General Information

Kovaltry is a recombinant, human DNA sequence derived, full length Factor VIII concentrate. It temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

Kovaltry is specifically indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for on-demand treatment and control of bleeding episodes, for the perioperative management of bleeding and for routine prophylaxis to reduce the frequency of bleeding episodes.

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 (% 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 % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).

Routine prophylaxis:

Adults and adolescents: 20-40 IU/kg 2 or 3 times per week

Children ≤12 years old: 25-50 IU/kg 2 times per week, 3 times per week or every other day

Clinical Results

FDA Approval

The 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% of cases (97.8% in the younger age group and 81.0% in the older age group). Majority of bleeds (89.7%) were successfully treated with ≤2 infusions. Response to treatment was similar for children aged 0 to <6 compared to 6 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 nonhemophilic patient).

Adults and Adolescents: The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, 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 (2 bleeds per year). In Study 2, 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 0 for all bleeds, and 0 for spontaneous and joint bleeds. The median ABR during prophylactic treatment independent of time of infusion was 1.9 for all bleeds, 0 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 (0 to <6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment was 0. The median annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was 0. The median annualized number of joint bleeds during prophylactic treatment independent of time of infusion was 0 in 0 to <6 years age group and 0 in 6 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%) subjects reported no bleeds during the six-month prophylaxis period.