Emgality Product Monograph

RECENT MAJOR LABEL CHANGES

Indications (1) 09/2020 Dosage and Administration, Dosing Considerations (3.1) 09/2020 Dosage and Administration, Recommended Dose and Dosage Adjustment (3.2) 09/2020 Dosage and Administration, Administration (3.3) 09/2020 Dosage and Administration, Missed Dose (3.4) 09/2020 Warnings and Precautions (7) 09/2020 Warnings and Precautions, Pregnant Women (7.1.1) 09/2020

TABLE OF CONTENTS

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

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

1.1 Pediatrics ..................................................................................................... 4 1.2 Geriatrics ..................................................................................................... 4

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

3 DOSAGE AND ADMINISTRATION ..................................................................... 4

3.1 Dosing Considerations................................................................................. 4 3.2 Recommended Dose and Dosage Adjustment ............................................ 4 3.3 Administration .............................................................................................. 5 3.4 Missed Dose ................................................................................................ 6

4 OVERDOSAGE .................................................................................................... 6

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

6 DESCRIPTION ..................................................................................................... 7

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

7.1 Special Populations ..................................................................................... 7 7.1.1 Pregnant Women ..................................................................................... 7 7.1.2 Breast-feeding .......................................................................................... 8 7.1.3 Pediatrics ................................................................................................. 8 7.1.4 Geriatrics .................................................................................................. 8

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

8.1 Adverse Reaction Overview ........................................................................ 8 8.2 Clinical Trial Adverse Reactions .................................................................. 9 8.3 Less Common Clinical Trial Adverse Reactions ........................................ 14 8.4 Immunogenicity ......................................................................................... 14 8.5 Post-Market Adverse Reactions ................................................................ 15

9 DRUG INTERACTIONS ..................................................................................... 15

9.1 Drug-Drug Interactions .............................................................................. 15 9.2 Drug-Food Interactions .............................................................................. 15 9.3 Drug-Herb Interactions .............................................................................. 15 9.4 Drug-Laboratory Test Interactions ............................................................. 15

10 ACTION AND CLINICAL PHARMACOLOGY ................................................... 16

10.1 Mechanism of Action .............................................................................. 16 10.2 Pharmacodynamics ................................................................................ 16 10.3 Pharmacokinetics ................................................................................... 16

11 STORAGE, STABILITY AND DISPOSAL ......................................................... 17

PART II: SCIENTIFIC INFORMATION ......................................................................... 18

12 PHARMACEUTICAL INFORMATION ............................................................... 18

13 CLINICAL TRIALS ............................................................................................. 18

13.1 Migraine Trial Design and Study Demographics .................................... 18 13.2 Migraine Study Results .......................................................................... 19 13.3 Episodic Cluster Headache Trial Design and Study Demographics ....... 22 13.4 Episodic Cluster Headache Study Results ............................................. 24

14 NON-CLINICAL TOXICOLOGY ......................................................................... 24

PATIENT MEDICATION INFORMATION ..................................................................... 27

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

EMGALITY^® (galcanezumab) is indicated for:

• the prevention of migraine in adults who have at least 4 migraine days per month.
• the reduction in the frequency of attacks throughout a cluster period in adults with episodic cluster headache with prior cluster headache periods lasting at least 6 weeks and who have had an inadequate response to, or tolerated poorly, or had contraindications to conventional preventive therapies established by Canadian practice guidelines.

For patients with episodic cluster headache, the treatment benefit should be assessed within 3 weeks after initiation of the treatment. In patients with no improvement within this time period, continuation of the treatment should be carefully considered based on individual patient basis and clinical judgement (see PART I: DOSAGE AND ADMINISTRATION and PART II: CLINICAL TRIALS).

EMGALITY should be initiated by physicians experienced in the diagnosis and treatment of migraine or episodic cluster headache.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): The safety and efficacy of EMGALITY has not been studied in patients aged 65 or older.

2 CONTRAINDICATIONS

EMGALITY is contraindicated in patients with known serious hypersensitivity to galcanezumab 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.

3 DOSAGE AND ADMINISTRATION

3.1 Dosing Considerations

EMGALITY is administered subcutaneously through a single-use prefilled syringe or prefilled pen. EMGALITY is intended for patient self-administration. Administration should be performed by an individual who has been trained to administer the product (see ADMINISTRATION and INSTRUCTIONS FOR USE).

3.2 Recommended Dose and Dosage Adjustment

Migraine

The recommended dose is an initial (loading) dose of 240 mg (administered as two consecutive subcutaneous injections of 120 mg), followed by once monthly doses of 120 mg (one injection).

Episodic Cluster Headache

The recommended dose is 300 mg once a month (administered as three consecutive subcutaneous injections of 100 mg each) at the onset of the cluster period. The dose regimen must be followed as prescribed.

