Hemophilia Treatment, MarzAA, Shown to Prevent & Prolong Time to Next Bleeds

Interim data from Catalyst Biosciences, Inc.’s phase 2/3 trial of subcutaneous prophylactic Factor VIIa (FVIIa) variant marzeptacog alfa (activated) (MarzAA) as a potential treatment for hemophilia A or B with inhibitors was released in an oral presentation at the 2018 Hemophilia Drug Development Summit held on in Boston, Massachusetts. Among the highlights were reduced bleeding rates and prolonged time to the next bleed.

In an exclusive interview with Rare Disease Report^® (RDR^®), Catalyst’s CMO, Howard Levy, MBBCh, PhD, MMM, highlighted the study’s hallmarks in addition to providing insight on what’s to come.

RDR: Can you provide some background on MarzAA? What makes it unique?

Levy: Hemophilia patients who develop inhibitors to either factor VIII or factor IX have to be treated with a bypassing agent, and there are really only 2; there is intravenous Novoseven and generics, and then an intravenous infusion of plasma—a very large volume that takes 40 minutes or so to get into the patient. These are both given intravenously, and they are clearly inconvenient, [as you have] to find a vein and infuse.

MarzAA is a far more potent version of factor VIIIa; It is the same type of medication as NovoSeven, but because it is about 9 times more potent, we can put it in a small volume and inject it subcutaneously instead of having to find a vein. The whole premise [is] to do what hasn’t been possible with NovoSeven or with the large volume infusion, which would have to be given daily, or at best, every second day. By giving a small injection under the skin daily, we can hope to provide good prophylaxis—prevention of bleeding—to these patients who have an extraordinarily high bleeding rate and excess mortality and morbidity.

RDR: Can you discuss the phase 2/3 trial and what you found?

The first thing is to show the pharmacokinetics. We compared intravenous dosing with MarzAA to the subcutaneous [injection]. What we showed was while the peaks are lower, blood levels are the same when given intravenously and subcutaneously at about 5 to 7 hours after the dose. It comes up slow—but thereafter, the subcutaneous levels are higher [than] the intravenous. What this means is we still have meaningful levels to prevent bleeding.

I then showed the pharmacodynamics on the prothrombin time (PT). When we give the dose intravenously, we shortened the PT to about 8 seconds, and I showed that with daily dosing subcutaneously, by day 7, you’ve decreased the PT almost exactly the same, to those 8 seconds. That illustrated accumulation of the drug and accumulation of effect, so a patient isn’t just getting the same effect as an intravenous dose; they are experiencing an effect pretty early on, but it is well established by 5 days to enhance the coagulation system.

I then went on to show what we are seeing as the early effects of this drug. I showed that 3 patients had completed dosing, and to qualify for the study, these patients needed to have a bleeding rate of over 12; automatically, that means at least 1 bleed a month. The patients ranged from about 16 bleeds a year to 27 bleeds a year.

Unfortunately, these are like clockwork bleeds. We referred to the barcodes of the patients, because if you imagine that you are looking at a barcode with the lines, that’s the bleeding history. A thin line is a 1-day bleed, and a thicker line is a 3-day bleed. Our patients had up to 3 days of bleeding. It’s not just about how often our patients bleed, but how many days they bleed for. We showed the graphic of how often they bled for the 6 months prior to starting dosing.

We had 3 patients who completed the study. One [patient] went 50 days without a bleed at the lowest dose, the second [patient] relocated on day 44, so we stopped dosing on day 43, but of course, he will be followed up with in the future when he resumes bleeding. Then 1 patient who we had disclosed earlier at the lowest dose went 46 days without a bleed because he bled on an average of every 13th day. The higher dose, he went 50 days without a bleed. Those are really excellent results, and our vision is to find the individualized dose—that means no bleeding for the patient. One patient did complete the study, which means he came off the study drug, and on day 16, he had a 3-day bleed because he was no longer protected and had gone back to his old way of sadly waiting for a bleed and then treating it. We are really encouraged by these results in these 3 patients.

The fourth [patient] experienced a serious adverse event that was not drug-related and ended the study on day 11. The lowest dose clearly did not work for that patient, but we didn’t have the opportunity to escalate and see what dose might have worked for him.

Taken as a totality, we really believe we have this visual of a significant and meaningful reduction in bleeding, or elimination of bleeding in these patients.

RDR: On the patient side, how did MarzAA impact their quality of life?

One patient reported to his doctor that he wants to stay on this drug [MarzAA] forever. He was able to start doing things without fear. These are compromised patients, and they have had so many bleeds over their lives. For instance, 1 patient was unable to walk down his stairs, but with MarzAA, he was feeling his mobility increase so that he could go down stairs and not just upstairs. I think it’s this withdrawal of the fear that they will bleed at any time and just get on with the business of life that we take for granted.

RDR: What are the next steps for this research?

We’ve always said that we wanted 12 completers in the program, so the program continues to screen, enroll, and treat. We’ve given the guidance that we plan to finish the trial by the end of this year. Of course, that depends on the bleeding rate of the patients and if we find their dose early rather than later.

This is a phase 2 of a phase 2/3 protocol. At the end of this, we will meet with the US Food and Drug Administration to see how they like the results and what they need as a pivotal trial for approval. We’ve already had our guidance from Europe on what they [would like] to see, and we’ll see if this trial goes towards satisfying their needs.

The downstream phase 3 [trial] has yet to be finalized. We have to satisfy the whole world at the same time.