Glassia Product Monograph

Recent Major Label Changes

None at time of the most recent authorization.

Table of Contents

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

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

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

Part 1: Health Professional Information ................................................................................... 4

1. 1.

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

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

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

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

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

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

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

   4.4. Administration ........................................................................................................... 5

   4.5. Missed Dose .............................................................................................................. 6

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

   Warnings and Precautions ................................................................................................ 6

   General .................................................................................................................................. 6

   Immune ................................................................................................................................. 7

   7.1. Special Populations ................................................................................................... 7

   7.1.1 Pregnancy ................................................................................................................. 7

   7.1.2 Breastfeeding ........................................................................................................... 7

   7.1.3 Pediatrics .................................................................................................................. 7

   7.1.4 Geriatrics .................................................................................................................. 7

7. 8.

   Adverse Reactions ............................................................................................................ 8

   8.1. Adverse Reaction Overview ....................................................................................... 8

   8.2. Clinical Trial Adverse Reactions ................................................................................. 8

   8.3. Less Common Clinical Trial Adverse Reactions .......................................................... 9

   8.5. Post-Market Adverse Reactions .............................................................................. 10

8. 9.

   Drug Interactions ............................................................................................................ 10

   9.4. Drug-Drug Interactions ............................................................................................ 10

9. 10.

   Clinical Pharmacology .................................................................................................... 10

   10.1. Mechanism of Action ............................................................................................... 10

   10.2. Pharmacodynamics ................................................................................................. 11

   10.3. Pharmacokinetics .................................................................................................... 11

   10.4. Immunogenicity ....................................................................................................... 11

10. 11. Storage, Stability and Disposal........................................................................................ 12

Part 2: Scientific Information ................................................................................................. 13

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

   Clinical Trials ................................................................................................................... 15

   14.1. Clinical Trials by Indication ...................................................................................... 15

   Emphysema Due To Alpha1-Antitrypsin Deficiency ........................................................ 15

3. 15. Microbiology .................................................................................................................. 17
4. 16. Non-Clinical Toxicology ................................................................................................... 17

Patient Medication Information ............................................................................................ 18

Part 1: Health Professional Information

1. Indications

GLASSIA (alpha-1 proteinase inhibitor [human] injection) is indicated for chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe hereditary deficiency of alpha1-PI, also known as alpha1-antitrypsin deficiency (AATD). GLASSIA increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels.

Limitations of Use:

• The effect of augmentation therapy with GLASSIA on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been demonstrated in randomized, controlled clinical trials.
• Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with GLASSIA are not available.
• GLASSIA is not indicated as therapy for lung disease in patients in whom severe alpha1-PI deficiency has not been established.

1.1. Pediatrics

Pediatrics (<18 years): No pediatric studies have been performed to assess efficacy and safety of GLASSIA; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥ 65 years of age): In clinical trials, 11 subjects of 65 years of age or older received GLASSIA. This number of subjects was not sufficient to determine whether they respond differently from younger subjects.

2. Contraindications

GLASSIA is contraindicated in:

• immunoglobulin A (IgA) deficient patients with antibodies against IgA.
• individuals with a history of anaphylaxis or other severe systemic reaction to alpha1-PI products.
• 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 6 Dosage Forms, Strengths, Composition and Packaging.

4. Dosage and Administration

4.1. Dosing Considerations

The recommended dose of GLASSIA is 60 mg/kg body weight of GLASSIA once weekly by intravenous infusion. Dose ranging studies using efficacy endpoints have not been performed.

GLASSIA may be given at a rate not to exceed 0.2 mL/kg/min and is determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg at a rate of 0.2 mL/kg/min will take approximately 15 minutes to infuse.

4.2. Recommended Dose and Dosage Adjustment

The recommended dose of GLASSIA is 60 mg/kg body weight of GLASSIA once weekly by intravenous infusion.

The carton and label on each vial of GLASSIA show the actual amount of functionally active alpha1-PI in milligrams.

4.4. Administration

For intravenous infusion only.

GLASSIA should be administered by a healthcare professional or self-administered by the patient/caregiver after appropriate training.

