TEGSEDI 284 MG SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Section 4.8 for how to report adverse reactions

Tegsedi 284 mg solution for injection in pre-filled syringe

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 284 mg inotersen (as sodium).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection (injection)

Clear, colourless to pale yellow solution (pH 7.5 – 8.8)

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Tegsedi is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

4.2 Posology and method of administration

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

Posology

The recommended dose is 284 mg inotersen by subcutaneous injection. Doses should be administered once every week. For consistency of dosing, patients should be instructed to receive the injection on the same day every week.

Dose adjustment in case of reduction in platelet count

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

Table 1. Inotersen 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.

J Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, and /or prior history of major bleeding events

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

Missed doses

If a dose of inotersen is missed, then the next dose should be administered as soon as possible, unless the next scheduled dose is within two days, in which case the missed dose should be skipped and the next dose administered as scheduled.

Special populations

Elderly

No dose adjustment is required in patients aged 65 and over (see section 5.2).

Renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment (see section 5.2). Inotersen should not be used in patients with a urine protein to creatinine ratio (UPCR) > 113 mg/mmol (1 g/g) or estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2 (see section 4.3).

Because of the risk of glomerulonephritis and possible renal function decline, UPCR and eGFR should be monitored during treatment with inotersen (see section 4.4). If acute glomerulonephritis is confirmed, permanent discontinuation of the treatment should be considered.

Hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (see section 5.2). Inotersen must not be used in patients with severe hepatic impairment (see section 4.3).

Patients undergoing liver transplant

Inotersen has not been evaluated in patients undergoing liver transplant. It is, therefore, recommended that dosing of inotersen should be discontinued in subjects undergoing liver transplantation.

Paediatric population

The safety and efficacy of inotersen in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration

Subcutaneous use 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.

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.

The pre-filled syringe should be allowed to reach room temperature prior to injection. It should be removed from refrigerated storage at least 30 minutes before use. Other warming methods should not be used.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Platelet count < 100 × 109/L prior to treatment.

Urine protein to creatinine ratio (UPCR) > 113 mg/mmol (1 g/g) prior to treatment.

Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73m2.

Severe hepatic impairment.

4.4 Special warnings and precautions for use

Thrombocytopenia

Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia (see section 4.8). Platelet count should be monitored every 2 weeks during treatment with inotersen and for 8 weeks following discontinuation of treatment.

Recommendations for adjustments to monitoring frequency and inotersen dosing are specified in Table 1 (see section 4.2).

Patients should be instructed to report to their physician immediately if they experience any signs of unusual or prolonged bleeding (e.g. petechia, spontaneous bruising, subconjunctival bleeding, nosebleeds), neck stiffness or atypical severe headache.

Special caution should be used in elderly patients, in patients taking antithrombotic medicinal products, antiplatelet medicinal products, or medicinal products that may lower platelet count (see section 4.5), and in patients with prior history of major bleeding events.

Glomerulonephritis/ renal function decline

Glomerulonephritis has occurred in patients treated with inotersen (see section 4.8). Renal function decline has also been observed in a number of subjects without signs of glomerulonephritis (see section 4.8).

UPCR and eGFR should be monitored every 3 months or more frequently, as clinically indicated, based on history of chronic kidney disease and/or renal amyloidosis. UPCR and eGFR should be monitored for 8 weeks following discontinuation of treatment. Patients with UPCR more than or equal to twice the upper limit of normal, or eGFR < 60 ml/min, which is confirmed on repeat testing and in the absence of an alternative explanation, should be monitored every 4 weeks.

In the case of a decrease in eGFR >30%, in the absence of an alternative explanation, pausing of inotersen 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 inotersen should be paused while further evaluation for acute glomerulonephritis is performed. Inotersen 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 (see section 4.3).

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 (see section 4.5).

Vitamin A deficiency

Based on the mechanism of action, inotersen is expected to reduce plasma vitamin A (retinol) below normal levels (see section 5.1).

