WAYLIVRA 285mg injection solution in pre-filled syringe medication leaflet

Waylivra 285 mg solution for injection in pre-filled syringe

Each ml contains 200 mg volanesorsen sodium, equivalent to 190 mg volanesorsen.

Each single-dose pre-filled syringe contains 285 mg of volanesorsen in 1.5 ml solution.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to slightly yellow solution with a pH of approximately 8 and osmolarity of 363-485 mOsm/kg.

Waylivra is indicated as an adjunct to diet in adult patients with genetically confirmed familialchylomicronemia syndrome (FCS) and at high risk for pancreatitis, in whom response to diet andtriglyceride lowering therapy has been inadequate.

Treatment should be initiated by and remain under the supervision of a physician experienced in thetreatment of patients with FCS. Prior to initiating Waylivra, secondary causes of hypertriglyceridemia(e.g. uncontrolled diabetes, hypothyroidism) should be excluded or appropriately addressed.

The recommended starting dose is 285 mg in 1.5 ml injected subcutaneously once weekly for 3months. Following 3 months, dose frequency should be reduced to 285 mg every 2 weeks.

However, treatment should be discontinued in patients with a reduction in serum triglycerides <25%or who fail to achieve serum triglycerides below 22.6 mmol/L after 3 months on volanesorsen 285 mgweekly.

After 6 months of treatment with volanesorsen, increase of dose frequency to 285 mg weekly shouldbe considered if response has been inadequate in terms of serum triglyceride reduction as evaluated bythe supervising experienced specialist and in the condition that platelet counts are in the normal range.

Patients should be re-downtitrated to 285 mg every 2 weeks if the higher 285 mg once weekly dosedoes not provide significant additional triglyceride reduction after 9 months.

Patients should be instructed to give the injection on the same day of the week, according to medicallydetermined frequency of administration.

If a dose is missed and noticed within 48 hours, the patient should be directed to give the missed doseas soon as possible. If not noticed within 48 hours, then the missed dose should be skipped and thenext planned injection given.

Platelet monitoring and dose adjustments

Before initiation of treatment, platelet count should be measured. If the platelet count is below 140 x109/L another measurement should be taken approximately a week later to reassess. If platelet countremains below 140 x 109/L upon a second measurement, Waylivra should not be initiated (see section4.3).

After commencing treatment, patients should have platelet levels monitored at least every two weeks,depending on the platelet levels.

Treatment and monitoring should be adjusted according to laboratory values in line with Table 1.

For any patient dose paused or discontinued due to severe thrombocytopenia, the benefits and risks ofreturning to treatment once platelet count ≥100 x 109/L should be carefully considered. Fordiscontinued patients, a haematologist should be consulted prior to resuming treatment.

Table 1. Waylivra monitoring and treatment recommendations

Dose

Platelet count (x109/L) Monitoring frequency(285 mg prefilled syringe)

Starting dose: Weekly

Normal (≥140) Every 2 weeks

After 3 months: Every 2 weeks100 to 139 Every 2 weeks Weekly

Pause treatment for ≥4 weeks and75 to 99 resume treatment after platelet levels ≥ Weekly100 x 109/L

Pause treatment for ≥4 weeks and50 to 74a resume treatment after platelet levels ≥ Every 2-3 days100 x 109/L

Less than 50a, b Discontinue treatment

Glucocorticoids recommended Dailya See section 4.4 for recommendations regarding use of antiplatelet agents/non-steroidal anti-inflammatory drugs (NSAIDs)/anticoagulantsb Consultation of a haematologist is needed to reconsider the benefit/risk for possible further treatmentwith volanesorsen.

No starting dose adjustment is necessary for elderly patients. There is limited clinical data for patientsaged 65 and over (see sections 5.1 and 5.2).

No starting dose adjustment is necessary in patients with mild to moderate renal impairment. Thesafety and efficacy in patients with severe renal impairment has not been established and these patientsshould be closely observed.

This medicinal product has not been studied in patients with hepatic impairment. The medicinalproduct is not metabolised via the cytochrome P450 enzyme system in the liver, therefore doseadjustment is unlikely to be required in patients with hepatic impairment.

The safety and efficacy of this medicinal product in children and adolescents below 18 years of agehave not yet been established. No data are available.

This medicinal product is intended for subcutaneous use only. It should not be administeredintramuscularly or intravenously.

Each pre-filled syringe is for single use only.