First infusions should be administered under the supervision of a healthcare professional experienced in the use of alpha1-proteinase (human)inhibitor or in the treatment of alpha1-proteinase inhibitor deficiency. Subsequent infusions can be administered by a caregiver or by the patient if appropriate training is provided and the use is reviewed at regular intervals. The decision of whether a patient is suitable for home-treatment/self-administration is made by the treating doctor. There are limited data regarding the use of this medicinal product in home-treatment/self-administration. Potential risks associated with home-treatment/self-administration are related to the administration itself as well as to the handling of adverse drug reactions, particularly hypersensitivity.

1. 1. Always use aseptic technique.
2. 2. Inspect the vial of GLASSIA for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to yellow-green.
3. 3. Administer GLASSIA alone. Do not mix with other agents or diluting solutions except when using the intravenous pooling infusion bag.
4. 4. When infusing directly from the vials, use a vented spike (not supplied). Peel clear plastic hanger from vial label. Hang on IV pole and administer product. If the contents of vials have been pooled to a sterile intravenous container, use an appropriate intravenous administration set.
5. 5. Always use a 5 micron in-line filter (not supplied) during infusion.
6. 6. Administer GLASSIA within 3 hours of entering the vials to avoid the potential ill effect of any inadvertent microbial contamination.
7. 7. Administer GLASSIA at room temperature through an appropriate intravenous administration set at a rate not to exceed 0.2 mL/kg body weight per minute, and as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg at a rate of 0.2 mL/kg/min will take approximately 15 minutes to infuse.
8. 8. Monitor the infusion rate closely during administration and observe the patient for signs of infusion related reactions. If infusion related adverse reactions occur, reduce the rate or interrupt the infusion as appropriate until the symptoms subside. Resume the infusion at a rate tolerated by the patient, except in the case of severe reaction [see 7 Warnings and Precautions].
9. 9. Record patient and product batch number information (see 6 Dosage Forms, Strengths, Composition and Packaging ).
10. 10. Following administration, discard all open vials, unused solution, vented spike and administration equipment in an appropriate manner, as per local requirements.

4.5. Missed Dose

Patients can proceed with their next scheduled dose immediately and continue at regular intervals, unless otherwise advised by their doctor or healthcare professionals.

5. Overdose

To date, there have been no reported cases of suspected overdose for GLASSIA. No data are available in regard to overdosage in humans.

6. Dosage Forms, Strengths, Composition and Packaging

It is strongly recommended that every time GLASSIA is administered, the patient name and batch number of the product are recorded to maintain a link between the patient and batch of the product.

Table 1: Dosage Forms, Strengths and Composition

Description

The drug product is a ready-to-use sterile solution for intravenous infusion. The solution is clear, ranging from colourless to yellow-green and may contain a few protein particles.

GLASSIA is available as a single-dose vial containing approximately 1 gram, 4 gram, and 5 gram of functional alpha1-PI in 50 mL, 200 mL and 250 mL respectively, of ready to use solution.

Packaging: The drug product s contained in a glass vial, which consists of clear, colorless, Type I borosilicate glass and is sealed with bromobutyl rubber stopper and a flip aluminium cap.

7. Warnings and Precautions

This product is prepared from large pools of human plasma. Thus, there is a possibility it may contain causative agents of viral or other undetermined diseases.

General

Because this product is made from human plasma, it may carry a risk of transmitting infectious agents such as viruses, the variant Creutzfeldt-Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of

transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and removing certain viruses during the manufacturing process. Despite these measures, such products may still potentially transmit human pathogenic agents.

All infections possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to Takeda Canada Inc. at 1-800-268-2772.

No seroconversions for hepatitis B or C (HBV or HCV) or human immunodeficiency virus (HIV) were reported with the use of GLASSIA during clinical trials.

Immune

GLASSIA may contain trace amounts of IgA. Patients with known antibodies to IgA, which can be present in patients with selective or severe IgA deficiency, have a greater risk of developing severe hypersensitivity and anaphylactic reactions. Monitor vital signs continuously and observe the patient carefully throughout the infusion. Discontinue the infusion if hypersensitivity symptoms occur and administer appropriate emergency treatment. Epinephrine and/or other appropriate supportive therapy should be available for the treatment of any acute anaphylactic or anaphylactoid reaction.

7.1. Special Populations

7.1.1 Pregnancy

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

GLASSIA should be given to a pregnant woman only if clearly needed.

