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PRIORITY PRESS - XXIII Congress of the International Society on Thrombosis and Haemostasis (ISTH)/ 57th Annual Scientific and Standardization Committee (SSC) Meeting

Kyoto, Japan / July 23-28, 2011

Kyoto - Hemophilia B is the inherited disorder characterized by a deficiency in blood coagulation factor IX (FIX). Current treatment for hemophilia B is plasma-derived FIX or recombinant FIX (rFIX). Although rFIX avoids the risk of viral infections associated with contaminants of plasma-derived FIX, it retains some of the same limitations, such as development of antibody responses and a relatively short half-life. Here at the ISTH congress, these issues were addressed in reports of new regimens and of modified FIX molecules seeking to improve potency, stability and circulating half-life of the clotting factor.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

International clinical trials have demonstrated the efficacy and safety of recombinant factor IX (rFIX) (nonacog alfa) for the control and prevention of hemorrhagic episodes as well as in prophylactic and surgical settings in previously treated and previously untreated patients with hemophilia B.

Prophylaxis therapy has been shown to decrease episodes of joint hemorrhage and effectively prevent the development of chronic joint arthropathy and disability (Manco-Johnson MJ. Semin Hematol 2003;40(suppl 3):3-9). As a result, prophylaxis is now considered an optimal strategy for individuals with severe hemophilia.

However, the half-life of rFIX is relatively short (18 to 34 h) and replacement therapy requires intravenous administration every 2 to 3 days to maintain FIX levels sufficient to prevent spontaneous bleeding and may have implications for adherence and ultimately long-term efficacy. Any reduction in dosing frequency of rFIX is expected to improve patient adherence and contribute to improved clinical outcomes, further supporting the cost-effectiveness of such interventions. Researchers have long sought a more convenient rFIX regimen as prophylaxis or long-acting preparations that would allow for less frequent dosing.

Optimal Secondary Prophylaxis Regimen

The optimal regimen has yet to be identified for secondary prophylaxis with nonacog alfa to prevent bleeding, including hemarthrosis, in patients with hemophilia B. Pivotal clinical trial data exist for twice-weekly dosing, but a once-weekly regimen may help preserve venous access and its more convenient dosing could improve adherence. Here at the congress, the first study comparing nonacog alfa in 2 prophylaxis regimens with on-demand treatment was presented by Dr. Leonard A. Valentino, Director, Rush Hemophilia and Thrombophilia Center and Section of Pediatric Hematology/Oncology, Rush University Medical Center, Chicago, Illinois. He reported that both prophylaxis regimens significantly reduced annualized bleeding rate (ABR) by >85% relative to on-demand treatment and that both regimens showed acceptable safety profiles.

The randomized, crossover, open-label study enrolled 50 male subjects aged 6 to 65 years with severe or moderately severe hemophilia B (FIX coagulant activity [FIX:C] =2%) and =12 bleeding episodes (including =6 hemarthrosis episodes) in the previous 12 months. All patients participated in 4 study periods over a total of approximately 59 weeks. During period 1, subjects received nonacog alfa to treat bleeding events episodically only as they occurred (i.e. on-demand) for 16 weeks using a regimen of the investigator’s choice. At the end of this period, subjects were randomly assigned to nonacog alfa prophylaxis for 16 weeks (period 2) at either 100 IU/kg once weekly or 50 IU/kg twice weekly, followed by 8 weeks of on-demand therapy (period 3) to mitigate the potential carry-over effect of the prior prophylaxis regimen on bleeding frequency. For period 4, subjects were crossed over to receive the alternative prophylactic regimen for 16 weeks. Of the 50 subjects screened at 18 investigational sites in the US, Canada and Europe, 41 completed the study.

