Current Status oC CHnical Studies oC Recombinant Factor VIII (Recombinate) in Patients With Hemophilia A Gordon L. Bray for the Recombinate Study Group
ABILITY to ~ynt~esize biologically actIve factor VIII In VItro was first demonstrated in 1984 by two groups of investigators working independently. l ,2 Application of their methodologies to the large scale production of recombinant factor VIII (rAHF) has resuIted in the development of two preparations for elinical use, which are currently being tested in elinical triais. This artiele will discuss the design, implementation, and outeome of clinical studies involving the Baxter/Hyland rAHF preparation, Recombinate, in patients with hemophilia A. In the clinical evaluation of rAHF preparations, it is essential to document the absence of serious adverse reaetions from their use over the short and long term and that their pharmaeokinetic properties (eg, reeovery and biologie half-life) are comparable to those of plasma-derived factor VIII. In clinical studies of high-purity, plasma-derived factor VIII conducted within the last 7 years, the issue of safety has focused on the relative risk of infection by blood-bome viruses. 3 ,4 Because rAHF preparations are not made from human plasma, the issue of transfusion-transmitted disease seems irrelevant to their clinical evaluation. With regard to the issue of efficacy, it is necessary to document that rAHF use results in consistent subjective and objective cessation of bleeding and that it prevents bleeding and promotes wound healing in high-risk situations such as dental and surgical procedures. Finally, rAHF clinical studies must address questions that pertain to product immunogenicity. Specifically, what (if any) risk is there of sensitization to foreign proteins (eg, Chinese hamster ovary proteins, murine immunoglobulin) that are involved in the biosynthesis and purification of the product? More importantly, what is the relative risk of antifactor VIII alloantibody formation associated with rAHF use? Whereas in vitro studies indicate that rAHF is identical to plasma-derived factor VIII in structure
T
H~
From the Department oj Hematology-Oncology, Chi/dren' s Hospital, Washington, DC. Address reprint requests to Gordon L. Bray, MD, Department ojHematology/Oncology, Chi/dren' s Hospital, III Michigan Ave NW, Washington, DC 20010. Copyright © 1992 by W.B. Saunders Company 0887-796319210604-0003$3.0010 252
15-7 h . concem about the pos· and f unc t lOn,' t ere IS sibility that subtle differences in its posttranslational processing and/or tertiary structure may resuIt in the formation of neoantigens, thereby rendering it more immunogenic than plasmaderived factor VIII.
CLlNICAL TRIALS IN PREVIOUSLY TREATED PATIENTS
White et al reported resuIts from the first pilot study of rAHF use that was designed to compare the pharmacokinetic properties of plasma-derived factor VIII with rAHF in two adults with severe hemophilia A. 5 Both patients exhibited a typical two-phase factor VIII disappearance curve for both plasma-derived factor VIII and rAHF when these were administered in the steady state 7 days apart. The mean half-life for the slower, 13 phase of factor VIII clearance was comparable for plasma-derived factor VIII and rAHF, 15.3 hours and 16.1 hours, respectively.5 Both patients infused rAHF on demand for the treatment of bleeding, one patient for 6 months, the other for l year. During these intervals, rAHF consistently provided good-toexcellent hemostasis with no adverse effects. 5 Follow-up factor VIII clearance studies performed on two occasions in one patient and on one occasion in the other gave resu1ts that were similar to those obtained at study entry, indicating that rAHF recovery and half-life did not change as a function of continued exposure to the product. 5 In August 1988 a phase lIlIII elinical trial of rAHF was initiated to develop a larger body of pharmacokinetic data as well as to assess longterm safety and efficacy of the product in a larger study population. Sixty-six previously treated patients with severe hemophilia A «2% of normal factor VIII activity) were enrolled in this prospective study and 55 completed at least 18 months of observation while receiving treatment with rAHF. As noted in the initial pilot studies, rAHF use consistently afforded good-to-excellent hemostasis with no significant adverse effects. * None of the
* The specific design and outcomes of the phase lIlIII dinica! triais of r-AHF in previously treated patients will be detailed in a separate publication that is currently in preparation. Transfusion Medicine Reviews, Vol VI, No 4 (October), 1992: pp 252-255
RECOMBINANT FACTOR VIII IN HEMOPHILIA A
participants in this study developed new inhibitors while receiving rAHF although the majority had a long history of exposure to plasma-derived products prior to study entry. CLlNICAL STUDlES IN NEWLY OR RECENTLY DIAGNOSED PATIENTS
