Tegsedi Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

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 BOX ............................................................ 5

4 DOSAGE AND ADMINISTRATION ................................................................................. 6

4.1 Dosing Considerations ............................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment ....................................................... 7

4.3 Reconstitution ........................................................................................................ 8

4.4 Administration ........................................................................................................ 8

4.5 Missed Dose ........................................................................................................... 9

5 OVERDOSAGE .............................................................................................................. 9

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

7 WARNINGS AND PRECAUTIONS ................................................................................ 10

7.1 Special Populations............................................................................................... 13

7.1.1 Pregnant Women ........................................................................................... 13

7.1.2 Breast-feeding ................................................................................................ 13

7.1.3 Pediatrics ........................................................................................................ 13

7.1.4 Geriatrics ........................................................................................................ 13

8 ADVERSE REACTIONS ................................................................................................ 13

8.1 Adverse Reaction Overview .................................................................................. 13

8.2 Clinical Trial Adverse Reactions Serious Adverse Drug Reactions ......................... 14

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................... 18

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 18

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics ............................ 18

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 19

8.5 Post-Market Adverse Reactions ........................................................................... 19

9 DRUG INTERACTIONS ................................................................................................ 19

9.2 Drug Interactions Overview .................................................................................. 19

9.3 Drug-Behavioural Interactions .............................................................................. 20

9.4 Drug-Drug Interactions ......................................................................................... 20

9.5 Drug- Food Interactions ........................................................................................ 20

9.6 Drug-Herb Interactions ......................................................................................... 20

9.7 Drug-Laboratory Test Interactions ........................................................................ 20

10 CLINICAL PHARMACOLOGY ....................................................................................... 20

10.1 Mechanism of Action ...................................................................................... 20

10.2 Pharmacodynamics ........................................................................................ 21

10.3 Pharmacokinetics ........................................................................................... 21

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 22

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 22

PART II: SCIENTIFIC INFORMATION ....................................................................................... 23

13 PHARMACEUTICAL INFORMATION ............................................................................ 23

14 CLINICAL TRIALS ........................................................................................................ 24

14.1 Clinical Trials by Indication ............................................................................. 24

15 MICROBIOLOGY ........................................................................................................ 26

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 26

PATIENT MEDICATION INFORMATION .................................................................................. 28

Parts of the Safety Syringe Device (SSD) ............................................................................... 33

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TEGSEDI™ (inotersen solution for subcutaneous injection) is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

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): Evidence from the pivotal clinical study suggests that use in the geriatric population is not associated with major differences in safety or efficacy. Caution should be used in these patients especially in regards to thrombocytopenia.

2 CONTRAINDICATIONS

TEGSEDI 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;
• Have a platelet count below 100 x 10⁹/L before the start of treatment;
• With urine protein to creatinine ratio UPCR ≥ 113 mg/mmol (1 g/g) before the start of treatment;
• With an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m² before the start of treatment;
• With severe liver impairment before the start of treatment.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The following factors should be considered when dosing TEGSEDI:

TEGSEDI is associated with reductions in platelet count, which may result in thrombocytopenia at any time during treatment [see Hematologic]. Therefore,

• Platelet count should be measured prior to treatment with TEGSEDI and as directed following treatment initiation (see Recommended Dose and Dosage Adjustment and Monitoring and Laboratory Tests).
• TEGSEDI should not be initiated in patients with platelet count < 100 x 10⁹/L.
• Platelet count tests should be monitored regularly (see Recommended Dose and Dosage Adjustment).
• Dosing should be adjusted according to laboratory values (see Recommended Dose and Dosage Adjustment).
• Glomerulonephritis has occurred in patients treated with TEGSEDI. Therefore,

Estimated glomerular filtration rate (eGFR) and urine protein to creatinine ratio (UPCR) should be measured prior to treatment with TEGSEDI and as directed following treatment initiation (see Monitoring and Laboratory Tests).

• TEGSEDI should not be initiated in patients with urine protein to creatinine ratio UPCR ≥ 113 mg/mmol (1 g/g) or an estimated glomerular filtration rate (eGFR)

  < 45 mL/min/1.73 m².

• Renal function tests should be monitored regularly [see Monitoring and Laboratory Tests].
• Plasma vitamin A (retinol levels) below the lower limit of normal (LLN) should be corrected and any ocular symptoms or signs of vitamin A deficiency should have resolved prior to initiation of TEGSEDI.
• Elevated liver transaminases occur commonly in patients treated with TEGSEDI. Serious cases of drug induced liver injury (DILI) have also been reported including cases of Hy’s law and those with onset up to 1 year following treatment [see 7 WARNINGS AND PRECAUTIONS - Hepatic]. Therefore,
• Liver function tests should be measured prior to initiating treatment with TEGSEDI and as directed during treatment (see 7 WARNINGS and PRECAUTIONS - Monitoring and Laboratory Tests).
• TEGSEDI should not be used in patients with severe hepatic impairment (see 2 CONTRAINDICATIONS).

