TEGSEDI 284mg injection solution in pre-filled syringe medication leaflet

Tegsedi 284 mg solution for injection in pre-filled syringe

Each ml contains 189 mg inotersen (as inotersen sodium).

Each pre-filled syringe contains 284 mg inotersen (as inotersen sodium) in 1.5 mL of solution.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

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

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

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

The recommended dose is 284 mg inotersen by subcutaneous injection. Doses should be administeredonce every week. For consistency of dosing, patients should be instructed to receive the injection onthe 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 dosing recommendations according to platelet count

Platelet count (x 109/L) Monitoring frequency Dosing> 100 Every 2 weeks Weekly dosing should becontinued.

≥ 75 to < 100* Every week Dosing frequency should bereduced to 284 mg every2 weeks.

< 75* Twice weekly until 3 Dosing should be paused untilsuccessive values above 75 3 successive values > 100.then weekly monitoring. On reinitiation of treatmentdose frequency should bereduced to 284 mg every 2weeks.

< 50‡† Twice weekly until 3 Dosing should be paused untilsuccessive values above 75 3 successive values > 100. Onthen weekly monitoring. reinitiation of treatment dose

More frequent monitoring frequency should be reduced toshould be considered if 284 mg every 2 weeks.additional risk factors for Corticosteroids should bebleeding are present. considered if additional riskfactors for bleeding are present.< 25† Daily until 2 successive values Treatment should beabove 25. Then twice weekly discontinued.monitoring until 3 successive Corticosteroids recommended.values above 75. Then weeklymonitoring until stable.

* If the subsequent test confirms the initial test result, then monitoring frequency and dosing should beadjusted as recommended in the table.‡ Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplateletmedicinal products, and /or prior history of major bleeding events.† It is strongly recommended that, unless corticosteroids are contraindicated, the patient receivesglucocorticoid therapy to reverse the platelet decline. Patients who discontinue therapy with inotersendue to platelet counts below 25 x 109/L should not reinitiate therapy.

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

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

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/1.73 m2 (seesection 4.3).

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

No dose adjustment is required for patients with mild or moderate hepatic impairment (see section5.2). 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, recommendedthat inotersen should be discontinued in subjects undergoing liver transplantation.

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

Subcutaneous use only. Each pre-filled syringe is for one-time use only.

The first injection administered by the patient or caregiver should be performed under the guidance ofan appropriately qualified health care professional. Patients and/or caregivers should be trained in thesubcutaneous administration of Tegsedi.

Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It isimportant to rotate sites for injection. If injected in the upper arm, the injection should be administeredby another person. Injection should be avoided at the waistline and other sites where pressure orrubbing 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 beremoved from refrigerated storage at least 30 minutes before use. Other warming methods should notbe used.

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

Platelet count < 100 x 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/1.73 m2 .

Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia at anytime during treatment (see section 4.8). Platelet count should be monitored every 2 weeks during theentire course of 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 ofunusual or prolonged bleeding (e.g. petechia, spontaneous bruising, subconjunctival bleeding,nosebleeds, bleeding from the gums, blood in urine or stools, bleeding in the whites of eyes), neckstiffness or atypical severe headache because these symptoms may be caused by bleeding in the brain.

Special caution should be used in elderly patients, in patients taking antithrombotic medicinalproducts, antiplatelet medicinal products, or medicinal products that may lower platelet count (seesection 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 functiondecline has also been observed in a number of subjects without signs of glomerulonephritis (seesection 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 bemonitored for 8 weeks following discontinuation of treatment. Patients with UPCR more than or equalto twice the upper limit of normal, or eGFR < 60 ml/min, which is confirmed on repeat testing and inthe 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 ofinotersen 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 inotersenshould be paused while further evaluation for acute glomerulonephritis is performed. Inotersen shouldpermanently be discontinued if acute glomerulonephritis is confirmed. If glomerulonephritis isexcluded, 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 ofglomerulonephritis is confirmed.

Caution should be used with nephrotoxic medicinal products and other medicinal products that mayimpair renal function (see section 4.5).

Vitamin A deficiency

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

Plasma vitamin A (retinol) levels below lower limit of normal should be corrected and any ocularsymptoms 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 Aper day in order to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral forophthalmological assessment is recommended if patients develop ocular symptoms consistent withvitamin A deficiency, including: reduced night vision or night blindness, persistent dry eyes, eyeinflammation, 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 associatedwith an increased risk of foetal malformation. Therefore, pregnancy should be excluded beforetreatment initiation and women of childbearing potential should practise effective contraception (seesection 4.6). If a woman intends to become pregnant, inotersen and vitamin A supplementation shouldbe discontinued and plasma vitamin A levels should be monitored and have returned to normal beforeconception is attempted.