Patients with extensive, prior exposure to plasmaderived factor VIII are a suitable population in which to assess the safety and efficacy of rAHF, but there is disagreement as to whether they are an optimal cohort to evaluate from the standpoint of inhibitor risk. Results from several prospective studies of inhibitor development in hemophilia A indicate that the majority of patients destined to develop inhibitors do so within the first 75 to 100 days of exposure to factor VIIL 8 - 11 Among patients who develop inhibitors, two thirds are identified before age 20. 8 Thus, the majority of subjects recruited for the previously treated patient clinical trial were beyond the period of greatest risk for inhibitor development when they initiated therapy with rAHF. In view of these observations, a prospective study of rAHF use in previously untreated patients (PUPs) was initiated in July 1990 to assess the risk of inhibitor development associated with its use. Eligible participants have severe hemophilia A «2% of normal factor VIII activity), no prior exposure to blood products, no serological evidence of infection by blood-bome viruses, and no evidence of factor VIII inhibitory activity in plasma. FolIowing enrolIment, study participants received rAHF exclusively for the treatment and prevention of bleeding. AlI patients will be folIowed-up for a minimum of 24 months or 50 rAHF exposure days, whichever occurs later. At the time of the first rAHF infusion, factor VIII recovery in plasma is measured 30 minutes and 24 hours postinfusion. FolIow-up recovery studies are performed in alI patients once every 6 months, whereas inhibitor assays are performed once every 3 months. AlI newly identified inhibitors are quantitated against both a recombinant and a plasma factor VIII standard in a central laboratory. Epitope mapping is being performed as part of the evaluation of alI newly identified inhibitors, using a series of Escherichia coli-derived factor VIII protein fragments and inhibitor plasma in immunoblotting and antibody neutralization assays.12 The availability of inhibitor incidence data from a prospective study of ultrapure, plasma-derived factor VIII (ie,
253
Hemofil-M Baxter/Hyland Div, Glendale, CA) in PUPs alIows for a comparison of inhibitor risk in recipients of the latter versus rAHF. 4 The characteristics of the rAHF PUP cohort are detailed in Table 1. Of the 78 patients enrolIed, 3 were subsequently determined to be ineligible and l voluntarily withdrew from the study. Fifty-eight patients have received at least one infusion of rAHF, although complete data is currently available on only 55 patients. Since inception, over 185,000 lU of rAHF from 16 different lots have been used for the treatment and prevention of bleeding in the PUP study. One or two infusions of rAHF has consistently provided good-to-excellent hemostasis in 87% of the bleeding episodes for which it has been used. Six surgical procedures (including evacuation of a subdural hematoma in two patients) have been performed with the use of rAHF, and in all cases bleeding was welI controlled. The only adverse reaction reported in association with 491 separate rAHF infusions has been the occurrence of rashes in two patients. In both cases the rash was not clearly related to the infusion of rAHF in a cause-and-effect fashion. Results from 112 30-minute postinfusion factor VIII recoveries in 42 patients have been evaluated to date. The mean ratio of actual to predicted factor VIII recovery is 112.4% ± 45.3. The large variTable 1. Characteristics of the Recombinate PUP Cohort No. patients enrolled No. patients evaluable (baseline factor VIII activity
ABILITY to ~ynt~esize biologically actIve factor VIII In VItro was first demonstrated in 1984 by two groups of investigators working independently. l ,2 Application of their methodologies to the large scale production of recombinant factor VIII (rAHF) has resuIted in the development of two preparations for elinical use, which are currently being tested in elinical triais. This artiele will discuss the design, implementation, and outeome of clinical studies involving the Baxter/Hyland rAHF preparation, Recombinate, in patients with hemophilia A. In the clinical evaluation of rAHF preparations, it is essential to document the absence of serious adverse reaetions from their use over the short and long term and that their pharmaeokinetic properties (eg, reeovery and biologie half-life) are comparable to those of plasma-derived factor VIII. In clinical studies of high-purity, plasma-derived factor VIII conducted within the last 7 years, the issue of safety has focused on the relative risk of infection by blood-bome viruses. 3 ,4 Because rAHF preparations are not made from human plasma, the issue of transfusion-transmitted disease seems irrelevant to their clinical evaluation. With regard to the issue of efficacy, it is necessary to document that rAHF use results in consistent subjective and objective cessation of bleeding and that it prevents bleeding and promotes wound healing in high-risk situations such as dental and surgical procedures. Finally, rAHF clinical studies must address questions that pertain to product immunogenicity. Specifically, what (if any) risk is there of sensitization to foreign proteins (eg, Chinese hamster ovary proteins, murine immunoglobulin) that are involved in the biosynthesis and purification of the product? More importantly, what is the relative risk of antifactor VIII alloantibody formation associated with rAHF use? Whereas in vitro studies indicate that rAHF is identical to plasma-derived factor VIII in structure
T
H~
From the Department oj Hematology-Oncology, Chi/dren' s Hospital, Washington, DC. Address reprint requests to Gordon L. Bray, MD, Department ojHematology/Oncology, Chi/dren' s Hospital, III Michigan Ave NW, Washington, DC 20010. Copyright © 1992 by W.B. Saunders Company 0887-796319210604-0003$3.0010 252
15-7 h . concem about the pos· and f unc t lOn,' t ere IS sibility that subtle differences in its posttranslational processing and/or tertiary structure may resuIt in the formation of neoantigens, thereby rendering it more immunogenic than plasmaderived factor VIII.
