Routine Prophylaxis

PTPs ≥ 12 years of age

The efficacy of IXINITY was evaluated in a prospective, open-label, uncontrolled multicenter study in which a total of 77 subjects (76 male, 1 female carrier in surgery study) were exposed to IXINITY for treatment of hemophilia B or for perioperative management. All male subjects either had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B, or had factor IX levels between 2-8 IU/dL and clinically severe hemophilia B with recurrent hemarthroses and required surgery (n = 3 in surgery study, one continued to treatment phase). Previously treated patients (PTPs) were defined as patients with a minimum of 150 exposures to another factor IX preparation. Of the 77 subjects, 68 PTPs between 7 and 64 years of age received IXINITY either as routine prophylaxis or on-demand treatment. Routine prophylaxis treatment was defined as PTPs who received a starting dose of 40-70 international units (IU) per kg twice weekly. Excluded from the study were patients with a history of a detectable factor IX inhibitor (≥ 0.6 BU), a history of hypersensitivity reactions following exposure to factor IX-containing products, a known allergic reaction to hamster proteins, evidence of severe liver impairment, evidence of impaired renal function, CD4 count < 400 cells/mm3, or any coagulation defect other than hemophilia B. In addition, there was a prospective, open-label, uncontrolled, multicenter substudy where 17 subjects (16 male, 1 female carrier) underwent surgeries (19 major procedures in males) receiving IXINITY for perioperative management; some of the surgery subjects also participated in the treatment trial.

Of the 68 PTPs in the treatment group, subjects were primarily prescribed a routine prophylaxis (n = 58) or an on-demand regimen (n = 9); one subject was not assigned a regimen. Subjects were allowed to switch regimens during the course of the study. As a result, 61 subjects were treated at some point with routine prophylaxis treatment and 12 were treated at some point with an on-demand regimen. Subjects in the routine prophylaxis therapy group received mean intravenous doses of 55 ± 12.8 IU/kg of IXINITY twice weekly. Subjects in the on-demand therapy group received mean doses of 60 ± 18.2 IU/kg (median 59.3, interquartile range 49.9, 71.8) for bleeding episodes. The mean number of exposure days (ED) was 138.2 (median 127.5), including 45 subjects with ≥ 100 ED and 55 subjects with ≥ 50 ED. Median duration on study for the on-demand group was 14.1 months (range 2.3-36.9).

Annualized bleeding rates for PTPs ≥12 years of age in prophylaxis arm are summarized in Table 7.

PTP < 12 years of age

The PK, safety and efficacy of IXINITY for treatment of hemophilia B was evaluated in a prospective multi-center, multi-country study of 21 previously treated patients (PTPs) (10 subjects < 6 years of age and 11 subjects 6 to < 12 years of age). PTP were defined as patients who were exposed to a factor IX containing product for ≥ 50 exposure days (ED). All subjects had severe to moderately severe (factor ≤ 2%). Subjects with history of hypersensitivity reactions following exposure to factor IX-containing products, a known allergic reaction to hamster proteins, evidence of severe liver impairment, evidence of impaired renal function, CD4 count < 400 cells/mm3, or any coagulation defect other than hemophilia B, evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC) were excluded from the trial.

Subjects received IXINITY prophylaxis once to twice weekly, the recommended dose range was 35 – 75 IU/kg. Subjects < 6 years received a mean intravenous dose of 58 (45-72) ± 8.9 IU/kg and subjects 6 to < 12 received a mean intravenous dose of 52 (46-60) ± 11.6 IU/kg. Twenty-one subjects completed the PK analysis, and 19 subjects completed a minimum of 50 ED. The mean number of ED was 159 (median 163), including 16 subjects with ≥ 100 ED and 7 subjects with ≥ 200 ED.

Annualized bleeding rates for PTPs <12 years of age are summarized in Table 8.

Control of Bleeding Episodes

PTPs ≥ 12 years of age

A total of 508 bleeding episodes were treated with IXINITY, of which 286 bleeds were recorded for subjects treated with the routine prophylaxis treatment regimen and 222 with the on-demand regimen. Bleeding resolved in 360 episodes (70.9%) after a single infusion of IXINITY and in 66 (13.0%) episodes after two infusions. For 24 bleeding episodes (4.7%), five or more infusions were required; these 24 bleeding episodes were predominantly related to trauma, target joints, or muscle bleeds.

Hemostatic efficacy to resolve a bleed was rated by subjects as excellent or good in 84% of treated bleeding episodes. Excellent was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size, and good was defined as pain relief or reduction in hemorrhage size that may have required an additional infusion for resolution.

PTP < 12 years of age

There were 52 bleeding episodes; nine did not require treatment and resolved with IXINITY routine prophylaxis once or twice-weekly treatment. In 45 of 52 (86.5%) of the episodes, hemostasis was achieved with zero to two infusions. For four bleeding episodes (7.7%) three infusions were required, two episodes (3.8%) four infusions were required, and one episode (1.9%) required five infusions for resolution.

Hemostatic efficacy to resolve a bleed was rated by subjects as excellent or good in 41 (95%) of the 43 bleeding episodes that required treatment; two bleeding episodes did not have efficacy assessments. Excellent was defined as a dramatic response with abrupt pain relief and clear reduction in joint or bleeding site size and good was defined as pain relief or reduction in bleeding site size that may have required an additional infusion for resolution.

Perioperative Management

The efficacy analysis of IXINITY in perioperative management included 19 major surgeries performed in 16 male PTPs between 12 and 56 years of age (female carrier not included in efficacy analysis). Efficacy of IXINITY for support of major surgery was based on the surgeon’s assessment of efficacy including: a) at the time of surgery as estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’; and b) at 12 and 24 hours post-surgical assessments of hemostasis as ‘adequate’, ‘better than adequate’, or ‘poorly controlled’. Transfusion requirements to support surgery were also monitored. There were no transfusions required during the procedures.

IXINITY was administered during major surgical procedures as bolus (n = 13) or continuous infusion (n = 6). IXINITY was rated as adequate or better in controlling hemostasis post-surgery as assessed by the surgeon when used in various procedures, including, knee arthroplasty (n = 8), elbow arthroplasty (n = 2), knee amputation (n = 1), percutaneous Achilles tendon lengthening (n = 1), open inguinal hernia repair (n = 1), tibiotalar fusion (n = 1), arthroscopic synovectomy (n = 2), and debridement (ankle, knee) (n = 3). In all instances, blood loss at surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon.