Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients

Clinical Evaluation of B-Domain Deleted Recombinant Factor VIII in Previously Untreated Patients S.G. Courter und C. L. Bedrosiun The safety and efficacy of B-domain deleted recombinant factor VIII (BDDrPVIII) were evaluated in previously untreated patients (PUPS) with severe hemophilia A. In an open-label multicenter study, 101 PUPS received routine prophylactic and/or on-demand treatment with BDDrPVIII, including treatment related to surgery for 50 exposure days for up to 5 years. The pharmacokinetic measurements (ie, elimination half-life and in vivo mean recovery) assessed at baseline and 12 months were stable for BDDrPVlll over time. A total of 1,362 hemorrhages occurred. Ninety-two percent (1,258/1,362) of bleeding episodes resolved after three infusions or fewer. Of the 2,375 infusions rated by investigators, 93% (2,215/2,375) were rated as providing an “excellent” or “good” response. Twenty-seven patients received routine prophylactic treatment, which significantly reduced breakthrough bleeding episodes by twofold when compared with patients who were treated on-demand. Administration in conjunction with 40 surgical procedures showed no adverse effects, and the overall assessment was either “very useful” or “useful.” The mean dose was 56 IU/kg for routine primary prophylaxis and 53 IU/kg for on-demand therapy for bleeding episodes in patients who were assessed to be inhibitor-free at the time of infusion. Thirty-two percent of patients developed inhibitors. Of these, 16 patients were high responders (peak titer zz 5 Bethesda units [Ml]). The inhibitor risk was comparable to that seen with full-length recombinant products. BDDrPVlll was found to be effective, safe, and well tolerated. Semin Hematol38(suppl4):52-59. Copyright 0 2001 by W. B. Saunders Company.

B

-DOMAIN deleted recombinant factor VIII (BDDrFVIII; ReFacto, Wyeth/Genetics Institute, Cambridge, MA) has been shown to be safe, effective, and well tolerated in previously treated patients (PTPs) with hemophilia A in phase III studies (refer to the PTP clinical study by Courter and Bedrosian in this supplement). With the successof BDDrFVIII in PTPs, clinical phaseIII studies in previously untreated patients (PUPS) were performed in the United States, Europe, Turkey, and South Africa. The first patient was enrolled on September 27, 1994. This study includes data available as of September 30, 1999. The study was designed to assess the safety and efficacy of BDDrFVIII in ondemand and/or prophylaxis treatment of PUPS with severe hemophilia A (factor VIII activity, VIII:C, <0.02 IUlmL). Special emphasis was placed on the incidence and prevalence of inhibitor formation.

From the Genetics Institute, Cambridge, MA. Address reprint requests to C. L. Bedrosian, MD, Institute, 87 Cambridge Park Dr, Cambridge, MA Copyright 0 2001 by W.B. Saunders Company 0037-1963/01/3802-4008$35.00/O doi:10.10S3lshem.2001.26299

52

Seminars in Hematology,

Genetics 02140.

Methods Study Design This trial was an open-label, multinational, phase III clinical trial of the coagulation recombinant factor, BDDrFVIII. After meeting the inclusion and exclusion criteria, patients received BDDrPVIII either as on-demand treatment for bleeding episodes (spontaneous or after trauma) or as routine prophylaxis. Patients were treated for 50 exposure days or up to 5 years, whichever came first. Development of inhibitors and antibodies was monitored at least every 3 months. Factor VIII activity measurementsi for calculation of recovery were performed at baseline; months 6, 12, 18, and 24; and then yearly thereafter. A total of 49 centers in 15 countries participated in the study, which involved 101 PUPS.

Inclusion and Exclusion Criteria Only patients with severe hemophilia A (VIII:C < 0.02 IU/mL) were included in the study. Patients were excluded if they presented any of the following: (1) prior use of blood or blood products; (2) exposure to hepatitis A, B, or C viruses (HAV, HBV, HCV, respectively) and human immunodeficiency virus (HIV); (3) any detectable inhibitors at the start of treatment; or (4) any other known coagulation disorders, abnormal renal function, diagnosed metabolic disease (eg, diabetes), or liver disease.