In the event of an unplanned pregnancy, inotersen should be discontinued. Due to the long half-life ofinotersen (see section 5.2), a vitamin A deficit may even develop after cessation of treatment. Norecommendation can be given whether to continue or discontinue vitamin A supplementation duringthe first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the dailydose should not exceed 3 000 IU per day, due to the lack of data supporting higher doses. Thereafter,vitamin A supplementation of 3 000 IU per day should be resumed in the second and third trimester ifplasma retinol levels have not yet returned to normal, because of the increased risk of vitamin Adeficiency in the third trimester.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to preventvitamin A deficiency if the pregnant female continues to receive inotersen. However, increasingvitamin A supplementation to above 3 000 IU per day during pregnancy is unlikely to correct plasmaretinol levels due to the mechanism of action of inotersen and may be harmful to the mother andfoetus.

Liver monitoring and drug-induced liver injury

Elevated transaminases occur commonly in patients treated with inotersen. Serious cases of druginduced liver injury (DILI) have also been reported, including cases with a long time to onset (up to 1year). Liver function should be assessed before initiating treatment with inotersen. Hepatic enzymesshould be measured 4 months after initiation of treatment with inotersen and annually thereafter ormore frequently as clinically indicated. Prompt clinical evaluation and measurement of liver functiontests should be performed preferably within 72 hours in patients who report symptoms that mayindicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, orjaundice. Dose interruption should be considered until clinical and liver function evaluation isperformed. If a patient is suspected to have developed liver injury induced by inotersen, inotersenshould be permanently discontinued.

Inotersen must not be used in patients with severe hepatic impairment (see sections 4.2 and 4.3).

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 aprior liver transplant should be monitored for signs and symptoms of transplant rejection duringtreatment with inotersen. In these patients liver function tests should be performed monthly.

Discontinuation of inotersen should be considered in patients who develop liver transplant rejectionduring treatment.

Precautions prior to initiation of inotersen

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

Transient increases of C-reactive protein (CRP) and platelet levels may occur in some patients afterinitiation of inotersen. This reaction typically resolves spontaneously after a few days of treatment.

Sodium Content

This medicinal product contains less than 1 mmol sodium (23 mg) per 1.5 mL, that is to say essentially“sodium free”.

Caution should be used with antithrombotic medicinal products, antiplatelet medicinal products, andmedicinal products that may lower platelet count, for example acetylsalicylic acid, clopidogrel,warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban andapixaban, and thrombin inhibitors such as dabigatran (see sections 4.2 and 4.4).

Caution should be exercised with concomitant use of nephrotoxic medicinal products and othermedicines that may impair renal function, such as sulfonamides, aldosterone antagonists, anilides,natural opium alkaloids and other opioids (see section 4.4). A systematic assessment of co-administration of inotersen and potentially nephrotoxic medicinal products has not been conducted.

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 therapyand women of child-bearing potential should practise effective contraception.

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

It is unknown whether inotersen/metabolites are excreted in human milk. Availablepharmacodynamic/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 Tegseditherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

There is no information available on the effects of inotersen on human fertility. Animal studies did notindicate any impact of inotersen on male or female fertility.

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

The most frequently observed adverse reactions during treatment with inotersen were eventsassociated with injection site reactions (50.9%). Other most commonly reported adverse reactions withinotersen 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%).

Table 2 presents the adverse drug reactions (ADRs) listed by MedDRA system organ class. Withineach 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 decreasingseriousness. In addition, the corresponding frequency category for each ADR is based on the followingconvention: 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); and not known (cannot be estimated from theavailable data).

Table 2. List of adverse reactions in clinical studies and post-marketing sources

System Organ Very Common Common Uncommon Not known

Class

Blood and Thrombocytopenia Eosinophilialymphatic system Anaemiadisorders Platelet count

Decreased

Immune system Hypersensitivitydisorders

Metabolism and Decreased appetitenutritiondisorders

Nervous system Headachedisorders

Vascular Orthostaticdisorders hypotension

Haematoma

Gastrointestinal Vomitingdisorders Nausea

Hepatobiliary Transaminases Drug-induceddisorders increased liver injury

Skin and Pruritussubcutaneous Rashdisorders

Renal and urinary Glomerulonephritisdisorders Proteinuria

Acute kidney injury

General disorders Pyrexia Influenza likeand Chills illnessadministration Injection site Peripheral swellingsite conditions reactions Injection site

Peripheral oedema discolouration

Injury, poisoning Contusionand proceduralcomplications

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

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 x 109/L ) were observed in54% of patients treated with inotersen and 13% of placebo patients; reductions to below 100 x 109/Lwere observed in 23% of patients treated with inotersen and 2% of the patients receiving placebo;confirmed platelet counts of < 75 x 109/L were observed in 10.7% of inotersen-treated patients. Three(3%) patients developed platelet counts < 25 x 109/L; one of these patients experienced a fatalintracranial haemorrhage. Patients should be monitored for thrombocytopenia during treatment withinotersen (see section 4.4).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Platelet and renal function tests should be monitored regularly.

