Altuviiio

Description

ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-dose vials containing nominal potencies of 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU). Each vial of ALTUVIIIO is labeled with the actual Factor VIII activity content in IU. The powder for injection is reconstituted with 3 mL sterile water for injection (sWFI) supplied in a sterile prefilled syringe. The reconstituted solution should be essentially free of particles. The final product contains the excipients: arginine hydrochloride (250 mM), calcium chloride dihydrate (5 mM), histidine (10 mM), polysorbate 80 (0.05% w/v), and sucrose (5% w/v).

The active ingredient in ALTUVIIIO is a fully recombinant fusion protein comprising a single chain B-domain deleted (BDD) analogue of human FVIII covalently fused to the Fc domain of human immunoglobulin G1 (IgG1), the FVIII-binding D’D3 domain of human von Willebrand factor (VWF), and 2 XTEN polypeptides. ALTUVIIIO contains 2829 amino acids with an apparent molecular weight of 312 kDa. ALTUVIIIO is synthesized as 2 polypeptide chains which are covalently linked by 2 Fc hinge disulfide bonds. The first FVIII-XTEN-Fc polypeptide chain contains the A1A2 domain of FVIII along with 5 amino acids from B-domain (1-745 amino acids) fused to the 288-XTEN polypeptide (in place of the natural FVIII B-domain), the A3C1C2 domain of FVIII (1649-2332), and the Fc domain of human IgG1. The second VWF-XTEN-a2-Fc polypeptide chain contains the D’D3 domain of VWF (1-477 amino acids) fused to the 144-XTEN polypeptide, a thrombin cleavable acidic region 2 sequence from FVIII and the Fc domain of human IgG1. The Fc domain includes the hinge, CH₂, and CH₃ domains of IgG1. The Fc, VWF, and XTEN portions of the molecule extend the half-life of ALTUVIIIO in plasma.

ALTUVIIIO is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line, which has been extensively characterized. ALTUVIIIO is manufactured without addition of human- or animal-derived components and purified by a combination of multiple chromatography steps, a detergent viral inactivation step, a nano filtration step for viral clearance, and ultrafiltration steps.

ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a von Willebrand Factor (VWF) independent recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

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

Limitation Of Use

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

Dosage And Administration

For intravenous use after reconstitution only.

Dose

• Each ALTUVIIIO vial label states the Factor VIII potency in international units (IU). One IU corresponds to the Factor VIII activity contained in one milliliter of normal human plasma, as defined by the current World Health Organization (WHO) international standard for Factor VIII concentrate.
• Potency assignment for ALTUVIIIO is determined using an activated partial thromboplastin time (aPTT)-based one-stage clotting assay. It is recommended to use a validated one-stage clotting assay to measure ALTUVIIIO Factor VIII activity in plasma. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid based aPTT reagent in one-stage clotting assay by approximately 2.5-fold [see WARNINGS AND PRECAUTIONS].

For the dose of 50 IU/kg, the expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula:

Estimated Increment of Factor VIII (IU/dL or % of normal) = 50 IU/kg x 2 (IU/dL per IU/kg)

To achieve a specific target Factor VIII activity level, use the following formula: Dosage (IU) = Body Weight (kg) x Desired Factor VIII Increase (IU/dL or % normal) x 0.5 (IU/kg per IU/dL).

Routine Prophylaxis

The recommended dosing for routine prophylaxis for adults and children is 50 IU/kg of ALTUVIIIO administered once weekly.

On-Demand Treatment And Control Of Bleeding Episodes

ALTUVIIIO dosing for the on-demand treatment and control of bleeding episodes is provided in Table 1.

Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes

For resumption of prophylaxis (if applicable) after treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last 50 IU/kg dose for treatment of a bleed and resuming prophylaxis dosing. Thereafter, prophylaxis can be continued as usual on the patient’s regular schedule.

Perioperative Management

ALTUVIIIO dosing for perioperative management is provided in Table 2.

