Differential Responses to Bypassing Agents
A Q&A with Jan Astermark (Sweden)
Patient responses to the two available bypassing agents, factor VIII inhibitor bypassing activity (FEIBA) and recombinant factor VIIa (rFVIIa), are variable. Although the two products can be combined to treat severe bleeding in patients with inhibitors, Dr. Jan Astermark of the Centre for Thrombosis and Hæmostasis, Skåne University Hospital, Malmö, Sweden, warns clinicians to be alert to the thrombotic problems that could result.
Q: What do we know so far about the way patients respond to these therapies?
A: “Each product has its own mechanism of action, and my talk covers the in vitro and clinical data on whether and how patients might respond better to one product compared to the other. The first head-to-head trial was our FENOC [FEIBA NovoSeven Comparative] study, which compared FEIBA with the current rFVIIa (NovoSeven) product for joint bleeds. Another trial by Young and colleagues was a three-arm study that also compared rFVIIa with FEIBA. We have since done further analysis of our own studies, looking at the influence of arthropathy on the use of these new drugs.
“One of the main messages from the FENOC study was the very high percentage of patients who rated the two products differently. Both drugs showed high efficacy at the two- and six-hour time points. But even though both drugs had an efficacy of around 80% at the primary end point, 43.8% of the patients rated their responses to the drug differently at two hours, and 31.9% did so at six hours. It meant that, in those patients, either rFVIIa was working better than FEIBA, or vice versa. This is a very important finding.”
Q: How do you explain the response?
A: “We do not have a clear finding, but we saw that the subgroup of patients who rated their responses differently had had more bleeds prior to the study than those who did not. They were more likely to have had more than eight bleeds in the previous 12 months. The effects of the drug were also more difficult to predict in patients with more severe arthropathy. With those patients, in particular, it may be that one drug will be more effective than the other.”
Q: Is there other research to support that conclusion?
A: “In the literature, there are several in vitro studies that show different effects with the two drugs in the tube. That’s actually what we would expect to see, due to the differences in their mechanisms of action. There have been in vitro assays of how these two drugs work, how much thrombin they can form in the tube in patient plasmas, and the results show that they differ in some ways.
“There are other potential factors that could explain the difference in patient response. The amount of tissue factor available at the site of the bleed could very well have an impact. It could have to do with the platelets available and how they bind proteins, and there is also the possibility of cross-reacting antibodies towards other factors besides the deficient factor VIII or IX in the patient.”
Q: What are the implications for future research and clinical practice?
A: “The results confirm what we see in the clinic. The problem is that we don’t have a reliable test to predict patient response. So now, we have to go back to the clinic, see what’s happening there, and come up with improved bypassing agents and better ways to monitor them.
“Several new options are in the pipeline. Factor VII drugs that have both higher potency and longer half-life are already in clinical trials. We may also see new molecules that bypass inhibitors in completely different ways. Or it may be that we can adopt a completely different set of strategies that activate the coagulation system in ways that we don’t know about today. A number of animal experiments and other studies going on around the world are looking at those possibilities.
“In the meantime, we need to make better use of the two drugs that we do have, and about which we know quite a lot. One option is to use them together in lower doses, either sequentially or in combination. That way, we can take advantage of the two different mechanisms of action. It could be one way to improve and optimize treatment and get a better hemostatic effect for the 10% to 20% of patients who are hard to treat, in whom the bleed doesn’t respond well to a single drug.
“This treatment option has been described in the literature. However, it must be delivered in a very strict way, since there is a risk of thrombotic problems when we mix these drugs. In severe cases that fail to respond to monotherapy, depending on the bleed, and taking into account the risk, this is definitely one way forward. But it’s an area where we still need more data.”
Jan Astermark’s presentation was part of a session titled Clinical Issues in Inhibitors held at the XXIX International Congress of the World Federation of Hemophilia, Buenos Aires, Argentina, July 10-14, 2010. Other speakers included Keith Hoots (U.S.A., Chair) and Elena Santagostino (Italy). Their state of the art paper, published in a special supplement of the WFH’s official journal Haemophilia, is available here.
Last Updated September 2010 |
