Alhemo Product Monograph

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TABLE OF CONTENTS

TABLE OF CONTENTS ........................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ............................................................... 4

1 INDICATIONS ............................................................................................................... 4

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

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

2 CONTRAINDICATIONS ................................................................................................ 4

3 SERIOUS WARNINGS AND PRECAUTIONS .............................................................. 4

4 DOSAGE AND ADMINISTRATION .............................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

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

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

4.5 Missed Dose ........................................................................................................... 8

5 OVERDOSAGE ............................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....................... 9

7 WARNINGS AND PRECAUTIONS ............................................................................... 9

7.1 Special Populations .............................................................................................. 11

7.1.1 Pregnant Women ......................................................................................... 11

7.1.2 Breast-feeding .............................................................................................. 11

7.1.3 Pediatrics ..................................................................................................... 11

7.1.4 Geriatrics ..................................................................................................... 12

8 ADVERSE REACTIONS ............................................................................................. 12

8.1 Adverse Reaction Overview.................................................................................. 12

8.2 Clinical Trial Adverse Reactions ........................................................................... 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ..................................................... 13

8.3 Less Common Clinical Trial Adverse Reactions .................................................... 13

9 DRUG INTERACTIONS .............................................................................................. 13

9.2 Drug Interactions Overview................................................................................... 13

9.3 Drug-Drug Interactions .......................................................................................... 13

9.4 Drug-Food Interactions ......................................................................................... 14

9.5 Drug-Herb Interactions ......................................................................................... 14

9.6 Drug-Laboratory Test Interactions ........................................................................ 14

10 CLINICAL PHARMACOLOGY .................................................................................... 14

10.1 Mechanism of Action .......................................................................................... 14

10.2 Pharmacodynamics ............................................................................................ 14

10.3 Pharmacokinetics ............................................................................................... 14

11 STORAGE, STABILITY AND DISPOSAL ................................................................... 16

12 SPECIAL HANDLING INSTRUCTIONS ...................................................................... 16

PART II: SCIENTIFIC INFORMATION ................................................................................... 17

13 PHARMACEUTICAL INFORMATION ......................................................................... 17

14 CLINICAL TRIALS ...................................................................................................... 17

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

Hemophilia Patients with Inhibitors .............................................................................. 17

14.3 Immunogenicity .................................................................................................. 19

15 MICROBIOLOGY ........................................................................................................ 19

16 NON-CLINICAL TOXICOLOGY .................................................................................. 20

PATIENT MEDICATION INFORMATION ............................................................................... 21

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Alhemo (concizumab injection) is indicated for the treatment of adolescent and adult patients (12 years of age or older) with hemophilia A (congenital factor VIII [FVIII] deficiency) who have FVIII inhibitors or hemophilia B (congenital factor IX [FIX] deficiency) who have FIX inhibitors and require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

There is limited clinical experience of Alhemo use in patients known to have mild or moderate hemophilia.

1.1 Pediatrics

• Pediatrics (aged 12 to less than 18 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Alhemo in adolescent patients aged 12 to less than 18 years of age has been established; therefore, Health Canada has authorized an indication for adolescent patients aged 12 to less than 18 years. The safety and efficacy of Alhemo has not been established in patients less than 12 years of age.

1.2 Geriatrics

• Geriatrics (≥ 65 years of age): Clinical studies did not include a sufficient number of patients aged 65 years and over to determine if the overall benefit-risk profile of Alhemo is favourable in these patients.

2 CONTRAINDICATIONS

Alhemo is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging [6].

3 SERIOUS WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions Box

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Treatment should be initiated under the supervision of a health professional experienced in treatment of hemophilia and/or bleeding disorders.
• Prior to initiation of Alhemo, patients should discontinue prophylactic treatment with bypassing agents. Treatment with recombinant activated Factor VII (rFVIIa) should be discontinued at least 12 hours before starting Alhemo and treatment with activated prothrombin complex concentrates (aPCC) should be discontinued at least 48 hours before starting Alhemo.
• Hemophilia A patients with FVIII inhibitors should discontinue emicizumab 6 months before starting treatment with Alhemo.
• Treatment should be initiated in a non-bleeding state.
• Alhemo is intended for patients’ self-administration or by a caregiver (e.g. parent) only after proper training by a health professional..
• Intramuscular injections should be avoided and these may occur inadvertently, particularly in lean and younger patients where it is recommended to inject into a loosely-held skin-fold.

