Two retrospective studies presented at the Thrombosis and Hemostasis Societies of North America 2016 Summit provided real-world data on recombinant porcine factor VIII (rpFVIII) for patients with acquired hemophilia A, both indicating that a lower dose of the drug than previously recommended by the U.S. Food and Drug Administration (FDA) still leads to effective bleeding control.
The FDA-recommended initial dose of the FVIII product is 200 U/kg followed by maintenance dosing titrated according to bleeding control and trough FVIII activity levels. In the clinical trial that served as the basis for rpFVIII's approval, a primary major adverse event (AE) was the development of anti-porcine FVIII antibodies. However, the results lack generalizability to the real-world patient population due to very specific eligibility criteria, according to Michael Tarantino, MD, lead author of one of the studies presented at this year's Summit.1
To characterize the real-world experience with rpFVIII, Dr. Tarantino, of the Bleeding & Clotting Disorders Institute in Peoria, Illinois, and colleagues conducted a chart review of seven patients with acquired hemophilia A who received rpFVIII at one of four institutions between November 2014 and October 2015.
Six of the seven patients were treated with rpFVIII for major bleeding, all in cases following unsatisfactory bisphenol A therapy. Five of the patients achieved good hemostatic efficacy with rpFVIII, meaning they required one or two infusions more than estimated to control a bleeding episode. Bleeding ceased within 24 hours in four patients, while another patient's bleeding ceased within four days. The majority of patients also had no bleeding recurrences.
Three patients experienced anti-porcine or cross-reactive anti-human antibodies, which resulted in one patient withdrawing from treatment. No rpFVIII-related AEs were reported.
- Four patients survived with inhibitor eradication.
- Two patients died with inhibitors present.
- One patient was discharged and died due to unrelated causes 4.5 months later.
The researchers found that patients benefited from a substantially lower dose of rpFVIII than the recommended U.S. FDA dose. An rpFVIII loading dose of 100 U/kg (n=6) or 200 U/kg (n=1) resulted in increased FVIII activity (from <1–9% to 109–650%, within 0.25–7 hours post-dose) in all but one patient.
Subsequent median doses ranged from 30 U/kg to 200 U/kg and were administered at intervals ranging from six to 48 hours.
"The doses of rpFVIII used were substantially less than in the registration study," Dr. Tarantino and colleagues concluded. "The ability to titrate rpFVIII dose using FVIII activity was considered advantageous, particularly where this allowed a dose reduction over time." However, the considerable delay observed in the diagnosis of acquired hemophilia may have affected treatment effectiveness in some cases, thus limiting the efficacy of the study outcomes.
In the second study, researchers, led by Karlyn A. Martin, MD, from the University of North Carolina, Chapel Hill, retrospectively reviewed medical records of three patients who received rpFVIII at their institution, including data on rpFVIII dosing, laboratory values, and clinical assessment of hemostasis.2
The patients received a total of 166 rpFVIII doses. The median patient age was 67 years. FVIII inhibitor titers at diagnosis were 54 BU/mL, 225 BU/mL, and 140 BU/mL for each patient, with baseline FVIII concentrate levels of â‰¤1 percent.
Prior to starting rpFVIII, all patients were treated with rFVIIa for a median duration of seven days with inadequate hemostasis. All patients started immunosuppressive therapy within four days of acquired hemophilia A diagnosis, with two receiving rituximab 375 mg/m2, and the third initiating prednisone and cyclophosphamide.
Their findings indicated that rpFVIII was well tolerated and controlled bleeding in all patients initially, with patients achieving hemostasis and goal trough FVIII activity levels with lower-than-recommended doses.
All patients initiated rpFVIII at 100 U/kg (half the FDA-recommended initial dosing), with subsequent doses titrated to control bleeding and attain trough FVIII concentration levels of 30 to 50 percent.
Within 12 to 24 hours after the initial rpFVIII dose, all three patients experienced clinical improvement, with patients achieving hemostasis at a median infusion dose of 50 U/kg. Bleeding episodes were controlled with a median of 12.5 infusions administered over 3.5 days.
"With time, many patients will â€˜saturate' the binding sites on the neutralizing autoantibodies and will experience a rise in the trough levels, allowing for fewer doses given per day," Alice Ma, MD, a co-author of the study and an associate editor for ASH Clinical News, said. "The [exciting] thing about the study is that we have shown we can give this expensive drug at much less than the FDA-approved doses."
Two patients experienced a decrease in anti-pFVIII after peaking at 34 BU/mL and 5 BU/mL, respectively, while the other patient had an elevation of anti-porcine FVIII titers to a level that rendered further doses of rpFVIII ineffective. No other AEs were reported.
The study is limited by the small patient population and the single-institution setting, and Dr. Ma elaborated on the limitations of the approach used in the study: "This will only work if the hospital has access to round-the-clock FVIII activity level monitoring; otherwise, the hematologist is flying blind and won't be nimble enough to modify doses and intervals appropriately."
- Tarantino M, Cuker A, Hardesty B, et al. Practical clinical experience with recombinant porcine FVIII for acquired hemophilia A. Abstract #44. Presented at the 3rd Annual Summit of the Thrombosis & Hemostasis Societies of North America, April 15, 2016; Chicago, Illinois.
- Martin KA, Kasthuri RS, Mooberry MJ, et al. Use of recombinant porcine factor VIII post licensure: a single-institution experience. Abstract #62. Presented at the 3rd Annual Summit of the Thrombosis & Hemostasis Societies of North America, April 15, 2016; Chicago, Illinois.