Kovaltry (Antihemophilic Factor (Recombinant) for Intravenous Administration): Side Effects, Uses, Dosage, Interactions, Warnings

Description for Kovaltry

KOVALTRY, Antihemophilic Factor (Recombinant), is a sterile, non-pyrogenic, white to slightly yellow powder for reconstitution contained in a single-use vial. The final product does not contain any preservative. The reconstituted product is indicated for intravenous administration. The product is available in 250 IU, 500 IU, 1000 IU, 2000 IU, or 3000 IU nominal potencies; however, for each dosage strength the actual, assayed Factor VIII potency is directly printed on each vial label. The container closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sterile water for injection (sWFI), prefilled diluent syringe. KOVALTRY is formulated with the following excipients: 2.2% glycine, 1% sucrose, 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine and 80 ppm polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. Intravenous administration of sucrose contained in KOVALTRY will not affect blood glucose level.

The active substance in KOVALTRY is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence. Post-translational modifications are similar to those of endogenous Factor VIII including glycosylation sites and sulfation of tyrosine sites. Manufacturing and quality controls ensure that both galactose-alpha-1,3-galactose (alpha-Gal) and N-glycolyl neuraminic acid (NGNA) content are below the 1% limit of detection established for each analytical method.

KOVALTRY is produced by a genetically engineered Baby Hamster Kidney (BHK) cell line into which the human Factor VIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. HSP 70 is an intracellular protein that improves proper folding of the Factor VIII protein. While KOVALTRY and Kogenate FS have the same protein backbone, human- and animal-derived raw materials are not added to the cell culture, purification, or formulation processes for KOVALTRY. In the manufacturing process for KOVALTRY, recombinant Factor VIII is secreted into cell culture medium and is purified from process- and product-related impurities using a series of chromatography and filtration steps. The production process incorporates two dedicated viral clearance steps: (1) a detergent treatment step for inactivation and (2) a 20 nanometer filtration step for removal of viruses and potential protein aggregates.

Uses for Kovaltry

KOVALTRY, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:

On-demand treatment and cfont rol of bleeding episodes
Perioperative management of bleeding
Routine prophylaxis to reduce the frequency of bleeding episodes

KOVALTRY is not indicated for the treatment of von Willebrand disease.

Dosage for Kovaltry

For intravenous use after reconstitution only.

Dose

Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard (IS) for Factor VIII concentrate.
Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field study involving 41 clinical laboratories from around the world measured recoveries of KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-stage clotting or chromogenic substrate assay according to routine methods of the testing laboratory.
The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

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)

The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

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

Examples (assuming patient's baseline Factor VIII is < 1%):

A peak of 50% is required in a 20 kg child. In this situation, the required dose of KOVALTRY would be 20 kg x 50 IU/dL x 0.5% (for recovery of 2 IU/dL per IU/kg) = 500 IU
A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL (80% of normal)
- Adjust dose to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, incremental recovery) and clinical responses to KOVALTRY.

On-Demand Treatment And Control Of Bleeding Episodes

A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

Table 1: Dosing for Control of Bleeding Episodes

Degree of Bleeding	Factor VIII Level Required (IU/dL or % of normal)	Frequency of Doses (hours)	Duration of Therapy (days)
Minor (Early hemarthrosis, minor muscle, oral bleeds)	20-40	Repeat every 12-24 hours	At least 1 day, until bleeding episode as indicated by pain is resolved or healing is achieved
Moderate (More extensive hemarthrosis, muscle bleeding, or hematoma)	30-60	Repeat every 12-24 hours	3 to 4 days or more until pain and acute disability are resolved
Major (intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life or limb threatening hemorrhage)	60-100	Repeat every 8-24 hours	Until bleeding is resolved

Perioperative Management Of Bleeding

A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see WARNINGS AND PRECAUTIONS].

Table 2: Dosing for Perioperative Management

Type of Surgery	Factor VIII Level Required (IU/dL or % of normal)	Frequency of Doses (hours)	Duration of Therapy (days)
Minor (Such as tooth extraction)	30-60 (pre- and postoperative)	Repeat every 24 hours	At least 1 day until healing is achieved
Major (Such as intracranial, intraabdominal, intrathoracic, or joint replacement surgery)	80-100 (pre- and postoperative)	Repeat every 8-24 hours	Until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain Factor VIII activity of 30-60% (IU/dL)

Routine Prophylaxis

Individualize the patient's dose based on clinical response.
Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per week.
Children ≤ 12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three times weekly, or every other day according to individual requirements [see Use in Specific Populations].

