Altuviiio Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part I: Healthcare Professional Information ............................................................................ 4

1. 1.

   Indications .................................................................................................................. 4

   1.1. Pediatrics ................................................................................................................... 4

   1.2. Geriatrics .................................................................................................................... 4

2. 2. Contraindications ........................................................................................................ 4
3. 4.

   Dosage and Administration ......................................................................................... 4

   4.1. Dosing Considerations................................................................................................ 4

   4.2. Recommended Dose and Dosage Adjustment ........................................................... 5

   4.3. Reconstitution ............................................................................................................ 6

   4.4. Administration ........................................................................................................... 7

4. 5. Overdosage ................................................................................................................. 7
5. 6. Dosage Forms, Strengths, Composition and Packaging ................................................ 7
6. 7.

   Warnings and Precautions ........................................................................................... 8

   Immune ............................................................................................................................ 8

   Monitoring and Laboratory Tests ..................................................................................... 9

   Reproductive Health ........................................................................................................ 9

   7.1. Special Populations ................................................................................................... 9

   7.1.1. Pregnancy ......................................................................................................... 9

   7.1.2. Breastfeeding ................................................................................................... 9

   7.1.3. Pediatrics ........................................................................................................ 10

   7.1.4. Geriatrics ........................................................................................................ 10

   7.1.5. Hepatic and Renal impairment ....................................................................... 10

7. 8.

   Adverse Reactions ..................................................................................................... 10

   8.1. Adverse Reaction Overview ..................................................................................... 10

   8.2. Clinical Trial Adverse Reactions ............................................................................... 10

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics ................................................... 11

   8.3. Less Common Clinical Trial Adverse Reactions ................................................... 11

   8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics ............................ 11

   8.5. Post-Market Adverse Reactions ......................................................................... 12

8. 9.

   Drug Interactions ...................................................................................................... 12

   9.4. Drug-Drug Interactions ....................................................................................... 12

   9.5. Drug-Food Interactions ....................................................................................... 12

   9.6. Drug-Herb Interactions ....................................................................................... 12

   9.7. Drug-Laboratory Test Interactions ...................................................................... 12

9. 10.

   Clinical Pharmacology ............................................................................................... 12

   10.1. Mechanism of Action ...................................................................................... 12

   10.2. Pharmacodynamics ........................................................................................ 13

   10.3. Pharmacokinetics ........................................................................................... 13

   10.4. Immunogenicity .............................................................................................. 14

10. 11. Storage, Stability, and Disposal ....................................................................................... 15

Part 2: Scientific Information ................................................................................................ 16

1. 13. Pharmaceutical Information ...................................................................................... 16
2. 14.

   Clinical Trials ............................................................................................................. 17

   14.1. Clinical Trials by Indication ............................................................................. 17

3. 16. Non-Clinical Toxicology ............................................................................................. 21

Patient Medication Information ........................................................................................... 23

Part I: Healthcare Professional Information

1. Indications

ALTUVIIIO® (Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein) is indicated in adults, adolescents and children with hemophilia A (congenital Factor VIII [FVIII] deficiency) for:

• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
• Treatment and control of bleeding episodes
• Perioperative management of bleeding (surgical prophylaxis)

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

1.1. Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of ALTUVIIIO in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use (See 10.3. Pharmacokinetics).

1.2. Geriatrics

Geriatrics (>65 years of age): Clinical studies of ALTUVIIIO did not include sufficient number of patients 65 years of age and older to determine whether or not they respond differently from younger patients.

2. Contraindications

ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its components. For a complete listing see 6 Dosage Forms, Strengths, Composition and Packaging.

4. Dosage and Administration

For intravenous use after reconstitution only.

4.1. Dosing Considerations

• Treatment with ALTUVIIIO should be initiated under the supervision of a qualified healthcare professional experienced in the treatment of hemophilia A.
• Each vial label of ALTUVIIIO states the FVIII potency in international units (IU). One IU corresponds to the activity of FVIII contained in one milliliter of normal human plasma.
• Potency assignment was determined in clinical studies using an activated partial thromboplastin time (aPTT)-based one-stage clotting assay with the Actin®-FSL reagent (see 10.3. Pharmacokinetics). It is recommended to use a validated one-stage clotting assay to measure FVIII activity.
• The FVIII activity level is higher (overestimated) when using 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, this fold-increase should be accounted for to normalize FVIII activity levels. The ALTUVIIIO Factor VIII activity may also be underestimated by approximately 40% by a specific silica-based/synthetic phospholipid containing aPTT reagent in the one-stage clotting assay (see 7 Warnings and Precautions).