4.2 Recommended Dose and Dosage Adjustment

Treatment should be initiated by and remain under the supervision of a physician knowledgeable in the treatment of patients with hereditary transthyretin amyloidosis.

The recommended dose of TEGSEDI is 284 mg inotersen (300 mg inotersen sodium) injected subcutaneously once-weekly by a single-dose, prefilled syringe with a Safety Syringe Device (SSD).

For consistency of dosing, patients should be instructed to give the injection on the same day every week.

Patients receiving TEGSEDI should take oral supplementation of the recommended daily allowance (RDA) of vitamin A (approximately 3000 IU vitamin A per day). Vitamin A supplementation should be continued throughout treatment (see 7 WARNINGS AND PRECAUTIONS - Ophthalmologic).

Reduced Platelet Count:

Dose adjustment in case of reduction in platelet count.

TEGSEDI is associated with reductions in platelet count, which may result in thrombocytopenia. Dosing should be adjusted according to laboratory values as follows:

Table 1 TEGSEDI Monitoring and Treatment Recommendations for Platelet Count

* If the subsequent test confirms the initial test result, then monitoring frequency and dosing should be adjusted as recommended in the table.

‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or anti-platelet medicinal products, and /or prior history of major bleeding events.

† It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives glucocorticoid therapy to reverse the platelet decline. Patients who discontinue therapy with TEGSEDI due to platelet counts below 25 x 10⁹/L should not reinitiate therapy.

Renal Impairment: Since TEGSEDI is highly protein bound and is minimally cleared by the kidneys, no dose adjustment is required for patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment.

Glomerulonephritis has occurred in patients treated with TEGSEDI.

Hepatic Impairment: TEGSEDI has not been evaluated in patients with known hepatic impairment or in patients with prior liver transplant. TEGSEDI is not metabolized by cytochrome P450 enzymes in the liver [see Metabolism].

TEGSEDI is contraindicated in patients with severe hepatic impairment. Liver enzymes should be monitored prior to initiation of treatment and every four months during treatment. Use of TEGSEDI should be permanently discontinued in patients suspected of having developed liver injury. In patients with a history of liver transplant, monthly monitoring of ALT, AST, and total bilirubin is necessary. Treatment with TEGSEDI should also be permanently discontinued in patients with prior liver transplant who develop signs of transplant rejection [see 7 WARNINGS AND PRECAUTIONS - Hepatic].

Pediatric Population: Health Canada has not authorized an indication for pediatric use. [See Pediatrics]

Geriatric Population: No dose adjustment is required for patients aged 65 years and over [see Geriatrics]

4.3 Reconstitution

TEGSEDI is supplied in a single-dose, prefilled syringe with an SSD, and therefore does not require reconstitution.

4.4 Administration

TEGSEDI should be administered as follows:

• TEGSEDI is intended for subcutaneous injection only.
• The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified health care professional. Patients and/or caregivers should be trained in the subcutaneous administration of TEGSEDI in accordance with the instructions provided under How to take TEGSEDI [see PATIENT MEDICATION INFORMATION].

• Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It is important to rotate sites for injection.

  • If injected in the upper arm, the injection should be administered by another person.
  • Injection should be avoided at the waistline and other sites where pressure or rubbing from clothing may occur.
  • TEGSEDI should not be injected into areas of skin disease or injury.
  • Tattoos and scars should also be avoided.

• TEGSEDI prefilled syringe should be allowed to reach room temperature prior to injection.

  • Remove from refrigerated storage (2 °C to 8 °C) at least 30 minutes prior to use.
  • Other warming methods should not be used.
• Use each prefilled syringe only once.

TEGSEDI should be inspected visually prior to administration. The solution should be clear and colorless to pale yellow. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy. TEGSEDI must not be injected if the expiration date on the carton has passed [see STORAGE, STABILITY AND DISPOSAL and SPECIAL HANDLING INSTRUCTIONS].

4.5 Missed Dose

If a dose is missed, patients should be instructed to take the missed dose as soon as possible, unless the next scheduled dose is within 2 days. In this case, the patient should be directed to skip the missed dose and take the next scheduled dose on the scheduled day.

5 OVERDOSAGE

During the premarketing evaluations of TEGSEDI, there were no reports of overdose.

In the event of an overdose, supportive medical care should be provided including consulting with a healthcare professional and close observation of the clinical status of the patient.

Platelet and renal function tests should be monitored regularly.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2: Dosage Forms, Strengths, Composition and Packaging

TEGSEDI is available as a sterile, clear, preservative-free, colourless to pale yellow solution for injection in a single-dose glass prefilled syringe containing 1.5 mL of solution (284 mg dose) with a Safety Syringe Device (SSD). TEGSEDI is available in cartons containing 4 prefilled syringes. Single use, discard unused portion.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Driving and Operating Machinery

TEGSEDI has not been shown to influence the ability to drive and use machines.

Hematologic

TEGSEDI is associated with reductions in platelet count, which may result in thrombocytopenia [See ADVERSE REACTIONS].