Preparation And Reconstitution

Reconstitute and administer KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component.
For any questions about the handling, reconstitution and administration of KOVALTRY, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

Usability Testing Of Vial Adapter

Usability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 10-17 years of age), 15 adult hemophilia A patients ( ≥ 18 years of age), 15 caregivers, and 15 healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given minimal training, which included participants performing a supervised reconstitution and later performing a single unaided reconstitution. Healthcare providers were untrained in this study and could learn the procedure from the provided Instructions for Use. All participants were able to successfully and safely use the vial adapter device for reconstitution.

Reconstitution

Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures.
Reconstitute KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component.
Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.

1. Warm both unopened KOVALTRY vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F).

2. Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.

Figure A

Remove the protective cap - Illustration

3. Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.

Figure B

Snap the adapter over the vial cap - Illustration

4. Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use.

Figure C

5. Now remove and discard the adapter plastic housing (D).

Figure D

Now remove and discard the adapter plastic housing - Illustration

6. Attach the prefilled syringe to the vial adapter thread by turning clockwise (E).

Figure E

Attach the prefilled syringe to the vial adapter - Illustration

7. Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F).

Figure F

8. Inject the diluent slowly by pushing down on the plunger rod (G).

Figure G

Inject the diluent slowly - Illustration

9. Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy.

Figure H

10. Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I).

Figure I

Turn the vial with syringe upside-down - Illustration

11. Withdraw all the solution into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial.

Figure J

Withdraw all the solution into the syringe - Illustration

12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K).

Note: follow instructions for infusion set provided.

Figure K

Attach the syringe to the administration set - Illustration

Pooling

If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into the syringe.

Administration

For intravenous use only.

Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to administration. Do not use if you notice any particulate matter or discoloration and immediately contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).
Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours.
Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient.

HOW SUPPLIED

Dosage Forms And Strengths

KOVALTRY is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 2000, or 3000 IU of recombinant Factor VIII per vial.

Each vial of KOVALTRY is labeled with actual Factor VIII potency expressed in IU determined using a chromogenic substrate assay. This potency assignment employs a Factor VIII concentrate standard that is referenced to the current WHO International Standard for Factor VIII concentrate, and is evaluated by appropriate methodology to ensure accuracy of the results.

KOVALTRY is available as a lyophilized powder in single-use glass vials, one vial per carton. It is supplied with a sterile vial adapter with 15-micrometer filter and a prefilled diluent glass barrel syringe, which together serve as a needleless reconstitution system. The prefilled diluent syringe contains Sterile Water for Injection, USP. An administration set is also provided in the package. Available sizes:

Nominal Strength (IU)	Diluent (mL)	Kit NDC Number	Color Code
250	2.5	0026-3821-25	Blue
500	2.5	0026-3822-25	Green
1000	2.5	0026-3824-25	Red
2000	5.0	0026-3826-50	Yellow
3000	5.0	0026-3828-50	Gray

Actual Factor VIII activity in IU is stated on the label of each KOVALTRY vial.

The product vial and diluent syringe are not made with natural rubber latex.

Storage And Handling

Product as Packaged for Sale

Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Do not freeze. Within this period, KOVALTRY may be stored for a single period of up to 12 months at temperatures up to +25°C or 77°F.
Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier.
Do not use KOVALTRY after the expiration date indicated on the vial.
Protect KOVALTRY from extreme exposure to light and store the vial with the lyophilized powder in the carton prior to use.

Product After Reconstitution

Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours.
Do not use KOVALTRY if the reconstituted solution is cloudy or has particulate matter.
Use the administration set provided.