4.2. Recommended Dose and Dosage Adjustment

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

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

Routine Prophylaxis

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

Treatment and Control of Bleeding Episodes

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

Table 1. Dosing for Treatment and Control of Bleeding Episodes

When resuming prophylaxis 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. Thereafter, prophylaxis can be continued as usual on the patient’s regular dosing schedule.

Perioperative Management

ALTUVIIIO dosing for perioperative management is provided in Table 2.

Table 2. Dosing for Perioperative Management

4.3. Reconstitution

Table 3 - Reconstitution

The reconstituted product can be stored at room temperature up to 30°C for 3 hours (see 0

1. 11. Storage, Stability, and Disposal).

4.4. Administration

For Intravenous Use Only After Reconstitution

ALTUVIIIO is administered by intravenous infusion after reconstitution of the drug powder with the diluent.

The entire dose of ALTUVIIIO should be injected intravenously slowly over 1 to 10 minutes, based on the patient’s comfort level.

Do not administer reconstituted ALTUVIIIO if it contains particles, is discolored, or is cloudy.

Healthcare professionals should administer the first dose of ALTUVIIIO and monitor the patient for hypersensitivity reactions during the infusion and to establish the rate of infusion most appropriate for the patient. Subsequent doses may be given by the patient or the patient’s caregiver only when they are properly trained in monitoring hypersensitivity reactions and the patient or caregiver are comfortable administering ALTUVIIIO outside of a healthcare setting.

Detailed instructions for preparation and administration are included in the Patient Medication Information section.

Dispose of all unused solution, empty vials, and used needles and syringes in an appropriate container and dispose of this container according to local requirements.

5. Overdosage

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6. Dosage Forms, Strengths, Composition and Packaging

Table 4 – Dosage Forms, Strengths, Composition and Packaging

ALTUVIIIO is supplied in kits comprising:

• a single-use pack containing a powder vial (type 1 glass) with a chlorobutyl rubber stopper and an aluminum seal with a colored polypropylene flip-off cap at various strengths (see Table 4)

• a pre-filled syringe with 3 mL sterile water for injection (type 1 glass) with a bromobutyl rubber plunger stopper and tamper proof tip cap
• a sterile vial adapter reconstitution device.

7. Warnings and Precautions

Immune

Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, are possible with FVIII replacement therapies, and have been reported following treatment with ALTUVIIIO. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and to contact a physician and/or seek immediate emergency care.

Neutralizing Antibodies (Inhibitors)

Neutralizing FVIII antibodies have been reported in hemophilia A patients treated with FVIII replacement therapies. Monitor all patients for the development of FVIII inhibitors, by appropriate clinical observations and laboratory tests. If the patient’s plasma FVIII 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 Monitoring and Laboratory results).

Monitoring and Laboratory Tests

Routine monitoring of FVIII activity levels for prophylactic dose adjustment is not necessary based on experience from clinical studies. If assessment of plasma FVIII activity is needed, it is recommended to use a validated aPTT-based one-stage clotting assay (see 4.1 Dosing Considerations). The same assay, reagent, qualified laboratory, and equipment are recommended when it is considered necessary to monitor a patient’s FVIII activity over time.

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

Reproductive Health

• Fertility

  ALTUVIIIO has not been evaluated in animal fertility studies. It is not known whether ALTUVIIIO can affect fertility or sperm development in hemophilia A patients, although ALTUVIIIO is not expected to interact with DNA or be mutagenic (see Repeat Dose toxicity). No impact on male or female reproductive organs was shown in toxicology studies.

7.1. Special Populations

7.1.1. Pregnancy

Animal reproductive studies have not been conducted with ALTUVIIIO. It is not known whether ALTUVIIIO can affect reproductive capacity or cause fetal harm when given to pregnant women.

7.1.2. Breastfeeding

Lactation studies have not been conducted with ALTUVIIIO. It is not known whether ALTUVIIIO is excreted into human milk.