Careful monitoring for thrombocytopenia is important during treatment with TEGSEDI and recommended monitoring and treatment recommendations for platelet count found in Table 1 should be followed [see Recommended Dose and Dosage Adjustment]. Platelet counts should be verified prior to initiation of treatment, monitored during treatment every two weeks during the entire course of treatment or more frequently, if needed (see Table 1), and continued for 8 weeks after discontinuation.

TEGSEDI should be used with special caution in patients treated with anti-thrombotic agents, antiplatelet agents, medications that may lower platelet count, in patients with a history of severe bleeding, or in the elderly, who may be at greater risk to bleeding.

Patients should be instructed to contact their physician immediately if they experience any signs of unusual or prolonged bleeding (e.g., petechia, spontaneous bruising, subconjunctival bleeding, bleeding from the gums or nose, blood in urine or stools, bleeding in the whites of eyes), neck stiffness or atypical severe headache because these symptoms may be caused by bleeding in the brain.

Hepatic/Biliary/Pancreatic

The liver is a site of accumulation of antisense oligonucleotides. TEGSEDI can cause elevations in serum aminotransferase levels. There have been reported cases of clinically significant liver injury that were considered possibly or probably related to TEGSEDI treatment in patients without liver transplant, including at least two cases that met Hy’s law (ALT or AST ≥3 x ULN and bilirubin ≥2 x ULN). Some patients did not have prior history of liver-related disorders. In some patients with prior liver transplant, TEGSEDI led to transplant rejection. In some cases, there was a long time to onset of serious drug-induced liver injury (up to one year).

In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN), compared to 3% of patients on placebo; 3% of TEGSEDI-treated patients had an ALT at least 8 times the ULN, compared to no patient on placebo. One clinical study patient experienced an increased ALT more than 30 times the ULN. After a course of corticosteroids and discontinuation of TEGSEDI, the patient’s ALT returned to normal levels. Some patients had resolution of the liver laboratory abnormalities with continued use of TEGSEDI.

In clinical studies, demonstrated or possible cases of immune-mediated biliary disease occurred in TEGSEDI-treated patients. There was a single case of autoimmune hepatitis with primary biliary cirrhosis in a patient with a family history of primary biliary cirrhosis, as well as a single case of biliary obstruction of unclear etiology.

Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline and every four months during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin. Alcohol consumption should be avoided during TEGSEDI treatment.

If a patient is suspected of having developed liver injury, TEGSEDI treatment should be permanently discontinued.

TEGSEDI is contraindicated in patients with severe hepatic impairment (see 2 CONTRAINDICATIONS).

Liver Transplant Rejection

In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting TEGSEDI in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting TEGSEDI. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of TEGSEDI. In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly.

Discontinue TEGSEDI in patients who develop signs of liver transplant rejection.

Immune

Hypersensitivity Reactions/Antibody Formation:

TEGSEDI can cause hypersensitivity reactions. In clinical studies, TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. Antibodies to TEGSEDI were present when the reactions occurred. These reactions generally occurred within 2 hours of administration of TEGSEDI and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms. If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI, and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reaction to TEGSEDI.

Immunogenicity:

In the pivotal Phase 2/3 study, 30.4% of patients treated with TEGSEDI tested positive for anti- drug antibodies following 15 months of treatment. No effect on the pharmacokinetic properties (C_max, AUC or half-life) and efficacy of TEGSEDI was observed in the presence of anti-drug antibodies, but patients with anti-drug antibodies had more reactions at the injection site.

Monitoring and Laboratory Tests

Hematology: Platelet count should be monitored every 2 weeks during treatment with TEGSEDI, and dosage adjustments made as appropriate [see Recommended Dose and Dosage Adjustment].

Glomerulonephritis: UPCR and eGFR should be monitored every two months. UPCR and eGFR should be monitored for 8 weeks following discontinuation of treatment.

In the case of a decrease in eGFR > 30%, in the absence of an alternative explanation, pausing of TEGSEDI dosing should be considered pending further evaluation of the cause.

In the case of UPCR ≥ 2 g/g (226 mg/mmol), which is confirmed on repeat testing, dosing of TEGSEDI should be paused while further evaluation for acute glomerulonephritis is performed. TEGSEDI should permanently be discontinued if acute glomerulonephritis is confirmed. If glomerulonephritis is excluded, dosing may be resumed if clinically indicated and following improvement of renal function.

Early initiation of immunosuppressive therapy should be considered if a diagnosis of glomerulonephritis is confirmed.

Caution should be used with nephrotoxic medicinal products and other medicinal products that may impair renal function.

Liver function: Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline prior to initiation of therapy, and every four months during treatment with TEGSEDI. Prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including unusual fatigue, unexplained flu-like symptoms, anorexia, right upper abdominal pain, tenderness or discomfort, dark urine, pale stools, or jaundice. In patients with a history of liver transplant, monthly monitoring of ALT, AST, and total bilirubin should be performed.

Ophthalmologic

Vitamin A

Patients receiving TEGSEDI should take oral supplementation of the recommended daily allowance (RDA) of vitamin A (approximately 3000 IU vitamin A per day) in order to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Vitamin A supplementation should be continued throughout treatment. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency.