Table 2: Dosing for Perioperative Management

Preparation And Reconstitution

POOLING: pooling is the process of combining two or more reconstituted vials into a larger luer lock syringe (not provided in the carton). If the dose requires more than one vial, reconstitute each vial as described above (See Steps 3-12) with the prefilled diluent syringe provided. Do not detach the prefilled diluent syringe until you are ready to attach the large luer lock syringe to the next vial. Keep the vial adapter attached to the vial as you will need it for attaching a large luer lock syringe. Use a larger luer lock plastic syringe to combine the contents of the reconstituted vials into the syringe, similar as described in the Steps 13-14. Repeat this pooling procedure with each vial you will be using. Once you have pooled the required dose, proceed with the administration steps using the larger luer lock syringe.

1. Use aseptic technique and a flat work surface during the reconstitution procedure.
2. Allow the ALTUVIIIO vial, containing the white to off-white lyophilized powder, and the prefilled diluent syringe to reach room temperature before use.
3. Remove the plastic cap from the ALTUVIIIO vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry.
4. Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package of the adapter.
5. Keep the vial on a flat surface. Hold the vial with one hand and using the other hand, place the vial adapter in its package over the vial. The spike should be placed directly above the center of the rubber stopper. Push the vial adapter straight down until the spike on the vial adapter punctures the center of the vial stopper and is fully inserted.
6. Lift the package cover away from the vial adapter and throw away the cover.
7. Only use the prefilled diluent syringe provided to reconstitute the powdered medicine. Hold the plunger rod by the circular disk. Place the tip of the plunger rod into the end of the prefilled diluent syringe. Turn the plunger rod to the right until it is firmly attached.
8. With one hand, hold the prefilled diluent syringe directly under the cap with the cap pointing up. Make sure you are holding the prefilled diluent syringe by the ridged part directly under the cap. Do not use if the cap has been removed or is not securely attached.
9. With your other hand, grasp the cap and bend it at a 90 degree angle until it snaps off. After the cap snaps off, you will see the glass tip of the prefilled diluent syringe. Do not touch the glass tip of the prefilled diluent syringe or the inside of the cap.
10. Be sure the vial is sitting on a flat surface. Insert the tip of the prefilled diluent syringe into the vial adapter opening. Turn the prefilled diluent syringe to the right until it is securely attached to the vial adapter.
11. Slowly push down on the plunger rod to inject all of the liquid (diluent) from the prefilled diluent syringe into the vial. The plunger rod may rise slightly afterward. This is normal.
12. With the prefilled diluent syringe still connected to the adapter, gently swirl the vial until the powder is completely dissolved. Check the solution through the vial to make sure the powder is fully dissolved. The solution should look clear and colorless to opalescent. Do not shake. Do not use the reconstituted ALTUVIIIO if it contains visible particles or is cloudy.
13. Make sure the plunger rod is pressed all the way down and the diluent syringe is firmly attached to the vial adapter. Turn the vial upside-down. Slowly pull down on the plunger rod to draw all the solution from the vial into the diluent syringe. Be careful not to pull the plunger rod completely out of the diluent syringe.
14. Gently unscrew the diluent syringe from the vial adapter by turning it to the right. Dispose of the vial with the adapter still attached. If you are not ready to inject, put the syringe cap carefully back onto the syringe tip. Do not touch the syringe tip or the inside of the cap.
15. Use the reconstituted ALTUVIIIO as soon as possible, but no later than 3 hours after reconstitution. Do not touch the glass tip of the syringe if not used immediately after reconstitution. Protect from direct sunlight. Do not refrigerate after reconstitution.

Administration

For intravenous use only.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ALTUVIIIO solution if particulate matter or discoloration is observed.
• Do not administer reconstituted ALTUVIIIO in the same tubing or container with other medications.

Administration Steps

1. Attach the syringe to the connector end of the infusion set tubing by turning it to the right until it is securely attached.
2. Push the plunger rod until all air is removed from the syringe and ALTUVIIIO has filled the infusion set needle. Do not push ALTUVIIIO solution through the needle.
3. Remove the protective needle cover from the infusion set needle.
4. Perform intravenous injection. The rate of administration should be determined by the patient’s comfort level and no faster than:
   • For adults and adolescents: 1-2 minutes per vial.
   • For children: 2-3 minutes per vial if body weight is greater than or equal to 20 kg; or 6 minutes per vial if body weight is less than 20 kg.
5. After infusing ALTUVIIIO, remove and properly discard the infusion set.