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

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 TTRmessenger 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 levelsof 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 retinollevels to below the lower limit of normal.

In the pivotal study, a phase 2/3 randomized, double-blind, placebo-controlled study to assess theefficacy and safety of ISIS 420915 in patients with Familial Amyloid Polyneuropathy (NEURO-TTR

Study), in the inotersen treatment group, robust reduction in circulating TTR levels was observedthroughout the 15-month treatment period, with mean percent changes from baseline in serum TTRranging 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 andthen remained fairly constant throughout the treatment period.

Transthyretin (TTR)

Least Squares Mean (LSM)

Standard Error (SE)

Figure 1 Percent change from baseline in serum TTR over time

The NEURO-TTR multicentre, double-blind, placebo-controlled trial was comprised of 172 treatedpatients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN). The diseasehATTR-PN is classified into 3 stages such that i) Stage 1 patients do not require assistance withambulation, ii) Stage 2 patients do require assistance with ambulation, and iii) Stage 3 patients arebound to wheelchair. Subjects with Stage 1 and Stage 2 hATTR-PN and a Neuropathy Impairment

Score (NIS) ≥ 10 and ≤ 130 were recruited in the pivotal NEURO-TTR study. The study evaluated284 mg inotersen administered as one subcutaneous injection once per week, for 65 weeks oftreatment. Patients were randomised 2:1 to receive either inotersen or placebo. The primary efficacyendpoints 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

Placebo Inotersen(N = 60) (N = 112)

Age (years), mean (SD) 59,5 (14,05) 59,0 (12,53)

Age 65 years and older, n (%) 26 (43,3) 48 (42,9)

Male, n (%) 41 (68,3) 77 (68,8)mNIS+7, mean (SD) 74,75 (39,003) 79,16 (36,958)

Norfolk QoL-DN, mean (SD) 48,68 (26,746) 48,22 (27,503)

Disease stage, n (%)

Stage 1 42 (70,0) 74 (66,1)

Stage 2 18 (30,0) 38 (33,9)

V30M TTR mutation1, n (%)

Yes 33 (55,0) 56 (50,0)

No 27 (45,0) 56 (50,0)

Previous treatment with tafamidis or diflunisal1, n(%)

Yes 36 (60,0) 63 (56,3)

No 24 (40,0) 49 (43,8)hATTR-CM2, n (%) 33 (55,0) 75 (66,4)hATTR-PN Disease Duration3 (months)mean (SD) 64,0 (52,34) 63,9 (53,16)hATTR-CM Disease Duration3 (months)mean (SD) 34,1 (29,33) 44,7 (58,00)1 Based on clinical database.2 Defined as all patients with a diagnosis of hereditary transthyretin amyloidosis withcardiomyopathy (hATTR-CM) at study entry or left ventricular wall thickness >1.3 cm onechocardiogram without a known history of persistent hypertension.

3 Duration from symptom onset to informed consent date.modified Neuropathy Impairment Score (mNIS)

Quality of Life-Diabetic Neuropathy (QoL-DN)hereditary transthyretin amyloidosis-polyneuropathy (hATTR-PN)

Standard deviation (SD)

The changes from baseline in both primary endpoints (mNIS+7 and Norfolk QoL-DN) demonstratedstatistically significant benefit in favour of inotersen treatment at Week 66 (Table 4). Results acrossmultiple 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 66showed statistically significant benefit in all subgroups based on mNIS+7 composite score and all butone 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 compositescores were consistent with the primary endpoint analysis, showing benefit in motor, sensory andautonomic neuropathies (Figure 2).

Table 4. Primary endpoint analysis mNIS+7 and Norfolk QoL-DNmNIS+7 Norfolk-QOL-DN

Placebo Inotersen Placebo Inotersen(N = 60) (N = 112) (N = 60) (N = 112)

Baselinen 60 112 59 111

Mean (SD) 74,75 (39,003) 79,165 (36,958) 48,68 (26,746) 48,22 (27,503)

Week 66 Changen 60 112 59 111

LSM (SE) 25,43 (3,225) 10,54 (2,397) 12,94 (2,840) 4,38 (2,175)95% CI 19,11, 31,75 15,85, 15,24 7,38, 18,51 0,11, 8,64

Difference in LSM(Tegsedi - Placebo) -14,89 -8,5695% CI -22,55 ; -7,22 -15,42 ; -1,71

P-value < 0,001 0,015

Quality of Life-Diabetic Neuropathy (QoL-DN)

Standard deviation (SD)

Least squares mean (LSM)