7.1.3. Pediatrics

Pediatrics (0-<18 years):

Safety, efficacy, and pharmacokinetics of ALTUVIIIO have been evaluated in 99 previously treated patients (PTPs) < 18 years of age, who received at least one dose of ALTUVIIIO as part of routine prophylaxis, treatment of bleeding episodes, or perioperative management. Adolescents (12 to < 18 years of age) were enrolled in the Phase 3 study (XTEND-1), and children < 12 years of age were enrolled in the Phase 3 pediatric study (XTEND-Kids). Thirty-eight subjects (38.4%) were <6 years of age, 36 (36.4%) subjects were 6 to <12 years of age, and 25 subjects (25.2%) were adolescents. Data from the pediatric study (74 subjects) showed no dosing adjustment was required for children < 12 years of age compared to adolescents and adults (see 10.3. Pharmacokinetics).

7.1.4. Geriatrics

Geriatrics (>65 years of age):

Clinical studies of ALTUVIIIO did not include sufficient number of patients 65 years of age and older to determine whether or not they respond differently from younger patients.

7.1.5. Hepatic and Renal impairment

Specific studies in patients with renal or hepatic impairment have not been performed.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Adverse events were monitored in 2 completed Phase 3 clinical studies in PTPs. Adverse drug reactions (ADRs) (summarized in Table 5) were reported in 79 (33.9%) of the 233 subjects treated with routine prophylaxis or on-demand therapy. The most common ADRs (>10%) in adults and adolescents were headache (20.1%) and arthralgia (16.4%). In children below 12 years, pyrexia (12.2%) was the most common ADR (>10%).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety of ALTUVIIIO has been evaluated in 159 subjects from a completed Phase 3 study (XTEND-1) in previously treated patients (PTPs) 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. Of the 159 evaluated subjects, 134 (84.3%) were adults (18 years of age and older) and 25 (15.7%) were adolescents (12 to < 18 years of age). There were 154 (96.9%) subjects treated for at least 26 weeks and 98 (61.6%) subjects treated for at least 52 weeks. A total of 152 (95.6%) subjects achieved at least 25 exposure days and 115 (72.3%) subjects achieved at least 50 exposure days with a median of 53.0 (range 2-63) for both exposure days and injections per subject. Adverse events (AEs) were monitored for a total of 151.5 subject-years.

In the pediatric study (XTEND-Kids), the safety of ALTUVIIIO prophylaxis was evaluated in 74 male PTPs <12 years of age with severe hemophilia A who received at least one dose of ALTUVIIIO. Sixty-six (89.2%) subjects achieved at least 50 exposure days with a median of 53.0 (range 3-72).

Table 5: Adverse Drug Reactions reported for ALTUVIIIO

* 233 subjects across two completed Phase 3 clinical studies

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

The observed safety profile of ALTUVIIIO was found to be consistent across pediatric and adult patients.

8.3. Less Common Clinical Trial Adverse Reactions

Thromboembolic events occurred in 1% (3/261) of patients in the long-term safety extension study; these three subjects had pre-existing risk factors for thromboembolic events.

8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics

Not Available.

8.5. Post-Market Adverse Reactions

In post-marketing experience, the following adverse reactions have been reported:

Allergic type hypersensitivity reactions, including anaphylaxis

Factor VIII inhibitor development.

9. Drug Interactions

9.4. Drug-Drug Interactions

There are no known drug interactions reported with ALTUVIIIO. No drug interactions studies have been performed.

9.5. Drug-Food Interactions

No drug-food interaction studies have been conducted with ALTUVIIIO. Interactions with foods have not been established.

9.6. Drug-Herb Interactions

No drug-herb interaction studies have been conducted with ALTUVIIIO. Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

No drug-laboratory test interaction studies have been conducted with ALTUVIIIO. Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

ALTUVIIIO (recombinant coagulation FVIII Fc-Von Willebrand Factor-XTEN Fusion Protein [FVIIIFc-VWF-XTEN]) is a recombinant fusion protein that temporarily replaces the missing coagulation FVIII needed for effective hemostasis and has demonstrated a 3- to 4-fold prolonged half-life relative to other standard and extended half-life FVIII molecules.

ALTUVIIIO is a FVIII protein that is designed to be 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 rFVIII-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 and thus prolonging the plasma half-life of the fusion protein.

ALTUVIIIO contains 2 XTEN polypeptides, which further increase its pharmacokinetics (PK). In ALTUVIIIO, the natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN polypeptide, inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN polypeptide is inserted in between the D’D3 domain and Fc.

