Guidelines for Emicizumab and aPCC Treatment of Hemophilia

Peter L. Salgo, MD: There is a black box warning we should talk about.

Robert F. Sidonio Jr, MD, MSc: On emicizumab, yes.

Peter L. Salgo, MD: On emicizumab. What is the black box warning? What is that about?

Robert F. Sidonio, Jr. MD, MSc: It was early in the clinical trials for adults. This is a preventive treatment; it doesn’t treat acute bleeds. When you have an acute bleed in an inhibitor patient, you still have to use one of those bypassing agents, such as aPCCs [activated prothrombin complex concentrates] or recombinant factor VII. What they didn’t know in the trial was that people were using the same doses that they were using before they were started on emicizumab, and this product elevates your ability to form clots. Since they used the same dose of something that elevates your ability to form a clot, what happened was they were forming excessive clots and thrombin generation was through the roof. What they discovered was that there were a few patients who developed thrombotic microangiopathy not in the standard way, which is ADAMTS13 deficiency or an antibody.

There were a couple of patients who developed blood clots. One developed a sinus thrombosis. The unifying factor they found was that when they used over 100 units per kilo in a 24-hour period of that aPCC, that’s when they saw it. There was a ‘Dear Investigator’ letter sent out. Once that was rectified and people didn’t use that dosing, we haven’t seen any more events like that. That’s the important thing. They made the change and we haven’t seen that issue, but that is a clear black box warning on the label. I think it’s important that people understand the risk.

Peter L. Salgo, MD: What do you do, other than stop the drug? If you’ve got somebody who has one of these terrible black box occurrences, what do you do?

Christopher E. Walsh, MD, PhD: The black box doesn’t necessarily tell you to not use the drug, but I think most clinicians would avoid it at all costs. What they did find during clinical trials was that this was dose related. If you use under a particular dose of an aPCC with emicizumab, you do not see these events at all.

Peter L. Salgo, MD: These black box warnings, to be very clear, are for emicizumab with an aPCC.

Christopher E. Walsh, MD, PhD: Yes.

Peter L. Salgo, MD: So for emicizumab left alone, that black box doesn’t apply.

Christopher E. Walsh, MD, PhD: Correct.

Peter L. Salgo, MD: What about breakthrough bleeding with this agent?

Christopher E. Walsh, MD, PhD: Bleeding with inhibitor patients can now be treated with NovoSeven. I do have a patient myself who’s on this, and we use FEIBA at a low dose. You can use those in addition.

Peter L. Salgo, MD: There is a pathway for each of these things.

Christopher E. Walsh, MD, PhD: Yes.

Peter L. Salgo, MD: And the black box warning is a very specific black box warning for a specific combination.

Christopher E. Walsh, MD, PhD: Yes, that’s correct. It’s important to note though that this is a disruptive drug because the frequency of bleeding, in my own experience and what has been published, is that these patients haven’t really bled.

Peter L. Salgo, MD: Really?

Christopher E. Walsh, MD, PhD: Yes.

Peter L. Salgo, MD: You just said in a broadcast about hemophilia that these patients don’t really bleed.

Christopher E. Walsh, MD, PhD: Right.

Peter L. Salgo, MD: That’s insanely great.

Christopher E. Walsh, MD, PhD: In the context of looking at all the factor preparations that are out there, if you take them as directed, the bleeding rates—what they call annualized bleeding rates—are somewhere between 1 to 3 or 0 to 3 a year. This is in that same ballpark, 0 to 1 or something like that. My own experience in treating about 20 patients now is that they don’t bleed.

Peter L. Salgo, MD: Is the interim guidance document you were talking about from MASAC [National Hemophilia Foundation’s Medical and Scientific Advisory Council]?

Robert F. Sidonio, Jr. MD, MSc: Yes. That group, MASAC, which I’m a member of, is a group of hematologists who set standards, make comments on things, and try to get ahead of issues. They made a comment about that and they supported that strategy. The FDA obviously wanted that strategy, but we supported that strategy as well. But we are actually looking into whether you can give low doses of FEIBA, and there are certainly cases in which that has worked. We have a case right now where we’re actually treating with low-dose FEIBA. That’s the key: close management with low-dose FEIBA. But right now, it’s still a backup option to recombinant VII.

Transcript edited for clarity.