The treatment benefit should be assessed within 3 weeks after initiation of the treatment. In patients with no improvement within this time period, any further decisions for continuation of the treatment during the current cluster period or initiation of the treatment for subsequent cluster periods should be carefully considered based on individual patient basis and clinical judgement (see PART II: CLINICAL TRIALS).

If further dosing is warranted, EMGALITY should not be administered more than once a month during a cluster period.

EMGALITY should not be used after the end of a cluster period and during the remission time.

Health Canada has not authorized an indication for pediatric use (see INDICATIONS).

3.3 Administration

EMGALITY is for subcutaneous use only.

EMGALITY may be administered by healthcare professionals, patients, and/or caregivers. Prior to use, provide proper training to patients and/or caregivers on the preparation and administration of EMGALITY prefilled syringe or prefilled pen, including aseptic technique (see INSTRUCTIONS FOR USE).

• Remove EMGALITY from the refrigerator. Prior to use, allow EMGALITY to sit at room temperature for 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave.
• Follow aseptic injection technique every time EMGALITY is administered.
• Inspect EMGALITY visually for particles or discolouration prior to administration. Do not use if the solution is cloudy, discoloured, or contains particles (see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).
• Do not shake the product.
• Administer EMGALITY by subcutaneous injection into areas of the abdomen, thigh, upper arm, or buttocks that are not tender, bruised, red, or indurated.
• For multiple injections, you may use the same body site, but not the exact location of the previous injection.
• Do not co-administer EMGALITY with other injectable drugs at the same injection site.

Migraine

EMGALITY for migraine is available both as a 120 mg/mL prefilled syringe and 120 mg/mL prefilled pen.

Two prefilled syringes or pens will deliver the initial 240 mg loading dose. One prefilled syringe or pen will deliver the monthly 120 mg dose. Deliver the entire contents of the prefilled syringe or pen.

Episodic Cluster Headache

EMGALITY for episodic cluster headache is only available as a 100 mg/mL prefilled syringe. Patients should be advised that one dose consists of three consecutive injections of 100 mg.

Three prefilled syringes will deliver the 300 mg dose. Deliver the entire contents of each prefilled syringe.

3.4 Missed Dose

Migraine

Instruct patients to inject a missed dose as soon as possible. Thereafter, resume monthly dosing.

Episodic Cluster Headache

The treatment benefit should be assessed within 3 weeks after initiation of the treatment. In patients with no improvement within this time period, any further decisions for continuation of the treatment during the current cluster period or initiation of the treatment for subsequent cluster periods should be carefully considered based on individual patient basis and clinical judgement (see PART II: CLINICAL TRIALS).

If patients administer a partial dose (inject only 1 or 2 of the three syringes), they should be instructed to inject the missed injection(s) as soon as possible.

If further dosing is warranted and required, inject the next complete dose one month from the date of administering the missed injection(s).

4 OVERDOSAGE

Doses up to 600 mg subcutaneously have been administered to healthy subjects (N = 7) in clinical trials with no evidence of dose limiting toxicity. In case of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

For management of a suspected drug overdose, contact your regional poison control centre.

5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

EMGALITY is a sterile, preservative-free, clear and colourless to slightly yellow solution.

For migraine, each single-use prefilled syringe or pen contains 120 mg EMGALITY in 1 mL (120 mg/mL) (see 3.2 RECOMMENDED DOSE and DOSAGE ADJUSTMENT).

For episodic cluster headache, each single-use prefilled syringe contains 100 mg EMGALITY in 1 mL (100 mg/mL) (see 3.2 RECOMMENDED DOSE and DOSAGE ADJUSTMENT).

6 DESCRIPTION

EMGALITY (galcanezumab) is a humanized IgG4 monoclonal antibody that binds calcitonin gene-related peptide (CGRP).

7 WARNINGS AND PRECAUTIONS

Sensitivity

Serious Hypersensitivity

Serious hypersensitivity reactions, including cases of anaphylaxis, angioedema and urticaria, have been reported with CGRP-class products, including EMGALITY, in clinical trials and in post-market experience.

These reactions may occur within minutes, although some may occur up to one month after administration.

If a serious hypersensitivity reaction occurs, administration of EMGALITY should be discontinued immediately and appropriate therapy initiated.

Patients with Cardiovascular Diseases

No safety data are available in these populations. In the migraine and episodic cluster headache studies, patients who had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, certain ECG abnormalities or deep vein thrombosis/pulmonary embolism within 6 months of screening, or had planned cardiovascular surgery or percutaneous coronary angioplasty were excluded (see PART II: CLINICAL TRIALS).

