Itacitinib Clinical Trials for Chronic and Acute GVHD

Transcript:

Joseph H. Antin, MD: The GRAVITAS study, the 309 study in chronic graft-versus-host disease [GvHD], starts off with a dose finding study, and then is followed by what I think is the more important component, which is the placebo-controlled trial where steroids plus itacitinib are compared with placebo plus steroids. And this is ultimately what’s going to tell us whether this drug is clinically useful in graft-versus-host disease.

We actually don’t know whether there is a real value in itacitinib. The notion is that ruxolitinib is a combined JAK1 and JAK2 inhibitor. The JAK1 component, of course, is inflammatory mediators, which are thought to be important in chronic graft-versus-host disease. The JAK2 component inhibits signal transduction from cytokines such as erythropoietin and thrombopoietin and G-CSF [granulocyte colony-stimulating factor].

Some of the toxicity of ruxolitinib is due to the JAK2 component. Itacitinib is a selective JAK1 inhibitor, so we don’t have to worry about inhibiting the hematopoietic aspects of this. But what’s not clear is whether that JAK2 component actually contributes or not. In experimental models it turns out that the combination of JAK1 and JAK2 inhibition is actually more effective in murine graft-versus-host disease than isolated JAK1 inhibition.

On the other hand, if the selective JAK1 inhibition data are good, then perhaps we can use a drug that’s less likely to suppress hematopoiesis, which of course would be beneficial.

In the GRAVITAS-301 study, this is in acute graph-versus-host disease. And many of the drugs that we have tried to develop to treat acute graft-versus-host disease have failed in the past. Part of this is due to clinical trial design. That is, if we develop a drug for steroid-resistant acute GvHD, and the definition of steroid resistant is that the patient either progresses by day 3 or fails to respond by day 7, and then you can start them on a new drug. If they respond by day 8 or day 9, we shout out “eureka,” and declare victory.

The problem is you can’t tell in a single-arm study whether that was just a delayed response to prednisone. And I think many of the dramatic responses that have been observed in the past were just that. And so several drugs, for instance, daclizumab, mycophenolate mofetil, which look like they were very effective in steroid-resistant GvHD, failed in randomized trials for primary therapy.

So the hope is that this will be a definitive trial for itacitinib. It is designed as primary therapy. The concern, of course, in patients with acute graft-versus-host disease would be that a drug like ruxolitinib would cause too much hematopoietic inhibition, and therefore a selective JAK1 inhibitor would be more useful. But I think that this will be the definitive trial. We will know unequivocally whether this drug is useful as primary therapy.

Transcript Edited for Clarity