4.2 Recommended Dose and Dosage Adjustment

The recommended Alhemo dosing regimen is a Day 1 loading dose of 1 mg/kg followed by an initial daily dose of 0.2 mg/kg, which is followed by an individualized daily maintenance dose according to the following schedule:

• Day 1: a loading dose of 1 mg/kg once.
• Day 2 and until individual maintenance dose setting (see below): once daily dosing of 0.20 mg/kg.
• 4 weeks after initiation of treatment: measurement of concizumab pre-dose plasma concentration by a validated concizumab enzyme-linked immunosorbent assay (ELISA) as determined by an accredited laboratory.
• Once the week 4 concizumab plasma concentration result is available the individual maintenance dose is set as indicated below in Table 1.

Table 1 Individual maintenance dose based on concizumab plasma concentration.

While Alhemo can be administered at any time point of the day, it is recommended to advise patients to inject at the same time each day, in order to prevent doses occurring too close together.

The individual maintenance dose should be established at the earliest convenience (after concizumab plasma concentration week 4 result is available) and no later than 6-8 weeks after initiation of treatment. The individual maintenance dose should only be determined in patients who adhere to their initial everyday dose. Patients who miss consecutive daily doses during this dose finding phase should inform their health professional so that a new 4 week uninterrupted daily dose period is established before plasma concizumab concentrations are measured.

In hemophilia study NN7415-4311 (explorer7), of the 97 patients who had a week 4 concizumab plasma concentration, 74.2% (n = 72) of patients remained on the 0.2 mg/kg daily dose, 24.7% (n = 24) of patients had their dose increased to 0.25 mg/kg per day, and 1.0% (n = 1) of patients had their dose decreased to 0.15 mg/kg.

For patients with a plasma concizumab concentration > 4000 ng/mL and who required a dose reduction to 0.15 mg/kg, a second concizumab concentration should be considered. Ideally, the second concizumab concentration should be taken 8 weeks after initiation of the lower dose to ensure patients reach steady-state. If the plasma concentration remains above 4000 ng/mL then the benefits of Alhemo should be evaluated versus the potential for an increased risk of thromboembolic events.

Additional concizumab plasma concentration measurements can also be taken after 8 weeks on the same maintenance dose according to the patient’s medical condition. For example, this should be considered if a patient experiences an increased bleeding frequency or acquires a comorbidity, which could affect their coagulation system or drug metabolism/excretion.

In some instances, a more frequent therapeutic type monitoring of plasma concizumab concentrations may be considered appropriate (semi- annual or annual) and this should be discussed in consultation with the patient.

Geriatrics (> 65 years of age)

No dose adjustments (besides individual maintenance dose setting) are recommended in patients ≥65 years of age.

Pediatrics (<12 years of age)

The efficacy and safety of Alhemo in children less than 12 years of age has not yet been established.

Patients with renal and hepatic insufficiency

No dose adjustments (besides individual maintenance dose setting) are required for patients with renal and hepatic impairment (see Clinical Pharmacology, Pharmacokinetics [10.3]). Patients with severe renal impairment (eGFR ≤ 30 mL/min/1.73 m²) and severe hepatic impairment (AST or ALT > 3x ULN combined with total bilirubin > 1.5x ULN) were not included in the clinical trials.

Guidance on the Use of Breakthrough Bleed Treatment

No dose adjustment of Alhemo should be done in case of breakthrough bleeds.

Health professionals should discuss with all patients and/or caregivers about the dose and schedule of bypassing agents to use, if required, while receiving Alhemo prophylaxis, including using the lowest possible effective dose to minimize the risk of thromboembolic events for mild and moderate bleeds, which includes a maximum aPCC dose of 100 U/kg within 24 hours. For severe bleeds, it may be necessary to follow the dosing scheme provided in the approved label for a bypassing agent but this should be based on clinical judgement taking into account the potential for life-threatening thromboembolic events.

Management in the perioperative setting

No dose adjustment of Alhemo is needed in case of minor surgeries.

For a major surgery, consult a health professional experienced in treatment of hemophilia and/or bleeding disorders. As there is no clinical experience in using Alhemo during major surgeries because it was not allowed in clinical trial protocols due to a potential for increased risks of thromboembolic events in these patients, it is generally recommended to pause Alhemo 4 days prior to a major surgery and resume at the normal daily maintenance dose (either 0.15, 0.20 or 0.25 mg/kg) 10-14 days after surgery, considering the overall clinical picture of the patient.