Pharmacokinetic Evaluation In vivo recovery was calculated for the first dose and for doses after 6, 12, 18, and 24 months of treatment, based

Vol38,

NO 2, kppl4

(April),

2001:

pp 52-59

BDDrFVIII

on samples The primary incremental VIII activity

drawn

before

and 30 minutes

after

in Previously

the dose.

assessment of in vivo recovery was the recovery (K-value), which is IU/mL factor increase per W/kg of BDDrFVIII adminis-

tered.’ In vivo recovery (%) was also calculated with the maximum factor VIII activity during the first hour postinfusion, the total factor VIII activity administered, and the plasma volume (mL).3-5 All factor VIII activity measurements for pharmacokinetic evaluation were performed using the chromogenic substrate assay.’

Treatment Schedules On-demand

treatment

was based on the standard

practice

at each treatment center. Dosage and dosing intervals were individualized at the discretion of the investigator, depending on the severity and nature of the bleeding episode, the clinical condition of the patient, and the patient’s response to treatment. Prophylaxis treatment (ie, Z 14-day period) was individualized and based on (1) the investigator’s judgment; (2) factor VIII activity measurements; and (3) the patient’s bleeding pattern. Some patients were treated with primary routine prophylaxis. Patients scheduled for elective surgery, who were escimated to require at least 1 week of perioperative and daily postoperative treatment, were enrolled in a separate surgical protocol for the entire postoperative period. Upon completion of the surgical protocol, the patient resumed the procedures stated in the PUP clinical trial protocol. Each patient’s total dose included all infusions given for the periand postsurgical procedure. Patients who developed inhibitors to factor VIII activity were rechallenged with a single infusion of 50 IUikg body weight of BDDrFVIII after a 3-day washout period. In vivo recovery of BDDrFVIII was assessed from the sample drawn before the dose and a sample drawn 30 minutes and 24 hours after the infusion. A confirmatory inhibitor test (ie, Bethesda assay; see Safety Assessments section) was performed after IL0 to 21 days, and if possible, after a S-day washout period. In addition, a sample was sent to Pharmacia AB, Stockholm, Sweden or the University of North Carolina Hospital, Chapel Hill, NC in the United States for analysis. Patients with high titers (25 Bethesda units [BU}) were offered participation in an immune tolerance (IT) protocol. IT was defined as an infusion frequency of more than four times per week and/or using more than 50 IUikg of BDDrFVIII three times per week in patients with inhibitors. The treatment schedule was one to two infusions per day of 100 IUikg for patients with titers between 5 and 10 BU, and 200 IUikg for those with titers greater than 10 BU. If a patient with a peak inhibitor of 25 BU did not participate in the IT protocol, he or she could be treated according to the investigator’s judgment or according to an alternative IT regimen. For these patients, inhibitor testing was performed at least monthly. For patients with low titers (<5 BU) treatment was continued with BDDrFVIII, according to the investiga-

Untreated

Patients

53

tor’s judgment. Patients with protocol inhibitor levels (~0.6 BU) who withdrew from the study or did not receive an IT treatment were followed up, if possible, with an inhibitor test at least once every 3 months.

Efficacy Assessments Achievement of hemostasis was rated by physicians or patients according to a four-point scale: 1, “excellent”dramatic response with abrupt pain relief and clear reduction in joint or bleeding site size within 8 hours; 2, “good’‘-pain relief or reduction in bleeding site size that was delayed or required more than one infusion; 3, “fair’‘-probable or slight beneficial response; and 4, “none’‘-no response. This scale allowed the investigator’s prior experience to be considered in accounting for confounding factors such as sites or severity of bleeding episodes. A five-point efficacy evaluation scale (“very useful,” “useful,” “slightly useful, ” “useless,” and “unfavorable”) was used to quantify the usefulness of treatment, taking into account the hemostatic effect, any adverse events, abnormal laboratory findings, and notes in patient diary cards.