10.2. Pharmacodynamics

Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation 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 exposure-response analyses, in a typical patient receiving an ALTUVIIIO 50 IU/kg once-weekly regimen, the probability of zero bleeds in 1 year was predicted to be 71% (95% CI: 50%-83%).

10.3. Pharmacokinetics

The pharmacokinetics (PK) of ALTUVIIIO were evaluated in 159 adults and adolescents and 74 children <12 years old, respectively, receiving weekly IV injections of 50 IU/kg. Among children <12 years old, 36 subjects had ALTUVIIIO single-dose PK profiles available.

PK parameters following a single dose of ALTUVIIIO are presented in Table 6. The PK parameters were based on plasma FVIII activity measured by the aPTT-based one-stage clotting assay using the Actin® FSL reagent. 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 decreasing AUC, and increasing clearance, with decreasing 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 6: Pharmacokinetic parameters following a single dose of ALTUVIIIO by age (one-stage clotting assay with the Actin® FSL reagent)

AUC_0-tau = area under the activity-time curve over the dosing interval, CL = clearance, MRT = mean residence time, SD = standard deviation, t_1/2z = terminal half-life, V_ss = volume of distribution at steady state

^aCalculation based on 128 profiles. ^b N=17

In XTEND-1, 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 adolescents 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 7 days (see Table 7).

Table 7: Pharmacokinetic parameters at steady-state of ALTUVIIIO by age (one-stage clotting assay with the Actin® FSL reagent)

Peak = 15 min post dose at steady state, IR = incremental recovery, Trough = predose FVIII activity value at steady state, SD = standard deviation

^a Steady state peak, trough and IR were computed using available measurements at week 52/End of study PK sampling visit ^b Time to FVIII activity was predicted using population PK model for pediatric study

^c Time to FVIII activity was predicted using population PK model for adult study

10.4. Immunogenicity

All subjects were monitored for neutralizing antibodies (inhibitors) to FVIII during the ALTUVIIIO Phase 3 clinical studies. No subjects developed neutralizing antibodies to FVIII, consistent with results expected for PTPs switching to a new treatment.

The detection of antibodies that are reactive to FVIII is highly dependent on many factors, including the patient population studied (PTPs vs previously untreated patients [PUPs]), sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, it may be misleading to compare the incidence of antibodies to ALTUVIIIO with the incidence of antibodies to other FVIII products. Since PUPs have not been enrolled in clinical studies, it is not yet possible to estimate inhibitor development to ALTUVIIIO.

During the ALTUVIIIO phase 3 studies (median treatment duration 96.3 weeks), 4/276 (1.4%) of evaluable patients developed transient treatment-emergent anti-drug antibodies (ADAs).

1. 11. Storage, Stability, and Disposal

Storage Conditions

Unopened vials should be stored under controlled refrigeration (2°C - 8°C). The product may be stored at room temperature (up to 30°C) for a single 6-month period. The date that the product is removed from refrigeration should be noted on the carton.

Do not use beyond the expiration date printed on the carton and the vial or six months after removing the carton from refrigeration, whichever is earlier.

Do not freeze. Protect from light.

In use shelf-life

The reconstituted product can be stored at room temperature (up to 30°C) for 3 hours. Protect product from direct sunlight. After reconstitution, if the product is not used within 3 hours, it must be discarded.

The appearance of the reconstituted product should be clear and colorless to slightly opalescent.

Do not use this medicine if you notice that it is cloudy or contains visible particles.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper name: Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein

Chemical name: Recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein (rFVIIIFc-VWF-XTEN)

Molecular formula and molecular mass:

ALTUVIIIO is a fully recombinant fusion protein comprising a single chain B-domain deleted (BDD) analogue of human Factor VIII (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. It has a molecular weight of approximately 312 kDa.

Physicochemical properties: Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein drug substance is a clear to slightly opalescent, colorless to slightly yellow solution, with pH of 6.5 to 7.2.

Product Characteristics:

Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line, which has been extensively characterized. Efanesoctocog alfa 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.