Based on the mechanism of action of TEGSEDI it is expected that plasma retinol levels will be below LLN in patients treated with TEGSEDI. Additional vitamin A supplementation above RDA should not be given to attempt to correct this.

Renal

Glomerulonephritis has occurred in patients treated with TEGSEDI. In the Phase 3 trial, NEURO-TTR, glomerulonephritis occurred in three (3%) subjects treated with TEGSEDI and no patients treated with placebo. Renal function decline without glomerulonephritis was also reported. [see ADVERSE REACTIONS].

Careful monitoring of UPCR and eGFR is important during treatment with TEGSEDI. Follow recommended monitoring and treatment recommendations for renal parameters [see 7 WARNINGS and PRECAUTIONS - Monitoring and Laboratory Tests].

Reproductive Health: Female and Male Potential

There are no published clinical data available on the effects of the use of TEGSEDI on the reproductive potential in females or males. TEGSEDI had no effect on the reproductive organs, mating, or pregnancy in animal studies [see Pregnant Women].

Fertility

There is no information available on the effects of TEGSEDI on human fertility. Animal studies have shown no observable effects on male or female fertility.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled clinical studies with TEGSEDI in pregnant women. Due to the potential teratogenic risk arising from unbalanced vitamin A levels, TEGSEDI should only be used during pregnancy if the potential benefits justify the potential risk to the fetus.

Vitamin A levels during early pregnancy, both too high and too low, can impact fetal development. If a woman intends to get pregnant, both TEGSEDI treatment and vitamin A supplementation should be interrupted.

Due to the effect of TEGSEDI on vitamin A levels, there is a potential for impact on pregnancy. It is recommended that treatment should not be initiated in pregnant women and interrupted if pregnancy occurs. Women of childbearing age should use contraception during treatment.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TEGSEDI during pregnancy. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to register themselves by calling: 1-877-465-7510, emailing: tegsedipregnancy@ubc.com, or visiting online at: www.tegsedipregnancystudy.com.

7.1.2 Breast-feeding

There is no information regarding the presence of TEGSEDI in human milk, the effects on the breast-fed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for TEGSEDI and any potential adverse effects on the breastfed infant from TEGSEDI or from the underlying maternal condition.

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): Clinical studies of TEGSEDI included 69 patients (45%) aged 65 and over. No differences in safety, pharmacokinetics, or effectiveness were observed between these patients and younger patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (22%). A > 5% difference between treatment groups was observed in the incidence of serious TEAEs in the SOCs of Metabolism and Nutrition Disorders and Renal and Urinary Disorders.

Five patients, all of whom received TEGSEDI, died during the study. Four of the deaths were consistent with progression of disease or a complication of the underlying disease. One fatal event (intracranial hemorrhage) occurred in association with Grade 4 thrombocytopenia with a platelet count of ~10 x 10⁹/L at the time of hospital admission.

Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 x 10⁹/L), which can have potentially fatal bleeding complications. Glomerulonephritis occurred in three (3%) TEGSEDI-treated patients (vs. no patient on placebo). (see WARNINGS AND PRECAUTIONS).

Eight TEGSEDI-treated patients withdrew from the study due to adverse events (Placebo: 1 patient). Adverse events leading to patient withdrawal included thrombocytopenia, cardiac failure congestive, intestinal perforation, cachexia, dementia, haemorrhage intracranial, myoclonus and acute kidney injury. The only TEAE leading to withdrawal from study observed in > 1 subject in the TEGSEDI group was cachexia, which is a common complication of hATTR-PN.

Sixteen TEGSEDI-treated patients permanently discontinued treatment due to adverse event including one case of stopping rule met (Placebo: 2 patients). Three TEGSEDI-treated patients discontinued due to thrombocytopenia and two patients discontinued due to glomerulonephritis. One additional patient developed glomerulonephritis at the end of treatment period and did not enter the open label extension study.

TEGSEDI dose was reduced in 3 patients due to adverse events such as visual field defect in one patient and thrombocytopenia in the other two patients. Twenty-seven TEGSEDI-treated patients had interruptions or delays in dosing due to adverse events (Placebo: 3 patients). The most common reasons for dose reductions or interruptions were decrease in platelet counts and/or kidney related issues such a glomerulonephritis.

8.2 Clinical Trial Adverse Reactions Serious Adverse Drug Reactions

Clinical trials are conducted under very specific conditions. The adverse drug 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.

A total of 112 adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) received TEGSEDI in NEURO-TTR Study and 60 patients received placebo. The mean age of the study patients was 59 years (27 to 81 years of age). Of the TEGSEDI-treated patients, 68.8% were male and 93.8% were Caucasian, with a mean exposure of 385 days, and median exposure of 449 days (mean 55.6 doses, median 66 doses). Baseline disease characteristics were largely similar in the TEGSEDI-treated patients and placebo-control patients. Sixty-seven percent of patients were in Stage 1 of the disease at baseline, with 33% being in Stage 2. Fifty-two percent of patients had Val30Met mutations in the TTR gene, with the remaining 48% comprised of 26 different other point mutations.

