The Effect of Inhibitory Antibodies on Acute Treatment of Bleeding Episodes with OΒΙ-1, an Antihemophilic Factor VIII (recombinant), Porcine Sequence, in Patients with Acquired Hemophilia Α

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder, caused by auto-antibodies that inhibit the activity of endogenous human factor VIII (hFVIII). In most cases, the inhibition is governed by non-linear non-saturable (Type II) kinetics, resulting in incomplete inhibition and thus, underestimation of the FVIII inhibitor titer. A highly pure, B-domain deleted, antihemophilic FVIII (recombinant), porcine sequence (OBI-1) that is less susceptible to the inhibitory activity of anti-hFVIII antibodies has been developed as a replacement therapy to manage bleeding episodes in AHA patients.

In one study of patients with AHA, the presence of pre-treatment anti-porcine FVIII (pFVIII) antibodies was reported not to correlate with the efficacy of a plasma-derived pFVIII¹. However, cross-reactivity of anti-hFVIII antibodies with the recombinant pFVIII OBI-1 or de novodevelopment of anti-pFVIII antibodies could impair efficacy of OBI-1 treatment in subjects treated with pFVIII replacement therapy.

This phase 2/3 open-label clinical trial investigated the efficacy and safety of OBI-1 in the treatment of serious bleeds in 28 adults with AHA. The primary efficacy endpoint was assessed at 24 hours (e.g., effective, partially effective). Subjects received an initial dose of OBI-1 (200 U/kg); additional doses were based on the subject’s target FVIII levels, anti-pFVIII titer, and clinical factors. This evaluation aims to address potential concerns regarding anti-pFVIII antibodies and their effect on the response to OBI-1 treatment in AHA patients.

Overall 10/28 subjects (36%) had detectable anti-pFVIII inhibitors (range 0.8-29 BU) prior to treatment, presumably due to cross-reactive anti-hFVIII auto-antibodies also neutralizing pFVIII. The rise in FVIII activity level immediately after the first OBI-1 infusion was lower in subjects with baseline anti-pFVIII inhibitors ≥5 BU/mL (median rise: 29%, n = 4) than in subjects without detectable or with low anti-pFVIII inhibitor levels (<5 BU/mL, median rise: 96%; n=6). However, with tailored dosing all 10 subjects achieved clinically relevant FVIII activity levels. Furthermore, all had a positive response to treatment at or before 24 hours.

All subjects received immunosuppressive therapy to treat their underlying autoimmune disease during the study. After treatment, 2 subjects with baseline anti-pFVIII inhibitors had an increase in anti-pFVIII titer (from 3 to 6 BU and from 15 to 183 BU); 8/10 subjects had a decline in anti-pFVIII titer to non-detectable levels. Five subjects did not have baseline anti-pFVIII but developed antibodies de novo (range 0.6-166 BU at final assessment). These de novo titers were first detected between 8 and 85 days after treatment initiation while the median duration of exposure to OBI-1 was 7 days. As 2 of these subjects had a concomitant increase in anti-hFVIII antibody titers, the de novoanti-pFVIII titers were possibly due to either, i) an anamnestic reaction to pFVIII that resulted in an increase in cross-reactive anti-hFVIII inhibitors, or ii) an immunogenic response to pFVIII yielding anti-pFVIII antibodies cross-reacting with hFVIII. Another 2/5 subjects had a concurrent decrease in anti-hFVIII antibody titers, suggesting an immunogenic response to pFVIII. These data indicate that immunosuppressive therapy used to treat auto-antibodies may not have the same suppressive effect on allo-antibodies.

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, particularly if the titer was greater than 5 BU. However, this early low FVIII activity level could be overcome by a tailored dosing regimen, guided by measuring FVIII activity levels. Consistent with previous reports with a plasma-derived pFVIII¹, our findings indicate a lack of correlation between baseline anti-pFVIII antibody titers and efficacy of OBI-1. OBI-1 replacement therapy facilitates objective and successful assessment of efficacy independently of inhibitors through monitoring of FVIII activity levels.

¹Morrison et al. (1993), Blood. 81:1513