Bayer HealthCare LLC Whippany, NJ 07981 USA. Revised: Mar 2016

Side Effects for Kovaltry

The most frequently reported adverse reactions in clinical trials ( ≥ 3%) were headache, pyrexia, and pruritus (see Table 3).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety profile of KOVALTRY was evaluated in 193 previously treated patients (PTPs) (inclusive of 51 pediatric patients < 12 years of age) with at least three months of exposure to KOVALTRY. The safety analysis was done using a pooled database from three multi-center, prospective, open-label clinical studies. The median time on study for patients ≥ 12 years of age was 372 days with a median of 159 exposure days (EDs). The median time on study for patients < 12 years of age was 182 days with a median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies (n=6) were excluded from safety analysis. Table 3 lists the adverse reactions reported during clinical studies. The frequency, type, and severity of adverse reactions in children are similar to those in adults.

Table 3: Adverse Reactions in PTPs (N=193)

MedDRA Primary System Organ Class Preferred term	Frequency N (%)
Blood and the Lymphatic System Disorders
Lymphadenopathy	2 (1.0%)
Cardiac Disorders
Palpitation	2 (1.0%)
Sinus tachycardia	2 (1.0%)
Gastrointestinal Disorders
Abdominal pain	4 (2.1%)
Abdominal discomfort	3 (1.6%)
Dyspepsia	4 (2.1%)
General Disorders and Administration Site Conditions
Pyrexia	8 (4.1%)
Chest discomfort	2 (1.0%)
Injection site reactions^a	5 (2.6%)
Immune System Disorders
Hypersensitivity	1 (0.5%)
Nervous System Disorders
Dizziness	2 (1.0%)
Dysgeusia Headache	1 (0.5%) 14 (7.3%)
Psychiatric Disorders
Insomnia.	5 (2.6%)
Skin and Subcutaneous Tissue Disorders
Dermatitis allergic	2 (1.0%)
Pruritus	6 (3.1%)
Rash^b	5 (2.6%)
Urticaria	1 (0.5%)
Vascular disorders
Flushing	1 (0.5%)
^aIncludes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling ^bIncludes rash, rash erythematous, and rash pruritic

Immunogenicity

All clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at defined intervals during the studies and at the completion visit.

Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A (Factor VIII < 1%) with previous exposure to Factor VIII concentrates ≥ 50 EDs, and no history of inhibitors.

In the completed studies, no PTP developed neutralizing antibodies to Factor VIII. In an ongoing extension study, a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg, annualized bleeding rate (ABR) was zero, and no change in therapy was required.

In an actively enrolling clinical trial in PUPs, 6 of 14 treated subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%) developed an inhibitor. Of these, 3 subjects (21.4%) had high titer inhibitors, and 3 subjects (21.4%) had transient low titer inhibitors for which no change in therapy was required.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products.

Drug Interactions for Kovaltry

No information provided.

Warnings for Kovaltry

Included as part of the PRECAUTIONS section.

Precautions for Kovaltry

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms occur and seek immediate emergency treatment.

KOVALTRY may contain trace amounts of mouse and hamster proteins [see DESCRIPTION]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Neutralizing Antibodies

Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products [see ADVERSE REACTIONS]. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor (neutralizing antibody) [see Monitoring Laboratory Tests].

Cardiovascular Risk Factors

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII.

Catheter-Related Infections

Catheter-related infections may be observed when KOVALTRY is administered via central venous access devices (CVADs). These infections have not been associated with the product itself.

Monitoring Laboratory Tests

Monitor plasma Factor VIII activity levels using a validated test to confirm that adequate Factor VIII levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION].
Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypersensitivity reactions are possible with KOVALTRY [see WARNINGS AND PRECAUTIONS]. Warn patients of the early signs of hypersensitivity reactions (including tightness of the chest or throat, dizziness, mild hypotension and nausea during infusion) which can progress to anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.
Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [see WARNINGS AND PRECAUTIONS]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to Factor VIII replacement therapy, as this may be a manifestation of an inhibitor.
Advise patients to discard all equipment, including any unused product, in an appropriate container.
Advise patients to consult with their healthcare provider prior to travel. Advise patients to bring an adequate supply of KOVALTRY while traveling based on their current regimen of treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of KOVALTRY or other studies to determine the effects of KOVALTRY on fertility have not been performed. KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. KOVALTRY is expected to have no mutagenic potential.

Use In Specific Populations

Pregnancy

Risk Summary

There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using KOVALTRY. It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. KOVALTRY should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

Risk Summary

There is no information regarding the presence of KOVALTRY in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition.