The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and that occurred more frequently than on placebo were injection site erythema, nausea, fatigue, diarrhea, headache and injection site pain.

Table 3 Adverse Reactions Reported in At Least 2% TEGSEDI-Treated Patients and that Occurred More Frequently than Placebo Patients (NEURO-TTR)

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.3 Less Common Clinical Trial Adverse Reactions

Not applicable.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Thrombocytopenia

TEGSEDI is associated with reductions in platelet count, which may result in thrombocytopenia. In the Phase 2/3, NEURO-TTR trial, platelet count reductions to below normal (140 x 10⁹/L ) were observed in 54% of patients treated with TEGSEDI and 13% of placebo patients; reductions to below 100 x 10⁹/L were observed in 23% of patients treated with TEGSEDI and 2% of the patients receiving placebo; confirmed platelet counts of < 75 x 10⁹/L were observed in 10.7% of TEGSEDI-treated patients. Three (3%) patients developed platelet counts < 25 x 10⁹/L; one of these patients experienced a fatal intracranial haemorrhage. Patients should be monitored for thrombocytopenia during treatment with TEGSEDI (see WARNINGS AND PRECAUTIONS).

Glomerulonephritis / Renal Function Decline

Three (3) patients developed glomerulonephritis in the course of the NEURO-TTR study. Severe and serious renal impairment were more common in TEGSEDI-treated subjects compared to placebo (4.5% vs. 1.7% and 5.4% vs. 0%) including glomerulonephritis, tubulointerstitial nephritis, acute kidney injury, renal failure and renal impairment. Patients should be monitored for signs of increased proteinuria and reduction in eGFR during treatment with inotersen (see WARNINGS AND PRECAUTIONS).

Injection Site Adverse Events

Adverse events at the injection site were commonly reported in TEGSEDI-treated patients. These reactions included injection site pain, erythema, pruritus, swelling, rash, induration, bruising and haemorrhage. These reactions were generally self-limiting and manageable.

Immunogenicity

See Immunogenicity.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during the post-approval use of inotersen:

• Hypersensitivity. See - 7 WARNINGS AND PRECAUTIONS - Immune, Hypersensitivity Reactions
• Drug induced liver injury. See 7 WARNINGS AND PRECAUTIONS - Hepatic

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

TEGSEDI is not a substrate of cytochrome P450 (CYP450) and did not induce or inhibit CYP450 in vitro. TEGSEDI was not a substrate or inhibitor of major transporters. These studies indicated a lack of interaction potential. No formal clinical drug-drug interaction studies have been conducted.

The effect of commonly used concomitant medications, which included diuretics, anti-thrombotics, and non-steroid anti-inflammatory drug (NSAID) analgesics, was evaluated by population PK analysis. None of the evaluated concomitant medications showed a clinically significant effect on the clearance of TEGSEDI.

Clinically relevant pharmacokinetic interactions are not expected for TEGSEDI.

Caution should be used with antithrombotic medicinal products, antiplatelet medicinal products, and medicinal products that may lower platelet count, for example acetylsalicylic acid, clopidogrel, warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban and apixaban, and thrombin inhibitors such as dabigatran [see 7 WARNINGS AND PRECAUTIONS -Hematologic].

Caution should be exercised with concomitant use of nephrotoxic medicinal products and other medicines that may impair renal function, such as sulfonamides, aldosterone antagonists, anilides, natural opium alkaloids and other opioids [see 7 WARNINGS AND PREACUTIONS - Renal].

9.3 Drug-Behavioural Interactions

Specific interaction between TEGSEDI and alcohol has not been studied. However, due to the potential effect of TEGSEDI on the liver, alcohol consumption should be avoided during treatment with TEGSEDI.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug- Food Interactions

Interactions with food are not expected with TEGSEDI.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been studied.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Inotersen is a 2′-O-(2-methoxyethyl) (2′-MOE) phosphorothioate antisense oligonucleotide (ASO) complementary to the molecular target transthyretin (TTR) messenger RNA (mRNA). Hereditary transthyretin amyloidosis (hATTR), is a rare autosomal dominant, progressive systemic disease caused by mutations in the gene that codes for the protein transthyretin (TTR). The mutations result in weakening of the bonds of the normal tetrameric structure, which disaggregate into monomers that are prone to misfolding. These misfolded proteins, self-assemble into amyloid fibrils in various organs and tissues throughout the body including peripheral neurons, the gastrointestinal tract and the heart. The selective binding of TEGSEDI to the TTR mRNA causes the degradation of both mutant and wild type (normal) TTR mRNA. Degradation of TTR mRNA prevents the synthesis of TTR in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation.

TTR is a carrier protein for retinol-binding protein 4 (RBP4) which is the principle carrier of vitamin A (retinol). Therefore, reduction in plasma TTR is expected to result in reduction of plasma retinol levels to lower limit of normal. TTR is also a carrier protein for thyroxine.

