinical responses were observed at cycle 7 of therapy. In addition, AVID200 therapy resulted in a significant reduction in TGFβ levels and improvements in platelet counts. AVID200 may be beneficial in combination with other agents in thrombocytopenic patients with MF. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

Yes, that was an abstract that was presented by my colleague John Mascarenhas. AVID200 is basically a trap TGF-beta-1. We did some preclinical work to show that the use of AVID200, at least in the laboratory led to the reversal of mesenchymal stromal cell proliferation, and also collagen deposition, and also had an effect on hematopoietic progenitor cells that were obtained from patients with myelofibrosis, leading to it in a subset of patients leading to increased number of wild type hematopoietic colonies, ex-vivo, and an increase in the number of wild type colonies...

Yes, that was an abstract that was presented by my colleague John Mascarenhas. AVID200 is basically a trap TGF-beta-1. We did some preclinical work to show that the use of AVID200, at least in the laboratory led to the reversal of mesenchymal stromal cell proliferation, and also collagen deposition, and also had an effect on hematopoietic progenitor cells that were obtained from patients with myelofibrosis, leading to it in a subset of patients leading to increased number of wild type hematopoietic colonies, ex-vivo, and an increase in the number of wild type colonies.

That was the preclinical work that went into the preclinical package for this Phase I trial. There were 22 patients that were treated. Basically there were spleen responses and also symptom responses, but the most profound effect was really on increased numbers of platelets and normalization of platelets. And we really haven’t had a drug that’s been available to increase platelet numbers in patients with myelofibrosis.

Our hope is basically that this drug is going to be helpful in those patients who have thrombocytopenia either alone or in combination with a JAK2 inhibitor. The marrows that were done on the patients in the AVID200 trial were done basically in those patients after six months of treatment. And to our surprise, there wasn’t any reversal of marrow fibrosis. And I think that’s really a consequence of the dynamic deposition of collagen and reticulin fibrosis during the phase of patients … during myelofibrosis and that perhaps the marrows were done for a limited time of administration of the drug.

Two patients continue on this trial and we’ve had clinical improvements and also stable disease in the majority of patients that were treated in very limited, virtually no toxicity. This drug, I think has promise, especially its effects on platelet production, accelerated platelet production is most impressive.

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