14. Clinical Trials

14.1. Clinical Trials by Indication

Routine Prophylaxis in Adults and Adolescents with Hemophilia A (congenital FVIII deficiency)

Study Design and Demographics

The safety and efficacy of ALTUVIIIO in adult and adolescent hemophilia A subjects (≥ 12 years of age) were evaluated in a Phase 3 multicenter open-label clinical study (XTEND-1), which enrolled a total of 159 PTPs (158 male and 1 female subjects) with severe disease (< 1% endogenous FVIII activity or a documented genetic mutation consistent with severe hemophilia A). Subjects were aged 12 to 72 years and included 25 adolescents aged 12 to 17 years.

Subjects enrolled on study were required to have platelet counts ≥ 100 x 10⁹ cells/L and controlled HIV (CD4 lymphocyte count > 200 x10⁶ cells/L and a viral load of < 400 copies/mL within 26 weeks of screening). Subjects were excluded if they had emicizumab treatment within 20 weeks of screening, serious infections, abnormal renal function (serum creatinine > 177 micromoles/L, abnormal, abnormal liver function (serum total bilirubin >3 x upper limit of normal [ULN] or investigator decision), any vaccination within 30 days of screening, a major surgery within 8 weeks of screening, and if they had a positive test for factor VIII inhibitor (≥0.6 Bethesda units [BU] per milliliter) at screening or a history of a positive inhibitor test, clinical signs or symptoms of a decreased response to factor VIII, other known coagulation disorders, a history of hypersensitivity or anaphylaxis to factor VIII therapies. A total of 149 subjects (93.7%) completed the study.

The study included 2 arms and in arm A, subjects received once-weekly prophylaxis with ALTUVIIIO (50 IU/Kg) intravenously for 52 weeks. In arm B, subjects received on-demand treatment with ALTUVIIIO (50 IU/Kg) intravenously for 26 weeks, followed by once-weekly prophylaxis with ALTUVIIIO (50 IU/Kg) intravenously for 26 weeks.

The primary end point was the mean annualized bleeding rate for treated bleeds in arm A and the key secondary end point was intrapatient comparison of the annualized bleeding rate (ABR) during prophylaxis in arm A with the ABR during pre-study factor VIII prophylaxis for subjects in Arm A who participated in a prospective observational study.

Table 8 – XTEND-1 Study Design to Assess the Safety and Efficacy of ALTUVIIIO in Adults and Adolescents with Hemophilia A (congenital FVIII deficiency)

Study Results

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). Of the 133 subjects, 128 subjects had at least 26 weeks of exposure to ALTUVIIIO and are included in the efficacy evaluation set. 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. A total of 149 subjects (93.7%) completed the study.

The ABR in subjects evaluable for efficacy are summarized in Table 9. 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). Eighty-two of 128 (64.1%) subjects experienced no bleeding episodes, and 92 of 128 (71.9%) of subjects experienced no joint bleeding episodes while on routine prophylaxis for a median of 52 weeks in Arm A.

Table 9: Summary of Annualized Bleeding Rate (ABR) with ALTUVIIIO prophylaxis, ALTUVIIIO on-demand treatment, and after switch to ALTUVIIIO prophylaxis in subjects ≥ 12 Years of Age

ABR = annualized bleed rate; CI = confidence interval; Q1 = 25th percentile; Q3 = 75th percentile.

¹ All analyses of bleeding endpoints are based on treated bleeds

²Subjects assigned to receive ALTUVIIIO prophylaxis for 52 weeks

³Subjects assigned to receive ALTUVIIIO for 26 weeks

⁴Based on negative binomial model

An intra-subject comparison of ABRs during on-study and pre-study prophylaxis yielded a reduction of 77% in ABR based on treated bleeds (95% CI: 58%, 87%) during routine prophylaxis with ALTUVIIIO compared to pre-study FVIII prophylaxis (see Table 10).

Table 10: Intra-Subject Comparison of Annualized Bleeding Rate (ABR) with ALTUVIIIO Prophylaxis versus Pre-study FVIII Prophylaxis in Subjects ≥ 12 Years of Age

ABR = annualized bleed rate based on treated bleeds; CI = confidence interval; Q1 = 25th percentile; Q3 = 75th percentile.

¹Based on negative binomial model

²Prospective observational study (OBS16221)

Routine Prophylaxis in Children with Hemophilia A (congenital FVIII deficiency)

Study Design and Demographics

The safety and efficacy of ALTUVIIIO as routine prophylaxis in hemophilia PTPs <12 years of age was evaluated as estimated by the mean ABR. A total of 74 subjects with severe hemophilia A (38 subjects <6 years of age and 36 subjects 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. Key inclusion and exclusion criteria were consistent with the pivotal Phase III study in adults and adolescents (XTEND-1).