Vascular Disorders

No safety data are available in these populations. In the episodic cluster headache study only, patients who had uncontrolled high blood pressure, characterized by systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg, and evidence of peripheral vascular disease or a diagnosis of Raynaud’s phenomenon were excluded (see PART II: CLINICAL TRIALS).

7.1 Special Populations

7.1.1 Pregnant Women

There are very limited human data to establish the safety of EMGALITY during pregnancy. Human IgG is known to cross the placental barrier; therefore, EMGALITY may be transmitted from the mother to the developing fetus.

EMGALITY has a half-life of approximately 27 days (see CLINICAL PHARMACOLOGY). This should be taken into consideration for women who are pregnant or plan to become pregnant while using EMGALITY (see NON-CLINICAL TOXICOLOGY).

EMGALITY should not be used by pregnant women unless the expected benefit to the mother justifies the potential risk to the fetus.

7.1.2 Breast-feeding

There are no data on the presence of EMGALITY in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EMGALITY and any potential effects on the breastfed infant. Human IgG is known to be excreted in breast milk; therefore, EMGALITY may be transmitted from the mother to the breastfed infant. Precaution should be exercised.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): The safety and efficacy of EMGALITY has not been studied in patients aged 65 or older.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

A total of 3459 patients and healthy volunteers were exposed to EMGALITY, representing more than 1807 patient years of exposure. Of these, 2129 patients were exposed to EMGALITY once monthly for at least 6 months and 750 patients were exposed for 12 months.

In the migraine and cluster headache studies, patients who had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, certain ECG abnormalities or deep vein thrombosis/pulmonary embolism within 6 months of screening, or had planned cardiovascular surgery or percutaneous coronary angioplasty, and BMI ≥ 40 kg/mg² were excluded.

In the cluster headache studies only, patients who had uncontrolled high blood pressure, characterized by systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg, and evidence of peripheral vascular disease or a diagnosis of Raynaud’s phenomenon were also excluded.

In three controlled migraine trials, 705 patients received at least one dose of EMGALITY (120 mg) once monthly. Of those patients, 1.8% of patients treated with EMGALITY discontinued double-blind treatment because of adverse events.

In the two controlled cluster headache trials, 166 patients received at least one dose of EMGALITY (300 mg) once monthly. Of those patients, 1.8% treated with EMGALITY discontinued double-blind treatment because of adverse events.

Adverse drug reactions (ADRs) were identified based on findings across Phase 3 efficacy and safety clinical studies in migraine and cluster headache.

The most common adverse reaction reported in ≥ 10% of patients in any study receiving galcanezumab were injection site reactions, and less frequent (≤ 2%) adverse reactions

included constipation, vertigo, pruritus and urticaria. Injection site reactions included multiple preferred terms, such as injection site pain, injection site erythema, injection site pruritus, injection site bruising, injection site swelling, and injection site induration.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials 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 is useful for identifying drug-related adverse events and for approximating rates.

Migraine

The data described below reflect exposure to EMGALITY in 1435 patients. In the pivotal studies, the following adverse events listed in Tables 2 and 3 were observed to occur at or above 1% during the double-blind treatment phase.

Table 2: Incidence of Treatment-emergent Adverse Events in ≥ 1% of Patients with Episodic Migraine in either EMGALITY Group (120 mg or 240 mg) in Studies EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH)

^a Denominator adjusted for female-specific event.

Table 3: Incidence of Treatment-emergent Adverse Events in ≥ 1% of Patients with Chronic Migraine in either EMGALITY Group (120 mg or 240 mg) in Study REGAIN (CGAI)

Injection site reactions

In the 3 integrated pivotal migraine placebo-controlled study periods, injection site pain was the most frequently (≥10%) reported event. In most patients, reported injection site pain occurred

within 1 hour of injection and resolved the same day. The majority of injection site reactions were reported within 1 day and most resolved within a few days. Most events were mild to moderate and did not lead to discontinuation of galcanezumab.

Constipation

In the 3 integrated pivotal migraine placebo-controlled study periods, all constipation events were mild or moderate in severity. There were no serious events.

Vertigo

In the 3 integrated pivotal migraine placebo-controlled study periods, the majority of vertigo events were mild or moderate in severity. There were no serious events.

Pruritus

In the 3 integrated pivotal migraine placebo-controlled study periods, the majority of pruritus events were mild or moderate in severity. There were no serious events.

Urticaria

In the 3 integrated pivotal migraine placebo-controlled study periods, cases of urticaria were uncommon. However, serious cases of urticaria have been reported in galcanezumab clinical studies.

Episodic Cluster Headache

The safety of EMGALITY (300 mg once a month) is based on the assessment of data from 2 placebo-controlled clinical studies: CGAL and CGAM. The efficacy assessment of EMGALITY 300 mg once a month is based on Study CGAL (episodic cluster headache). Study CGAM was performed in patients with chronic cluster headache and used for the safety assessment only.