Safety Assessments Clinical safety was monitored by physical examination and vital signs. Laboratory safety was assessed by determining the presence of inhibitors to factor VIII activity through assays conducted by Pharmacia AB, Stockholm, Sweden (for European samples), or at the University of North Carolina Hospital, Chapel Hill, NC (for US samples). The presence of inhibitors was determined by the Bethesda assay.6 The lower end point for inhibitor detection was 0.6 BUlmL. This definition was chosen by the United States Inhibitor Study Group, an expert group funded by the National Institutes of Health, and has been applied to other clinical trials.7,8 Two different test samples (normal plasma and BDDrFVIII) were used in the analysis. In order to interpret borderline test results, samples were retested using the Nijmegen modification of the inhibitor assay to rule out false positives.9 All patients with any positive Bethesda assay results in the central laboratory (Stockholm) were evaluated further. Monitoring for the presence of antibodies to factor VIII, components derived from Chinese hamster ovary (CHO) cells, and mouse immunoglobulins type G (IgG) was determined by the central laboratory at Pharmacia AB. The presence of antibodies was determined by using spectrophotometric enzyme-linked immunosorbent assays (ELISAs).’ Hematology and clinical chemistry assessments included hemoglobin, hematocrit, platelet count, white blood cell count, red blood cell count (RBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and creatinine. Any test falling significantly outside the laboratory’s normal range was repeated and followed up until normalized. Before the start of the study, baseline laboratory samples were taken for viral serology determinations of HAV, HBV, HCV, HIV-l, HIV-2, and hepatitis B surface

54

Cowter and Bedrosian

the 101 treated patients withdrew from the study: five withdrew due to protocol violations; one withdrew consent; one withdrew after developing inhibitors and failing to achieve IT; one developed anaphylaxis during IT; and one died of cerebral hemorrhage. The average age at inclusion was 10 months, with a range of 0 to 52 months. Ninety-one patients were white, three were black, two were Hispanic, and five were of unspecified race or ethnicity. The average patient weight was 8.8 kg, with a range of 2.7 to 20 kg. Sixty-nine patients had a family history of hemophilia, including seven patients with a known family history of inhibitor development .

antigen (HB,Ag). Subsequent assessments were performed every 6 months for HAV, HCV, and HIV in order to evaluate viral safety. An adverse event (AE) was any undesirable event occurring to a patient in the trial, whether or not it was considered related to BDDrFVIII. An AE included any change in a patient’s condition or laboratory results, which had or could have a deleterious effect on the patient’s health or well-being. A serious adverse event (SAE) included any event that was fatal, life-threatening, permanently disabling, was cancer, a congenital anomaly, an overdose, or required prolonged hospitalization. Inhibitor formation to facror VIII activity (2 10 BU) or positive seroconversion of a previously negative viral marker was considered a SAE, and was immediately reported, unless it was the consequence of an active immunization. Patients who required elective surgery were transferred to the specific surgery study during the time of their surgery. These expected hospitalizations were not regarded as SAEs.

Pharmacokinetic Evaluation The pharmacokinetic measurements of efficacy did not change over time. The average elimination half-life at baseline was 7.5 2 2.7 hours (n = 39) and 8.8 t 3.0 hours at month 12 (n = 14). There were 11 patients who had measurements at both baseline and month 12. The mean half-life in these patients was very similar at these visits, 8.8 + 3.7 and 8.7 + 3.3 hours, respectively. The in vivo mean recovery (Kvalue) was 1.9 IU/dL per IU/kg at baseline (n = 46) and was observed to remain consistent over time in nine patients (Table 1). The mean recovery (%) for all patients ranged from 84.2% to 95.3%.

Statistical Methods Efficacy and safety evaluations were descriptive. Quantitative variables were summarized by descriptive statistics including the number of observations, mean, standard deviation, median, minimum, and maximum. Qualitative variables were described by number and percent. The Kaplan-Meier technique was used to estimate the inhibitor-free probability distribution with the corresponding survival plots. The number of BDDrFVIII exposure days (up to the day before inhibitor development) was analyzed in the survival analysis.

Results Patient Characteristics All of the 101 patients enrolled received at least 1 dose of BDDrFVIII, including treatment related to surgery, if required. As of September 30, 1999, 54 patients had completed the study (150 exposure days or up to 5 years). Nine of Table

1. In Vivo Recovery

Week 0 K-Value* (IU/dL oer IU/krZ) N Mean Median SD Min Max

46

Month

Recovery? (%)

46

1.9

95.3

2.0 0.5 0.3 3.2

97.5 24.7 13.0 161.0

Patients experienced a total of 1,362 bleeding episodes that required infusions of BDDrFVIII for on-demand treatment (Fig 1). Sixty-five

for Inhibitor-Free 6

Patients Month

K-Value (IU/dL per IU/kK)

Recovery 06)

37 2.0 1.9 0.4 1.0 2.9

37 92.4 90.0 18.4 47.0 134.0

* K value = IU/dL factor VIII increase t Recovery (%) = increase in plasma

Control of Bleeding Episodes

K-Value (IU/dL per Wkg)

or Until Inhibitor

12

Month

Detection 18

Recovery W)

K-Value (IU/dL Per NJ/W

Recovery W)

19 84.2 90.0 22.0 15.0 110.0

4 1.8 1.9 0.3 1.5 2.1

4 87.3 89.0 12.8 70.0 101.0

19 1.8 1.8 0.5 0.3 2.4

per IU/kg BDDrPVlll given. VIII:C (IU)/Total VIII:C administered

(IU) X 100.