Following a major surgery, a patient may not achieve effective control of bleeds on Alhemo for at least two weeks after resuming therapy since it may take this long for concizumab plasma concentrations to reach the appropriate therapeutic levels. Consult the product monographs for bypassing agents for their instructions of use in hemophilia patients following major surgeries.

Immune tolerance induction (ITI)

The safety and efficacy of Alhemo in patients receiving ongoing immune tolerance induction have not been established.

Calculation of dose

The dose (in mg) is calculated as follows:

Patient body weight (kg) x dose (1, 0.15, 0.20 or 0.25 mg/kg) = total amount (mg) of Alhemo to be administered.

The dose is dialled at increments of

• 0.1 mg on the 15 mg/1.5 mL (10 mg/mL) pen (blue),
• 0.4 mg on the 60 mg/1.5 mL (40 mg/mL) pen (brown), and
• 1.0 mg on the 150 mg/1.5 mL (100 mg/mL) and 300 mg/3 mL (100 mg/mL) pens (gold).

The health professional should assist the patient in rounding off and identifying the appropriate injectable dose on the pen. Ideally, patients should be prescribed and use a pen that can deliver the required daily maintenance dose in one injection.

4.4 Administration

• Alhemo is available in a pre-filled pen designed to be used with NovoFine® 32G TIP ETW or NovoFine® Plus needles with a gauge of 32 and a length of 4 mm. The pen contains multiple doses.
• Administer Alhemo by subcutaneous injection to the abdomen or thigh with rotation of injection site every day. Subcutaneous injections should not be given in areas where the skin is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks.
• Always use a new needle for each injection.

• Alhemo is a clear to slightly opalescent and colorless to slightly yellow solution. Translucent particles of protein are acceptable. Do not use if the solution is discoloured

  • or contains solid foreign particles.
• Alhemo may be self-administered or administered by a caregiver after appropriate training by a healthcare provider and after reading the instructions for use.
• Each Alhemo prefilled pen is for use by a single patient. An Alhemo pen must not be shared between patients, even if the needle is changed.
• Intramuscular injections should be avoided and these may occur inadvertently, particularly in lean and younger patients where it is recommended to inject into a loosely-held skin-fold.

4.5 Missed Dose

It is important that each patient adheres to their daily dosing regimen (see Warnings and Precautions [7], General).

Missed Doses Before the Maintenance Dose has been Determined

Patients who miss doses prior to measurement of their week 4 concizumab plasma concentration are at risk of not having a proper maintenance dose determined. Patients should resume treatment as soon as possible and inform their health professional so a new uninterrupted 4- week dosing period is started prior to measuring concizumab plasma concentrations.

Missed Doses After the Maintenance Dose has been Determined

The following dosing guidelines based on PopPK modeling could apply ONLY when a patient has forgotten to or neglected to take their once daily maintenance dose. This does not apply to patients who have missed doses for other reasons (e.g. surgery).

• 1 missed daily dose: the patient should resume the daily maintenance dose without an additional dose.
• 2 to 6 missed consecutive daily doses: the patient should contact their health professional right away. While concizumab can be resumed at the maintenance dose, after careful consideration of the clinical picture, the patient may take the daily dose twice (as two separate injections each corresponding to a daily dose), and then continue taking the daily maintenance dose the next day. The double dose can be administered under the supervision of a health professional.
• 7 or more missed consecutive daily doses: the patient should contact their health professional right away. The patient may need to receive a new loading dose before continuing their daily maintenance dose the next day, after careful consideration of the clinical picture.

For missed doses due to other reasons (e.g. surgery), the patient should follow the instructions in the product monograph (see Recommended Dose and Dosage Adjustment [4.2]) or resume the daily maintenance dose as instructed by their health professional.

When in doubt, the patient should contact their health professional.

5 OVERDOSAGE

There is limited experience with overdose of Alhemo.

Patients who receive an accidental overdose should also immediately contact their health professional and be monitored closely.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognize the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 3 Dosage Forms, Strengths, Composition and Packaging

Alhemo is a clear to slightly opalescent and colorless to slightly yellow solution that may contain translucent particles of protein. Alhemo is available in the following presentations:

• 15 mg/1.5 mL (10 mg/mL) in a single-patient-use prefilled pen with a blue colour-coded dose button and cartridge holder
• 60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled pen with a brown colour-coded dose button and cartridge holder
• 150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled pen with a gold colour-coded dose button and cartridge holder
• 300 mg/3 mL (100 mg/mL) in a single-patient-use prefilled pen with a gold colour-coded dose button and cartridge holder

The pre-filled pen is packed in a carton. Alhemo is available in a pack containing 1 pen. Injection needles are not included.