The data described below reflect exposure to EMGALITY in 166 patients. In the placebo-controlled studies, the following adverse events listed in Table 4 were observed to occur in ≥ 1% of patients during the double-blind treatment phase.

Table 4: Incidence of Treatment-emergent Adverse Events in ≥1% of Patients in the EMGALITY Safety Population Group (300 mg) (Studies CGAL and CGAM)

^a Denominator adjusted for female-specific event.

^b Denominator adjusted for male-specific event.

Injection site reactions

In two integrated cluster headache placebo-controlled study periods, injection site pain was the most frequently reported event (10.2%). The majority of injection site reactions, including pain, were reported within 1 day and most resolved within a few days. Most events were mild to moderate and did not lead to discontinuation of galcanezumab. There were no serious adverse events.

Constipation

In two integrated cluster headache placebo-controlled study periods, three patients reported constipation. None led to discontinuation. One event was reported as serious, which resolved.

Vertigo

In two integrated cluster headache placebo-controlled study periods, two patients reported vertigo both of mild severity, one led to discontinuation. There were no serious adverse events.

Pruritus

In two integrated cluster headache placebo-controlled study periods, three patients reported pruritus of mild to moderate severity and did not lead to discontinuation. There were no serious adverse events.

Urticaria

In two integrated cluster headache placebo-controlled study periods, no patients reported urticaria.

8.3 Less Common Clinical Trial Adverse Reactions

From all clinical trials with EMGALITY in adult patients with episodic and chronic migraine, and episodic and chronic cluster headache, the following less common adverse events of < 1% have been observed. The causality to EMGALITY has not been established.

Cardiac disorders: palpitations, angina pectoris, acute myocardial infarction Eye disorders: amaurosis

Hepatobiliary disorders: cholelithiasis, cholecystitis

Psychiatric disorders: anxiety, confusion state, disorientation

Skin and subcutaneous tissue disorders: swelling face

8.4 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of EMGALITY has been evaluated using an immunoassay for the detection of binding anti-galcanezumab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro ligand-binding immunoassay was performed to detect neutralizing antibodies.

In placebo-controlled clinical studies [EVOLVE -1 (CGAG), EVOLVE-2 (CGAH), and REGAIN (CGAI)] with EMGALITY administration up to 6 months, the incidence of anti-galcanezumab antibody development was 4.8% (33/688) in patients receiving EMGALITY once monthly (32 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, 12.5% (16/128) of EMGALITY-treated patients developed anti-galcanezumab antibodies (all 16 of whom had in vitro neutralizing activity). With up to 3 months of double-blind treatment, up to 0.9% of galcanezumab treated patients with cluster headache developed antidrug antibodies of low titer with neutralizing activity in vitro.

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

In clinical trials, the presence of anti-drug antibodies did not affect the efficacy or safety of EMGALITY.

8.5 Post-Market Adverse Reactions

The following adverse reactions are based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency.

Immune System disorders: Anaphylaxis, Angioedema

Skin and subcutaneous tissue disorders: Rash

9 DRUG INTERACTIONS

9.1 Drug-Drug Interactions

Interactions with other drugs have not been studied.

EMGALITY is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

9.2 Drug-Food Interactions

Interactions with food have not been studied.

9.3 Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.4 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been studied.

10 ACTION AND CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Galcanezumab is a humanized IgG4 monoclonal antibody that binds calcitonin gene-related peptide (CGRP) and prevents its biological activity.

Galcanezumab targets CGRP with high affinity (K_D = 31 pM) and does not bind to the CGRP receptor or related peptides adrenomedullin, amylin, calcitonin and intermedin.

10.2 Pharmacodynamics

There are no relevant data on the pharmacodynamic effects of galcanezumab.

10.3 Pharmacokinetics

Galcanezumab exhibits linear pharmacokinetics (PK) and exposure increases proportionally across the dose range of 5-300 mg.

Steady-state galcanezumab concentrations at 120 mg monthly are achieved with an initial loading dose of 240 mg. Steady-state PK parameters after a 240 mg loading dose followed by 5 consecutive monthly doses of 120 mg are shown in Table 5.

A dose of 300 mg monthly achieves steady-state concentration after the fourth dose administration. Table 5 shows steady-state PK parameters at 300 mg monthly.

Based upon population PK modelling, there were no significant differences in PK parameters between healthy volunteers, patients with episodic or chronic migraine, and patients with episodic cluster headache.

Table 5: Steady-State Pharmacokinetic Parameters of EMGALITY at 120 mg Monthly (Migraine) and 300 mg Monthly (Episodic Cluster Headache)^{a, b}

^a Based on population PK analysis.