Plasma vitamin A (retinol) levels below lower limit of normal should be corrected and any ocular symptoms or signs of vitamin A deficiency should have resolved prior to initiation of inotersen.

Patients receiving inotersen should take oral supplementation of approximately 3,000 IU vitamin A per day in order to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency, including: reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening, corneal perforation.

During the first 60 days of pregnancy, both too high and too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before treatment initiation and women of childbearing potential should practise effective contraception (see section 4.6). If a woman intends to become pregnant, inotersen and vitamin A supplementation should be discontinued and plasma vitamin A levels should be monitored and have returned to normal before conception is attempted.

In the event of an unplanned pregnancy, inotersen should be discontinued. Due to the long half-life of inotersen (see section 5.2), a vitamin A deficit may even develop after cessation of treatment. No recommendation can be given whether to continue or discontinue vitamin A supplementation during the first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the daily dose should not exceed 3000 IU per day, due to the lack of data supporting higher doses. Thereafter, vitamin A supplementation of 3000 IU per day should be resumed in the second and third trimester if plasma retinol levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive inotersen. However, increasing vitamin A supplementation to above 3000 IU per day during pregnancy is unlikely to correct plasma retinol levels due to the mechanism of action of inotersen and may be harmful to the mother and foetus.

Liver monitoring

Hepatic enzymes should be measured 4 months after initiation of treatment with inotersen and annually thereafter or more frequently as clinically indicated, in order to detect cases of hepatic impairment (see section 4.8).

Liver Transplant Rejection

Inotersen was not evaluated in patients undergoing liver transplantation in clinical trials (section 4.2). Cases of liver transplant rejection have been reported in patients treated with Inotersen. Patients with a prior liver transplant should be monitored for signs and symptoms of transplant rejection during treatment with Inotersen. In these patients liver function tests should be performed monthly. Discontinuation of Inotersen should be considered in patients who develop liver transplant rejection during treatment.

Precautions prior to initiation of inotersen

Platelet count, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR) and hepatic enzymes should be measured prior to treatment with Tegsedi.

Transient increases of CRP and platelet levels may occur in some patients after initiation of inotersen. This reaction typically resolves spontaneously after a few days of treatment.

4.5 Interaction with other medicinal products and other forms of interaction

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 section 4.4).

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 section 4.4). Although the population PK analysis did not identify clinically relevant effects of some nephrotoxic medicines on the clearance of inotersen or on the potential for an effect on renal function, a systematic assessment of co-administration of inotersen and potentially nephrotoxic medicinal products has not been conducted.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

Inotersen will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus (see section 4.4). For this reason, pregnancy should be excluded before initiation of inotersen therapy and women of child-bearing potential should practise effective contraception.

Pregnancy

There are no or limited amount of data from the use of inotersen in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising from unbalanced vitamin A levels, inotersen should not be used during pregnancy, unless the clinical condition of the woman requires treatment with inotersen. Women of child-bearing potential have to use effective contraception during treatment with inotersen.

Breast-feeding

It is unknown whether inotersen/meta­bolites are excreted in human milk. Available pharmacodynamic/to­xicological data in animals have shown excretion of inotersen metabolites in milk (see section 5.3). A risk to the breastfed newborn/infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Tegsedi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There is no information available on the effects of inotersen on human fertility.

Animal studies did not indicate any impact of inotersen on male or female fertility.

4.7 Effects on ability to drive and use machines

Tegsedi has no or negligible influence on the ability to drive and use machines

4.8 Undesirable effects

Summary of the safety profile

The most frequently observed adverse reactions during treatment with inotersen were events associated with injection site reactions (50.9%). Other most commonly reported adverse reactions with inotersen were nausea (31.3%), headache (23.2%), pyrexia (19.6%), peripheral oedema (18.8%), chills (17.9%), vomiting (15.2%), anaemia (13.4%), thrombocytopenia (13.4%) and platelet count decreased (10.7%).

