Adult ITP: Promising Therapeutic Agents in Development

Transcript: Ivy Altomare, MD: We do have a few more minutes to discuss emerging therapies. Let’s start with PRN1008, a BTK [Bruton tyrosine kinase] inhibitor similar to ibrutinib, but with some very important distinctions from that molecule.

Ralph V. Boccia, MD: Yes, the important distinctions are in the adverse event profile, where there’s virtually no interference with platelet function, which would be the first thing I think everyone would think of; you’re going to give a patient with thrombocytopenia a BTK inhibitor. And the other is a very low rate of atrial fibrillation.

To the physiology, the cellular physiology of it, building on what Amit said earlier in the path, in the same pathway downstream from Syk [spleen tyrosine kinase] is BTK. The signal goes from Syk down toward BTK. And so instead of inhibiting Syk, we thought after already having a Syk inhibitor, let’s see what happens if we inhibit BTK. PRN1008 was presented by Dave Kuter, MD, on Saturday morning, as an oral presentation. And again, a very refractory group of patients beyond third-line therapy, and it saw almost a 40% response rate in this very highly refractory population of patients with a very good safety profile. So inhibiting BTK is one of the newest kids on the block and stay tuned.

Terry B. Gernsheimer, MD: Yes. And a relatively rapid response.

Ralph V. Boccia, MD: Very rapid responses within a couple of days.

Terry B. Gernsheimer, MD: Yes.

Ivy Altomare, MD: So that was presented at this meeting. There were a few other abstracts for another class of agents—FcRn inhibitors, neonatal Fc receptor inhibitors. Amit, do you want to talk about the mechanism of action of those drugs? And there were 2—rozanolixizumab and efgartigimod—that showed data at this meeting.

Amit Mehta, MD: Excellent job pronouncing those.

Ivy Altomare, MD: I practiced in front of the mirror for that.

Amit Mehta, MD: Yes, it’s also an exciting class of drugs where we’re trying to abrogate the IgG [immunoglobulin G] autoantibody levels that are circulating, and that’s really what’s driving the same macrophage destruction process. Both of these agents had encouraging responses in small studies. The first one you mentioned was one that is an intravenous or subcutaneous medication given weekly. And they saw responses approximately at a 50% level as far as achieving a 50,000 platelet count threshold. There weren’t long-term or even several months data presented in the abstract form. But encouraging. The adverse effect profile that was reported in the abstract as well seemed to be fairly favorable. Headaches were listed as the most prominent adverse effects that were noted by patients. So that’s once weekly intravenous or subcutaneous medication.

And the other one, an oral medication, also targeting the same pathway to reduce IgG antibody levels. And that one had a response rate of approximately 45%. Oral medication, short follow-up duration in a smaller trial. But encouraging that there seems to be a real signal of benefit. And again, these patients typically have been refractory to all of the standard options, or at least several of them over their history.

Ivy Altomare, MD: Right. And if you’re rapidly disintegrating IgG, that’s applicable not only for this autoimmune disease but many others. So maybe more to come from FcRn antibodies.

Amit Mehta, MD: Maybe more to come, and also in the studies they did again trend the IgG levels and they saw that they were indeed reducing those levels. So it seemed to be working in the mechanism by which they were targeted.

Terry B. Gernsheimer, MD: Still at a safe level. They were safe enough that they weren’t getting into trouble with very low levels.

Ivy Altomare, MD: Right. You’re not rendering patients hypogammaglobulinemic. They still have enough to have an intact immune response.

Richard F. McDonough, MD: Yes.

Ivy Altomare, MD: From my understanding. There were a couple of other key abstracts. Low-dose decitabine. Rick, do you want to tell us?

Richard F. McDonough, MD: The low-dose decitabine, they were looking at working on changes in the microenvironment in the bone marrow so that you may get better megakaryocyte maturation, changes in some of the factors involved there. And then as an offshoot from that platelet production. So it looks like there are some early results suggesting that that’s moving in that direction.

Ivy Altomare, MD: Fantastic. There are so many promising things, it’s very exciting. And the last was, Terry, I’m going to ask you, Tamiflu. Tell us about Tamiflu and dexamethasone for ITP.

Terry B. Gernsheimer, MD: It was very interesting because they did not have a control group that got just Tamiflu, which I find interesting because we’ve known for several years that just by chance some patients who get Tamiflu who have ITP [immune thrombocytopenic purpura] have increased their platelet count. Which of course was surprising because we’re always telling our patients: “You must get a flu vaccine because although that might lower your platelet count initially, it’s going to be a lot worse and a lot longer if you get the flu.” And so these patients got treated with Tamiflu.

Ivy Altomare, MD: Is this first line?

Terry B. Gernsheimer, MD: It was really just an observation that people noted that the patients, and I had a patient like this, the patients who got the flu, and of course we were very worried about them because they’ve already got a low platelet count, what if they dropped further? Got on Tamiflu and their platelet count increased. I’m not sure what to make of the data of mixing dexamethasone with Tamiflu because nobody has yet done that trial looking at Tamiflu alone, and I think we need to do that.

Ivy Altomare, MD: But I think a promising response rate for an improvement in platelet count with or without the benefit, maybe, without steroids.

Amit Mehta, MD: By the way, is there anything unique about the fact that there is a Chinese study if I remember, anything unique about Tamiflu in the Chinese population in the literature as far as we know? I’m not aware.

Terry B. Gernsheimer, MD: I don’t know. The patients I’ve seen it in were Caucasians. So I have no idea. But I think that brings up that interesting point of there are differences, ethnic and racial differences, in response, and also in the numbers of patients and incidents. There was actually an interesting paper that suggested that we’ve seen much less ITP in African Americans and blacks.

Ivy Altomare, MD: Right. And so you mentioned that that study was from the Chinese literature, which it was. There was another abstract that was presented looking at ATRA [all-trans retinoic acid], and that was in the first line I believe, with really remarkable response rates.

Amit Mehta, MD: Yes, correct. It was also a fascinating effort that was done by a group from China, and they were treating treatment naïve ITP patients, first line, with ATRA in addition to steroids.

So quite interesting that it was being utilized; ATRA is an oral medication. So an all-oral approach, so to speak, and there were significant responses. I believe in the range of 80% with the response rate. Their response definition by the way, interestingly enough, was a 30,000 threshold. In their abstract that’s what they had, just so we’re aware.

Now also what they saw, because there was a short-term follow-up study, once they stopped the ATRA there was a high relapse rate. It’s unclear what that implies for the patients, did they just happen to be, in a small study, more refractory type patients? Or just resistant patients by chance? Or why was that happening when they stopped the steroids and the ATRA?

Ivy Altomare, MD: Yes. Much more can be studied on that combination, but I thought it an interesting signal, and it’s not something that was known previously.

Transcript Edited for Clarity