CLlNICAL TRIALS IN PREVIOUSLY TREATED PATIENTS
White et al reported resuIts from the first pilot study of rAHF use that was designed to compare the pharmacokinetic properties of plasma-derived factor VIII with rAHF in two adults with severe hemophilia A. 5 Both patients exhibited a typical two-phase factor VIII disappearance curve for both plasma-derived factor VIII and rAHF when these were administered in the steady state 7 days apart. The mean half-life for the slower, 13 phase of factor VIII clearance was comparable for plasma-derived factor VIII and rAHF, 15.3 hours and 16.1 hours, respectively.5 Both patients infused rAHF on demand for the treatment of bleeding, one patient for 6 months, the other for l year. During these intervals, rAHF consistently provided good-toexcellent hemostasis with no adverse effects. 5 Follow-up factor VIII clearance studies performed on two occasions in one patient and on one occasion in the other gave resu1ts that were similar to those obtained at study entry, indicating that rAHF recovery and half-life did not change as a function of continued exposure to the product. 5 In August 1988 a phase lIlIII elinical trial of rAHF was initiated to develop a larger body of pharmacokinetic data as well as to assess longterm safety and efficacy of the product in a larger study population. Sixty-six previously treated patients with severe hemophilia A «2% of normal factor VIII activity) were enrolled in this prospective study and 55 completed at least 18 months of observation while receiving treatment with rAHF. As noted in the initial pilot studies, rAHF use consistently afforded good-to-excellent hemostasis with no significant adverse effects. * None of the
* The specific design and outcomes of the phase lIlIII dinica! triais of r-AHF in previously treated patients will be detailed in a separate publication that is currently in preparation. Transfusion Medicine Reviews, Vol VI, No 4 (October), 1992: pp 252-255
RECOMBINANT FACTOR VIII IN HEMOPHILIA A
participants in this study developed new inhibitors while receiving rAHF although the majority had a long history of exposure to plasma-derived products prior to study entry. CLlNICAL STUDlES IN NEWLY OR RECENTLY DIAGNOSED PATIENTS
Patients with extensive, prior exposure to plasmaderived factor VIII are a suitable population in which to assess the safety and efficacy of rAHF, but there is disagreement as to whether they are an optimal cohort to evaluate from the standpoint of inhibitor risk. Results from several prospective studies of inhibitor development in hemophilia A indicate that the majority of patients destined to develop inhibitors do so within the first 75 to 100 days of exposure to factor VIIL 8 - 11 Among patients who develop inhibitors, two thirds are identified before age 20. 8 Thus, the majority of subjects recruited for the previously treated patient clinical trial were beyond the period of greatest risk for inhibitor development when they initiated therapy with rAHF. In view of these observations, a prospective study of rAHF use in previously untreated patients (PUPs) was initiated in July 1990 to assess the risk of inhibitor development associated with its use. Eligible participants have severe hemophilia A «2% of normal factor VIII activity), no prior exposure to blood products, no serological evidence of infection by blood-bome viruses, and no evidence of factor VIII inhibitory activity in plasma. FolIowing enrolIment, study participants received rAHF exclusively for the treatment and prevention of bleeding. AlI patients will be folIowed-up for a minimum of 24 months or 50 rAHF exposure days, whichever occurs later. At the time of the first rAHF infusion, factor VIII recovery in plasma is measured 30 minutes and 24 hours postinfusion. FolIow-up recovery studies are performed in alI patients once every 6 months, whereas inhibitor assays are performed once every 3 months. AlI newly identified inhibitors are quantitated against both a recombinant and a plasma factor VIII standard in a central laboratory. Epitope mapping is being performed as part of the evaluation of alI newly identified inhibitors, using a series of Escherichia coli-derived factor VIII protein fragments and inhibitor plasma in immunoblotting and antibody neutralization assays.12 The availability of inhibitor incidence data from a prospective study of ultrapure, plasma-derived factor VIII (ie,
253
Hemofil-M Baxter/Hyland Div, Glendale, CA) in PUPs alIows for a comparison of inhibitor risk in recipients of the latter versus rAHF. 4 The characteristics of the rAHF PUP cohort are detailed in Table 1. Of the 78 patients enrolIed, 3 were subsequently determined to be ineligible and l voluntarily withdrew from the study. Fifty-eight patients have received at least one infusion of rAHF, although complete data is currently available on only 55 patients. Since inception, over 185,000 lU of rAHF from 16 different lots have been used for the treatment and prevention of bleeding in the PUP study. One or two infusions of rAHF has consistently provided good-to-excellent hemostasis in 87% of the bleeding episodes for which it has been used. Six surgical procedures (including evacuation of a subdural hematoma in two patients) have been performed with the use of rAHF, and in all cases bleeding was welI controlled. The only adverse reaction reported in association with 491 separate rAHF infusions has been the occurrence of rashes in two patients. In both cases the rash was not clearly related to the infusion of rAHF in a cause-and-effect fashion. Results from 112 30-minute postinfusion factor VIII recoveries in 42 patients have been evaluated to date. The mean ratio of actual to predicted factor VIII recovery is 112.4% ± 45.3. The large variTable 1. Characteristics of the Recombinate PUP Cohort No. patients enrolled No. patients evaluable (baseline factor VIII activity