Tabulated summary of adverse reactions

Table 2 presents the adverse reactions (ADRs) listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Table 2. List of adverse reactions in clinical studies

Description of selected adverse reactions

Injection site reactions

The most frequently observed events included events associated with injection site reactions (includes injection site pain, erythema, pruritus, swelling, rash, induration, bruising and haemorrhage). These events are usually either self-limiting or can be managed using symptomatic treatment.

Thrombocytopenia

Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia. In the Phase 3, NEURO-TTR trial, platelet count reductions to below normal (140 × 109/L ) were observed in 54% of patients treated with inotersen and 13% of placebo patients; reductions to below 100 × 109/L were observed in 23% of patients treated with inotersen and 2% of the patients receiving placebo; confirmed platelet counts of < 75 × 109/L were observed in 10.7% of inotersen-treated patients.

Three (3%) patients developed platelet counts < 25 × 109/L; one of these patients experienced a fatal intracranial haemorrhage. Patients should be monitored for thrombocytopenia during treatment with inotersen (see section 4.4).

Glomerulonephritis / renal function decline

Patients should be monitored for signs of increased proteinuria and reduction in eGFR during treatment with inotersen (see section 4.4).

Immunogenicity

In the pivotal Phase 2/3 study, 30.4% of patients treated with inotersen tested positive for anti-drug antibodies following 15 months of treatment. Development of anti-drug antibodies to inotersen was characterised by late onset (median onset > 200 days) and low titer (median peak titer of 284 in the pivotal study). No effect on the pharmacokinetic properties (Cmax, AUC or half-life) and efficacy of inotersen was observed in the presence of anti-drug antibodies, but patients with anti-drug antibodies had more reactions at the injection site.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other Nervous System Drugs, ATC code: N07XX15

Mechanism of action

Inotersen is a 2-O-2-methoxyethyl (2'-MOE) phosphorothioate antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) production. The selective binding of inotersen to the TTR messenger RNA (mRNA) causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein 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 principal carrier of vitamin A (retinol). Therefore, reduction in plasma TTR is expected to result in reduction of plasma retinol levels to below the lower limit of normal.

Pharmacodynamic effects

In the pivotal NEURO-TTR study, in the inotersen 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 ranging from 68.41% to 74.03% (median range: 74.64% to 78.98%) from Week 13 to Week 65 (Figure 1). In the placebo group, mean serum TTR concentration decreased by 8.50% at Week 3 and then remained fairly constant throughout the treatment period.

Figure 1 Percent Change from Baseline in Serum TTR Over Time

Clinical efficacy and safety

The NEURO-TTR multicentre, double-blind, placebo-controlled trial was comprised of 172 treated patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN). The disease hATTR-PN is classified into 3 stages such that i) Stage 1 patients do not require assistance with ambulation, ii) Stage 2 patients do require assistance with ambulation, and iii) Stage 3 patients are bound to wheelchair.

Subjects with Stage 1 and Stage 2 hATTR-PN and an NIS >10 and <130 were recruited in the pivotal NEURO-TTR study. The study evaluated 284 mg inotersen administered as one subcutaneous injection once per week, for 65 weeks of treatment. Patients were randomised 2:1 to receive either inotersen or placebo. The primary efficacy endpoints were the change from baseline to Week 66 in the modified Neuropathy Impairment Score + 7 tests (mNIS+7) composite score and in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. 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). Baseline demographic and disease characteristics are shown in Table 3.

Table 3. Baseline demographics

Based on clinical database

2

Defined as all patients with a diagnosis of hereditary transthyretin amyloidosis with cardiomyopathy (hATTR-CM) at study entry or left ventricular wall thickness >1.3 cm on echocardiogram without a known history of persistent hypertension

Duration from symptom onset to informed consent date

The changes from baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstrated statistically significant benefit in favour of inotersen treatment at Week 66 (Table 4). Results across multiple disease characteristics [TTR mutation (V30M, non-V30M)], disease stage (Stage 1, Stage 2), previous treatment with tafamidis or diflunisal (yes, no), presence of hATTR-CM (yes, no) at Week 66 showed statistically significant benefit in all subgroups based on mNIS+7 composite score and all but one of these subgroups (CM-Echo Set; p=0.067) based on Norfolk QoL-DN total score (Table 5). 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 (Figure 2).