Final

K-Value (IU/dL per We)

9 1.9 1.9 0.7 0.4 2.8

Visit

Recovery VJ)

9 88.6 88.0 33.3 16.0 134.0

BDDrFVIII

in Previously Untreated Patients

1000 900

4

, bS% --^ Total infusions for bleeding episodes:

J::

1 a 2

1,362

8oo~I, 700

600

p

500

c

400

B E z

200

55

muscle/soft tissue, and 96% for other specified tissues. Of 562 global assessmentsby investigators over time, 558 (99%) were assessedas “very useful” or “useful.” At no time was any treatment assessedas “useless” or “unfavorable.”

Surgical Efficacy

300

19%

100

~ 02

-,1

2

3

4

Number of infusions given a bleeding episode

5

3% 26

for

Figure 1. Number of infusions given in all bleeding episodes. Percent of total infusions indicated by number above the bar. Please note that percentages were rounded up to a whole number, and thus the total percentage is lOlo%.

percent (881/1,362) of episodes resolved with one infusion. The mean dose was 53 IU/kg per infusion for bleeding episodesprior to inhibitor development. All bleeding episodes resolved with the exclusive use of BDDrFVIII in the absence of inhibitor. Twenty-seven patients were treated with a routine prophylaxis. These patients received 4,278 prophylactic infusions over a mean duration of 45 weeks. During the prophylactic period, these patients experienced a mean of five breakthrough bleeding episodes, which corresponds to four bleeding episodesper year. The mean dose for prophylactic treatment was 56 IUikg. When the same 27 patients had been treated on-demand, they experienced a mean of 14 bleeding episodes over a mean of 41 weeks, which corresponds to a mean of 18 bleeding episodes per year. Four of the 27 (15 %) patients receiving a prophylaxis regimen did not have any breakthrough bleeding episodes.

Response Ratings A summary of hemostatic efficacy response ratings for 2,375/2,411 infusions that were given for on-demand treatment were rated by investigators (Fig 2). Hemostatic efficacy was rated as “excellent” or “good” for 93% (2,215/2,375) of infusions. “Excellent” or “good” responseratings were similar for all three types of bleeding episodes: 90% for hemarthroses, 95% for

Thirty patients required 40 surgical interventions and were successfully treated with BDDrFVIII. Pre- and postoperative coverage ranged from 500 IU to 39,000 IU over 1 to 15 exposure days. Estimated blood loss was as expected in all procedures, and transfusion was only required in one procedure (epidural hematoma evacuation on the day of surgery). The overall assessmentof efficacy was consistently described as “very useful” or “useful” at the time of discharge from the surgical protocol.

Inhibitor

Development

Thirty-two patients developed inhibitors to factor VIII activity during the study (Table 2). The median exposure days up to inhibitor development were 12 days (mean, 32 days), ranging from 3 to 49 days. Of the 69 patients who showed no evidence of inhibitors, 43 patients had 50 or more exposure days. A life-table estimation (Kaplan-Meier method) was performed for the number of patients with no inhibitor development by exposure days (Fig 3). A plateau in the risk of developing inhibitors appears to have been reached. Sixteen of the patients who developed inhibitors had a high inhibitor response (25 BU/mL), 12 of whom

2400

--.

2100

-

I

1800

-

.o 8 E T;

1500

-

H Exe/good (2,215 infusions) 0 Fair (158 infusions) 0 No response (2 infusions)

1200

-

Total

900

-

600

-

2 E P

300

93%

0

infusions

assessed:

2,375

7% Excellent/good

Fair

No response

Figure 2. Response rating summary for bleeding episodes in PUPS who were inhibitor-free or until inhibitor detection. Please note that percentages were rounded up to a whole number.