Waylivra should be inspected visually prior to administration. The solution should be clear andcolourless to slightly yellow. If the solution is cloudy or contains visible particulate matter, thecontents must not be injected and the medicinal product should be returned to the pharmacy.

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 theadministration of this medicinal product in accordance with the patient information leaflet.

The pre-filled syringe should be allowed to reach room temperature prior to injection. It should beremoved from refrigerated storage (2 ° to 8 °C) at least 30 minutes before use. Other warming methodsshould not be used. It is normal to see a large air bubble. It should not be attempted to remove the airbubble.

It is important to rotate sites for injection. Sites for injection include the abdomen, upper thigh region,or outer area of the upper arm. If injected in the upper arm, the injection should be administered byanother person. Injection should be avoided at the waistline and other sites where pressure or rubbingmay occur from clothing. This medicinal product should not be injected into tattoos, moles,birthmarks, bruises, rashes, or areas where the skin is tender, red, hard, bruised, damaged, burned, orinflamed.

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

Chronic or unexplained thrombocytopenia. Treatment should not be initiated in patients withthrombocytopenia (platelet count <140 x 109/L).

Waylivra is very commonly associated with reductions in platelet count in patients with FCS, whichmay result in thrombocytopenia (see section 4.8). Patients with lower body weight (less than 70 kg)may be more prone to thrombocytopenia during treatment with this medicinal product. Carefulmonitoring for thrombocytopenia is important during treatment with this medicinal product in patientswith FCS (see section 4.2). Recommendations for adjustments to monitoring frequency and dosing arespecified in Table 1 (see section 4.2).

Discontinuation of antiplatelet medicinal products/NSAIDs/anticoagulants should be considered forplatelet levels < 75 x 109/L. Treatment with these medicinal products must be discontinued at plateletlevels < 50 x 109/L (see section 4.5).

Patients should be instructed to report to their physician immediately if they experience any signs ofbleeding, which can include petechiae, spontaneous bruising, subconjunctival bleeding, or otherunusual bleeding (including nosebleeds, bleeding from gums, stools, or unusually heavy menstrualbleeding), neck stiffness, atypical severe headache, or any prolonged bleeding.

LDL-C levels

With treatment with Waylivra, LDL-C levels may rise but will usually remain within the normalrange.

Renal toxicity

Renal toxicity has been observed after administration of volanesorsen and other subcutaneously andintravenously administered antisense oligonucleotides. Monitoring for evidence of nephrotoxicity byroutine urine dipstick is recommended on a quarterly basis. In the case of a positive assessment, abroader assessment of renal function, including serum creatinine and a 24-hour collection to quantifythe proteinuria and assess creatinine clearance, should be performed. Treatment should bediscontinued if: proteinuria of ≥ 500 mg/24 hour is recorded, or an increase in serum creatinine ≥ 0.3mg/dL (26.5 μmol/L) that is >ULN is recorded, or creatinine clearance estimated by the CKD-EPIequation is ≤ 30 mL/min/1.73m2. Treatment should also be discontinued for any clinical symptoms orsigns of renal impairment pending the previous confirmatory assessments.

Elevations of liver enzymes have been observed after administration of other subcutaneously andintravenously administered antisense oligonucleotides. Monitoring for hepatotoxicity through serumliver enzymes and bilirubin should be assessed on a quarterly basis. Treatment should be discontinuedif there is a single increase in ALT or AST > 8 x ULN, or an increase > 5 x ULN, which persists for ≥2 weeks, or lesser increases in ALT or AST that are associated with total bilirubin > 2 x ULN or INR> 1.5. Treatment should also be discontinued for any clinical symptoms or signs of hepatic impairmentor hepatitis.

Immunogenicity and inflammation

No evidence of altered safety profile or clinical response was associated with presence of anti-drugantibodies. If formation of anti-drug antibodies with a clinically significant effect is suspected, contactthe marketing authorisation holder to discuss antibody testing.

Monitoring of inflammation should be assessed through quarterly assessment of erythrocytesedimentation rate (ESR).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose of 285 mg, that is to sayessentially ‘sodium-free’.

No clinical drug interaction studies have been conducted.

Clinically relevant pharmacokinetic interactions are not expected between volanesorsen andsubstrates, inducers or inhibitors of cytochrome P450 (CYP) enzymes, and drug transporters. It isunknown whether triglyceride lowering by volanesorsen and the potentially ensuing decrease ininflammation leads to normalisation of CYP enzyme expression.