How Supplied

Dosage Forms And Strengths

ALTUVIIIO is available as a white to off-white lyophilized powder for reconstitution in single-dose vials containing nominally 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU) per vial.

ALTUVIIIO is supplied in kits comprising a single-dose vial containing nominally, 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU) of Factor VIII potency, a prefilled syringe with 3 mL sterile water for injection, and a sterile vial adapter (reconstitution device). The actual amount of ALTUVIIIO in IU is stated on the label and carton of each vial.

Not made with natural rubber latex.

Not all pack sizes may be marketed.

Storage And Handling

Prior to reconstitution:

• Store ALTUVIIIO in the original package to protect the ALTUVIIIO vials from light.
• Store ALTUVIIIO in powder form at 2°C to 8°C (36°F to 46°F). Do not freeze to avoid damage to the prefilled diluent syringe.
• ALTUVIIIO may be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months, within the expiration date printed on the label.
• If stored at room temperature, record the date that ALTUVIIIO is removed from refrigeration on the carton in the area provided. After storage at room temperature, do not return the product to the refrigerator.
• Do not use beyond the expiration date printed on the vial or 6 months after the date that was written on the carton, whichever is earlier.

After Reconstitution:

• The reconstituted product may be stored at room temperature, not to exceed 30°C (86°F), for up to 3 hours. Protect from direct sunlight. After reconstitution, if the product is not used within 3 hours, it must be discarded.
• Do not use ALTUVIIIO if the reconstituted solution is cloudy or has particulate matter.
• Discard any unused ALTUVIIIO.

Manufactured by: Bioverativ Therapeutics Inc. Waltham, MA 02451 A SANOFI COMPANY. Revised: Feb 2023

The most common adverse reactions (>10% of subjects) reported in clinical trials were headache and arthralgia.

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 the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ALTUVIIIO has been evaluated in 159 previously treated patients (PTPs) (134 adults and 25 adolescents) with severe Hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe Hemophilia A) who received at least one dose of ALTUVIIIO for either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. A total of 152 (96%) subjects achieved at least 25 exposure days and 115 (72%) subjects achieved at least 50 exposure days with a median of 53.0 (range 2-63) for both exposure days and injections per subject. Overall exposure was monitored for a total of 151.5 subject-years. Adverse drug reactions (ADRs) (summarized in Table 3) were reported in 57 (36%) of the 159 subjects treated with routine prophylaxis or on-demand therapy. There were no age-specific differences in ADRs observed between adolescent and adult subjects. In the study, no inhibitors were detected and no ADRs of anaphylaxis were reported.

Table 3: Adverse Drug Reactions with Frequency of ≥3% Reported for ALTUVIIIO

In the ongoing pediatric study, the safety of ALTUVIIIO was evaluated in 67 male PTPs <12 years of age with severe hemophilia A who received at least one dose of ALTUVIIIO. At the time of the interim analysis, a total of 23 (34%) subjects achieved at least 25 exposure days with a median of 14.0 (range 1-46) for both exposure days and injections per subject.

Adverse drug reactions, headache, were reported in 1 (1%) of subjects. In the study, no inhibitors were detected and no ADRs of anaphylaxis were reported.

Thromboembolic events occurred in 1% (3/206) of subjects in the long term safety extension study; these three subjects had pre-existing risk factors.

Immunogenicity

All subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII in the clinical program. No subjects developed neutralizing antibodies to Factor VIII [see Immunogenicity].

Drug Interactions

No Information Provided

Include as a part of “PRECAUTIONS” section

Precautions

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, may occur with ALTUVIIIO. Allergic-type hypersensitivity reactions were not reported in the clinical trials. Inform patients of signs of hypersensitivity reactions that may progress to anaphylaxis (including hives, shortness of breath, chest tightness, wheezing, hypotension and itching). Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.

Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to Factor VIII are possible following administration of ALTUVIIIO. Neutralizing antibodies were not reported in the clinical trials. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the patient’s plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after ALTUVIIIO administration, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed [see WARNINGS AND PRECAUTIONS].