Alhemo is recommended to be used with NovoFine^® 32G TIP ETW or NovoFine^® Plus needles with a gauge of 32 and a length of 4 mm. If needles longer than 4 mm are used, injection techniques that minimize the risk of intramuscular injection should be used.

7 WARNINGS AND PRECAUTIONS

See Serious Warnings And Precautions [3].

General

Health professionals should discuss with patients or caregivers at the start of treatment with Alhemo that one or more missed doses of Alhemo may significantly affect the efficacy of the product and the ability to establish a proper maintenance dose. If a patient or caregiver can not follow the every day dosing regimen then alternative treatment options should be considered.

Driving and Operating Machinery

There is no evidence that Alhemo affects one’s ability to drive and use machines.

Hematologic

Thromboembolic Events

Serious thromboembolic events (TEEs) reported in association with Alhemo resulted in a pause in clinical development from March to August 2020, and a new dosing regimen based on plasma concizumab concentrations was implemented (see Dosage and Administration [4]).

Patients treated with Alhemo should be informed of and monitored for the occurrence of signs and symptoms of thromboembolic events. Patients who experienced thromboembolic events in clinical trials were exposed to additional hemostatic agents in close proximity with administration of Alhemo.

The half-life of bypassing agents and emicizumab should be considered when switching to Alhemo (see Dosage and Administration [4]).

Patients should be advised on how to treat breakthrough bleeds. In the case where other hemostatic agents are required to treat mild or moderate breakthrough bleeds, it is recommended to treat with the lowest possible effective dose (see Dosage and Administration [4]).

Patients were to be excluded from clinical studies if they were at high risk for developing thromboembolic events and there should be careful consideration whether the potential benefit of Alhemo treatment outweighs the potential risk of thromboembolic complications in these patients. Risk factors include a history or family history of TEEs, obesity, arrhythmias, hypertension, diabetes, hypercholesterolaemia, smoking, recent major surgeries, and old age taking into consideration the totality of risk factors for the individual patient. In addition, patients in which tissue factor is overexpressed (e.g. advanced atherosclerotic disease, crush injury, cancer or septicaemia), may have further risks of thromboembolic events or disseminated intravascular coagulation (DIC) with Alhemo treatment.

In clinical studies, there was a positive correlation with concizumab plasma concentrations and D-dimer and prothrombin fragment 1+2 plasma levels (see Adverse Reactions [8]).

In case of suspicion of thromboembolic events, Alhemo should be permanently discontinued and further investigations and appropriate medical treatment should be initiated.

Immune

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions have occurred with Alhemo, including hospitalization and permanent discontinuation of therapy. Patients should be informed of the signs of acute hypersensitivity reactions while receiving Alhemo. Discontinue use of Alhemo if hypersensitivity symptoms occur and initiate appropriate treatment.

Immunogenicity

Anti-concizumab antibodies and neutralizing anti-concizumab antibodies have been reported in 25% and 6.5% of patients treated with Alhemo in clinical trials, respectively (see Clinical Trials, Immunogenicity [14.3]). Most patients found to have anti-concizumab antibodies did not experience a change in concizumab plasma concentrations, an increase in bleeding events or any additional safety concerns; however, there were two cases (one in a clinical trial and one in a compassionate use program) where reduction of effectiveness of Alhemo was reported.

In case of clinical signs of loss of efficacy (e.g. increase in breakthrough bleeding events), prompt evaluation by a physician should be sought to assess the etiology and a possible change in treatment should be considered.

Reproductive Health: Female and Male Potential

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see Non-Clinical Toxicology [16]). No fertility data are available in humans. Thus, the effect of Alhemo on male and female fertility is unknown.

Contraception

Women of childbearing potential receiving Alhemo should use highly effective contraception during treatment with Alhemo and until 7 weeks after end of treatment. The benefits and risks of the type of contraceptives used should be evaluated by the treating health professional.