Pediatric Use

Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs. Body weight adjusted clearance of Factor VIII in children ≤ 12 years of age is higher than in adults and adolescents. Consider higher or more frequent dosing in children to account for this difference in clearance [see CLINICAL PHARMACOLOGY].

Geriatric Use

Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients. As with any patient receiving recombinant Factor VIII, dose selection for an elderly patient should be individualized.

Overdose Information for Kovaltry

No information provided.

Contraindications for Kovaltry

KOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins [see DESCRIPTION].

Clinical Pharmacology for Kovaltry

Mechanism Of Action

KOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

Pharmacodynamics

Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT.

Pharmacokinetics

The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in Table 4 (one-stage clotting assay) and Table 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis).

Table 4: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay

Parameter [unit]	12 to 17 yrs (N=5)	≥ 18 yrs (N=21)
AUC [IU*h/dL]	1013.9 ± 286.8	1601.3 ± 520.0
Cmax [IU/dL]	91.7 ± 28.7	99.7 ± 14.9
t½ [h]	11.7 ± 1.11	14.3 ± 3.7
MRTiv [h]	16.1 ± 0.8	19.8 ± 5.7
Vss [dL/kg]	0.85 ± 0.24	0.63 ± 0.11
CL [dL/h/kg]	0.053 ± 0.017	0.035 ± 0.012
AUC: area under the curve Cmax: maximum drug concentration in plasma after single dose t½ : terminal half-life MRTIV: mean residence time after an IV administration Vss: apparent volume distribution at steady-state CL: clearance

The PK parameters of KOVALTRY for 8 subjects in age group 0 to < 6 years and 10 subjects in age group 6 to < 12 years are shown in Table 5. In general, children < 12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥ 12 years of age.

Table 5: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay

Parameter [unit]	0 to < 6 yrs (N=8)	6 to < 12 yrs (N=10)^b	12 to 17 yrs (N=5)	≥ 18 yrs (N=21)
AUC [IU*h/dL]	1544.7 ± 387.1^a	1214.5 ± 395.1	1572.0 ± 448.0	2103.4 ± 702.8
Cmax [IU/dL]	89.6 ± 27.4	81.6± 17.8	132.5 ± 46.3	133.1 ± 20.4
t½ [h]	12.1 ± 2.7^a	12.0 ± 2.1	14.4 ± 5.5	14.2 ± 3.5
MRTiv [h]	17.7 ± 3.6^a	17.8 ± 2.9	19.8 ± 5.8	19.9 ± 4.9
Vss [dL/kg]	0.57 ± 0.13^a	0.79 ± 0.23	0.71 ± 0.39	0.50 ± 0.11
CL [dL/h/kg]	0.033 ± 0.009^a	0.045 ± 0.016	0.034 ± 0.010	0.027 ± 0.010
^a n=7 ^b One subject considered PK outlier was excluded

Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see Table 6).

Table 6: Incremental Recovery in PTPs

	0 to < 6 yrs N=25	2 to 12 yrs N=25	≥ 12 yrs N=115
Chromogenic substrate assay results^a
Median (Q1; Q3) (IU/dL per IU/kg)	1.6 (1.3; 1.9)	1.7 (1.4; 2.0)	2.3 (1.8; 2.6)
One-stage assay results^a
Median (Q1; Q3) (IU/dL per IU/kg)	-	-	2.2 (1.8; 2.4)
^aStart of study

Clinical Studies

The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A ( < 1% Factor VIII) was evaluated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤ 1%) and no history of Factor VIII inhibitors were eligible for the trials.

Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject's individual requirements.

Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the superiority of prophylaxis over on-demand treatment with KOVALTRY over a one-year treatment period (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 40 IU/kg three times per week and the treatment group was assigned by randomization.

Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤ 12 years) PTPs ( ≥ 50 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 8). The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours following previous prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per week or every other day and could be adapted to individual subject's need by the investigator.

In all studies, treatments of breakthrough bleeds and perioperative management were at the investigator's discretion based on standard of care.

A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥ 12 years of age and 51 subjects < 12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, and 43 of these subjects were treated for 24 months.