^b PK parameters reported as geometric mean (percent coefficient of variation).

Absorption: Following administration of galcanezumab at steady-state, the median time to maximum concentration was 5 days (range: 3 to 14 days).

Injection site location did not significantly influence the absorption of galcanezumab.

Distribution: Based on a population PK analysis, the apparent volume of distribution (V/F) of galcanezumab was estimated to be 7.3 L (34% Inter Individual Variability [IIV]).

Metabolism: As a humanized IgG4 monoclonal antibody, galcanezumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Elimination: Based on a population PK analysis, the apparent clearance (CL/F) of galcanezumab was estimated to be 0.008 L/h and the half-life of galcanezumab was approximately 27 days.

Special Populations and Conditions

Based on a population PK analysis, age (18-65), sex, race, injection site, anti-drug antibodies, or ethnicity had no clinically meaningful effects on the PK of galcanezumab.

Hepatic Insufficiency: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the PK of galcanezumab. Based on a population PK analysis, bilirubin concentration did not significantly influence the CL/F of galcanezumab.

Renal Insufficiency: No clinical studies have been conducted to evaluate the effect of renal impairment on the PK of galcanezumab. Population PK analysis of integrated data from the galcanezumab clinical studies revealed that creatinine clearance did not affect the CL/F of galcanezumab in patients with mild or moderate renal impairment. Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied.

11 STORAGE, STABILITY AND DISPOSAL

The prefilled syringes or pens should be stored under refrigeration at 2°C to 8°C until time of use. Keep the syringe or pen in the carton in order to protect from exposure to light. DO NOT FREEZE OR SHAKE the syringe or pen. The shelf life is 24 months when the syringes or pens are stored at 2°C to 8°C.

The chemical and physical stability for the EMGALITY solution was demonstrated for up 7 days outside of refrigeration when stored at temperatures up to 30°C. If these conditions are exceeded, EMGALITY must be discarded.

Discard the EMGALITY single-use prefilled syringe or pen in a puncture-resistant container.

PART II: SCIENTIFIC INFORMATION

12 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: galcanezumab

Chemical name: Immunoglobulin G4, anti-(human calcitonin gene-related peptide) (human-Mus musculus clone III heavy side chain), disulfide with human-Mus musculus clone III κ-chain, dimer

Molecular mass: The observed molecular weight of the non-glycosylated, disulfide linked form of galcanezumab is 144,084 Da

Structural formula: Galcanezumab is a humanized immunoglobulin G4 (IgG4) isotype monoclonal antibody composed of two identical immunoglobulin light (κ) chains consisting of 214 amino acids each of relative molecular weight 23,330 Da, and two identical immunoglobulin heavy (γ) chains consisting of 445 amino acids each of molecular weight 48,728 Da. The heavy chain subunit contains an N-linked glycosylation, which is modified with oligosaccharides.

Physicochemical properties: Clear to colourless to slightly yellow solution. The solution pH is 5.3 to 6.3. The osmolality is 255 to 345 mOsm/kg.

13 CLINICAL TRIALS

13.1 Migraine Trial Design and Study Demographics

EMGALITY was evaluated as a preventive treatment (a treatment expected to decrease migraine headache frequency) of episodic or chronic migraine in three Phase 3 randomized, multicenter, double-blind, placebo-controlled studies in adult patients. Studies enrolled patients with a history of migraine according to the International Classification of Headache Disorders (ICHD-3). Patients who had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, certain ECG abnormalities or deep vein thrombosis/pulmonary embolism within 6 months of screening, or had planned cardiovascular surgery or percutaneous coronary angioplasty were excluded. Patients with a persistent daily headache, history of headache other than migraine and BMI ≥40 kg/m² were also excluded.

Demographics for these studies are outlined in Table 6.

Table 6: Summary of patient demographics for clinical trials in Migraine

13.2 Migraine Study Results

Episodic Migraine

EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH) were identically designed, randomized, 6-month, double-blind, placebo-controlled studies. In EVOLVE-1 (CGAG), a total of 858 patients with a history of episodic migraine (4 to 14 migraine days per month) were randomized to receive either galcanezumab 120 mg (EMGALITY, N = 213), galcanezumab 240 mg (N = 212), or placebo (N = 433) by subcutaneous injection once monthly (QM). In EVOLVE-2 (CGAH), a total of 915 patients with a history of episodic migraine were randomized to receive either galcanezumab 120 mg (EMGALITY, N = 231), galcanezumab 240 mg (N = 223), or placebo (N = 461) by subcutaneous injection once monthly (QM). All patients in the 120 mg dose group received an initial loading dose of 240 mg.

