The results of the SIPPET (Survey of Inhibitors in Plasma-Products Exposed Toddlers) study were published May 26, 2016 in the New England Journal of Medicine. The paper suggests that, in previously untreated patients (PUPs), the risk of developing an inhibitor when using recombinant factor VIII products is significantly higher than when using plasma-derived factor VIII concentrates that contain von Willebrand factor.
The WFH has reviewed the SIPPET study results and consulted with clinicians, regulators, medical advisory boards and other experts. The WFH has also requested comment from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). What follows is a description of the SIPPET study and a discussion of its findings.
The SIPPET study
The study was a prospective, randomized, multicenter open-label trial conducted in 14 countries. It compared PUPs treated with recombinant factor VIII (rFVIII) produced from hamster cell cultures to those treated with plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF). The results showed a significantly higher rate of inhibitor (neutralizing antibody) development in the rFVIII-treated subjects compared to pdFVIII/VWF-treated subjects.
The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with pdFVIII/VWF and 44.5% (95% CI, 34.7 to 54.3) with rFVIII. This represents an 87% higher rate. The cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) with pdFVIII/VWF and 28.4% (95% CI, 19.6 to 37.2), with rFVIII, a 69% higher rate. These data were obtained from 125 PUPs using recombinant and 126 using plasma-derived products.
Eight products were used in the study: the recombinant products were Recombinate and Advate (manufactured by Baxalta, now part of Shire), Kogenate FS/Helixate NexGen (Bayer AG), and ReFacto AF (Pfizer); and the plasma-derived products were Alphanate and Fanhdi (Grifols), Emoclot (Kedrion Biopharma), and Factane (LFB).
Because pdFVIII/VWF is made from pooled human plasma, it may carry a risk of transmitting infectious agents such as viruses. Stringent procedures designed to reduce the risk of viral transmission have been employed in the manufacture of these products, from the screening of plasma donors and the collection and testing of plasma, through the application of viral elimination/reduction steps such as solvent detergent and heat treatment in the manufacturing process. Despite these measures, such products can still potentially transmit disease; therefore, the risk of infectious agents cannot be totally eliminated. The confirmed risk of inhibitor development must be weighed against the theoretical risk of a pathogenic infectious agent being transmitted by pdFVIII.
Based on currently available evidence, there are different options depending on the status of the patient and the availability of specific treatment products.
1- In many countries only one FVIII product is available. That product should be used no matter what it is. Not treating carries a much higher risk of much more serious outcomes. Every FVIII product carries a risk of causing inhibitors but a majority of patients will never develop inhibitors, so the decision not to treat is not justified.
2- When the treatment products available are of the 2 “classes” in the SIPPET study (pdFVIII/VWF or rFVIII)
a) In the case of newly diagnosed individuals (PUPs) with severe hemophilia A who are not yet treated, the new data from the SIPPET study should be considered in the choice of product classes with which to initiate therapy. The treatment options are:
Initiate therapy with a pdFVIII/VWF product, or,
Initiate therapy with rFVIII
b) Individuals with more than zero and less than 50 exposure days to rFVIII should consider staying on their current recombinant FVIII product, since the differences between SIPPET and numerous other studies may not warrant switching patients who have already initiated a treatment regimen.
c) Individuals with greater than 50 exposure days to any FVIII product (i.e. Previously Treated Patients or PTPs) should remain on their current therapy, since multiple clinical studies have shown that they are not at increased risk for inhibitor development.
3- High purity plasma-derived FVIII which does not contain VWF, newer rFVIII products and longer-acting rFVIII products were not used in the SIPPET study, so no conclusion can be made regarding their associated risks.
Finally, the risk for inhibitor formation in PUPs, regardless of class of treatment product, is today the most serious concern of patients and treaters. All efforts by governments, hemophilia treatment centers, patient advocates, and industry should be directed at reducing the risk of inhibitors. An international registry to monitor inhibitors in PUPs is essential in working towards this goal.
The WFH will continue to monitor the situation as it evolves and continue its own deliberations on the subject. We will report on any new developments in the thinking about the SIPPET study and on inhibitor risk in general.
The paper can be accessed here: http://www.nejm.org/doi/full/10.1056/NEJMoa1516437?query=featured_home