7.1.2 Breastfeeding

There is no information regarding the presence of GLASSIA in human milk, the effect 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 GLASSIA and any potential adverse effects on the breastfed infant from GLASSIA.

7.1.3 Pediatrics

Pediatrics (<18 years): No pediatric studies have been performed to assess efficacy and safety of GLASSIA; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

In clinical trials, 11 subjects of 65 years of age or older received GLASSIA. This number of subjects was not sufficient to determine whether they respond differently from younger subjects. Dosing for geriatric patients should be appropriate to their overall situation.

Safety and effectiveness in patients over 65 years of age have not been established.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The serious adverse reaction observed during clinical trials with GLASSIA was exacerbation of chronic obstructive pulmonary disease (COPD).

The most common adverse reactions (>0.5% of infusions) in clinical trials were headache and upper respiratory infection.

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.

The safety profile of GLASSIA was evaluated in a randomized, double-blind, active-control trial (API-002) and an open-label, non-parallel, dose-escalation trial (API-001), in 67 subjects with pre-augmentation therapy serum alpha1-PI levels less than 11 microM. In the open label, non-parallel, dose-escalation trial, 18 subjects received a single infusion of GLASSIA at dosages of 30, 60 or 120 mg/kg (n = 6 per dose). In the randomized, double-blind, active-control trial, 50 subjects received weekly infusions of GLASSIA or the comparator alpha1-PI product at a dosage of 60 mg/kg for a total of 12 weeks after which all subjects remaining in the trial were treated for another 12 weeks with GLASSIA only. During the first 12 weeks of the trial, 33 subjects were treated with GLASSIA and 17 subjects were treated with comparator product, representing 66% and 34% of trial participants, respectively. Overall, 17 subjects received 12 doses and 32 subjects received 22 - 24 doses of GLASSIA during the trial. One subject randomized to the comparator alpha1-PI product did not receive any treatment with GLASSIA during the last 12 weeks of the trial. 22 subjects in the GLASSIA treatment arm and 15 subjects in the comparator arm experienced adverse reactions during the initial 12 weeks (double-blind portion) of the trial. Table 2 compares the adverse reactions reported in >5% of subjects during the initial 12 weeks in subjects treated with GLASSIA with reactions in the concurrent comparator group. Table 3 shows the adverse reactions reported in >5 % of subjects receiving GLASSIA for the entire 24-week treatment period.

Table 2: Adverse Reactions Occurring in > 5% of Subjects During the First 12 Weeks of Treatment

¹ An adverse reaction is any adverse event which met any of the following criteria: (a) an adverse event that began on the same day or within 3 days following the Glassia infusion, or (b) an adverse event considered by either the investigator or sponsor to be at least possibly related to Glassia administration, or (c) an adverse event for which causality assessment was missing or indeterminate.

Sinusitis was classified into either System Organ Class (SOC) ‘Infections and Infestations’ or ‘Respiratory Thoracic and Mediastinal Disorders’. In Table 2, Sinusitis occurrences of both SOCs are counted.

Table 3: Adverse Reactions Occurring in > 5% of Subjects Treated with Alpha-1 proteinase inhibitor for 24 Weeks

¹ An adverse reaction is any adverse event which met any of the following criteria: (a) an adverse event that began on the same day or within 3 days following the Glassia infusion, or (b) an adverse event considered by either the investigator or sponsor to be at least possibly related to Glassia administration, or (c) an adverse event for which causality assessment was missing or indeterminate.

Rate by subject = total number of subjects experiencing the ADR divided by total number of subjects (N) and multiplied by 100.

Both Sinusitis and Nasopharyngitis were classified into either System Organ Class (SOC) Infections and Infestations or Respiratory Thoracic and Mediastinal disorders. In Table 3, Sinusitis and Nasopharyngitis, occurrences of both SOCs are counted.

Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

During the 12-week double blind portion of the randomized, active comparator trial, 4 subjects (12%) had exacerbations of chronic obstructive pulmonary disease (COPD) during GLASSIA treatment and 5 subjects (29%) had exacerbations of COPD during comparator treatment. In the 12-week open-label treatment period with GLASSIA, 14 subjects (29%) had exacerbations.