The primary efficacy endpoint for EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH) was the mean change from baseline in the number of monthly migraine headache days over months 1 to 6. Key secondary endpoints included response rates (the mean percentages of patients with ≥50% reduction) and mean change from baseline in the number of monthly migraine headache days that acute medication was taken over months 1 to 6.

Patients were 18 to 65 years of age (mean age of 40.7 in EVOLVE-1 and 41.9 in EVOLVE-2) with a history of migraine for at least 1 year (mean 20 years in EVOLVE-1 and 2 trials) and migraine onset prior to age 50. The mean number of monthly migraine headache days at baseline was 9.1 in each study. Most patients were female (84% EVOLVE-1, 85% EVOLVE-2), white (80% EVOLVE-1, 70% EVOLVE-2) and had failed one or more migraine preventive therapies in the past. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. Patients were not allowed any treatments for the prevention of migraine. Both studies excluded patients with medication overuse headache. A total of 60% and 65% of patients in EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH), respectively, had taken preventive treatments for migraine prior to baseline. A total of 177 (83%) patients in the EMGALITY 120 mg dose group and 351 (81%) patients on placebo completed the double-blind phase in EVOLVE-1 (CGAG), and a total of 203 (88%) patients in the EMGALITY 120 mg dose arm and 387 (84%) patients on placebo completed the double-blind phase in EVOLVE-2 (CGAH).

The results of the studies are presented in Table 7.

Table 7: Efficacy Results in Studies EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH)

^a LS mean change from baseline, difference from placebo, and p-value are based on a mixed effects repeated measures model including treatment group, region or country (North America, Europe, or Other), month, interaction of treatment and month, baseline value, and interaction of baseline value and month. For the key secondary endpoints, the model also includes mean reduction in baseline migraine headache day category (<8 vs. ≥8).

^b A superchain procedure adjusting for multiple testing was used to maintain the 2-sided type I error at 0.05 for the primary and key secondary endpoints.

^c Monthly migraine headache days that acute medication was taken was calculated as the number of calendar days in a 30-day period on which migraine or probable migraine occurred and acute medication was used

A treatment effect was observed in a prespecified monthly analysis as early as month one.

Data from EVOLVE-1 (CGAG) and EVOLVE-2 (CGAH) studies were pooled and in 453 (26%) patients who failed one or more preventive treatments for efficacy reasons, the difference in the reduction of mean monthly migraine headache days observed between EMGALITY and placebo was -2.7 days. In 173 (10%) patients who failed two or more preventive treatments for efficacy reasons, the difference in the reduction of mean monthly migraine headache days observed between EMGALITY and placebo was -2.6 days.

Chronic Migraine

REGAIN (CGAI) was a randomized, 3-month, double-blind, placebo-controlled study. A total of 1113 patients with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month) were randomized to receive either galcanezumab 120 mg (EMGALITY, N = 278), galcanezumab 240 mg (N = 277), or placebo (N = 558) by subcutaneous injection once monthly (QM). All patients in the 120 mg dose group received an initial loading dose of 240 mg.

The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over months 1 to 3. Key secondary endpoints included response rates (the mean percentages of patients with ≥50% reduction) and mean change from baseline in the number of monthly migraine headache days that acute medication was taken over months 1 to 3.

Patients were 18 to 65 years of age (mean age of 41.0 in REGAIN) with a history of migraine for at least 1 year (mean duration 21.1 years). The mean number of monthly migraine headache days at baseline was 19.4.Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. A total of 78% of patients had taken preventive treatments for migraine prior to baseline, 15% of patients were taking concomitant stable doses of topiramate or propranolol for prevention of migraine. Patients with medication overuse headache were not excluded.

A total of 263 (95%) patients in the EMGALITY 120 mg dose group and 508 (91%) patients on placebo completed the double-blind phase in REGAIN (CGAI).

The results of this study are shown in Table 8.

Table 8: Efficacy Results in REGAIN (CGAI)

^a LS mean change from baseline, difference from placebo, and p-value are based on a mixed effects repeated measures model including treatment group, baseline medication overuse [yes vs. no], use of concurrent migraine prophylaxis [yes vs. no], and country, month, interaction of treatment and month, baseline value, and interaction of baseline value and month.

^b A superchain procedure adjusting for multiple testing was used to maintain the 2-sided type I error at 0.05 for the primary and key secondary endpoints.

^c Monthly migraine headache days that acute medication was taken was calculated as the number of calendar days in a 30-day period on which migraine or probable migraine occurred and acute medication was used. ^d Not statistically significant versus placebo after multiplicity adjustment.

A treatment effect was observed in a prespecified monthly analysis as early as month one.

In the 355 (64%) patients from the REGAIN (CGAI) Study who had acute headache medication overuse at baseline, the difference in the reduction of mean monthly migraine headache days observed between EMGALITY and placebo was -2.53 days.