The primary end point was the occurrence of inhibitor development in children <12 years of age. The key secondary end points reported are the ABR for treated bleeds, including a breakdown by spontaneous and joint bleeds, as well as the ABR based on all bleeding episodes (Table 11).

Table 11: Summary of Annualized Bleeding Rate (ABR) with ALTUVIIIO Prophylaxis in Patients <12 Years of Age

ABR = annualized bleed rate; CI = confidence interval; Q1= 25th percentile, Q3=75th percentile.

* Reflects all bleeds reported by patients including those where no ALTUVIIIO was administered.

† A subject in the 6 to <12 years old age group who received an intense consolidation treatment (2 to 3 injections per week for 15 weeks) after treatment of 2 traumatic hip joint bleeds was excluded from the efficacy analysis as the subject did not receive the weekly prophylaxis treatment as specified in the protocol for an extended period.

‡ Based on negative binomial model.

Perioperative Management of Bleeding (Surgical Prophylaxis)

Major surgeries

Perioperative hemostasis was assessed in 14 major surgeries in 13 subjects (11 adults and 2 pediatrics) across the two Phase 3 studies. Of the 14 major surgeries, 13 surgeries required a single pre-operative dose to maintain hemostasis during surgery; for 1 major surgery occurring during routine prophylaxis, no pre-operative loading dose was administered on the day of/or on the day before surgery. 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 14 of 14 surgeries (100%).

Minor surgeries

Perioperative hemostasis was assessed in 32 minor surgeries in 28 subjects (15 adults and 13 adolescents and children) across the Phase 3 studies. The hemostatic response was evaluated by the investigator/surgeon in 25 of these minor surgeries; an excellent response was reported in all (100%).

16. Non-Clinical Toxicology

General Toxicology

Single dose toxicity

No single-dose toxicology studies were performed with ALTUVIIIO.

Repeat Dose toxicity

A repeat-dose IV toxicity study in healthy monkeys administered up to 750 IU/kg/dose ALTUVIIIO every 4 days for 4 weeks showed increased activated partial thromboplastin time (aPTT). This is consistent with development of neutralizing antibodies against Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein, which cross-reacted to endogenous FVIII, as indicated by the prolonged aPTT and decreased endogenous FVIII activity. ADA-induced acquired hemophilia resulted in the death of one monkey on Day 30 due to excessive bleeding following blood sample collection. Greater group mean aPTT values persisted in females given 750 IU/kg/dose after the recovery period. There were no other adverse findings directly attributed to the pharmacologic activity/intended mechanism of ALTUVIIIO.

No specific nonclinical immunogenicity studies have been conducted with ALTUVIIIO. However, dose-related increases in ADA to Antihemophilic Factor VIII (Recombinant, B-Domain deleted), Fc-VWF-XTEN fusion protein were observed in rats and monkeys dosed every 3 or 4 days, respectively, for 4 weeks at doses up to 750 IU/kg/dose. Due to the formation of antibodies, which resulted in limited exposure in rats and monkeys by Day 28 or Day 29, respectively, it was not feasible to conduct meaningful toxicology studies beyond 4 weeks of dosing.

Genotoxicity

ALTUVIIIO has not been evaluated in mutagenicity or chromosomal aberration assays since it is a replacement protein factor for coagulation activity.

Carcinogenicity

No animal studies investigating carcinogenic effects of ALTUVIIIO have been conducted since it is a replacement protein factor for coagulation activity.

Reproductive and Developmental Toxicology

ALTUVIIIO has not been evaluated in animal reproduction studies. It is not known whether ALTUVIIIO can affect fertility or sperm development in hemophilia A patients. No adverse effects on male or female reproductive organs were observed in toxicology studies. Based on a well understood mechanism of action, FVIII replacement products are not expected to affect embryo-fetal development. Therefore, the developmental risk in humans is considered low for ALTUVIIIO.

Local tolerance

Local tolerance studies have not been conducted with ALTUVIIIO. However, ALTUVIIIO was well tolerated in 4-week repeat-dose IV toxicity studies in rats and monkeys.

Hemocompatibility

ALTUVIIIO showed no potential for hemolysis and no flocculation in an in vitro hemocompatibility study with human whole blood at concentrations up to 4.1 mcg/mL.