Dr. Valentino reported that in the intent-to-treat (ITT) population, least-squares mean ABR was 35.1 for on-demand treatment vs. 4.6 and 2.6 for prophylaxis with 100 IU/kg once weekly and 50 IU/kg twice weekly, respectively (Figure 1). Differences in ABR between on-demand treatment and each prophylaxis regimen were significant (P<0.0001), but there was no significant difference between the 2 prophylaxis regimens. Joint, traumatic and spontaneous ABRs were lower with both prophylaxis regimens than with on-demand treatment. Compared with the 100 IU/kg regimen, bleeding events (spontaneous and traumatic) were more frequent with the 50 IU/kg regimen =72 h post-infusion (29 vs. 12) and less frequent >72 h post-infusion (6 vs. 40). Subjects reported significant improvement in pain and physical function with both prophylaxis regimens. There were no reports of serious adverse events or events of special interest (thrombosis, FIX inhibitor development or allergic reactions) related to study drug.

According to the investigators, once-weekly prophylaxis with nonacog alfa 100 IU/kg would be a safe and effective alternative to twice-weekly prophylaxis with 50 IU/kg and might be more convenient for both patients and caregivers.

Figure 1.

New Developments

Results of a first human dose trial of a glycopegylated recombinant factor IX (N9-GP) in patients with hemophilia B were reported here at the ISTH congress by Prof. Claude Négrier, Hôpital Édouard Herriot, Centre Régional de Traitement de l’Hémophilie, Université Claude Bernard Lyon 1, France, and colleagues. N9-GP was designed in an attempt to prolong the half-life (t½) of factor IX, thereby reducing dosing frequency. This was achieved by attachment of a 40KDa polyethylene glycol (PEG) molecule to the activation peptide of factor IX. In animal models, N9-GP exhibited up to a twofold increased in vivo recovery and a markedly prolonged t½ compared with rFIX.

Prof. Négrier’s group investigated the safety and pharmacokinetics of 3 ascending doses of N9-GP (25, 50 and 100 U/kg) in 16 previously treated patients with hemophilia B. N9-GP was shown to have a t½ of 93 h, fivefold higher than the patients’ previous FIX products. The incremental recovery of N9-GP was 94% and 20% higher compared with currently available rFIX and plasma-derived FIX, respectively. N9-GP was generally well-tolerated; none of the patients developed neutralizing antibodies but one patient experienced a transient allergic reaction. The investigators concluded that N9-GP has the potential to reduce dosing frequency as compared to current treatment. N9-GP is being studied as prophylaxis as well as treatment of bleeding episodes in hemophilia B patients.

The pharmacokinetics of recombinant coagulation factor IX albumin fusion proteins (rIX-FPs) with cleavable linker peptides derived from the FIX activation sequence were reported here at the congress by researchers from Marburg, Germany. They explained that the recombinant albumin portion of the molecule prolongs the t½ of rFIX in the absence of factors that activate FIX, but is removed in the presence of physiological activators of FIX, thus preventing the albumin portion from interfering with the biological activity of activated factor IX (rFIXa).

Dr. Hubert Metzner and colleagues monitored pharmacokinetics of rFIX and rIX-FPs in rats. With nonactivated rIX-FPs, pharmacokinetic investigations showed an increase in recovery (42% vs. 30%) and terminal t½ (11.4 h vs. 4.9 h) by fusion. As expected, the activated rIX-FPs with cleavable linker revealed pharmacokinetic properties comparable to rFIXa, whereas activated rIX-FPs with non-cleavable linker retained a higher recovery (22%) and terminal t½ (6.3 h) than rFIXa and activated rIX-FP with cleavable linker. The researchers concluded that rIX-FPs with cleavable linker show improved pharmacokinetic properties prior to activation. Upon activation, however, they behave like activated rFIX, avoiding an increased prothrombotic risk due to an extended t½. The safety and efficacy of an rIX-FP are currently being studied in the control and prevention of bleeding episodes in subjects who have previously received recombinant factor replacement therapy for hemophilia B.

Summary

Recurrent bleeding episodes can have long-term consequences for hemophilia patients. Promising new compounds that have a much longer half-life and improved pharmacokinetics are anticipated. For the moment, once-weekly prophylaxis with nonacog alfa appears to offer optimal results in outcomes and preserves venous access. This may help promote greater patient adherence to therapy.