ASH 2021 | Phase Ib trial of AVID200 in refractory myelofibrosis

So AVID200 is a selective TGF-beta 1 and 3 trap. It is an infusional agent that down-regulates TGF-beta signaling and has rationale and preclinical data supporting its use in myelofibrosis, probably by accomplishing two things in murine modeling and in primary cell work in the lab. One is by down-regulating, TGF-beta, I should say, is a negative regulator of normal hematopoietic stem cell activity, and inhibiting TGF-beta releases that repression through reduction in phospho-SMAD2 and cyclin-dependent kinase inhibitor p57 expression, thereby reactivating normal hematopoiesis.

But also, TGF-beta is a well-recognized pro-fibrotic cytokine and many studies now have demonstrated that there’s over-expression of TGF-beta 1 in patients with myelofibrosis. The source is thought to be MF megakaryocytes and monocytes and mesenchymal stromal cells. So there’s a lot of rationale for blockade of TGF-beta, and this infusional agent was taken into the clinic based on a lot of really sound preclinical work by Lilian Varricchio, Anna Rita Migliaccio and Ronald Hoffman and others. And this was a Phase Ib study evaluating three dose cohorts of this infusional agent given every three weeks.

And there was no DLT scene with the drug. It was a well-tolerated, safe drug with minimal grade 3/4 toxicity, minimal related toxicity to the drug and no infusional related reactions. And what we saw at the two highest doses that were expanded in the Ib portion of the trial was some signal of activity. So 21 patients altogether were treated, 12 in the dose expansion phase, and we saw anemia response in a patient. One patient had anemia, spleen and symptom response at week 24. Another patient had a total symptom improvement of 50% or greater at week 24. But if you looked at best or maximal responses and changes in spleen and symptom burden, there were a number of patients who actually achieved a symptom and spleen burden at some point in their treatment course.

Unfortunately, none of the patients in 16 paired samples had reduction in bone marrow fibrosis grade, but there was a biomarker assay looking at both TGF-beta levels. So there was significant elevation of baseline of TFG-beta 1, but not two and three in the patients who were treated. There was some variability in the height of elevation, but the drug did seem to suppress TGF-beta 1 levels in the majority of patients that were treated. And there was a hint in some of the cytokine expression analysis of reduction in inflammatory cytokines with AVID200 treatment, and some of that has to be explored further.

But there was a clear signal of safety and a signal of clinical activity. I think the conclusion of our study was that this is a drug that is best explored further in clinical testing as a combination partner, either with a JAK inhibitor or other mechanism based therapies, many of which have rationale in MF. That’s a subject of our MPNRC consortium grant, and perhaps earlier in the disease process. So I think one of the things we’ve learned is that to use a drug like this, you probably need to use it earlier, and you may need a longer assessment, longer time point assessment for reduction of bone marrow fibrosis. And again, in combination with other active agents that can synergize.