In clinical studies, this medicinal product has been used in combination with fibrates and fish oils withno impact on the medicinal product pharmacodynamics or pharmacokinetics. There were no adverseevents related to drug-drug interactions reported during the clinical program, however this is based onlimited data.

The effect of concomitant administration of this medicinal product with alcohol or medicinal productsknown to have potential for hepatotoxicity (e.g., paracetamol) is unknown. If signs and symptoms ofhepatotoxicity develop, use of the hepatotoxic medicinal product should be discontinued.

Antithrombotic agents and medicinal products that may lower platelet count

It is not known whether the risk of bleeding is increased by concomitant use of volanesorsen andantithrombotic agents or medicinal products that may lower platelet count or affect platelet function.

Discontinuation of antiplatelet medicinal products/NSAIDs/anticoagulants should be considered forplatelet levels <75 x 109/L and treatment with these medicinal products should be stopped at plateletlevels < 50 x 109/L (see section 4.4).

There are no data on the use of volanesorsen in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

As a precautionary measure, it is preferable to avoid the use of this medicinal product duringpregnancy.

In non-clinical studies, levels of volanesorsen in milk were very low in lactating mice. Availablepharmacodynamic/toxicological data in animals have shown excretion of very low amounts ofvolanesorsen in milk (see section 5.3). Due to the poor oral bioavailability of this medicinal product, itis considered unlikely that these low milk concentrations would result in systemic exposure fromnursing.

It is unknown whether volanesorsen or metabolites are excreted in human milk.

A risk to the newborn infant cannot be excluded.

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

No clinical data on the effect of this medicinal product on human fertility are available. Volanesorsenhad no effect on fertility in mice.

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

In clinical studies in patients with FCS, the most commonly reported adverse reactions duringtreatment were platelet count decreased occurring in 29%, thrombocytopenia occurring in 21% (seesection 4.4), and injection site reactions occurring in 82% of patients during the pivotal studies.

Table 2 presents the adverse reactions from the Phase 3 studies in patients with FCS in receivingvolanesorsen subcutaneously.

The frequency of adverse reactions is defined using 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); and not known (cannot be estimated from available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Summary of adverse reactions in clinical studies in patients with FCS (N=87)

System organ class Very common Common

Blood and lymphatic Thrombocytopenia Leukopeniasystem disorders Lymphopenia

Eosinophilia

Immune thrombocytopenicpurpura

Spontaneous haematoma

Immune system disorders Immunisation reaction

Hypersensitivity Serum sickness-like reaction

Metabolism and nutrition Diabetes mellitusdisorders

Psychiatric disorders Insomnia

Nervous system disorders Headache Syncope

Hypoaesthesia

Presyncope

Retinal migraine

Dizziness

Tremor

Eye disorders Conjunctival haemorrhage

Vision blurred

Vascular disorders Hypertension

Haematoma

Hot flush

Respiratory, thoracic and Dyspnoeamediastinal disorders Pharyngeal oedema

Wheezing

Epistaxis

Cough

Nasal congestion

Gastrointestinal disorders Nausea

Abdominal distension

Abdominal pain

Dry mouth

Gingival bleeding

Mouth haemorrhage

System organ class Very common Common

Parotid gland enlargement

Dyspepsia

Gingival swelling

Skin and subcutaneous Erythematissue disorders Pruritus

Urticaria

Hyperhidrosis

Petechiae

Ecchymosis

Night sweats

Papule

Skin hypertrophy

Swelling face

Musculoskeletal and Myalgia Arthralgiaconnective tissue disorders Pain in extremity

Arthritis

Musculoskeletal pain

Back pain

Neck pain

Pain in jaw

Muscle spasms

Joint stiffness

Myositis

Peripheral arthritis

Renal and urinary Haematuriadisorders Proteinuria

General disorders and Injection site erythema Injection site haematomaadministration site Injection site pain Astheniaconditions Injection site swelling Fatigue

