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18 May 2011

The New and Improved (?) Recombinant Activated Factor VII Molecules

The Clinical Development Challenges of Recently Announced Modified and Biosimilar rFVIIas

Anastassios D. Retzios, Ph.D.


A number of new recombinant activated Factor VII (rFVIIa) molecules are currently in various phases of development.  Some of these molecules have been structurally modified from the original rFVIIa (NovoSeven®), to increase their platelet surface-dependent activity or their half-life (or both) and some are biosimilars that possess no specific enhancements.  These molecules are being developed at a time when rFVIIa efficacy in hemophilia has substantially improved by the introduction of higher dosing, and the hemostatic role of rFVIIa in non-hemophilia patients is seriously challenged by the results of various clinical studies.

In the past two decades, the original rFVIIa has been tested in hemophilia A and B complicated by inhibitors, in surgical situations with anticipated substantial blood loss, in acute intracerebral hemorrhage, in blunt and penetrating trauma and in a variety of other situations associated with excessive bleeding. 

In hemophilia, the originally approved dosing of rFVIIa led to less-than-optimal hemostasis.  Recent studies with substantially higher doses showed that these were both safe and highly effective, providing effective hemostasis with a single infusion in >90% of cases.  If there is a scope for improvement in hemophilia care by these new rFVIIa analogs, it must be established with clinically meaningful endpoints and appropriate sample sizes.  Certain possibilities are discussed in this review.  In addition, safety must at least meet if not exceed that of rFVIIa.  An extensive safety record with the original rFVIIa (NovoSeven®) is now available, a record that the newer molecules will require a substantial amount of time to challenge effectively.

In surgeries with anticipated substantial blood loss and high transfusion requirements, the issues are more complex.  Various studies with rFVIIa failed to establish a clinical benefit.  However, most of these studies have been exploratory in nature utilizing aggressive assumptions. With improvements in surgical techniques and extensive use of antifibrinolytic agents, it was not surprising that these aggressive assumptions were not been met in these clinical studies.  Any new development effort in this indication (prophylactic use in major surgery) may have to assess these assumptions; carefully consider the enrollment criteria in order to include patients more likely to experience substantial blood loss; and utilize more sensitive and more statistically efficient endpoints. Certain suggestions towards these improvements are included in this review.

In acute intracerebral hemorrhage (ICH), there is likely little scope for further development.  The proposition that hematoma growth after presentation is connected to poor outcome and higher mortality remains unproven and available opinion in support of this proposition is substantially skewed by bias.  Furthermore, decrease in hematoma growth can be achieved more efficiently by other methodologies.  In addition, there are a large number of technical issues in development in this indication that make further development very risky.  These include insensitive endpoints and substantial difficulties in balancing randomized groups in anything else than very large studies.  The development program by Novo Nordisk has failed to identify a clinical benefit due to a combination of the problems mentioned above.

In trauma, the situation is as ambivalent as in major surgery.  Clinical trials have failed to establish a role for rFVIIa and the latest pivotal clinical trial in this indication (CONTROL) has been terminated early for futility.  However, recent studies on trauma coagulopathy may point the way forward. These studies have indicated that trauma coagulopathy has an independent and substantial effect on mortality.  Unfortunately, the rFVIIa studies in trauma performed thus far did not limit enrollment to patients with strong evidence of coagulopathy.  Nor have the patients been evaluated for the potential requirement of massive transfusion.  Future efforts may have to incorporate more stringent enrollment criteria in order to be successful.

In summary, the challenges remain substantial in establishing a role for rFVIIa in a variety of clinical situations in which adequate control of hemostasis is important.  Obviously, these challenges have not deterred the introduction of new rFVIIa molecules and biosimilars.  It remains to be seen, however, if these challenges would be adequately addressed in future clinical studies.

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