8.3. Less Common Clinical Trial Adverse Reactions

The following related adverse reactions have also occurred in subjects treated with GLASSIA:

General disorders and administration site conditions: Influenza like illness, lethargy

Immune system disorders: Urticaria

Investigations: Platelet count decreased

Musculoskeletal and connective tissue disorders: Joint swelling

Nervous system disorders: Headache NOS

Skin and subcutaneous tissue disorders: Pruritus

Vascular disorders: Hypertension

8.5. Post-Market Adverse Reactions

The following adverse reactions have been identified during post-approval use of GLASSIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, thoracic, and mediastinal Disorders: Dyspnea

Gastrointestinal disorders: Nausea

General disorders and administration site conditions: Fatigue

9. Drug Interactions

9.4. Drug-Drug Interactions

Interactions with other drugs have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

GLASSIA administration is intended to inhibit serine proteases such as neutrophil elastase (NE) in the lung. In the healthy lung, NE is produced by activated neutrophils during inflammation (respiratory infection, smoking) and can be regulated by the inhibitory action of alpha-1 PI. Uninhibited activity of NE results in a protease-protease inhibitor imbalance and can destroy the alveolar wall, resulting in conditions like chronic obstructive lung disease or emphysema which is observed in alpha-1 PI deficiency. Alpha1-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and alveolar levels of alpha1-PI. Individuals with severe alpha-1 PI deficiency have little protection against NE released during inflammation which can lead to progressive, moderate-to-severe chronic obstructive lung disease (emphysema) that eventually manifests with clinical symptoms in the third to fourth decades of life.

Smoking is an important risk factor for the development of emphysema including in patients with alpha1-PI deficiency. Because emphysema affects many, but not all individuals with the more severe genetic variants of alpha1-PI deficiency, augmentation therapy with alpha1-proteinase (human)

inhibitor is indicated only in patients with severe alpha1-PI deficiency who have clinically evident emphysema.

10.2. Pharmacodynamics

Administration of GLASSIA to patients with Alpha1-PI deficiency augments the level of circulating levels of the deficient protein following intravenous administration. Normal individuals have levels of Alpha1-PI greater than 22 microM.

The clinical efficacy of GLASSIA in influencing the course of pulmonary emphysema or the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials.

The clinical benefit of the increased circulating levels of Alpha1-PI at the recommended dose has not been established for A1PI augmentation therapy.

10.3. Pharmacokinetics

A prospective, open-label, uncontrolled multicenter pharmacokinetic trial was conducted in 7 females and 11 males with congenital alpha1-PI deficiency, ranging in age from 40 to 69 years. Subjects received a single dose of GLASSIA either 30 mg/kg, 60 mg/kg or 120 mg/kg (n=6 per dose level). Blood samples for pharmacokinetic assessment were taken prior to and within 5 minutes of completion of the infusion, and then at 1 hour, 6 hours, 12 hours, 24 hours, 3 days and at 7 days post-dose.

The mean results for pharmacokinetic parameters are shown in Table 4. The pharmacokinetics of GLASSIA were linear over the dose range of 30-120 mg/kg.

Table 4: Pharmacokinetic Parameters (Mean and %CV) for Functional Alpha1-PI

1. 3.57 14.13

10.4. Immunogenicity

All therapeutic proteins have the potential for immunogenicity.

The detection of antibody formation 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 incidence of antibodies in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.

In the double-blind, randomized, active comparator trial of GLASSIA, low level anti-GLASSIA antibodies were detected in one subject (out of 50 subjects) at one time point (Week 12) and returned to negative at the end of the study (Week 24) despite continuous exposure to GLASSIA. No immune system adverse reactions were reported.

11. Storage, Stability and Disposal

Each carton of GLASSIA contains a single use vial containing the labeled amount of functional active alpha1-PI in solution.

Store GLASSIA at 2°C to 8°C (36°F to 46°F). Do not freeze.

Product may be stored at room temperatures not exceeding 25°C (77°F) for up to one month. Once removed from refrigeration use within one month.

Keep vial in carton until required for use.