Injection site reaction

Injection site discolouration Pyrexia

Injection site induration Injection site hypoaesthesia

Injection site pruritus Injection site haemorrhage

Injection site bruising Injection site warmth

Chills Injection site dryness

Injection site oedema Injection site pallor

Injection site urticaria

Injection site vesicles

Malaise

Feeling hot

Influenza-like illness

Injection site discomfort

System organ class Very common Common

Injection site inflammation

Injection site mass

Oedema

Injection site paraesthesia

Injection site scab

Injection site papule

Injection site rash

Non-cardiac chest pain

Vessel puncture sitehaemorrhage

Investigations Platelet count decreased Haemoglobin decreased

White blood cell count decreased

Blood creatinine increased

Blood urea increased

Creatinine renal clearancedecreased

Hepatic enzyme increased

International normalised ratioincreased

Transaminases increased

Injury, poisoning and Contusionprocedural complications

In the pivotal Phase 3 study in patients with FCS (the APPROACH study), confirmed reductions inplatelet counts to below normal (140 x 109/L) were observed in 75% of FCS patients treated withvolanesorsen and 24% of placebo patients; confirmed reductions to below 100 x 109/L were observedin 47% of patients treated with volanesorsen compared with no placebo patients. In APPROACH 5patients who discontinued therapy due to platelet levels included 2 patients with platelet counts <25 x109/L and 3 with platelet counts between 50 x 109/L and 75 x 109/L. It was also reported in this studythat platelet count decreased was reported in 11 (33%) patients versus 1 (3%), and thrombocytopeniawas reported in 4 (12%) patients vs none for subjects treated with volanesorsen compared to placebo,respectively.

In the open-label extension (CS7), confirmed reductions in platelet counts to below normal (140 x109/L) were observed in 52 (79%) patients overall, including 37 (74%) patients in the treatment-naïvegroup. Confirmed reductions to below 100 x 109/L were observed in 33 (50%) patients overallincluding 24 (48%) treatment naïve patients. In the open-label extension, 11 patients discontinued dueto thrombocytopenia and platelet-related events. None of these patients had any major bleeding eventsand all recovered to normal platelet count following drug discontinuation and administration ofglucocorticoids where medically indicated. In this open-label extension study, platelet count decreasedwas reported in 16 (24%) and thrombocytopenia was reported in 14 (21%) patients.

For pooled data with the APPROACH study and the CS7 study, platelet count decreased was reportedin 25 (29%) patients, and thrombocytopenia was reported in 18 (21%).

In the Phase 3 clinical studies (CS16 and APPROACH), 16% and 33% of volanesorsen-treatedpatients tested positive for anti-drug antibodies during 6-month and 12-month treatment, respectively.

No evidence of altered safety profile or clinical response was associated with presence of anti-drugantibodies; however this is based on the limited long-term data (see section 4.4).

Injection site reactions defined as any local cutaneous reaction at the injection site persisting morethan 2 days occurred in 79% of volanesorsen-treated patients in the APPROACH study and 81% ofpatients in its open-label extension (CS7). Injection site reactions occurred in 80% of volanesorsen-treated patients across both studies. These local reactions were mostly mild and typically consisted of1 or more of the following: erythema, pain, pruritus, or local swelling. Injection site reactions did notoccur with all injections and resulted in discontinuation for 1 patient in the APPROACH study and 1patient in the open label extension (CS7).

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.

There is no clinical experience with overdose of this medicinal product. In the case of overdose,patients should be carefully observed and supportive care administered, as appropriate. Symptoms ofoverdose are expected to be limited to constitutional symptoms and injection site reactions.

Haemodialysis is unlikely to be beneficial given that volanesorsen is rapidly distributed into cells.

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents, ATC code:

C10AX18

Volanesorsen is an antisense oligonucleotide designed to inhibit the formation of apoC-III, a proteinthat is recognised to regulate both triglyceride metabolism and hepatic clearance of chylomicrons andother triglyceride-rich lipoproteins. The selective binding of volanesorsen to the apoC-III messengerribonucleic acid (mRNA) within the 3′ untranslated region at base position 489-508 causes thedegradation of the mRNA. This binding prevents translation of the protein apoC-III, thus removing aninhibitor of triglyceride clearance and enabling metabolism through an LPL-independent pathway.

Effects of Waylivra on lipid parameters

In APPROACH, the Phase 3 clinical study in patients with FCS, Waylivra reduced fastingtriglycerides, total cholesterol, non-HDL cholesterol, apoC-III, apoB-48, and chylomicron triglyceridelevels and increased LDL-C, HDL-C, and apoB (see Table 3).

