Side Effects

Adverse effects associated with the use of Kovaltry may include, but are not limited to, the following:

Headache

Pyrexia

Pruritus

Dosing/Administration

Kovaltry is supplied as a powder for solution for intravenous use after reconstitution only. The recommended dose is as follows:

Control of bleeding episodes and perioperative management

Required dose (IU) = body weight (kg) x desired Factor VIII rise (percentage of normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg).

Estimated increment of Factor VIII (IU/dL or percentage of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).

Routine prophylaxis

Adults and adolescents: 20-40 IU/kg two or three times per week

Children ≤12 years old: 25-50 IU/kg two times per week, three times per week or every other day

Clinical Trial Results

FDA approval of Kovaltry was based on the LEOPOLD trials:

LEOPOLD 1 was a multi-center, open-label, cross-over, uncontrolled study in adolescent and adult (age >12 years to <65 years) previously treated patients (PTPs) evaluating the pharmacokinetics, efficacy and safety of routine prophylaxis and perioperative management of bleeding with Kovaltry. The annualized bleeding rate (ABR) was the primary efficacy variable.

LEOPOLD 2 was a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age 12 years to <65 years) PTPs evaluating the superiority of prophylaxis over on-demand treatment with Kovaltry over a one-year treatment period. ABR was the primary efficacy variable.

LEOPOLD Kids Part A was a multi-center, open-label, uncontrolled study in pediatric (<12 years of age) PTPs evaluating the pharmacokinetics, efficacy and safety of routine prophylaxis and perioperative management of bleeding with Kovaltry. The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours of previous prophylaxis infusion.

Results

The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or “excellent” in 90.1 percent of cases (97.8 percent in the younger age group and 81.0 percent in the older age group). Majority of bleeds (89.7 percent) were successfully treated with ≤2 infusions. Response to treatment was similar for children aged 0 to <6 compared to six to 12 years of age.

The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient).

Adults and Adolescents: The mean and median ABR for the ITT population in study one was 3.8 ± 5.2 and one bleed/year, respectively. In study two, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p<0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (two bleeds per year). In study two, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis.

Children 12 years of age and younger: In children 12 years of age and younger (n=51), the median ABR within 48 hours after prophylactic infusion was zero for all bleeds, and zero for spontaneous and joint bleeds. The median ABR during prophylactic treatment independent of time of infusion was 1.9 for all bleeds, zero for spontaneous bleeds and 0 for joint bleeds. The mean ABR within 48 hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis regimen was 3.75 ± 4.98. In both age groups (zero to <6 years and six to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment was zero. The median annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was zero. The median annualized number of joint bleeds during prophylactic treatment independent of time of infusion was zero in zero to <6 years age group and zero in six to 12 years age group. The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion were trauma related. Twenty-three (45.1 percent) subjects reported no bleeds during the six-month prophylaxis period.