In the 549 (49%) patients from the REGAIN (CGAI) Study who failed one or more preventive treatment for efficacy reasons, the difference in the reduction of mean monthly migraine headache days observed between EMGALITY and placebo was -3.5. In 328 (30%) patients who failed two or more preventive treatments, the difference in the reduction of mean monthly migraine headache days observed between EMGALITY and placebo was -4.5 days.

13.3 Episodic Cluster Headache Trial Design and Study Demographics

The safety of EMGALITY (300 mg once a month) is based on the assessment of data from 2 placebo-controlled clinical studies: CGAL and CGAM.

Study CGAM was conducted in patients with chronic cluster headache and used for the safety assessment only.

The efficacy assessment of EMGALITY 300 mg once a month is based on Study CGAL (episodic cluster headache).

EMGALITY was evaluated as a preventive treatment (a treatment expected to decrease the frequency of cluster headache attacks throughout a cluster period) in adult patients with episodic cluster headache. Study CGAL included adults who met the International Classification of Headache Disorders 3rd edition (ICHD-3-beta version) diagnostic criteria for episodic cluster headache and had a prior history of a cluster period lasting 6 weeks or longer.

Study CGAL excluded patients on other preventive treatments; patients with medication overuse headache; patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, certain ECG abnormalities or deep vein thrombosis/pulmonary embolism within 6 months of screening; and patients who had planned cardiovascular surgery or percutaneous coronary angioplasty. Patients with any history of stroke, intracranial or carotid aneurysm, intracranial hemorrhage, or vasospastic angina; clinical evidence of peripheral vascular disease; diagnosis of Raynaud’s disease or BMI ≥ 40 kg/m² were also excluded.

Table 9: Summary of patient demographics for clinical trials in Episodic Cluster Headache (CGAL)

The study was composed of: I) screening/washout phase; II) a prospective baseline phase; III) 8-week double-blind treatment phase; IV) post-treatment follow up. Patients who entered phase I in an active cluster period and did not need to wash out any excluded medications moved directly to phase II. Patients could enter screening in an active cluster period, or in remission, but were required to be an active cluster period to enter the prospective baseline phase which was used to establish baseline attack frequency. During the prospective 7-day baseline assessment, patients were required to have a maximum of 8 attacks per day, a minimum of one attack every other day, and at least 4 attacks.

All patients were randomized at the initiation of phase III (1:1) to receive subcutaneous injections of either EMGALITY 300 mg once a month or placebo once a month, over an 8-week treatment period. Patients were allowed to use pre-specified acute/abortive cluster headache treatments, including triptans, oxygen, acetaminophen, and NSAIDs during the study.

No preventive medications were allowed during the double-blind 8-week treatment period.

Randomization was stratified based on sex, average daily attack frequency (≤ 4 attacks per day, > 4 attacks per day), and investigative site.

Headache information was captured daily using the electronic patient-reported outcome (ePRO) diary device during study phases II and III.

A total of 106 (18 females, 88 males), ranging age 19 to 65 years of age (mean age of 46) patients were randomized and treated with either EMGALITY (galcanezumab) 300 mg (N = 49)

or placebo (N = 57) by subcutaneous injection once a month (QM). In the prospective baseline phase, a majority of patients had ≤ 4 cluster headache attacks per day at baseline (85.9%) and the mean number of weekly cluster headache attacks was 17.3 for placebo group and 17.8 for galcanezumab group, with an average severity of pain of moderate to severe. A total of 90 (84.9%) patients completed the 8-week double-blind treatment phase.

The primary efficacy endpoint was the mean change from baseline (defined as 7 consecutive days from the daily ePRO diary during the prospective baseline assessment) in weekly cluster headache attack frequency across Weeks 1 to 3. The key secondary endpoint was the proportion of patients achieving response (defined as a reduction from baseline of 50% or greater in the weekly cluster headache attack frequency) at Week 3. The primary endpoint (Weeks 1-3) and gated secondary endpoint (at Week 3) of Study CGAL measured the effect of only one dose of galcanezumab. Results are summarized in Table 10.

13.4 Episodic Cluster Headache Study Results

Table 10: Efficacy Results in Episodic Cluster Headache Study CGAL

^a LS mean change from baseline, difference from placebo, and p-value are based on a mixed effects repeated measures model including treatment group, sex, pooled investigative site, week, interaction of treatment and week, and baseline value. The key secondary analysis is based on an ANCOVA model including treatment group, sex, baseline value, and stratified by pooled investigative site.

^b A sequential testing procedure adjusting for multiple testing was used to maintain the 2-sided type I error at 0.05 for the primary and key secondary endpoints.