Table 3: Mean baseline and percent change in lipid parameters from baseline to month 3

Lipid parameter (g/L for Placebo VolanesorsenapoC-III, apoB, apoB-48; (N=33) 285 mgmmol/L for cholesterol, (N=33)triglycerides)

Baseline % Change Baseline % Change

Triglycerides 24.3 +24% 25.6 -72%

Total cholesterol 7.3 +13% 7.6 -39%

LDL-C 0.72 +7% 0.73 +139%

HDL-C 0.43 +5% 0.44 +45%

Non-HDL-C 6.9 +14% 7.1 -45%

ApoC-III 0.29 +6% 0.31 -84%

ApoB 0.69 +2% 0.65 +20%

ApoB-48 0.09 +16% 0.11 -75%

Chylomicron triglycerides 20 +38% 22 -77%

At a drug concentration 4.1 times the peak drug plasma concentrations (Cmax) of the maximumrecommended dose (285 mg subcutaneous injection), volanesorsen did not prolong the heart-ratecorrected QT (QTc) interval.

APPROACH study in patients with FCS

The APPROACH study is a randomised, double-blind placebo-controlled 52-week multicentre clinicalstudy in 66 patients with FCS, evaluating volanesorsen 285 mg administered as a subcutaneousinjection (33 treated with volanesorsen, 33 with placebo). Main inclusion criteria were a diagnosis of

FCS (Type 1 hyperlipoproteinemia) in combination with a history of chylomicronemia evidenced bydocumentation of lactescent serum or documentation of fasting TG measurement ≥ 880 mg/dl.

Diagnosis of FCS required documentation of at least one of the following:a) Confirmed homozygote, compound heterozygote, or double heterozygote for known loss-of-function mutations in Type 1-causing genes (such as LPL, APOC2, GPIHBP1, or LMF1)b) Post heparin plasma LPL activity of ≤ 20% of normal.

Patients taking Glybera within 2 years prior to screening were excluded from the study.

Nineteen of the 33 patients in the volanesorsen group completed 12 months of study treatment.

Thirteen of these patients had dose adjustment/pause on the study. Out of the 13, 5 had a dose pause, 5had a dose adjustment and 3 had both a dose pause and dose adjustment.

Mean age was 46 years (range 20-75 years; 5 patients ≥65 years old); 45% were men; 80% were

White, 17% were Asian, and 3% were of other races. Mean body mass index was 25 kg/m2. A historyof documented acute pancreatitis was reported for 76% of patients and a history of diabetes wasreported for 15% of patients; 21% of patients had a recorded history of lipaemia retinalis and 23% ofpatients had a recorded history of eruptive xanthomas. The median age at diagnosis was 27 years, with23% shown to lack a known FCS genetic mutation.

At study entry, 55% of patients were on lipid lowering therapies (48% on fibrates, 29% on fish oils,20% HMG-CoA reductase inhibitors), 27% were on pain medicinal products, 20% were on plateletaggregation inhibitors, and 14% were on nutritional supplements. Background lipid-lowering therapiesremained consistent throughout the study. Patients were prohibited from receiving plasma apheresiswithin 4 weeks prior to screening or during the study; 11% of patients had previously received genetherapy for lipoprotein lipase deficiency (i.e., alipogene tiparvovec), on average 8 years prior tostarting this study. After a 6-week diet run-in period, the mean fasting triglyceride level at baselinewas 2,209 mg/dL (25.0 mmol/L). Compliance with diet and alcohol restriction was reinforced throughperiodic counselling sessions during the study.

Waylivra led to a statistically significant reduction in triglyceride levels as compared to placebo at theprimary efficacy endpoint, defined as percent change from baseline to Month 3 in fasting triglycerides,in addition to a lower incidence of pancreatitis over the 52-week treatment period in a post-hocanalysis (Table 4).

At the primary efficacy endpoint, the treatment difference between volanesorsen and placebo in meanfasting triglyceride percent change was -94% (95% CI: -122% -67%; p˂0.0001, with a decrease of -77% from baseline (95% CI: -97, -56) in patients receiving volanesorsen and an increase of 18% frombaseline (95% CI: -4, 39) in patients receiving placebo (Table 4).

Table 4: Mean change from baseline in fasting triglycerides in the phase 3 placebo-controlledstudy in patients with FCS at month 3 (APPROACH)

Placebo Volanesorsen 285 mg Relative difference in(N=33) (N = 33) change vs placebo

LS mean percentchange (95% CI) +18% (-4, 39) -77% (-97, -56) -94%* (-122, -67)

LS mean absolutechange (95% CI) +92 (-301, +486) mg/dL -1,712 (-2,094, -1,330) -1,804 (-2,306, -1,302)+1 (-3, +5) mmol/L mg/dL mg/dLmg/dL or mmol/L -19 (-24, -15) mmol/L -20 (-26, -15) mmol/L