7.1 Special Populations

7.1.1 Pregnant Women

There are no clinical studies of Alhemo use in pregnant women. Animal reproduction studies have not been conducted with Alhemo as most patients treated with Alhemo are male. It is not known whether Alhemo can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Alhemo should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

7.1.2 Breast-feeding

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

7.1.3 Pediatrics

Forty-two adolescent patients (aged 12 to less than 18 years) were included in the main NN7415-4311 (explorer7) clinical study to evaluate the safety and efficacy of Alhemo in hemophilia patients with inhibitors. There is limited clinical experience with Alhemo in patients who are less than 12 years of age. (see Adverse Reactions, Clinical Trial Adverse Reactions [8.2.1] and Clinical Trials, Study Results [14.2]).

The safety profile was similar between adolescent and adult patients.

7.1.4 Geriatrics

Clinical studies did not include a sufficient number of patients aged 65 years and over to determine the overall benefit-risk profile of Alhemo in these patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Hemophilia Patients with Inhibitors

Treatment-emergent adverse events (TEAEs) are reported from the main NN7415-4311 (explorer7) clinical study. Patients included in the safety and efficacy analyses were randomized 1:2 to Arm 1 (n = 19) and received on-demand therapy with bypassing agents or to Arm 2 (n = 33) and received Alhemo prophylaxis (see efficacy results in Clinical Trials [14]). Additional nonrandomized patients treated with Alhemo in Arms 3 and 4 of the study were included in the overall Alhemo safety population for a total of 114 hemophilia patients with inhibitors (78 adults and 36 adolescents).

The safety analysis includes events reported in patients receiving Alhemo before a clinical trial treatment pause with a 1.0 mg/kg loading dose on Day 1 followed by a daily 0.25 mg/kg daily dose and events reported in patients treated with the recommended Alhemo dosing regimen after the clinical pause (see Dosage and Administration [4]).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Hemophilia Patients with Inhibitors

Fourteen patients treated with Alhemo experienced 18 serious adverse events, including one hypersensitivity reaction (0.9%) and one thromboembolic event (0.9%); both led to permanent discontinuation of Alhemo.

Common TEAEs (≥ 5%) are reported in Table 4.

Table 4 Treatment-Emergent Adverse Events (≥ 5%) in Hemophilia Patients with Inhibitors Treated with Alhemo from Study NN7415-4311 (explorer7)

*Injection site reactions: Include the preferred terms injection site rash, injection site erythema, injection site urticaria, injection site reaction, injection site bruising, injection site hematoma, injection site swelling, injection site pruritus, injection site hemorrhage, injection site hypoesthesia, injection site induration, and injection site pain.

Injection site reactions

Injection site reactions were reported in 26 (22.8%) of the patients. The most frequently reported symptoms were injection site erythema (7.9%) and injection site bruising (3.5%). One event of moderate injection site rash led to interruption of Alhemo therapy.

Increased laboratory values of Fibrin D-dimer and prothrombin fragment 1.2

Increased levels of fibrin D-dimer were reported in 6 (5.3%) of patients and increased levels of fragment 1.2 were seen in 7 (6.1%) patients. Concizumab plasma concentration is positively correlated with fibrin D-dimer and prothrombin fragments 1.2 indicating hemostatic effect of concizumab.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Hemophilia Patients with Inhibitors

The safety profile of Alhemo was similar between adolescent and adult patients. There is limited clinical data in children below 12 years of age.

8.3 Less Common Clinical Trial Adverse Reactions

Hemophilia Patients with Inhibitors

The following less common but significant clinical trial adverse reactions have been reported in association with Alhemo.

Vascular disorders: thromboembolic events (0.9%)

Immune System Disorders: hypersensitivity (2.6%)

Skin and subcutaneous tissue disorders: pruritus (0.9%)

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Studies were conducted to determine if additive and synergistic interactions exist between Alhemo and other hemostatic factors, including activated recombinant FVII (rFVIIa).

9.3 Drug-Drug Interactions

Pharmacodynamic interaction studies in vitro and ex vivo showed that the effects of concizumab co-administered with rFVIIa, aPCC, rFVIII or rFIX were mainly additive with a synergistic effect accounting for up to 40% of the total observed effect.

Following the treatment pause, new safety measures were introduced recommending the lowest possible effective dose of bypassing agents to treat mild or moderate breakthrough bleeds for patients who are receiving Alhemo to decrease the risk thromboembolic risks. For severe bleeds, this may require the recommended label dose taking into account clinical judgement (see Dosage and Administration [4]).

Hemophilia A patients with FVIII inhibitors were required to discontinue emicizumab for at least 180 days before receiving Alhemo (see Dosage and Administration [4]).