56

COW-Wdad Bedrasian

Table

2. Demographics of Patients Who Developed Inhibitors (n = 32) Demographic

Months (*days)

Median age at inclusion for inhibitor patient Median age at first infusion Median interval between first infusion and inhibitor detection Median age at inhibitor detection Median no. of exposure days up to inhibitor detection

6 8

NOTE. Three of the inhibitor inhibitors.

patients

had a family

6 16 12* history

of

had a peak value of 2 10 BU/mL, and I6 patients were low responders (<5 BU/mL). Fourteen of the high responders received IT treatment, and 11 of these patients showed a decrease in BU/mL. Seven of the high responders had less than 0.6 BU/mL in their latest available test after IT. In addition, IT treatment was started in seven of the low responders (<5 BU/mL), six of whom had less than 0.6 BU/mL for their latest value. Also, nine patients, two of whom were high responders, did not have IT. Eight of the nine patients, which included the two high responder patients, had a decrease in BU/mL. Five of these patients had results of less than 0.6 BU/mL for their latest value.

tients. These events were as follows: venous access catheter complication (n = 2>, fever (n = I), anaphylactic reaction in an inhibitor patient (n = l), bleeding/h ematoma in a patient receiving irregular prophylaxis (n = l), leg bleeding episode in an inhibitor patient (n = l), and forehead bruises in an inhibitor patient (n = 1). These SAEs were assessed as having possible or probable relation to BDDrFVIII treatment.

Antibody Development Fifteen patients developed antibodies to CHO cell-derived components, and 12 patients developed antibodies to mouse IgG. The development of antibodies to CHO cell-derived components was transient in all patients (n = 15), and it was transient in 10 of the 12 patients who developed antibodies to mouse IgG. No clinical signs or symptoms were associated with any significant increases in the AI for antibodies to CHO cell-derived components or to mouse IgG. All AI values were determined by ELISA.

Clinical Safety and Tolerability Five patients experienced changes in health status between initiation of the study and their final visit. One patient who was fully healthy at the time of inclusion was mildly ill at the final

Adverse Events A total of 69 AEs were reported in 54 patients to be possibly or probably related to BDDrFVIII treatment by the investigator. Excluding reports of inhibitor development to factor VIII activity, and increases in the antibody index (AI; a measure of an individual’s actual antibody level compared to that of a normal serum pool) to factor VIII antibodies, CHO cellderived components, or mouse IgG, 19 AEs were reported to be possibly or probably related to BDDrFVIII treatment in 16 patients. These events were: fever (n = 3), venous access catheter complications (n = 2), fatigue (n = l), nausea (n = l), diarrhea (n = l), anorexia (n = l), somnolence (n = l), infusion site reaction (n = l), anaphylaxis (n = l), rash (n = l), urticaria (n = l), neck hematoma (n = l), leg bleed (n = l), coagulation disorder (n = l), bruising of forehead (n = l), and surgical intervention (n = 1). Seven SAEs were reported in seven pa-

.-s

1.11

2 0.8,3 .! 0.65 B $ 0.4z

1 Ojl Ii , I I , 0

10 20 30 40 50 Exposure days

Figure 3. Estimate of the inhibitor-free probability distribution. The vertical projection at 12 exposure days indicates the median number of exposure days at inhibitor development among patients developing inhibitors (n = 32).

BDDrFVIII

in Previously Untreated Patients

visit with an upper respiratory tract infection and otitis media. Another patient had eczema at his final visit, which was not noted at inclusion. A third patient had a mild neurological deficit due to an intracerebral hemorrhage caused by head trauma. One patient had easy bruising at the final visit due to the presence of factor VIII inhibitors, and the fifth patient was sleepy at the final visit. Vital signs (blood pressure, pulse, body temperature, and respiration rate) measured during treatment (before and after each infusion at the clinic) showed no clinically significant changes postinfusion.

Clinical Chemistry and Hematology The most frequently reported clinically significant changes in hematology were decreasesin hematocrit (n = 6), hemoglobin (n = 7), and RBC count (n = 4), presumably due to hemorrhage. One patient had a clinically significant increase in ALT levels at month 12 (85 III/L), which normalized at month 18 (28 ILJIL). A second patient had a clinically significant ALT level at the start of the study (132 III/L), which decreased during the study (41 IU/L at month 6). Two patients had clinically significant increasesin AST levels (AST increases: 37 to 58 IU/L and 30 to 48 IU/L) during the trial, and one patient began the study with a high AST (58 IU/L) and remained elevated throughout the trial.