Table 7: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2

	Study 1 (N=62)	Study 2 (N=80)
Age: mean ± SD	31.5 ± 12.7 years	29.6 ± 11.0 years
Previous treatment: %	Prophylaxis: 80.6%	On-demand: 100%
Number of Target joints at baseline: mean ± SD	1.4 ± 1.3	3.0 ± 2.1
Joint hemorrhage history (during 12 months prior to study): mean ± SD of joint bleeds	8 0 ± 119	32.1 ± 23.8

Table 8: Overview of Study 3

	Study 3
	PTPs 0 to < 6 yrs (N=25)	PTPs 6 to 12 yrs (N=26)
Age: mean ± SD (range)	3.8 ± 1.3 years (1-5)	8.8 ± 1.8 years (6-11)
Previous treatment: %	Prophylaxis: 92.0%	Prophylaxis: 65.4%
Number of Target joints at baseline: mean ± SD	0.2 ± 0.4	0.7 ± 1.1

On-demand Treatment And Control Of Bleeding Episodes

Adolescents And Adults

A total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and Study 2 (see Table 9). The majority of the bleeding episodes were spontaneous, localized in joints, and mild to moderate in severity.

In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the subjects compared to their previous treatment experience.

Table 9: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults Treated with KOVALTRY

Characteristics of Bleeding Episodes	Study 1		Study 2
Characteristics of Bleeding Episodes	Prophylaxis Main Study N=62	Prophylaxis Extension N=55	Prophylaxis N=59	On-demand N=21
Total number of bleeds	241	154	293	1204
Spontaneous: n/total (%)	153/241 (63.5%)	79/150^a(52.7%)	209/283a (73.9%)	943/1202^a(78.5%)
Trauma: n/total (%)	79/241 (32.8%)	70/150^a(46.7%)	74/283a (26.1%)	258/1202^a(21.5%)
Joint bleeds: n/total (%)	191/241 (79.3%)	120/154 (77.9%)	255/293 (87.0%)	924/1197^a(77.2%)
Mild/moderate: n/total (%)	215/241 (89.2%)	130/153^a(84.9%)	260/293 (88.8%)	1092/1196^a(91.3%)
% of bleeds treated with ≤ 2 infusions	87.0%		96.2%	95.3%
Response to treatment of bleeds assessed as “Excellent” or “Good”: n/total^b (%)	190/235 (80.9%)	107/149 (71.8%)	172/279 (61.6%)	834/1196 (69.7%)
Median dose per infusion (range)	31.6 IU/kg (14-67 IU/kg)		29.4 IU/kg (19-49 IU/kg)	22.0 IU/kg (11-35 IU/kg)
^aTotal number excluding uncharacterized bleeds ^bThe % is calculated from number of treated bleeds assessed for response

Children 12 Years Of Age And Younger

A total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority (96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8–71.6 IU/kg).

Assessment of response to treatment of bleeds was as follows:

Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement in signs of bleeding with at least one additional infusion for complete resolution; Poor: No improvement at all between infusions or condition worsens.

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 (see Table 10).

Table 10: On-demand Treatment and Control of Bleeding Episodes in Children Treated with KOVALTRY

Characteristics of Bleeding Episodes	Study 3
Characteristics of Bleeding Episodes	PTPs 0 to < 6 yrs (N=25)	PTPs 2 to 12 yrs (N=22)	PTPs 0 to 12 yrs (N=51)
Total number of bleeds	52	45	97
Spontaneous: n/total (%)	8/44^a(18.2%)	12/37^a(32.4%)	20/81^a(24.7%)
Trauma: n/total (%)	36/44^a(81.8%)	23/37^a (62.2%)	59/81^a(72.8%)
Joint bleeds: n/total (%)	10/52 (19.2%)	22/45 (48.9%)	32/97 (33.0%)
Mild/moderate: n/total (%)	50/52 (96.2%)	44/45 (97.8%)	94/97 (96.9%)
% of bleeds treated with ≤ 2 infusions	92.4%	86.7%	89.7%
Response to treatment of bleeds assessed as “Excellent” or “Good”: n/total^b (%)	43/44 (97.8%)	30/37 (81.0%)	73/81 (90.1%)
Median dose per infusion (range)	38.7 IU/kg (20.8-71.6 IU/kg)	32.4 IU/kg (21.7-50.0 IU/kg)	36.9 IU/kg (20.8-71.6 IU/kg)
^aTotal number of treated bleeds ^bThe % is calculated from number of treated bleeds assessed for response

Perioperative Management

A total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg).

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).