Monitoring Laboratory Tests

If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay [see DOSAGE AND ADMINISTRATION]. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient’s ALTUVIIIO Factor VIII activity level. Use of a reference laboratory is recommended when a qualified one-stage clotting assay or chromogenic assay is not available locally.

Monitor for the development of Factor VIII inhibitors. If bleeding is not controlled with ALTUVIIIO and the expected factor VIII activity plasma levels are not attained, perform an assay to determine if Factor VIII inhibitors are present (use Bethesda Units to titer inhibitors).

Patient Counseling Information

Advise the patients to:

• Read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
• Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing.
• Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to Factor VIII therapy because this may be a sign of inhibitor development.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity or mutagenicity studies have been conducted with of ALTUVIIIO. No studies have been conducted to evaluate the effects of ALTUVIIIO on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

There are no data with ALTUVIIIO use in pregnant women to inform a drug-associated risk. Animal developmental and reproductive studies have not been conducted with ALTUVIIIO. Therefore, it is not known whether ALTUVIIIO can affect reproductive capacity or cause fetal harm when given to pregnant women.

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 ALTUVIIIO in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALTUVIIIO and any potential adverse effects on the breastfed infant from ALTUVIIIO or from the underlying maternal condition.

Pediatric Use

Safety, efficacy, and pharmacokinetics (PK) have been evaluated in 92 previously treated, pediatric patients <18 years of age who received at least one dose of ALTUVIIIO as part of routine prophylaxis, treatment of bleeding episodes, or perioperative management. Adolescent subjects were enrolled in the adult and adolescent study and pediatric subjects <12 years of age were enrolled in an ongoing pediatric trial. Thirty-one subjects (33.7%) were <6 years of age, 36 (39.1%) subjects were 6 to <12 years of age, and 25 subjects (27.2%) were adolescents (12 to <18 years of age). Interim data from a pediatric study of the 67 subjects <12 years of age showed that no dosing adjustment was required [see CLINICAL PHARMACOLOGY].

Geriatric Use

Clinical studies of ALTUVIIIO did not include sufficient numbers of subjects 65 years of age and older to determine whether or not they respond differently from younger subjects. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients.

No Information Provided

Contraindications

ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients [see DESCRIPTION].

Mechanism Of Action

ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] temporarily replaces the missing coagulation factor VIII needed for effective hemostasis. ALTUVIIIO has demonstrated 3- to 4-fold prolonged half-life relative to other standard and extended half-life FVIII products.

Mechanism Of Half-Life Extension

ALTUVIIIO is a recombinant FVIII analogue fusion protein that is independent of endogenous VWF in order to overcome the half-life limit imposed by FVIII-VWF interactions. The D’D3 domain of VWF is the region that interacts with FVIII. Appending the D’D3 domain of VWF to a recombinant FVIII-Fc fusion protein provides protection and stability to FVIII, and prevents FVIII interaction with endogenous VWF, thus overcoming the limitation on FVIII half-life imposed by VWF clearance.

The Fc region of human immunoglobulin G1 (IgG1) binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by recycling them back into circulation, thus prolonging the plasma half-life of the fusion protein.

ALTUVIIIO contains 2 XTEN polypeptides, which alter the hydrodynamic radius of the fusion protein, thus reducing rates of clearance and degradation, and improving pharmacokinetic properties. In ALTUVIIIO, the natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN, inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN is inserted in between the D’D3 domain and Fc.

Pharmacodynamics

Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation factor VIII (FVIII), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT)-based one-stage clotting assay. Administration of ALTUVIIIO increases plasma levels of FVIII, temporarily correcting the coagulation defect in hemophilia A patients.

Based on FVIII pharmacokinetic/pharmacodynamic analyses, the risk of bleeding is negatively correlated with FVIII activity. Once weekly 50 IU/kg ALTUVIIIO provided factor VIII activity levels that were associated with a low bleed risk.

Pharmacokinetics

The PK of ALTUVIIIO were evaluated in prospective, open-label clinical studies, enrolling 159 adults and adolescents, and 67 children <12 years old, respectively, receiving weekly IV injection of 50 IU/kg. Among children <12 years old, 32 subjects had ALTUVIIIO single dose PK profiles available.