Viral Serology There were 24 patients who had tested negative for HAV before the study and seroconverted during the trial. No seroconversions for HIV or HCV were observed during the trial. Of the 101 patients tested for antibodies to HB,Ag, 76 had negative results at baseline and data were not available for 21 patients. An additional four patients had no baseline value, but testing for HB,Ag yielded negative results later in the study. According to the protocol, there were no planned samplings for HB,Ag after the baseline visit.

Conclusions This clinical trial study of factor VIII

is the largest prospective concentrates in PUPS with

57

severe hemophilia A (N = 101). The efficacy of BDDrFVIII was similar for all types of bleeding episodes (eg, joint, soft tissue/muscle, and &her types). In the absenceof inhibitor to factor VII? activity, there was no attenuation of efficacy over time. In no casewas it necessaryto use another factor VIII concentrate other than BDDrFVIII to control a bleeding episode. Sixty-five percent of bleeding episodesresolved with one infusion, and 92% of bleeding episodes resolved with three infusions or fewer. Investigators rated 93% of all infusions assessedfor bleeding episodes as “excellent” or “good.” As a result, hemostatic efficacy was comparable to published literature for other recombinant factor VIII products.7J0J1 BDDrFVIII was effective in minimizing breakthrough bleeding episodes in 27 patients, where a mean dose of 56 III/kg was given for routine prophylaxis. A fourfold reduction in bleeding episodes was observed during the prophylactic periods compared with the ondemand treatment period. From the analyses of the prophylactic regimen, the administration of BDDrFVIII two to three times/week was clearly indicated as beneficial to a patient with hemophilia. A reduction in bleeding episodes markedly affects the quality of life of the patient with hemophilia by reducing unpredictable disruption of daily life. While further evaluation in different patient subgroups is required for the optimization of dosing regimens, these data provide compelling evidence of the efficacy of BDDrFVIII for routine prophylaxis in PUPS with severe hemophilia A. In this very young population, the mean dose for treating on-demand bleeding episode was 53 IU/kg. In the absence of inhibitor development, dosesfor subsequent follow-up infusions were similar to the initial infusion. Administration in conjunction with surgery showed no untoward effects, and the efficacy was assessed overall as “very useful” or “useful.” The incidence of inhibitor development was similar to that reported for other factor VIII products in PUPS (Table 3).7,8,12-19Approximately 32% (32/101) of patients developed inhibitors, 50% (16/32) of whom were assessed as high titer (25 BU/mL) and 50% (16132) as low titer ((5 BU/mL). Although a higher dose was required (96 IUikg), hemostasis was

58

Courter and Bedrosian

Table

3. Comparison

of Incidence

of Inhibitor

Product Types(s)

factor

* Not taken t Of normal

PUPS/severe (<2%t) Children/severe (<5%t) PUPS/severe (
Vlil

from direct comparative factor VIII activity.

studies

against

Acknowledgment tigators in their Hospital General de

authors

like

to thank

the following

inves-

that were held (International

of Istanbul, Turkey); R.J. Cohn (Johannesburg Hospital, South Africa); C. Gazengel (Centre

Traitements

France); Victoria

would

who coordinated the clinical trials respective countries: L. Agaoglu

I. Hann Hospital,

des

Hemophiles,

Hopital

Necker,

(Department of Hematology, United Kingdom); J. Ingerslev

Royal (Uni-

versity Hospital Skejby, Denmark); W. Kreuz (Klinikum DJW Goethe-Universitat, Germany); R. Ljung (University of Lund, MalmS General Hospital, Sweden); J. Lusher Michigan,

(Division USA);

of Hematology, P.M. Mannucci

Children’s (Centro

Hospital of A Bianchi

Bobomi per 1’Emofilia e la Trombosi LJniversiotP, G. Sas (National Institute of Hematology, Blood,

and Reported

Data for Other

No. of Patients

Study Source

101 27 89 55

PUP clinical study Ehrenforth et al** Addiego et ali3 Lusher et aP4J5

Factor

VIII Products* Reported

64

Lusher

69

Gruppo

et aP6J7 et aW8Js

Incidence

of Inhibitors

(%)

32 52 28 16-18 28 24-32

BDDrFVIII.

also achieved in patients with low-titer inhibitor. In all, the data presented in this phase III clinical trial are based on a significant exposure to BDDrFVIII over an extended period of time (250 exposure days). As an albuminfree formulated, recombinant coagulant factor, BDDrFVIII was found to be effective, safe, and well-tolerated by PUPS for on-demand and routine prophylactic treatment of bleeding episodes. Further investigation is warranted in addressing the issue of optimal dosing schedules for minimizing inhibitor development.