*p-value < 0.0001 (primary efficacy endpoint)

Difference= LS Mean of [volanesorsen % Change - Placebo % Change] (ANCOVA model)

Onset of the reduction was rapid with separation from placebo seen as early as 4 weeks and maximumresponse seen at 12 weeks, with clinically and statistically significant triglyceride reductionmaintained over 52 weeks (Figure 1). The mean fasting triglyceride percent change was significantlydifferent between volanesorsen and placebo arms at 3, 6, and 12 months; the volanesorsen armincluded patients who did not complete dosing but who returned for assessments over the 52-weekstudy. There were no significant differences in treatment effect across the stratification factors ofpresence or absence of concurrent omega-3 fatty acids or fibrates.

Figure 1: LS mean percent change in fasting triglycerides in phase 3 study in patients with FCS(APPROACH)

Percent Change from Baseline in Fasting Triglycerides:

Subset of Patients with Non-Missing Endpoints, Full Analysis Set18%20%10%0%

- 10% Placebo Waylivra

- 20%

- 30%

- 40%

- 50%

- 60%

- 70% -77%

- 80%0 2 4 6 8 10 12

Month

LS mean percent change from baseline in fasting triglycerides based on the observed data aredisplayed.

Difference= LS mean of [volanesorsen % change - placebo % change] (ANCOVA model)

LS Mean % Change from Baselinep-value from ANCOVA model < 0.0001 at month 3 (primary efficacy endpoint), month 6 and month

Additional efficacy results for changes in triglyceride are presented in Table 5. Most patients receivingvolanesorsen experienced a clinically significant reduction in triglycerides.

Table 5: Additional results for changes in triglycerides in the APPROACH study (primaryendpoint at month 3)

Placebo Volanesorsen 285 mg

Parameter at month 3a (N=31) (N=30)

Percent of patientsb with fasting 10% 77%plasma triglyceride < 750 mg/dL(8.5 mmol/L)*

Percent of patientsc with ≥ 40% 9% 88%reduction in fasting triglycerides**a The month 3 endpoint was defined as the average of week 12 (Day 78) and week 13 (Day 85) fastingassessments. If 1 visit was missing, then the other visit was used as the endpoint.

b The denominator for percentage calculation was the total number of patients in FAS with baselinefasting triglyceride ≥ 750 mg/dL (or 8.5 mmol/L) in each treatment group.

c The denominator for percentage calculation was the total number of patients in each treatment group.

* p-value =0.0001

**p-value < 0.0001

P-values from logistic regression model with treatment, presence of pancreatitis and presence ofconcurrent omega-3 fatty acids and/or fibrates as factors, and logarithm-transformed baseline fastingtriglycerides as a covariate.

In the APPROACH study, the numerical incidence of pancreatitis in patients treated with volanesorsenwas lower compared with placebo (3 patients 4 events in 33 placebo patients vs 1 patient 1 event in 33volanesorsen patients).

An analysis of patients with a history of recurrent pancreatitis events (≥ 2 events in the 5 years prior to

Study Day 1) showed a significant reduction in pancreatitis attacks in volanesorsen-treated patientscompared to placebo treated patients (p=0.0242). In the volanesorsen group, of the 7 patients who had24 adjudicated pancreatitis attacks in the prior 5 years, none of the patients experienced a pancreatitisattack during the 52 week treatment period. In the placebo group, of the 4 patients who had 17adjudicated pancreatitis attacks in the prior 5 years, 3 patients experienced 4 pancreatitis attacksduring the 52-week treatment period.

Open-label extension study in patients with FCS

CS7 is a multicentre, open-label extension Phase 3 study designed to evaluate the safety and efficacyof dosing and extended dosing with volanesorsen in patients with FCS. All patients enrolled either hadparticipated in the APPROACH Study, in the CS16 Study, or were new FCS patients and hadcompleted qualification assessments prior to receiving volanesorsen 285 mg once per week or areduced frequency for safety or tolerability reasons determined in their index study. A total of 68patients have been treated in this study including 51 treatment-naïve patients, 14 patients who hadreceived volanesorsen in Study CS6, and 3 patients who had received volanesorsen in Study CS16.

Fifty patients had a dose pause, 45 had a dose adjustment and 41 had both a dose pause and a doseadjustment.