Important baseline characteristics such as time from cluster onset before randomization, the historical length of cluster periods, and historical number of cluster headache attacks per day were not collected in pivotal Study CGAL. More patients in the EMGALITY treatment group had attacks in last 7 days prior to screening (visit 1) than in the placebo treatment group. No differences between the treatment groups have been observed in pain severity, attack duration, use of acute medication through week 1 to 8. The statistical significance for the primary and gated secondary endpoints was observed only up to week 3.

When interpreting the efficacy results of the trial, these observations should be taken into consideration.

14 NON-CLINICAL TOXICOLOGY

General Toxicology

Galcanezumab was well tolerated in cynomolgus monkeys and Sprague Dawley rats at weekly subcutaneous doses of up to 100 mg/kg and 20 mg/kg (72 and 3.7 times greater than the human exposure at the 300 mg once monthly dose based on AUC), respectively, for up to 6 months. There was no evidence of galcanezumab-related systemic toxicity in cynomolgus monkeys; however, in rats, two male deaths were observed at a dose of 250 mg/kg (8.7 times greater than the human exposure at 300 mg once monthly dose based on AUC) for which a drug-related effect could not be ruled out. In both rats and monkeys, galcanezumab-related non-adverse macroscopic and microscopic changes were limited to the injection sites and were consistent with inflammation. There were no galcanezumab-related effects on cardiovascular, respiratory, or central nervous systems as assessed in cynomolgus monkeys.

Carcinogenesis

Non-clinical studies have not been conducted to evaluate the carcinogenic potential of galcanezumab.

Genotoxicity

Non-clinical studies have not been conducted to evaluate the genotoxic potential of galcanezumab.

Reproductive and Developmental Toxicity

Male fertility and female fertility were assessed in separate studies in Sprague Dawley rats. In the male fertility study, males were administered subcutaneous doses up to 250 mg/kg once weekly prior to and during mating. In combined female fertility and embryo-fetal development studies, females were administered subcutaneous doses up to 250 mg/kg once every three days prior to and during mating and continuing throughout organogenesis. No galcanezumab-related adverse effects on male or female fertility parameters, including adverse effects on reproductive organs, estrous cycle, sperm motility and concentration, and mating and fertility indices, were observed at a dose of 250 mg/kg (3.6 and 18 times greater than the human exposure at the 300 mg once monthly dose based on AUC in males and females, respectively).

No galcanezumab-related malformations or embryo-fetal toxicity were observed in the combined female fertility and embryo-fetal development studies conducted in Sprague Dawley rats at maternal doses up to 250 mg/kg or in an embryo-fetal development study conducted in New Zealand White Rabbits at maternal doses up to 100 mg/kg administered on gestation day 7, 12, 16, and 20. Exposures (AUC) were 18 and 29 times higher than the human exposure at the 300 mg once monthly dose in rats and rabbits, respectively. While galcanezumab-related increases in the number of fetuses and litters with skeletal variations, consisting of short ribs and a decrease in the mean number of ossified caudal vertebrae, occurred at 250 mg/kg in the rat embryo-fetal development study, these deviations were considered non-adverse.

In a pre- and post-natal development study conducted in Sprague Dawley rats, there were no effects on survival, growth, sexual maturation, behaviour or reproduction in offspring exposed to galcanezumab in utero and through lactation at maternal doses up to 250 mg/kg administered once every three days (16 times greater than the human exposure at the 300 mg once monthly dose based on AUC).

Juvenile Toxicity

In a juvenile toxicology study, Sprague Dawley rats were administered galcanezumab at doses of 30 and 250 mg/kg twice weekly from Postnatal Day 21 through 90. There were no galcanezumab-related adverse effects on survival, clinical observations, body weight, food consumption, sexual maturation, behavioral assessments, reproduction, bone length, clinical pathology and histopathology. Decreases in metaphysis total bone mineral content associated with decreases in trabecular bone mineral content and bone mineral density occurred at 250 mg/kg. In males only, decreases in metaphysis and diaphysis total surface area and diaphysis periosteal circumference were also observed at 250 mg/kg. No galcanezumab-related findings were observed upon histopathological examination of bone.

Galcanezumab-related microscopic changes were limited to the injection sites and consisted of an increased incidence and severity of mononuclear inflammatory cell infiltrates in the subcutaneous tissue at the administration site in males and females given 30 and 250 mg/kg. Minimal to mild increases in fibrinogen and minimal increases in globulins occurred in males at 250 mg/kg and in females at 30 and 250 mg/kg. These changes were supportive of a minimal to mild inflammatory process and correlated with the injection site histopathology findings. At the end of the recovery period, the incidence of the injection site histopathology findings as well as the correlating clinical pathology changes were decreased, suggesting partial recovery.