10.2 Pharmacodynamics

Effects of TEGSEDI on Transthyretin (TTR)

In the pivotal NEURO-TTR study, in the TEGSEDI treatment group, robust reduction in circulating TTR levels was observed throughout the 15-month treatment period, with mean percent changes from Baseline in serum TTR from Week 13 to Week 65 ranging from 68% to 74% (median range: 74.64% to 78.98%). In the placebo group, mean serum TTR concentration decreased by 8.50% at Week 3 and then remained fairly constant throughout the treatment period.

The relationship between the TTR concentration and disease progression is unknown. It is unclear what level of reduction of TTR protein produces benefits to polyneuropathy measurements. There was no correlation with the 300 mg dose between the absolute or relative change from baseline in serum transthyretin levels and the change from baseline scores for either of the two primary scales [modified Neuropathy Impairment Scale + 7 (mNIS+7) composite score, and Norfolk Quality of Life –Diabetic Neuropathy (QoL-DN)]. No other doses were included in the phase 2/3 NEURO-TTR study.

Cardiac Electrophysiology

A Thorough QT prolongation (TQT) study has not been conducted but electrocardiogram (ECG) monitoring was done in clinical trials. There is no evidence that treatment with TEGSEDI prolongs the QTc interval. Inotersen was negative in the human ether-a-go-go-related gene (hERG) assay.

10.3 Pharmacokinetics

Single- and multiple-dose pharmacokinetics (PK) of TEGSEDI were determined in healthy volunteers (range 50 to 400 mg weekly), with additional data from a small subset (n = 10) of patients with hATTR (300 mg weekly), and from a population pharmacokinetic (PK) analysis.

Absorption:

Following subcutaneous (SC) administration, TEGSEDI is absorbed rapidly into systemic circulation in a dose-dependent fashion with the median time to maximum plasma concentrations (Cmax) of TEGSEDI of 2 to 4 hours.

Distribution:

TEGSEDI is highly bound to human plasma proteins (>94%) and the fraction bound is independent of drug concentration. Mean plasma concentrations decreased by > 90% from the peak by 24 hours after SC injections. Based on population PK analysis, the apparent volume of distribution of TEGSEDI at steady-state is 293 L in patients with hATTR. The high volume of distribution suggests inotersen extensively distributes into tissues following SC administration. This is consistent with animal studies (mouse, rat and monkey), showing that TEGSEDI rapidly and extensively distributes to various tissues, with the highest concentrations observed in the kidney followed by the liver, as well as mesenteric lymph nodes, bone marrow, thyroid, spleen, bone and pancreas. TEGSEDI does not readily cross the blood-brain barrier.

Metabolism:

As expected for an antisense oligonucleotide, in-vitro studies indicate that TEGSEDI is not a substrate for cytochrome CYP 450 metabolism, and clinical data indicate that it is metabolized slowly in tissues by endonucleases to form shorter inactive oligonucleotides that are the substrates for additional metabolism by exonucleases. Unchanged TEGSEDI is the predominant circulating component after four weeks of dosing in healthy subjects (approximately 74% of the total oligonucleotides detected in human plasma).

Elimination:

The elimination of TEGSEDI involves both metabolism in tissues and excretion of primarily the chain-shortened metabolites in urine. Urinary recovery of the parent drug is limited to less than 1% within the 24 hours post dose consistent with minimal glomerular filtration due to being highly bound to plasma protein. Following subcutaneous administration, elimination half-life for TEGSEDI is approximately 1 month.

Special Populations and Conditions:

Based on the population PK analysis, age, body weight, sex or race appears to have no clinically relevant effect on TEGSEDI exposure. Definitive assessments were limited due to low numbers.

• Hepatic Insufficiency The pharmacokinetics of TEGSEDI in patients with hepatic impairment has not been studied.
• Renal Insufficiency A population pharmacokinetic analysis suggests that mild and moderate renal impairment has no clinically relevant effect on the systemic exposure of TEGSEDI. No data are available in patients with severe renal impairment.

11 STORAGE, STABILITY AND DISPOSAL

TEGSEDI is a clear, colorless to pale yellow solution supplied in a single-dose, prefilled syringe with a Safety Syringe Device (SSD). Each prefilled syringe of TEGSEDI is filled to deliver a 284 mg dose of inotersen.

Store under refrigeration at 2 °C to 8 °C in the original container and protect from exposure to direct light. Keep out of reach and sight of children.

Remove from refrigerated storage (2 °C to 8 °C) at least 30 minutes before use. TEGSEDI prefilled syringe should be allowed to reach room temperature (20 °C to 25 °C) prior to injection.

TEGSEDI may be stored unrefrigerated (2 °C to 30 °C) in the original container for up to 6 weeks; if not used within the 6 weeks, discard TEGSEDI.

