Expert panelists review the challenging setting of factor VIII inhibitors in hemophilia and reflect on how the emergence of emicizumab has addressed previously unmet clinical needs.
Peter L. Salgo, MD: We’ve got this “Kumbaya” moment here. We’ve got a disease, there is a specific factor that’s missing, and we’ve got factors that match. You don’t bleed. Along comes inhibitors. What the heck are they?
Robert F. Sidonio Jr, MD: Those have been around as early as factor concentrates have been around. These are neutralizing antibodies, typically against the exogenous factor VIII, so they are infused factor VIII products. That could come from cryoprecipitate or plasma or our standard products. Unfortunately, the rate of inhibitor development has not changed. The prevalence in severe hemophilia A is about 13%. When we have a new child, as we just had this week, I tell that family, “There’s about a 30% chance or 35% chance that your child will develop one of these neutralizing antibodies.” Typically, that happens in the first 20 exposures, usually around 10 to 15 exposures. We have to be on constant alert. Every time they get factor, we bring them back and evaluate.
But what this does effectively is make therapy that worked so well—that replaced what you’re missing, as you said—become totally ineffective. And so now we have to use therapies, those bypassing agents, which are not as effective.
Peter L. Salgo, MD: You’re basically back to naked hemophilia.
Robert F. Sidonio Jr, MD: Yes, and if anything, it’s worse. You see these families, and with an inhibitor, we’ve had these families say, “I wish I just had regular hemophilia again,” which is just a devastating thing to hear because that’s just a next level of just badness. The therapy escalates 100-fold. You’re now giving therapy every day. And even everyday therapy is not good enough.
Peter L. Salgo, MD: But does it affect your goals?
Robert F. Sidonio Jr, MD: Yes.
Peter L. Salgo, MD: In other words, with these inhibitors, are you still shooting for no bleeding?
Robert F. Sidonio Jr, MD: You can’t get there with inhibitors unfortunately. You can significantly reduce their chance of life-threatening bleeds. Your goals have changed dramatically, unfortunately, so you can’t get to the point where they’re having very few bleeds and a relatively normal life. Now you’re trying to protect them from dying from a life-threatening bleed.
Peter L. Salgo, MD: You’re back to square one.
Tim Boonstra, RPh: Yes, absolutely.
Robert F. Sidonio Jr, MD: It’s pretty awful.
Peter L. Salgo, MD: That’s brutal. What do you say to patients who have the inhibitors and talk to you about it?
Lacey Chapman, RPh: I was actually wondering if you can use factor VII.
Robert F. Sidonio Jr, MD: We use bypassing agents, so recombinant factor VII or APCCs [activated prothrombin complex concentrates]. But we know we’re not actually treating the deficiency, right? If you’re deficient in factor VIII or IX, you’re not actually addressing that issue, so you’re just providing other concentrates or other factor products that are going to help out and prevent bleeding. But you’re still going to have multiple joint bleeds: on average, 1 joint bleed per month, which is obviously not acceptable.
Peter L. Salgo, MD: All right, let’s fast-forward into the new millennium, the era of genetic medicine. There’s something out there; there’s emicizumab. What is that?
Robert F. Sidonio Jr, MD: For many years, we’ve been mostly focused on replacing the factor VIII product, and we’ve been dealing with this issue even though with every new factor product, the rate of inhibitor development is approximately the same. It’s unacceptably high. If one-third of your patients have a horrible serious adverse event, that’s not an acceptable thing.
What one Japanese scientist did was say, “We’re going to make a humanized monoclonal antibody, and it’s not going to have any structural homology to factor VIII.” That means that your body sees it, and it doesn’t look like factor VIII. It’s an antibody. The benefit of being that antibody is that the half-life is much longer. Instead of 8 hours or 12 hours, you’re talking about up to a month, 28 days on average. What it does is it replaces what factor VIII normally does, but doesn’t look like factor VIII.
Peter L. Salgo, MD: It has the function of VIII, but it doesn’t look like VIII.
Robert F. Sidonio Jr, MD: Yes. It doesn’t look factor VIII. A patient who has an inhibitor can get this therapy and almost return back to what they were before.
Peter L. Salgo, MD: Why does this remind me of that old commercial? It feels like a pump, but it looks like a sneaker.
Robert F. Sidonio Jr, MD: Exactly.
Peter L. Salgo, MD: Or the other way around. But that’s fascinating.
Robert F. Sidonio Jr, MD: Yes.
Peter L. Salgo, MD: Because the real problem here was the immunogenic response to exogenous VIII.
Robert F. Sidonio Jr, MD: Yes.
Peter L. Salgo, MD: Suddenly, that doesn’t exist.
Robert F. Sidonio Jr, MD: Before, we determined this is a fantastic option for those who develop inhibitors. It doesn’t address the issue of treating the inhibitor and getting rid of it, but it definitely reduces the bleeding significantly to where it’s just a dramatic improvement. Recently, it was approved for noninhibitor patients—those who didn’t develop that inhibitor—because it works the same way as factor VIII, and it’s highly effective in the clinical trials.
Peter L. Salgo, MD: The reason that you would use this, even in the absence of inhibitors, is half-life?
Robert F. Sidonio Jr, MD: Yes. If you’re talking about therapy, in a typical trial they’d have to infuse at least 3 times a week with intravenous therapy. If you’re born with good veins, great. If you were born with crappy veins, you’re out of luck, right? This is a subcutaneous therapy, everybody can give it, and it’s similar to like doing an insulin injection. You’ve removed the level of skill that’s involved, and you’re providing a higher level of protection for longer periods.