9.4 Drug-Food Interactions

Interactions with food have not been established as Alhemo is administered subcutaneously.

9.5 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.6 Drug-Laboratory Test Interactions

In vitro studies showed no relevant interference of Alhemo on standard prothrombin and activated partial thromboplastin time assays or FVIII or FIX activity measurement using clot and chromogenic assays. Further, no relevant influence on assays for inhibitory antibodies to FVIII or FIX (Bethesda assay) was observed.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Concizumab is an anti-Tissue Factor Pathway Inhibitor (anti-TFPI) antibody that binds to the Kunitz-2 domain of TFPI and prevents TFPI from binding to activated Factor X (FXa). The reduced TFPI activity by concizumab allows FXa, produced by the activated coagulation Factor VII (FVIIa)/tissue factor (TF) complex, to increase thrombin generation and subsequent clot formation, which aids in achieving hemostasis in hemophilia patients.

10.2 Pharmacodynamics

In study NN7415-4311 (explorer7), geometric mean (CV%) of free TFPI (plasma TFPI not bound to concizumab) for patients on concizumab prophylaxis decreased from 88.3 (20%) ng/mL at baseline to 10.7 (105%) ng/mL at week 24 and mean thrombin peak increased to the range of normal plasma.

10.3 Pharmacokinetics

Concizumab exhibited non-linear pharmacokinetics with systemic exposure to concizumab, as measured by AUC and C_max, increasing in greater than a dose-proportional manner. This non-linear pharmacokinetic behaviour is caused by target-mediated drug disposition (TMDD) which occurs when concizumab binds to endothelial cell-anchored TFPI with subsequent elimination of the drug-target complex.

Exposure to concizumab was similar between hemophilia A and B patients.

Steady-state concentration was approximately reached at week 4 following once-daily dosing of 0.20 mg/kg with a loading dose of 1 mg/kg on day 1, as estimated by the pharmacokinetic model.

Geometric mean steady-state concizumab concentrations in adolescent and adult hemophilia patients (≥ 12 years of age) with inhibitors who received the recommended dosing regimen are shown in Table 5.

Table 5 Steady-State concizumab Concentrations During 24-hour Dosing Interval at Week 24 (Study NN7415-4311 [explorer7])

C_max,ss, maximum plasma concentration at steady state; C_trough,ss, trough plasma concentration at steady state.

^aOn Alhemo dosing regimen.

Absorption

Following a single-dose subcutaneous administration of 0.05 – 3 mg/kg concizumab in healthy subjects and hemophilia patients, the time to maximum plasma concentration of concizumab (t_max) was in the range from 8 hours to 99 hours (4.1 days). The bioavailability of concizumab after subcutaneous administration was estimated as 77.7% by population pharmacokinetic modelling.

Distribution

The model-based estimate of the steady-state volume of distribution for a typical subject is 5.92 L.

Metabolism

The metabolism of concizumab has not been studied. IgG antibodies are mainly catabolized by lysosomal proteolysis and then eliminated from or reused by the body.

Elimination

Both linear and non-linear pathways contribute to the elimination of concizumab. Due to the non-linear elimination, the half-life is dependent on the concizumab concentration. A terminal half-life in healthy subjects and hemophilia patients who received a single subcutaneous dose of 0.25 – 3 mg/kg was measured in the range from 39 hours (1.6 days) to 195 hours (8.1 days). Following multiple subcutaneous injections and based on a population PK analysis, the linear clearance was approximately 0.192 L/day (0.008 L/h), and the estimated half-life at steady-state C_trough (665 ng/mL) was approximately 38 hours.

Special Populations and Conditions

• Pediatrics: The mean concizumab exposure was slightly lower in adolescents (≥ 12 years) compared to adults.
• Geriatrics: Clinical studies of concizumab did not include sufficient numbers of patients aged 65 and over to determine whether there are differences in exposure compared with younger patients.
• Hepatic Insufficiency: Dedicated trials have not been conducted on the effect of hepatic impairment on the pharmacokinetics of concizumab. Of the 112 patients treated with concizumab in explorer7, 4 patients had elevated liver enzymes (ALT or AST ≥ 1.5 x ULN). No impact on exposure of concizumab was observed.

• Renal Insufficiency: Dedicated trials have not been conducted on the effect of renal

  • impairment on the pharmacokinetics of concizumab. Of the 112 patients treated with the concizumab dosing regimen in explorer7, 5 patients had eGRF <90 mL/min/1.73m² at the time when the loading dose was administered. No impact on exposure of concizumab was observed.
• Body Weight: Based on the population pharmacokinetic analysis, the steady-state concizumab exposure increases with increasing body weight.