Do not use after the expiration date printed on the label. GLASSIA contains no preservatives and no latex.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper name: Alpha-1 proteinase inhibitor

Chemical name: Human alpha-1 proteinase inhibitor, alpha-1 proteinase inhibitor human Molecular formula and molecular mass: 51-54 kDa

Structural formula: This drug substance has one Cysteine residue at position 232, which was found to be covalently linked to a free single Cysteine by a disulfide bridge. Drug substance has three Nglycosylation sites at Asn-46, Asn-83 and Asn-247, equipped with either diantennary or triantennary N-glycans.

Physicochemical properties:

Product Characteristics

GLASSIA is a purified, ready-to-use liquid biologic containing human alpha-1 proteinase inhibitor (alpha1-PI) as the active ingredient, with a nominal concentration of 20 mg/mL. GLASSIA is a plasma-derived medicinal product manufactured from human plasma as the starting material. GLASSIA can be produced from either source or recovered plasma collected from donors in the United States. Source plasma is the liquid component of human blood, collected by either manual or automated plasmapheresis whereas recovered plasma is obtained from a single unit of whole blood using a separation process.

Alpha1-PI is isolated using a modified Cohn-Oncley cold ethanol fractionation process to isolate the intermediate known as the Fraction IV-1 precipitate. The Fraction IV-1 precipitate then undergoes additional purification steps, including a series of anion-exchange and cation-exchange chromatography steps using 2 DEAE Sepharose Fast Flow columns and 1 CM Sepharose Fast Flow column. To enhance viral safety, the downstream purification process includes two dedicated virus inactivation/reduction steps: nanofiltration followed by solvent/detergent (S/D) treatment. Lastly, following ultra/diafiltration, the final formulation is adjusted to meet release specifications.

The final GLASSIA drug product has a specific activity of 0.7 mg to 1.1 mg active alpha1-PI/mg total protein, a pH of 6.8 to pH 7.2, and an active A1PI content of 16 mg/mL to 24 mg/mL. The formulation also contains sodium chloride (7 mg/mL) and monobasic sodium phosphate dihydrate (3 mg/mL), which serve as stabilizing and buffering agents. No sugars or preservatives are added, and the overall manufacturing process is designed to maintain the native structural and functional integrity of the alpha1-PI molecule.

Viral Inactivation

Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of GLASSIA is collected only at FDA approved blood establishments and is tested by FDA-licensed serological assays for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus Types 1 and 2 (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements.

As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found to be negative. Each plasma unit must be non-reactive (negative) in all tests. Plasma is also tested by in-process NAT procedures for parvovirus B19 and the limit for B19 DNA in the manufacturing pool is set not to exceed 10⁴ IU per mL.

To further improve the safety margin, validated virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely 15 nm nanofiltration and solvent/detergent (S/D) treatment. Nanofiltration (NF) through a 15 nm filter which can remove both enveloped and non–enveloped viral agents. The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, and polysorbate 80 at +20°C to 25°C for a minimum of 4 hours and 30 minutes. S/D treatment inactivates the lipid enveloped viruses investigated to below detection limits within minutes. Additionally, the ethanol fractionation process provides an additional virus clearance capacity.

In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. In addition, Fractionation II+III and PEG precipitation further contribute to virus clearance.

Virus clearance studies for GLASSIA performed in accordance with good laboratory practices are summarized in Table 5.

Table 5: Log10 Virus Reduction during Manufacture of GLASSIA

HIV-1 Human immunodeficiency virus Type 1, WNV West Nile virus, PRV Pseudorabies virus,

HAV Hepatitis A virus, BVDV Bovine viral diarrhea virus, PPV Porcine parvovirus, B19V Parvovirus B19

14. Clinical Trials

14.1. Clinical Trials by Indication

Emphysema Due To Alpha1-Antitrypsin Deficiency

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

A randomized, double-blind trial with a partial cross-over (Study # API-002) was conducted to compare GLASSIA to a comparator product in 50 alpha1-PI-deficient subjects. The trial objectives were to demonstrate that the mean trough levels (average of Weeks 7-12) of antigenic and/or functional alpha1-PI in GLASSIA were not inferior to those of the control product and to determine whether GLASSIA maintained antigenic and/or functional plasma levels of at least 11 microM (57 mg/dL).