Table 4. Primary Endpoint Analysis mNIS+7 and Norfolk QoL-DN

Table 5. Subgroup Analysis of mNIS+7 and Norfolk QoL-DN

mNIS+7 (pcO.OOl) ■

NIS (p<O.OOl) ■

Modified +7 (p=O.O2O) ■ NIS-W (pcO.OOl) ■

NIS-R (p=0.177) ■

NIS-S (p<0.001) ■

HRDB (p=0.704) ■

Nerve Conduction (p=O.O51) ■ Touch-Pressure (p=0.101) ■

Heat-Pa in (p=0.007) ■

–25

5       10

Favors Inotersen Favors Placebo

LSM Difference in Change from Baseline at Week 66 (Inotersen-Placebo Effect Size, 95% Cl)

Figure 2 Difference in Least Squares Mean (LSM) Change from Baseline Between Treatment Groups in mNIS+7 and Components

A responder analysis of mNIS+7 using thresholds ranging from a 0– to 30-point increase from baseline (using the safety set), showed the inotersen group had approximately a 2-fold higher response rate than the placebo group at each threshold tested, demonstrating consistency of response. A responder was defined as a subject who had a change from baseline that was less than or equal to the threshold value. Subjects that terminate the treatment early irrespective of the reason or have missing week 66 data are considered as non-responders. Statistical significance in favour of inotersen was demonstrated at all thresholds beyond a 0-point change.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Tegsedi in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

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

Distribution

Inotersen is highly bound to human plasma protein (> 94%) and the fraction bound is independent of drug concentration. The apparent volume of distribution of inotersen at steady-state is 293 L in patients with hATTR. The high volume of distribution suggests inotersen extensively distributes into tissues following SC administration.

Biotransformation

Inotersen is not a substrate for CYP450 metabolism, and is metabolised in tissues by endonucleases to form shorter inactive oligonucleotides that are the substrates for additional metabolism by exonucleases. Unchanged inotersen is the predominant circulating component.

Elimination

The elimination of inotersen involves both metabolism in tissues and excretion in urine. Both inotersen and its shorter oligonucleotide metabolites are excreted in human urine. Urinary recovery of the parent medicinal product is limited to less than 1% within the 24 hours post dose. Following subcutaneous administration, elimination half-life for inotersen is approximately 1 month.

Special populations

Based on the population pharmacokinetic analysis, age, body weight, sex or race has no clinically relevant effect on inotersen exposure. Definitive assessments were limited in some cases as covariates were limited by the overall low numbers.

Elderly population

No overall differences in pharmacokinetics were observed between other adult and elderly patients.

Renal impairment

A population pharmacokinetic analysis suggests that mild and moderate renal impairment has no clinically relevant effect on the systemic exposure of inotersen. No data are available in patients with severe renal impairment.

Hepatic impairment

The pharmacokinetics of inotersen in patients with hepatic impairment has not been studied. Inotersen is not primarily cleared by metabolism in the liver, not a substrate for CYP450 oxidation, and metabolized broadly by nucleases in all tissues of distribution. Thus, pharmacokinetics should not be altered in mild to moderate hepatic impairment.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

4 years.

Tegsedi may be stored unrefrigerated for up to 6 weeks below 30 °C. If not used within 6 weeks, it should be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

1.5 mL solution in a clear Type 1 glass pre-filled syringe.

Tray with tear-off lid.

Pack sizes of 1 or 4 pre-filled syringes. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Tegsedi should be inspected visually prior to administration. The solution should be clear and colourless to pale yellow. If the solution is cloudy or contains visible particulate matter, the contents must not be injected.

Each pre-filled syringe should be used only once and then placed in a sharps disposal container for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Akcea Therapeutics Ireland Ltd

Regus House,

Harcourt Centre, Harcourt Road

Dublin 2, Ireland