Data from Study CS7 is provided in Table 6. The percent change in fasting TG from Index Study

Baseline to Open-label Month 3 for the APPROACH- and CS16-volanesorsen patients was -49.2%and -64.9%, respectively. The percent change in fasting TG from index study baseline to open-labelmonth 6, month 12 and month 24 for the APPROACH-volanesorsen patients was -54.8%, -35.1% and

- 50.2%, respectively.

Table 6: Summary of fasting triglycerides (mean (SD, SEM), mg/dL) over time in study CS7(N=68)

Time Treatment-naïve group APPROACH-volanesorsen CS16-volanesorsenpoint (open-label study (index study baselinea, N=14) (index study baselinea,baselinea, N=51) N=3)% %change % change change

Observed from Observed from Observed fromn value baseline n value baseline n value baseline

Baselinea 2341 2641 228851 (1193, - 14 (1228, - 3 (1524, -167) 328) 880)

Month 347 804 (564, -59.8 126682) (37.0, 14 (812, -49.2 (34.8, 855 (651, -64.95.4) 217) 9.3) 3 376) (9.1, 5.3)

Month 6 -45.5 1248 1215 -43.049 1032 -54.8 (23.8,(695, 99) (42.9, 13 (927, 3 (610, (19.7,6.1) 257) 6.6) 352) 11.4)

Month 1332 -36.3 1670 1351 -41.612 45 (962, (44.2, 12 (1198, -35.1 (45.6, 3 (929, (36.3,143) 6.6) 346) 13.2) 536) 21.0)

Month 1328 -35.6 1886 1422 3.415 34 (976, (48.1, 10 (1219, -26.5 (57.4,18.1) 2 (190, (23.3,167) 8.2) 386) 135) 16.5)

Month 1367 -37.5 1713 1170 -24.018 27 (938, (45.6, 7 (1122, -38.4 (32.2,12.2) 2 (843, (31.9,181) 8.8) 424) 596) 22.6)

Month 1331 -40.5 182624 21 (873, (47.4, 5 (1743, -50.2 (32.2, 1198 -26.314.4) 2 (1177, (56.0,190) 10.3) 780) 832) 39.6)a Baseline values for treatment-naïve group were taken from the open-label study CS7 and baseline for

APPROACH-volanesorsen and CS16-volanesorsen groups were taken from the respective indexstudy.

Clinical studies included 4 patients with FCS aged 65 treated with volanesorsen in randomised controlstudies (phase II study CS2, 1 patient; APPROACH 3 patients), and 6 patients aged 65 and over in theopen-label extension study (CS7). No overall differences in safety or effectiveness were observedbetween these patients and younger patients, however data are limited in this subpopulation.

The European Medicines Agency has deferred the obligation to submit the results of studies withvolanesorsen in one or more subsets of the paediatric population in the treatment of familialchylomicronemia syndrome (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

Following subcutaneous injection, peak plasma concentrations of volanesorsen are typically reached in2 to 4 hours. The absolute bioavailability of volanesorsen following a single subcutaneousadministration is approximately 80% (most likely higher because an AUC of 0 to 24 hours was usedand volanesorsen has a half-life of >2 weeks).

Following a dose of 285 mg once weekly in patients with FCS, the estimated geometric mean(coefficient of variation % of geometric mean) steady-state Cmax is 8.92 µg/ml (35%), AUC0-168h is 136µg*h/ml (38%), and Ctrough is 127 ng/ml (58%) in patients who remain negative for anti-drug antibody.

An alternative dosing regimen of 285 mg volanesorsen every two weeks results in a Ctrough,ss ofapproximately 58.0 ng/ml with Cmax and AUC similar compared to the once weekly dosing regimen.

Volanesorsen was rapidly and widely distributed to tissues following subcutaneous or intravenousadministration in all species evaluated. The estimated steady-state volume of distribution (Vss) inpatients with FCS is 330 L. Volanesorsen is highly bound to human plasma proteins (>98%) and thebinding is concentration independent.

In vitro studies show that volanesorsen is not a substrate or inhibitor of P-glycoprotein (P-gp), breastcancer resistance protein (BCRP), organic anion transporting polypeptides (OATP1B1, OATP1B3),bile salt export pump (BSEP), organic cation transporters (OCT1, OCT2), or organic aniontransporters (OAT1, OAT3).

Volanesorsen is not a substrate for CYP metabolism, and is metabolised in tissues by endonucleases toform shorter oligonucleotides that are then substrates for additional metabolism by exonucleases.

Unchanged volanesorsen is the predominant circulating component.