Table 5. Subgroup analysis of mNIS+7 and Norfolk QoL-DNmNIS+7 Norfolk QOL-DN

Change from Baseline Change from Baseline

Inotersen - Placebo Inotersen - Placebo

Subgroup N LSM P-value n LSM P-value(Placebo, Difference (Placebo, Difference

Inotersen) (SE) Inotersen) (SE)

Week 66

V30M 32, 58 -13,52 p < 0,001 32, 58 -8,14 p = 0,042(3,795) (3,998)

Non-V30 28, 54 -19,06 p < 0,001 27, 53 -9,87 p = 0,034(5,334) (4,666)

Stage I 39, 74 -12,13 p = 0,002 38, 73 -8,44 p = 0,023

Disease (3,838) (3,706)

Stage II 21, 38 -24,79 p < 0,001 21, 38 -11,23 p = 0,033

Disease (5,601) (5,271)

Previous 33, 61 -18,04 p < 0,001 32, 60 -9,26 p = 0,022use of (4,591) (4,060)stabilisers

Treatment 27, 51 -14,87 p < 0,001 27, 51 -10,21 p = 0,028naïve (4,377) (4,659)

CM-Echo 33, 75 -14,94 p < 0,001 33, 75 -7,47 p = 0,067

Set (4,083) (4,075)

Non-CM- 27, 37 -18,79 p < 0,001 26, 36 -11,67 p = 0,006

Echo Set (5,197) (4,213)

Least squares mean (LSM)

Quality of Life-Diabetic Neuropathy (QoL-DN)modified Neuropathy Impairment Score (mNIS)

NIS-W - sub-score for weakness

NIS-R - sub-score for muscle stretch reflexes

NIS-S - sub-score for clinical sensation

Heart Rate during Deep Breathing (HRDB)

Figure 2 Difference in least squares mean (LSM) change from baseline between treatmentgroups in mNIS+7 and components

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

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 forinformation on paediatric use).

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

Inotersen is highly bound to human plasma protein (> 94%) and the fraction bound is independent ofconcentration. The apparent volume of distribution of inotersen at steady-state is 293 L in patientswith hATTR. The high volume of distribution suggests inotersen extensively distributes into tissuesfollowing subcutaneous administration.

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

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

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

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

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

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

Decreased platelet counts were observed in chronic toxicity studies in mice, rats and monkeys at 1.4 to2-fold the human AUC at the recommended therapeutic inotersen dose. Severe platelet declines inassociation with increased bleeding or bruising were observed in individual monkeys. Platelet countsreturned to normal when treatment was stopped but dropped to even lower levels when inotersenadministration was resumed. This suggests an immunologically related mechanism.

Extensive and persistent uptake of inotersen was observed by various cell types in multiple organs ofall tested animal species including monocytes/macrophages, kidney proximal tubular epithelia,

Kupffer cells of the liver, and histiocytic cell infiltrates in lymph nodes and injection sites. The kidneyaccumulation of inotersen was associated with proteinuria in rats at 13.4-fold the human AUC at therecommended therapeutic inotersen dose. In addition, reduced thymus weight due to lymphocytedepletion was observed in mice and rats. In monkeys, perivascular cell infiltration bylymphohistiocytic cells in multiple organs was noted. These pro-inflammatory organ changes wereobserved at 1.4 to 6.6-fold the human AUC at the recommended therapeutic dose in all animal speciestested and were accompanied by increases of various plasma cytokines/chemokines.

Genotoxicity/ carcinogenicity

Inotersen did not exhibit genotoxic potential in in vitro and in vivo and was not carcinogenic intransgenic rasH2 mice.

Subcutaneous administration of inotersen to Sprague-Dawley rats for up to 94 weeks at doses of 0.5,2, and 6 mg/kg/week resulted in a dose-related incidence of subcutaneous pleomorphic fibrosarcomaand subcutaneous fibrosarcoma (monomorphic type) at 2 and 6 mg/kg/week in the injection site orinjection site regions. The human relevance of these findings is considered to be low.

Inotersen showed no effects on fertility, embryo-foetal, or postnatal development in mice and rabbitsat approximately 3-fold the maximum recommended human equivalent dose. Milk transfer ofinotersen was low in mice. However, inotersen is not pharmacologically active in mice and rabbits.

Consequently, only effects related to the chemistry of inotersen could be captured in theseinvestigations. Still, no effect on embryo-foetal development was noted with a mouse-specificanalogue of inotersen in mice, which was associated with ~60% inhibition (individual range up to 90%reduction) of TTR mRNA expression.

Water for injections

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

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

5 years.

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

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

Do not freeze.

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

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.

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

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

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

Akcea Therapeutics Ireland Ltd

St. James House,72 Adelaide Road, Dublin 2

D02 Y017, Ireland

EU/1/18/1296/001

EU/1/18/1296/002

Date of first authorisation: 06 July 2018

Date of latest renewal: 24 March 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.