For inclusion in the trial, subjects were required to have lung disease related to alpha1-PI deficiency and ‘at-risk' alleles associated with alpha1-PI plasma levels < 11 microM. Subjects already receiving alpha1-PI therapy were required to undergo a 5-week wash-out period of exogenous alpha1-PI prior to dosing.

Fifty subjects received either GLASSIA (33 subjects) or the comparator product (17 subjects) at a dose of 60 mg/kg intravenously per week for 12 consecutive weeks. From Week 13 to Week 24 subjects received open-label weekly infusions of GLASSIA at a dose of 60 mg/kg.

Trough levels of functional and antigenic alpha1-PI were measured prior to treatment, at baseline and throughout the trial until Week 24. The serum alpha1-PI trough levels rose substantially in all subjects by Week 2 and remained stable during Weeks 7 to 12. GLASSIA was shown to be non-inferior to the comparator product.

The lower bounds of the 95% confidence intervals for the difference in means (GLASSIA minus Comparator) were greater than – 3 microM for both antigenic and functional alpha1-PI levels thereby demonstrating the non-inferiority of GLASSIA to comparator. See results in Table 7.

Table 7: Circulating Trough Levels of Antigenic and Functional API (Average of Weeks 7-12) (ITT Population) (Study API-002)

*The confidence interval (CI) was derived from a t-test stratified by center for the difference GLASSIA - Comparator.

*Non-inferiority was defined as the lower bound of 95%CI for the difference in means between Week 7 and Week 12 (GLASSIA minus Comparator) being greater than -3 μM .

All subjects receiving GLASSIA had mean serum trough antigenic alpha1-PI levels greater than 11 microM during Weeks 7-12. Ten of 33 subjects (30.3%) receiving GLASSIA had mean trough functional alpha1-PI levels below 11 microM.

A subset of subjects (n = 7 receiving GLASSIA) underwent broncho-alveolar lavage (BAL) and were shown to have increased levels of antigenic alpha1-PI in the epithelial lining fluid at Week 10-12 over levels found at baseline.

The clinical efficacy of GLASSIA in influencing the course of pulmonary emphysema or the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology

The thrombogenic potential of alpha-1 proteinase inhibitor was assessed after a single IV administration at 200 mg/kg rabbits. Alpha-1 proteinase inhibitor was shown not to be thrombogenic in this study. The acute toxicity of alpha-1 proteinase inhibitor was evaluated in rats and rabbits. A single IV administration of 60 and 640-650 mg/kg and 60 and 600 mg/kg alpha-1 proteinase inhibitor in the rats and rabbits, respectively, resulted in no overt toxicity. Repeat-dose toxicity of alpha-1 proteinase inhibitor was assessed in rabbits when administered IV daily for 5-days at 300 mg/kg. Overall, five once daily administrations of 300 mg/kg alpha-1 proteinase inhibitor were well tolerated in rabbits. Any potential test article changes were minor in nature and/or of unknown significance and resolved by the end of the 14-day recovery period. No overt toxicity was observed. Repeat-dose toxicity of alpha-1 proteinase inhibitor was also assessed in Sprague-Dawley rats when administered IV every alternate day for 19 days at a dose of 612 mg/kg. The No-observed-adverse-effect-level was set at 612 mg/kg, which was the highest dose tested and the maximum feasible dose in rats. No specific local tolerance studies were conducted with alpha-1 proteinase inhibitor, but local tolerance was assessed within the repeat-toxicity studies where intravenous injection of alpha-1 proteinase inhibitor was well-tolerated locally. A neoantigenicity study was performed in rabbits to assess whether the inclusion of viral removal/inactivation steps in the manufacturing of alpha-1 proteinase inhibitor resulted in protein structural changes and novel epitope presentation. After immunization of rabbits for 25 weeks, blood samples were collected for detection of neoantigenicity. The results indicate that the viral inactivation step in the manufacturing process does not result in neoantigenic changes to alpha-1 proteinase inhibitor.

Genotoxicity

No studies have been performed to evaluate the genotoxic potential of alpha-1 proteinase inhibitor.

Carcinogenicity

No long-term animal studies have been performed to evaluate the carcinogenic potential of alpha-1 proteinase inhibitor.

Reproductive and developmental toxicology

No dedicated animal fertility studies have been performed for alpha-1 proteinase inhibitor.