12 SPECIAL HANDLING INSTRUCTIONS

Avoid exposure to temperatures above 30 °C.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: inotersen

Chemical name: 2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3′-O→5′-O)-2′-O-(2- methoxyethyl)-5-methyl-P-thiocytidylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-5-methyl-P- thiouridylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3′-O→5′-O)-2′-O-(2- methoxyethyl)-P-thioguanylyl-(3′-O→5′-O)-2′-deoxy-P-thioguanylyl-(3′-O→5′-O)-2′-deoxy-P- thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′- O→5′-O)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′-O→5′-O)-2′- deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thioguanylyl-(3′-O→5′-O)-2′-deoxy-P- thioadenylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-P- thioadenylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3′-O→5′-O)-2′-O-(2- methoxyethyl)-5-methyl-P-thiocytidylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-5-methyl-P- thiocytidylyl-(3′-O→5′-O)-2′-O-(2-methoxyethyl)-5-methylcytidine, nonadeca sodium salt.

Molecular formula and molecular mass: The molecular formula of inotersen sodium is C230H299N69O121P19S19Na19 and the molecular weight is 7600.8 Da.

Structural formula:

Physicochemical properties:

Inotersen sodium comprises 20 nucleotides connected via 19 phosphorothioate linkages that are fully ionized as the sodium salt.

R = OCH₂CH₂OCH₃

Inotersen sodium is a white to pale yellow solid. Inotersen sodium is freely soluble in water, methanol and in phosphate buffer (pH 7.5 and pH 8.5) and insoluble in acetonitrile.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

hATTR

Efficacy of TEGSEDI was demonstrated in a Phase 3 randomized, double-blind, placebo- controlled, multicenter clinical trial (NEURO-TTR trial) in patients with hATTR.

The NEURO-TTR study was a multicenter, placebo-controlled trial with 172 hereditary Transthyretin Amyloidosis with Polyneuropathy (hATTR-PN) patients treated. hATTR-PN patients can be divided into 3 diseases stages according to their ambulatory status: stage 1 need no assistance, stage 2 need assistance with one or two devices (e.g. canes), and stage 3 are wheelchair or bed bound. Only patients with Stage 1 or Stage 2 hATTR-PN and a neuropathy impairment score (NIS) ≥10 and ≤130 were evaluated. Patients were randomized 2:1 to receive either TEGSEDI or placebo. TEGSEDI (284 mg inotersen) was administered as a subcutaneous injection 3 times in the first week and then once weekly in Weeks 2 to 65.

Sixty-two percent (62%) of patients also had TTR cardiomyopathy at baseline. Patients were randomized 2:1 to receive either TEGSEDI or placebo.

The primary efficacy endpoints were the change from baseline to Week 66 in the modified NIS+7 (mNIS+7) composite score and in the Norfolk Quality of Life (QoL)-Diabetic Neuropathy questionnaire total score. The mNIS +7 is a composite measure that consists of 2 components: the NIS composite score and the modified SUM7 Test (+7) composite score. The NIS component measures deficits in the strength of muscles innervated by the cranial nerves, muscle strength, reflexes, and sensation of the big toe and index finger. The modified +7 component of the mNIS+7 includes 4 elements: nerve conduction, heart rate to deep breathing (HRDB), touch-pressure sensation, and heat-pain (i.e., heat as pain) sensation testing. The total score ranges from 0 to 346.3 points, where an increasing score indicates worsening impairment. The Norfolk QoL-DN questionnaire is a patient-reported measure of the impact of neuropathy symptoms on quality of life. Both primary endpoints were also assessed at Week 35.

Baseline demographic and disease characteristics are shown in Table 4.

Table 4 Summary of patient demographics for clinical trials in hATTR

The changes from Baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstrated statistically significant benefit in favor of TEGSEDI treatment as early at Week 66 (Table 5).

Table 5 Primary Endpoint Analysis mNIS+7 and Norfolk QoL-DN

Patients were stratified for stage of disease (Stage 1 versus Stage 2), TTR mutation (V30M versus non-V30M) and previous treatment with either tafamidis or diflunisal (yes versus no). Results across these characteristics at Week 66 showed statistically significant benefit in all subgroups based on mNIS+7 composite score in all but one of these subgroups (CM-Echo Set) based on Norfolk QoL-DN total score. Furthermore, results across the components of mNIS+7 and domains of Norfolk QoL-DN composite scores were consistent with the primary endpoint analysis, showing benefit in motor, sensory and autonomic neuropathies. Results from secondary and exploratory endpoints failed to consistently show significant improvement of cardiomyopathy.

15 MICROBIOLOGY

TEGSEDI is not an antimicrobial drug.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Decreased platelet count was observed in monkeys after approximately 13 weeks or longer of treatment with inotersen. The decreases were sufficiently severe in 2 males (platelet count < 50 x10⁹/L), one at each of 10 and 20 mg/kg/week, as to cause bleeding or bruising. The inability to maintain platelet count with continued treatment lead to the cessation of dosing and euthanasia of both animals. Moderate decreases (platelet count > 100 x 10⁹/L) were observed at least once in the 4 other affected male and female monkeys ≥ 6 mg/kg/week. Platelet counts recovered after short-term dosing holidays; until the end of study for one low dose male with a moderate decrease, but only temporarily for the high dose male with a severe decrease. The effect was attributed to increased peripheral platelet consumption, since there was no evidence of bone marrow toxicity or thrombosis. Decreased platelet counts also occurred in mice and rats given inotersen; however, they were less severe and without clinical consequences.

