Two studies reported at the 2014 ASH Annual Meeting described how to best optimize OBI-1 (antihemophilic factor [recombinant], porcine sequence), which was recently approved by the U.S. Food and Drug Administration for the treatment of bleeding episodes in adults with acquired hemophilia A (AHA).
AHA is a rare, but potentially life-threatening, bleeding disorder caused by the development of antibodies directed against the body’s own factor VIII (FVIII) – a protein important for blood clotting. Unlike hereditary forms of hemophilia A, about half of AHA cases result from medical conditions such as pregnancy, malignancies, or as a drug side effect, while the remaining half are spontaneous.
The recombinant analogue of porcine FVIII (pFVIII) contained in OBI-1 is similar enough to human FVIII to be effective in blood clotting, the investigators, led by Heinrich D. Farin, MD, noted, but is less likely to be affected by the antibodies against human FVIII that are present in people with AHA.
In one phase 2/3, open-label study, Dr. Farin and colleagues explored whether anti-pFVIII antibodies would limit OBI-1’s efficacy in the treatment of serious bleeds in adults with AHA. Twenty-eight patients with AHA received an initial dose of OBI-1 (200 U/kg); additional doses were determined by each patient’s target FVIII levels, anti-pFVIII concentration, and clinical factors.
Ten of 28 subjects (36%) had detectable anti-pFVIII antibodies prior to treatment. Patients with higher concentrations of anti-pFVIII antibodies at baseline (≥5 BU/mL) did experience a lower rise in FVIII activity level immediately after the first infusion of OBI-1, compared to patients without detectable or with low anti-pFVII inhibitor levels (median rise = 29% vs. 96%).
“The presence of anti-pFVIII antibodies prior to treatment appears to have had an effect on the immediate FVIII activity level rise after the first dose,” the researchers concluded, particularly if the concentration was >5 BU. However, with tailored dosing all 10 subjects achieved clinically relevant FVIII activity levels.
The Benefits of FVIII Monitoring
Because OBI-1 can be used without consideration of anti-human FVIII antibody, the drug fills an important unmet clinical need for AHA patients. As researchers noted in a post-hoc analysis of utilization data from the phase 2/3 study, use of OBI-1 does not interfere with measurement of FVIII levels – which can lead to better tailoring of treatment, a reduction in safety concerns, and minimization of cost impact. In a post-hoc analysis, researchers, including Dr. Farin, analyzed utilization data from the phase 2/3 study to examine the impact of FVIII monitoring on OBI-1 dosing.
First, investigators compared the initial administered dose to the subsequent doses infused in the treatment period; then, they compared total administered dose within the first 24 hours of treatment to the doses infused in the subsequent 24-hour periods.
Of the 28 subjects with AHA, two (7.1%) successfully responded to their initial administered dose (100 U/kg and 200 U/kg). Two more patients were successfully treated within the first 24 hours. After the first 24 hours of the treatment period, there were significant reductions in OBI-1 dosing:
- After the initial dose, there was a subsequent median dose reduction of 41.2 percent (IQR=50%; p<0.01).
- After the first 24-hour period, there was a median dose reduction of 65.4 percent (IQR=32.5%; p<0.0001) during subsequent 24-hour periods.
According to the results of this post-hoc analysis, the authors concluded, the ability to measure FVIII levels likely has a significant impact on dosing decisions to control bleeding episodes in adults with AHA.
- Farin HD, Novack A, Mo M, et al. “The effect of inhibitory antibodies on acute treatment of bleeding episodes with OBI-1, an antihemophilic factor VIII (recombinant), porcine sequence, in patients with acquired hemophilia A.” Abstract #2831. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.
- Oladapo A, Epstein J, Novack A, Farin HD. “The benefit of FVIII measurement: tailored treatment with OBI-1, a recombinant porcine sequence factor FVIII, in subjects with acquired hemophilia A.” Abstract #3509. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.