The

of BDDrFVlll

Patient Group/Severity

BDDrFVlll Various cryoprecipitate and low-purity plasma-derived products Monoclonal antibody purified, plasmaderived factor VIII Recombinant factor VIII Recombinant

Formation

Italy); Trans-

fusion, and Immunology, Hungary); K. Schmitt (Landerskinderklinik Linz, Austria); M. Schmugge (Kinderspital Zurich, Switzerland); J.W. ten Cate (Centre of Thrombosis, Hemostasis, and Atherosclerosis Research, the Netherlands); J.M. Tusell-Puigbert (Unidat d’Hemofilia, Hospital Vall d’Hebron, Spain); and J. Vermylen (Katholieke Universitci Leuven, Belgium).

References 1. Wyeth/Genetics Institute, Cambridge, MA, data on file 2. Morfini M, Lee M, Messori A: The design and analysis of elimination half-life and recovery studies for factor VIII and factor IX. Thromb Haemost 6:384-386, 1991 3. Biggs R: Plasma concentrations of factor VIII and factor IX and treatment of patients who do not have antibodies against these factors, in Biggs R (ed): The Treatment of Hemophilia A and B and von Willebrand’s Disease. Oxford, UK, Blackwell Scientific, 1978, pp 1 lo-126 4. Allain JP, Verroust F, Soulier JP: In vitro and in vivo characterisation of factor VIII preparations. VOX Sang 38:68-80, 1980 5. Nilsson IM, Hedner U: Characteristics of various factor VIII concentrates used in treatment of haemophilia A. Br J Haematol 37:543-557, 1977 6. Kasper CK, Aledort LM, Counts RB, et al: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 34:860, 1975 S, Abildgaard CF, et al, and the 7. Lusher JM, Arkin Kogenate Previously Untreated Patient Study Group: Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 328:453-459, 1993 8. Bray GL, Gomperts ED, Courter S, et al: A multicenter study of recombinant factor VIII (Recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 83: 2428-2435, 1994 B, Novakova I, Wessels H, et al: The 9. Verbruggen Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: Improved specificity and reliability. Thromb Haemost 73:247-251, 1995 10. Schwartz RS, Abildgaard CF, Aledort LM, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 323:1800-1805, 1990

BDDrFVIII

11.

12.

13.

in Previously

White GC, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. Thromb Haemost 77:660-667, 1997 Ehrenforth S, Kreuz W, Scharrer I, et al: Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 339:594-598, 1992 Addiego J, Kasper C, Abildgaard C, et al: Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancer 342:462-464,

1993 14. Lusher JM, S&man PM, and Monoclate Safety Group: Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. Semin Hematol 27:1-7, 1990 (suppl) 15. Lusher JM: Viral safety and inhibitor development associated with monoclonal antibody-purified FVIIIC. Ann Hematol 63:138-141, 1991 S, Abildgaard CF, et al: Inhibitor 16 Lusher JM, Arkin development in previously untreated patients (PUPS)

Untreated Patients

with low-up

hemophilia data,

(IT) with abstr) 17.

Lusher binate

59

receiving

including

Kogenate.

Kogenate:

response Blood

4.5

to immune

82:596,

1993

JM, Arkin S, Abildgaard CF, FVIII (Kogenate) treatment

year

fol-

tolerance (suppl

1,

et al: Recomof previously

untreated patients (PUPS) with hemophilia A: Update of safety, efficacy, and inhibitor development after seven study years. 1997 (suppl, abstr) 18.

Thromb

Haemost

PD-664,

Gruppo R, Bray GL, Schroth immunogenicity of recombinant

P, et al: Safety and factor VIII (Recom-

binate) in previously untreated 5.5 year update. Haemophilia

patients (PUPS): A 2:37, 1996 (suppl,

abstr) 19.

Gruppo R, Bray GL, Schroth munogenicity of recombinant

P, et al: Safety and imfactor VIII (Recombi-

nate) in previously untreated patients (PUPS): year update. Thromb Haemost PD-663, 1997 abstr)

A 6.5 (suppl,