Microscopic evidence of inotersen accumulation was evident as basophilic granules and vacuolation in renal tubular epithelial cells and tissue macrophages, often accompanied by hypertrophy, in multiple organs of mice, rats, and monkeys at virtually all dose levels tested. The principal organs affected were the kidneys and liver, which have the highest concentration of inotersen with lymph nodes and injection sites also consistently affected. These findings were generally not considered adverse, but evidence of renal toxicity was seen in monkeys (tubular epithelial degeneration/regeneration, erythrocytic tubular casts, multifocal mononuclear cell infiltration, fibroconnective tissue proliferation and hemorrhage correlating with hematuria and elevated protein/creatinine ratios) at the highest dose tested (40 mg/kg/week) and in rats (increased glomerular cellularity and matrix and proteinuria) at 15 and 40 mg/kg/week, with some evidence of hepatotoxicity also evident in rats at 15 and 40 mg/kg/week. Systemic exposure to inotersen, at the no effect doses was, 1.7 and 6.6 times that at the human dose for rats and monkeys respectively. Another common effect of inotersen was inflammatory changes in numerous organs in mice, rats and monkeys. This included mononuclear cell infiltrates and increases in lymphoid organ weights, associated with increases in plasma cytokines, chemokines and/or total serum IgG and IgM. In addition, reduced thymus weight due to lymphocyte depletion was observed in mice and rats and perivascular cell infiltration by lymphohistiocytic cells in multiple organs noted in monkeys.

Complement activation and increases in D-dimer concentration were observed at all subcutaneous inotersen dose levels in a 39-week study in monkeys.

Findings in rats given inotersen at 5, 15 and 40 mg/kg/week for 26 weeks included hypertrophy/hyperplasia of ovarian interstitial stromal cells and increased ovary weight, increased endometrial thickness due to expansion/edema of the stroma in the uterus, increases in hematopoietic cellularity and proliferation of vacuolated eosinophilic cells in the bone marrow and increased trabecular bone occurred in one or both sexes given inotersen at all dose levels. However, similar findings were not observed in mice and monkeys dosed for up to 26 and 39 weeks, respectively, and therefore the significance of these findings for patients is considered limited.

Carcinogenicity:

In a subcutaneous carcinogenicity study in rasH2 transgenic mice, inotersen was administered for 26 weeks at doses of 10, 30, and 80 mg/kg/week. There was no evidence of carcinogenicity for inotersen following 26 weeks of treatment in mice.

Subcutaneous administration of inotersen to Sprague-Dawley rats for up to 94 weeks at dose levels of 0.5, 2, and 6 mg/kg/week resulted in dose-dependent incidences of subcutaneous malignant pleomorphic fibrosarcoma and increased incidences of malignant fibrosarcoma of the monomorphic type in the injection sites or injection site regions (once weekly doses rotated between intrascapular and dorsal to tail areas) of both sexes at 2 and 6 mg/kg/week.

Genotoxicity:

Inotersen did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using Chinese Hamster Lung (CHL) cells, and an in vivo micronucleus assay in mice.

Reproductive and Developmental Toxicology:

Transfer of antisense oligonucleotides, such as inotersen, across the placenta is restricted because of their size, molecular charge, water solubility, and high plasma protein binding. Thus, there was no detectable inotersen in fetal tissues in fetal mouse liver after subcutaneous dosing during the period of organogenesis. In reproductive and developmental toxicity studies in mice and rabbits, at doses (administered every second day) that exceeding the maximum recommended human equivalent dose, there were no effects on organogenesis. Lower fetal body weight at the highest dose tested in rabbits was attributed to reduced maternal food consumption and body weight.

Inotersen had no effect on fertility in mice at doses up to 87.5 mg/kg/week administered as subcutaneous injections of 25 m/kg every second day.

Juvenile Toxicity:

A pre- and post-natal development study in pregnant/lactating female mice conducted to evaluate potential adverse effects of subcutaneous administration of inotersen from gestation day 6 through lactation day 20, development of the conceptus, and development of the offspring following exposure of the female from implantation through weaning showed concentrations of inotersen in breast milk were very low compared to liver concentrations (at subcutaneous doses up to 80 mg/kg/week). Due to the poor oral bioavailability of inotersen it is considered unlikely that these low milk concentrations will result in systemic exposure from nursing.

Inotersen had no effect on fertility in mice at doses up to 87.5 mg/kg/week administered as subcutaneous injections of 25 mg/kg every second day.

Since inotersen is not pharmacologically active in mice, the developmental consequences of TTR reduction were evaluated using a mouse-specific TTR analog. Approximately 40% reduction in TTR mRNA of maternal liver was produced with a 40 mg/kg dose. There were no developmental effects in mice associated with this level of TTR reduction. A rabbit-specific TTR inhibitor was not evaluated.