PK parameters following a single dose of ALTUVIIIO are presented in Table 4. The PK parameters were based on plasma FVIII activity measured by the aPTT-based one-stage clotting assay. After a single dose of 50 IU/kg, ALTUVIIIO exhibited high sustained FVIII activity with prolonged half-life across age cohorts. There was a trend of increasing area under the curve (AUC), and decreasing clearance, with increasing age in the pediatric cohorts. The PK profile at steady state (Week 26) was comparable with the PK profile obtained after the first dose.

Table 4: Pharmacokinetic Parameters Following a Single Dose of ALTUVIIIO by age (one-stage clotting assay)

ALTUVIIIO at steady state maintained normal to near normal (>40 IU/dL) FVIII activity for a mean (SD) of 4.1 (0.7) days with once weekly prophylaxis in adults. The FVIII activity over 10 IU/dL was maintained in 83.5% of adults and adolescent subjects throughout the study. In children <12 years ALTUVIIIO maintained normal to near normal (>40 IU/dL) FVIII activity for 2 to 3 days and >10 IU/dL FVIII activity for approximately 6 to 7 days. The majority of children <12 years maintained FVIII activity in mild hemophilia range (>5 IU/dL) 7 days after the dosing (see Table 5).

Table 5: Pharmacokinetic Parameters at Steady State of ALTUVIIIO by age (one-stage clotting assay)

Specific Populations

The following factors have no clinically meaningful effect on the pharmacokinetics of ALTUVIIIO: age (1.4 to 72 years), sex, race (White, Asian), VWF antigen activity (40 to 339 IU/dL), hematocrit level (28% to 57%), blood type, HCV status, or HIV status. Body weight (12.5 to 133 kg) is expected to alter weight normalized clearance (dL/h/kg) by 79% to -18% compared to a typical patient.

Immunogenicity

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, or of other Factor VIII products.

All subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII in the clinical program. No subjects developed neutralizing antibodies to Factor VIII.

During treatment (up to 49.64 weeks) in the clinical studies, 4/277 (2.2%) of ALTUVIIIO patients developed anti-drug antibodies.

No impact of ADAs on the FVIII activity-time profiles and PK exposure parameters was observed.

No impact of ADAs with respect to bleeding episodes and in the pharmacodynamic response was noted.

Clinical Studies

The safety, efficacy, and pharmacokinetics of ALTUVIIIO were evaluated in two multicenter, prospective, open-label clinical studies (one study in adults and adolescents ≥12 years of age and one pediatric study in children <12 years of age) in previously treated patients (PTPs) with severe hemophilia A (<1% endogenous Factor VIII activity or a documented genetic mutation consistent with severe hemophilia A).

All studies evaluated the efficacy of routine prophylaxis with a weekly dose of 50 IU/kg and determined hemostatic efficacy in the treatment of bleeding episodes and during perioperative management in subjects undergoing major or minor surgical procedures.

The completed adult and adolescent study enrolled a total of 159 PTPs (158 male and 1 female subjects) with severe hemophilia A. Subjects were aged 12 to 72 years and included 25 adolescent subjects aged 12 to 17 years. All 159 enrolled subjects received at least one dose of ALTUVIIIO and were evaluable for efficacy. A total of 149 subjects (93.7%) completed the study.

The ongoing pediatric study enrolled 67 male PTPs <12 years of age with severe hemophilia A (31 subjects were 1 to 5 years of age and 36 were 6 to 11 years of age) at data cut-off. Of the 67 enrolled subjects, all received at least 1 dose of ALTUVIIIO.

Routine Prophylaxis To Reduce Bleeding Episodes

Adult and Adolescent Study

The efficacy of weekly 50 IU/kg ALTUVIIIO as routine prophylaxis was evaluated as estimated by the mean annualized bleed rate (ABR) and by comparing the ABR during on-study prophylaxis vs. the ABR during pre-study FVIII prophylaxis. A total of 133 adults and adolescents, who were on pre-study FVIII prophylaxis, were assigned to receive ALTUVIIIO for routine prophylaxis at a dose of 50 IU/kg IV once weekly for 52 weeks (Arm A). An additional 26 subjects, who were on pre-study episodic (on-demand) treatment with FVIII, received episodic (on-demand) treatment with ALTUVIIIO at doses of 50 IU/kg IV for 26 weeks, followed by routine prophylaxis at a dose of 50 IU/kg IV once weekly for 26 weeks (Arm B). Overall, 115 subjects received at least a total number of 50 exposure days (EDs) in Arm A and 17 subjects completed at least 25 EDs of routine prophylaxis in Arm B.