11 STORAGE, STABILITY AND DISPOSAL

Before use: Store in a refrigerator at 2°C to 8°C.

After first use: Store for up to 28 days in a refrigerator at 2˚C to 8˚C or at room temperature below 30˚C. Write the date of first use in the space provided on the carton.

Store unused Alhemo with the cap on and in the original carton to protect from light. Alhemo should not be stored in direct sunlight, and the Alhemo pen should be kept away from direct heat. Do not freeze or store it close to a cooling element in a refrigerator. Do not use Alhemo if it has been frozen or stored at temperatures above 30˚C.

Always remove and safely discard the needle after each injection and store the Alhemo prefilled pen without an injection needle attached. Always use a new needle for each injection to prevent contamination.

12 SPECIAL HANDLING INSTRUCTIONS

Patients are advised to read the Instructions for Use very carefully before using Alhemo pen. Instructions for Use of Alhemo pen are provided within the carton.

Alhemo should appear clear to slightly opalescent and colourless to slightly yellow. Translucent particles of protein are acceptable. Do not use if the solution is discoloured or contains solid foreign particles.

The flow of the Alhemo pen should be checked before each injection.

Store the pen without a needle attached. This ensures accurate dosing, and prevents contamination, infection, and leakage.

The Alhemo pen must not be refilled.

The Alhemo pen is for use by one person only.

Patients are advised to discard injection needles after each injection.

Any waste material should be disposed of in accordance with local requirements.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Alhemo

Chemical name: concizumab

Molecular formula and molecular mass: C₆₄₆₂H₁₀₀₀₄N₁₇₁₂O₂₀₄₆S₄₆ and 149 kDA

Product Characteristics:

Concizumab is a humanised IgG4 monoclonal antibody produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. To retain the high affinity for the Kunitz 2 (K2) domain in tissue factor pathway inhibitor (TFPI), 7 back mutations were included. Finally, in order to prevent formation of half-antibodies, the serine at position 241 (Kabat annotation) in the heavy chain was replaced with a proline (Ser241Pro).

No raw materials of animal or human origin are used in the concizumab manufacturing process.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Hemophilia Patients with Inhibitors

Trial Design and Study Demographics

Table 6 Summary of patient demographics for clinical trials in patients with hemophilia A with inhibitors and hemophilia B with inhibitors

Study NN7415-4311 (explorer7), was a multi-national, multi-centre, open-label, phase 3 trial that investigated the safety and efficacy of Alhemo (concizumab injection) for routine prophylaxis in hemophilia A patients with inhibitors (HAwI) and hemophilia B patients with inhibitors (HBwI) who were 12 years of age and older and weighed at least 25 kg. Patients were randomized 1:2 to receive either on-demand treatment with bypassing agents (Arm 1, n = 19) or daily prophylactic treatment with Alhemo (Arm 2, n =33). Two additional arms (arms 3 and 4) enrolled non-randomized patients treated with Alhemo who contributed to the overall safety assessment of this anti-TFPI monoclonal antibody (see Adverse Reactions [8]).

Patients were excluded from the study if they had platelets ≤ 100 x 10⁹/L, fibrinogen below lower normal laboratory value, hepatic impairment (AST and/or ALT > 3X the upper limit of normal [ULN] combined with total bilirubin > 1.5X the ULN), renal impairment (estimated serum creatinine clearance rate ≤ 30 ml/min/1.73 m²), history or high risk of thromboembolic disease, and any systemic inflammatory condition requiring systemic treatment or treatment with emicizumab within 180 days before screening.

The majority of hemophilia patients randomized to arms 1 and 2 had one documented inhibitor of > 0.6 Bethesda units (BU)/mL reported prior to study entry or at screening. Two patients randomized to the control arm did not have documented inhibitors recorded. Patients were stratified by prior 24-week bleeding rate (< 9 or ≥ 9 total bleeds) according to medical records and according to hemophilia type (HAwI, HBwI). The exact number of baseline bleeds per patient in the prior 24 weeks were not known. While the study was open to hemophilia patients of any severity, the vast majority of patients had either severe or moderately severe disease (≤ 2% FVIII or FIX activity). Demographics and baseline disease characteristics were generally balanced between the two arms (Table 7).

