Emicizumab for the Treatment of Hemophilia

Peter L. Salgo, MD: We have a recently approved agent—I’m going to try to pronounce this, and

everybody knows this is a high wire act for me—emicizumab. How did I do?

Christopher E. Walsh, MD, PhD: Very well.

Peter L. Salgo, MD: Great. I’m not going to do that again. Talk about the indication, the dosage, and the mechanism of action. Go through this agent.

Christopher E. Walsh, MD, PhD: This is basically a relatively new drug. It was approved last November for inhibitor patients, and literally a week ago it was approved for all other patients, whether they have an inhibitor or not. This is a monoclonal antibody, basically to replace factor VIII. How factor VIII works is that it allows factor IX and X to touch each other. Factor IX, which is active, triggers the activation of factor X, and then we go down this cascade.

This is an antibody where one arm binds to factor IX or IXa, and the other allows binding to factor X. It allows these 2 to kiss, if you will, and triggers coagulation. It’s an elegant system that has a number of properties that are going to change the field. One is that it can be given subcutaneously in a relatively small volume. It can last up to a month. The drug itself will last for several months. The half-life is a month, but the clinical action is really good for a month. Basically, it’s an easier to give drug that lasts a long time, whereas the other factors that we use have to be given multiple times intravenously over a week.

Peter L. Salgo, MD: So this emicizumab is similar to factor VIII in terms of its activity, its actions, but it has advantages.

Christopher E. Walsh, MD, PhD: Yes.

Peter L. Salgo, MD: Smaller volume, longer acting.

Christopher E. Walsh, MD, PhD: Yes. Easier to give.

Peter L. Salgo, MD: It seems to me, if I hear you correctly, that there may not be antibodies to it.

Christopher E. Walsh, MD, PhD: There are, but at a rate that we talked about. With the way these monoclonal antibodies were created—historically, as you know, there are a number of monoclonal antibodies now in medicine—the rate is anywhere from 1% to 5%, and odds are even that’s too high an estimate. It is probably less than 1%.

Peter L. Salgo, MD: They’re low.

Christopher E. Walsh, MD, PhD: They’re low. They’ve already documented in clinical studies 1 patient who has developed an antibody, and I believe over 600 patients have received it.

Peter L. Salgo, MD: How does the emicizumab molecule differ from factor VIII?

Robert F. Sidonio Jr, MD, MSc: The way that they approached it was that we know if you give any other thing that looks like factor VIII, your body is going to neutralize it, right? It doesn’t care what it is. The antibody is pretty specific, but it’s a little bit promiscuous and can bind to other things. Somebody thought, “Well, what if I make a monoclonal antibody that replaces the function of factor VIII but has no structural homology?” It doesn’t look anything like factor VIII, so your body does not recognize it as factor VIII, but it replaces the function.

A Japanese scientist worked on this for almost a decade, which is unheard of in this day. In the grand cycles now, you have to develop something pretty quickly. He toiled away on this and came up with this drug. He screened 40,000 antibodies and found the right combination that worked. It’s a bispecific antibody that brings factor IXa and factor X together and activates the coagulation cascade, so it does basically what factor VIII does. It replaces a lot of the function. It’s not exactly the same. The great thing about it is that it was brilliantly designed where if factor VIII is there, it will just dislodge and factor VIII can bind. The binding affinity is much lower than factor VIII, so it won’t interfere with your normal factor VIII or infused factor VIII.

Peter L. Salgo, MD: How is this not immunogenic? How is it that you don’t generate antibodies to this?

Robert F. Sidonio Jr, MD, MSc: If you watch TV and you watch any kind of sport, you see a thousand rheumatoid arthritis or plaque psoriasis commercials, right? They’re all biologic agents, and we know there is a risk of developing antidrug antibodies. They tried to reduce the immunogenicity. It’s a humanized antibody, and because of that they’ve only had 1 definite case of a neutralizing antibody against this that made a patient unable to receive it.

Peter L. Salgo, MD: The answer is that they were very smart.

Robert F. Sidonio Jr, MD, MSc: They were very careful. They understood the science of this. There has been 1 patient on trial who has developed a neutralizing antibody and basically can’t get the drug, and they developed that in week 5. We haven’t seen it in other cases such that they would have to stop the drug. We do expect to see some cases, but obviously, after almost a thousand patients, it’s pretty rare.

Peter L. Salgo, MD: Let’s run through some of the basic checklist items for any new drug.

