Researchers reviewed the current hemophilia research that focuses on the development of improved longer-acting factor replacement therapies, particularly PEGylated products. The new clinical research advances lead the scientific community to look at such developments with optimism, but also some caution.
The study, “Potential role of a new PEGylated recombinant factor VIII for hemophilia A,” published in the Journal of Blood Medicine, describes the advantages of these longer-acting products and discusses questions still to be answered about the novelty medicines.
Hemophilia A is caused by a deficiency in the activity of the coagulation factor (F) VIII. Current treatment practices rely on administration of recombinant or plasma-derived FVIII preparations. Patients with severe forms of this condition have been successfully managed with primary prophylaxis (a treatment given to prevent disease or severe disease consequences).
However, such treatments are faced with a major adverse event, the development of inhibitors (neutralizing antibodies). Such events may be overcome with an increase in factor activity, namely through higher doses for infusion, although higher levels of inhibitors are more difficult to treat. Inhibitors lead to frequent bleeds and the elimination of the benefits of prophylaxis. The doses of factor necessary in these patients is very high and even prohibitive.
Setbacks associated with the highly effective factor replacement therapy have led current research efforts to focus on the creation of new factor replacement treatments with longer half-lives and less probability of leading to an adverse immune reaction.
“The availability of longer-acting factor concentrates would reduce the number of infusions during acute bleeding episodes and prolong the time between prophylactic infusions,” the researchers said.
Among the new techniques, attachment of the FVIII to polyethylene glycol (PEG), a procedure named PEGylation, leads to the increase of the protein’s size and molecular weight, which might reduce its susceptibility to degradation and clearance. Some studies have shown that, compared to non-PEGylated protein, the half-life of PEGylated factor is more than doubled.
There are currently several PEG factor products that are approved or in clinical trials. The authors give the examples of Rurioctocog alfa pegol; Turoctocog alfa pegol; and BAY 94-9027, for which no reports of inhibitor development have been presented. The benefits of such products include the need for fewer doses, higher possibility of conducting treatments at home, increased productivity when recovering from bleeds, and reduced costs associated with hospitalization and absence from work.
Also, the fewer doses required for prophylaxis potentially decrease the burden of infusion and increase treatment compliance.
PEGylated medicines and other extended half-life FVIII replacement products give rise to some questions regarding the suitability of treatment, namely dosing challenges, as there is inter-patient variability regarding the product’s half-life.
Other unanswered questions refer to the products’ effect on immune tolerance and how previously untreated patients respond to these medicines.
“With all the promise of these new agents, many questions still remain. Over the decades, we have learned much about the treatment of hemophilia A. The collective experience gathered, as the care of hemophilia has improved, provides caution and optimism. We will come to learn how to best use these tools and the answers to our questions will come with the new lessons learned,” the authors conclude.