The ABR in subjects evaluable for efficacy with at least 26 weeks of exposure are summarized in Table 6. Routine prophylaxis resulted in a mean ABR (95% CI) of 0.7 (0.5, 1.0), a median (Q1, Q3) ABR of 0 (0, 1.0), and a median (Q1, Q3) annualized joint bleeding rate of 0 (0, 1.0).

Table 6: Summary of Annualized Bleeding Rate (ABR) with ALTUVIIIO Prophylaxis, ALTUVIIIO On-demand Treatment, and After Switch to ALTUVIIIO Prophylaxis in Patients ≥12 Years of Age

An intra-subject comparison (N = 78) between mean ABR during on-study prophylaxis with ALTUVIIIO and that during pre-study FVIII prophylaxis yielded a 77% reduction in treated bleeds (95% CI: 58%, 87%).

All subjects with target joints at baseline (defined as ≥3 spontaneous bleeding episodes in a major joint which occurred in a consecutive 6-month period) achieved resolution of all target joints (45/45, 100%) with 12 months of prophylactic treatment with ALTUVIIIO (defined as ≤2 bleeding episodes in the target joint in 12 months).

Pediatric Study

The efficacy of weekly 50 IU/kg ALTUVIIIO as routine prophylaxis in children <12 years was evaluated as estimated by the mean annualized bleed rate (ABR). At the time of the interim analysis, a total of 67 children (31 children <6 years of age and 36 children 6 to <12 years of age) were enrolled to receive ALTUVIIIO for routine prophylaxis at a dose of 50 IU/kg IV once weekly for 52 weeks. In subjects with at least 26 weeks of exposure (N=23), routine prophylaxis resulted in a mean ABR (95% CI) of 0.5 (0.2, 1.3) and a median (Q1, Q3) ABR of 0 (0, 1.3) for treated bleeds. For all bleeds (treated and non treated), the mean ABR (95% CI) was 3.6 (1.6, 8.4) and the median (Q1, Q3) ABR was 0 (0, 4.5).

Efficacy In Control Of Bleeding

In the adult and adolescent study, a total of 362 bleeding episodes were treated with ALTUVIIIO, most occurring during on-demand treatment in Arm B. Majority of bleeding episodes were localized in joints. Response to the first injection was assessed by subjects at least 8 hours after treatment. A 4-point rating scale of excellent, good, moderate, and no response was used to assess response. Bleeding was resolved with a single 50 IU/kg injection of ALTUVIIIO in 96.7% of bleeding episodes. The median (Q1; Q3) total dose to treat a bleeding episode was 50.9 IU/kg (50.0; 51.9). Control of bleeding episodes was similar across the treatment arms.

Perioperative Management Of Bleeding

Perioperative hemostasis was assessed in 13 major surgeries in 12 subjects (11 adults and 1 child). Of the 13 major surgeries, 12 surgeries required a single pre-operative dose to maintain hemostasis during surgery; for 1 major surgery during routine prophylaxis no pre-operative loading dose was administered on the day of/or before surgery. The median dose per pre-operative injection was 49.96 IU/kg (range 12.7 – 61.9).

The clinical evaluation of hemostatic response during major surgery was assessed using a 4-point scale of excellent, good, moderate, or poor/none. The hemostatic effect of ALTUVIIIO was rated as “excellent” in 13 of 13 surgeries (100%). No surgery had an outcome rated as “poor/none” or “missing.”

Types of major surgeries assessed include major orthopedic procedures such as joint arthroplasties (joint replacements of knee, hip, and elbow), joint revisions and ankle fusion. Other major surgeries included molar extractions and rhinoplasty/mentoplasty.

Perioperative hemostasis was assessed in 22 minor surgeries in 19 subjects (12 adults and 7 children). The hemostatic response was evaluated by the investigator/surgeon in 15 of these minor surgeries; an excellent response was reported in all (100%).