Robert F. Sidonio Jr, MD, MSc: Sure.

Peter L. Salgo, MD: Are there patient factors where you would avoid using this drug?

Robert F. Sidonio Jr, MD, MSc: I could start with the other side. If a patient has an inhibitor, this is a fantastic therapy. The clinical trial showed superiority, which is unusual in a lot of clinical trials. They actually took patients who were on factor VIII and patients who were on a previous regimen and they looked at the bleeding rate reduction. In most of the cases, it was in the 80% to 90% reduction range. Patients typically had 0 to 2 bleeds per year on the study, and this is a population that bleeds a lot.

Just recently, they received the indication for non-inhibitor patients. For patients with inhibitors, I think it’s pretty straightforward. It’s very efficacious and has good quality of life, so it’s a no-brainer. On the non-inhibitor side, we obviously have to think a little bit more because we do have a cohort of patients who are doing really well. We see these patients and they haven’t had a joint bleed in 3 to 4 years. They’re undergoing their infusions. They’re locked in. They’re very comfortable in their therapy. It’s just like anything else. There will be early adapters who will say, “Yes, I want something different. I want to try this because the route is different. Instead of IV [intravenous], it’s subcutaneous.”

Peter L. Salgo, MD: How long is the half-life? How often do you give it?

Robert F. Sidonio Jr, MD, MSc: The half-life of a factor VIII product is about 8 to 15 hours at the most. This is a 28-day half-life.

Peter L. Salgo, MD: This is a huge difference, in order of magnitude.

Robert F. Sidonio Jr, MD, MSc: They have the label indication for once a week, once every 2 weeks, or once every 4 weeks. We’ll obviously choose kids where there may be some reasons—if they’re playing in competitive sports—that we want to have fewer peaks and troughs. We might go once a week or once every 2 weeks. But if you think about the patients who are home, they may be not as active. They don’t want to do IV therapy. They could do once a month emicizumab, and there’s really no reason they couldn’t do something like that.

Peter L. Salgo, MD: I vote for once a month.

Robert F. Sidonio Jr, MD, MSc: Yes.

Peter L. Salgo, MD: Now, does every patient who forms inhibitors—or should they, in your view—get emicizumab or not?

Robert F. Sidonio Jr, MD, MSc: I think it should be strongly considered, and there’s a huge debate. We went to a meeting before where they actually had a really interesting debate style. They had one doctor say, “We should still use immune tolerance, we should still try to get rid of the inhibitors.” Another doctor would argue, “Why would we do that? We have this drug, so just put them on the drug and stop all this nonsense.” It was a vigorous debate. People were standing up saying, “That’s ridiculous.” There’s an ongoing debate now, and we actually have some early pilot studies in which you can potentially use both. It’s not FDA approved for this indication, but we’re going to present these data in 2 months. We think, as with everything else, there is a common ground and maybe we can use both.

Peter L. Salgo, MD: Let’s bring up one of the contraindications.

Robert F. Sidonio Jr, MD, MSc: Sure.

Peter L. Salgo, MD: Money.

Robert F. Sidonio Jr, MD, MSc: Yes.

Peter L. Salgo, MD: How much does this drug cost?

Robert F. Sidonio Jr, MD, MSc: When you look at inhibitor patients, it’s actually significantly cheaper.

Peter L. Salgo, MD: But what’s cheaper?

Robert F. Sidonio Jr, MD, MSc: In the hemophilia world, it’s like Monopoly money sometimes. Let’s take a 15-year-old boy, and we’re trying to treat his inhibitor. The standard of care, which is high-dose factor and prophylaxis with FEIBA or NovoSeven, could range in cost from $1 million to $5 million per year for that 1 patient. This drug, on average, for that same child will be somewhere between $300,000 and $400,000 dollars.

Peter L. Salgo, MD: It’s still expensive.

Robert F. Sidonio Jr, MD, MSc: It’s still expensive, but obviously just dramatically cheaper. There have been cases where some of these patients are causing disruptions in the market because it’s not sustainable to spend $5 million per patient. Obviously, we’re trying to do what we can, and we work really hard. The debate’s going to come down to the non-inhibitor patients. That same child’s factor replacement is somewhere between $200,000 to $400,000. It’s awfully close. For people who utilize high amounts of factor to not bleed, it’s a no-brainer, right? But for some patients, it might actually be cheaper to use factor concentrates. That’s the ongoing debate, and the insurance companies are going to look at this.

Transcript edited for clarity.