In vitro studies indicate that volanesorsen is not an inhibitor of CYP1A2, CYP2B6, CYP2C8,

CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 or inducer of CYP1A2, CYP2B6, or CYP3A4.

Elimination involves both metabolism in tissues and excretion in urine. Urinary recovery of the parentdrug was limited in humans with < 3% of administered subcutaneous dose recovered within 24 hourspost dose. The parent drug and 5- to 7-mer chain-shortened metabolites accounted for approximately26% and 55% of oligonucleotides recovered in urine, respectively. Following subcutaneousadministration, terminal elimination half-life is approximately 2 to 5 weeks.

In animals, elimination of volanesorsen was slow and occurred mainly via urinary excretion, reflectingrapid plasma clearance principally to tissues. Both volanesorsen and shorter oligonucleotidemetabolites (predominantly 7-mer metabolites (generated either from 3′-deletions or 5′-deletions))were identified in human urine.

Single- and multiple-dose pharmacokinetics of volanesorsen in healthy volunteers and patients withhypertriglyceridemia have shown that the Cmax of volanesorsen is dose-proportional over a dose rangeof 100 to 400 mg and the AUC is slightly more than dose-proportional over the same dose range.

Steady-state was reached approximately 3 months after starting volanesorsen. Accumulation in Ctroughwas observed (7- to 14-fold) and little or no increase in Cmax or AUC was observed following weekly

SC administration over a dose of 200 to 400 mg. Some accumulation in AUC and Cmax was observedfor the 50 to 100 mg dose. Since the administered dose will be 285 mg every two weeks, or 142.5 mgweekly, little increase in Cmax or AUC is expected upon multiple dosing in the clinical setting.

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

The pharmacokinetics of volanesorsen in patients with hepatic impairment is unknown.

Age, sex, weight, and race

Based on the population pharmacokinetic analysis, age, body weight, sex, or race has no clinicallyrelevant effect on volanesorsen exposure. There are limited data available in subjects >75 years of age.

Anti-volanesorsen antibody formation affecting pharmacokinetics

The formation of binding antibodies to volanesorsen appeared to increase total Ctrough by 2- to 19-fold.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenicity or toxicity to reproduction and development.

Dose and time-dependent reductions in platelet counts were observed in Cynomolgus monkeyrepeated dose studies. The decrease was gradual, self-sustaining and did not decrease to adverselevels. In individual monkeys, severe thrombocytopenia was noted in the 9 month study of drugtreated groups at clinically relevant exposures and has also been observed in clinical studies. Thedecrease in platelet counts was not acute and decreased to below 50,000 cells/μl. Platelet countsrecovered after cessation of treatment, but decreased again below 50,000 cells/μl after treatment wasresumed in some monkeys. Decreased platelet counts were also observed in rodent repeated dosestudies. A mode of action for the observed thrombocytopenia is currently not known.

In nonclinical studies, levels of volanesorsen in milk were very low in lactating mice. Theconcentrations in breast milk of mice were >800 fold lower than effective tissue concentrations inmaternal liver. Due to the poor oral bioavailability of volanesorsen, it is considered unlikely that theselow milk concentrations would result in systemic exposure from nursing (see section 4.6).

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections.

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

5 years

This medicinal product can be removed from refrigeration and stored, in the original carton, at roomtemperature (below 30 °C) for up to 6 weeks. In this 6-week period, it can be kept as needed betweenrefrigerated and room temperature (up to 30 °C). This medicinal product must be discardedimmediately if not used within the 6 weeks after the first time it is removed from refrigerated storage.

Store in a refrigerator (2 ° - 8 °C).

Do not freeze.

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

Single-dose, type I glass pre-filled syringe with a siliconised chlorobutyl rubber stopper and stakedneedle with shield, filled to deliver 1.5 ml of solution.

Pack sizes of one pre-filled syringe or multipacks containing 4 (4 packs of 1) pre-filled syringes.

Not all pack sizes may be marketed.

This medicinal product should be inspected visually prior to administration. The solution should beclear and colourless to slightly yellow. If the solution is cloudy or contains visible particulate matter,the contents must not be injected and the medicinal product should be returned to the pharmacy.

Use each pre-filled syringe only once and then place in a sharps disposal container for disposalaccording to community guidelines.

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

Akcea Therapeutics Ireland Ltd.

St. James House72 Adelaide Road, Dublin 2

D02 Y017

Ireland

EU/1/19/1360/001

EU/1/19/1360/002

Date of first authorisation: 03 May 2019

Date of latest renewal: 14 February 2022

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

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