Table 7 Key Demographic and Baseline Characteristic Comparisons for Arms 1 and 2

Patients randomized to the Alhemo arm were initially enrolled and treated with 1 mg/kg on the Day 1 and a once-daily dose of 0.25 mg/kg starting on Day 2. However, the study was paused in March 2020 due to thromboembolic events associated with Alhemo. The study resumed in August 2020 with 29 of the 33 patients randomized to Alhemo arm continuing in the study. Following the study pause, patients were treated with the same 1 mg/kg loading dose on Day 1 but now with a lower 0.2 mg/kg daily maintenance dose of Alhemo starting day 2. At or around week 4, patients were required to give blood for determination of their plasma concizumab concentration by a validated ELISA. Patients who had a concizumab concentration between 200 – 4000 ng/mL remained on the 0.20 mg/kg daily dose. For the other patients, the dose was individualized to 0.25 mg/kg or 0.15 mg/kg if concizumab plasma concentration measured after 4 weeks of treatment was <200 ng/mL or >4000 ng/mL, respectively. The efficacy results reported for Alhemo treated patients were based on data obtained after the study pause.

Study Results

Efficacy was evaluated in hemophilia A and B patients with inhibitors when all patients in the on-demand and Alhemo prophylaxis arms had completed at least 24 or at least 32 weeks, respectively, by comparing the number of treated spontaneous and traumatic bleeding episodes between the treatment arms. The primary outcome was annualized bleeding rate (ABR) comparisons between the treatment arms. The findings are shown in Table .

Table 8 Mean Annualized Bleeding Rate with Alhemo Prophylaxis versus On-demand Treatment in Patients with Hemophilia A with Inhibitors and Hemophilia B with Inhibitors ≥12 Years of Age

During the treatment pause, twenty-four patients randomized to Alhemo were followed while receiving on-demand treatment (median exposure of 42.5 weeks). These 24 patients had a mean ABR of 14.7. After the pause, these 24 patients were on Alhemo prophylaxis (median exposure of 44.1 weeks) with an observed mean ABR of 2.3.

14.3 Immunogenicity

In clinical studies, 47 out of 185 treated patients (25%) who were tested developed anti-concizumab antibodies. For 12 out of the 185 patients (6.5%), neutralizing antibodies against concizumab were identified. In one patient who permanently discontinued therapy, free TFPI levels were restored to baseline identifying that the effectiveness concizumab was likely affected by the neutralizing antibodies in this patient.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: The cynomolgus monkey was selected for the nonclinical safety assessment based on cross-reactivity of concizumab to monkey TFPI. Concizumab has been administered to male and female cynomolgus monkeys by weekly intravenous injections for up to 26 weeks and by daily subcutaneous injections for up to 52 weeks. Safety pharmacology endpoints (CNS, cardiovascular, respiratory system), fertility endpoints (testicular size, sperm functionality or menstrual cycle duration) and cytokine release evaluations were included in the general toxicology studies.

Across the toxicology studies, pharmacology mediated formation of thrombi was observed in lung, heart and other organs in the animals at higher doses (≥1 mg/kg/day), consistent with the risk of thromboembolic events reported in patients treated with Alhemo. In the 52-week toxicology study with subcutaneous administration of 0.5, 1 and 9 mg/kg/day (corresponding to 85, 310 and 4400-fold the human exposure based on AUC_0-24h), the NOAEL was observed at 0.5 mg/kg/day.

A number of observed findings were consistent with the expected pharmacology of concizumab (i.e. activation of the coagulation system). These included increases in coagulation markers (i.e. D-dimers and thrombin-anti thrombin) occurring 24 h after the first dose and decreases in fibrinogen starting after repeat dosing. At subcutaneous doses ≥ 3 mg/kg/day (resulting in exposures ≥ 630-fold the human AUC_0-24h) there were slight and occasional prolongations in clotting time parameters (i.e. activated partial thromboplastin time and prothrombin time), and/or a decrease in platelet counts.

Carcinogenicity: Long-term studies in animals to evaluate the carcinogenic potential of concizumab have not been performed.

Genotoxicity: No studies have been performed to establish the genotoxic potential of concizumab.

Reproductive and Developmental Toxicology: No data are available with respect to potential side effects of concizumab on embryofoetal development.

Fertility: In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC_0-24h), concizumab did not affect fertility (testicular size, sperm functionality or menstrual cycle duration) and did not cause any toxicological changes in the male or female reproductive organs.