PRALUENT 150mg injection for pre-filled pen medication leaflet

Praluent 75 mg solution for injection in pre-filled pen

Praluent 150 mg solution for injection in pre-filled pen

Praluent 75 mg solution for injection in pre-filled syringe

Praluent 150 mg solution for injection in pre-filled syringe

Praluent 300 mg solution for injection in pre-filled pen

Praluent 75 mg solution for injection in pre-filled pen

Each single-use pre-filled pen contains 75 mg alirocumab in 1 ml solution.

Praluent 75 mg solution for injection in pre-filled syringe

Each single-use pre-filled syringe contains 75 mg alirocumab in 1 ml solution.

Praluent 150 mg solution for injection in pre-filled pen

Each single-use pre-filled pen contains 150 mg alirocumab in 1 ml solution.

Praluent 150 mg solution for injection in pre-filled syringe

Each single-use pre-filled syringe contains 150 mg alirocumab in 1 ml solution.

Praluent 300 mg solution for injection in pre-filled pen

Each single-use pre-filled pen contains 300 mg alirocumab in 2 ml solution.

Alirocumab is a human IgG1 monoclonal antibody produced in Chinese Hamster Ovary cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear, colourless to pale yellow solution.

pH: 5.7 - 6.3

Osmolality:

Praluent 75 mg solution for injection293 - 439 mOsm/kg

Praluent 150 mg solution for injection383 - 434 mOsm/kg

Praluent 300 mg solution for injection383 - 434 mOsm/kg

Primary hypercholesterolaemia and mixed dyslipidaemia

Praluent is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial)or mixed dyslipidaemia, and in paediatric patients 8 years of age and older with heterozygous familialhypercholesterolaemia (HeFH) as an adjunct to diet:

- in combination with a statin or statin with other lipid lowering therapies in patients unable to reach

LDL-C goals with the maximum tolerated dose of a statin or,

- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, orfor whom a statin is contraindicated.

Established atherosclerotic cardiovascular disease

Praluent is indicated in adults with established atherosclerotic cardiovascular disease to reducecardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors:

- in combination with the maximum tolerated dose of a statin with or without other lipid-loweringtherapies or,

- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, orfor whom a statin is contraindicated.

For study results with respect to effects on LDL-C, cardiovascular events and populations studied see section5.1.

Prior to initiating alirocumab secondary causes of hyperlipidaemia or mixed dyslipidaemia (e.g., nephroticsyndrome, hypothyroidism) should be excluded.

The usual starting dose for alirocumab is 75 mg administered subcutaneously once every 2 weeks. Patientsrequiring larger LDL-C reduction (>60%) may be started on 150 mg once every 2 weeks, or 300 mg onceevery 4 weeks (monthly), administered subcutaneously.

The dose of alirocumab can be individualised based on patient characteristics such as baseline LDL-C level,goal of therapy, and response. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration,and dose adjusted accordingly (up-titration or down-titration). If additional LDL-C reduction is needed inpatients treated with 75 mg once every 2 weeks or 300 mg once every 4 weeks (monthly), the dosage may beadjusted to the maximum dosage of 150 mg once every 2 weeks.

HeFH in paediatric patients 8 years of age and older

Recommended dose if additional

Body weight of patients Recommended dose

LDL-C reduction is needed*

Less than 50 kg 150 mg once every 4 weeks 75 mg once every 2 weeks50 kg or more 300 mg once every 4 weeks 150 mg once every 2 weeks

* Lipid levels can be assessed 8 weeks after treatment initiation or titration and dose adjusted accordingly.

If a dose is missed, the dose should be administered as soon as possible and thereafter, dosing should beresumed on the original schedule.

No dose adjustment is needed for elderly patients.

No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are availablein patients with severe hepatic impairment (see section 5.2).

No dose adjustment is needed for patients with mild or moderate renal impairment. Limited data areavailable in patients with severe renal impairment (see section 5.2).

No dose adjustment is needed in patients based on weight.

The safety and efficacy of Praluent in children less than 8 years of age have not been established. No data areavailable.

Subcutaneous use.

Alirocumab is injected as a subcutaneous injection into the thigh, abdomen or upper arm.

Each pre-filled pen or pre-filled syringe is for single use only.

To administer the 300 mg dose, either one 300 mg injection or two 150 mg injections should be givenconsecutively at two different injection sites.

It is recommended to rotate the injection site with each injection.

Alirocumab should not be injected into areas of active skin disease or injury such as sunburns, skin rashes,inflammation, or skin infections.

Alirocumab must not be co-administered with other injectable medicinal products at the same injection site.

The solution should be allowed to warm to room temperature prior to use (see section 6.6).

Paediatric patients 8 years of age and older

In adolescents 12 years of age and older, it is recommended that Praluent be administered by or under thesupervision of an adult.

In children less than 12 years of age, Praluent must be given by a caregiver.

Adult patients may either self-inject alirocumab, or a caregiver may administer alirocumab, after guidancehas been provided by a healthcare professional on proper subcutaneous injection technique.

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

In order to improve the traceability of biological medicinal products, the name and the batch number of theadministered product should be clearly recorded.

General allergic reactions, including pruritus, as well as rare and sometimes serious allergic reactions such ashypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in clinicalstudies. Angioedema has been reported in the postmarketing setting (see section 4.8). If signs or symptomsof serious allergic reactions occur, treatment with alirocumab must be discontinued and appropriatesymptomatic treatment initiated (see section 4.3).

In clinical studies, there was limited representation of patients with severe renal impairment (defined aseGFR < 30 ml/min/1.73 m2) (see section 5.2). Alirocumab should be used with caution in patients withsevere renal impairment.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 5.2). Alirocumabshould be used with caution in patients with severe hepatic impairment.

Effects of alirocumab on other medicinal products

Since alirocumab is a biological medicinal product, no pharmacokinetic effects of alirocumab on othermedicinal products and no effect on cytochrome P450 enzymes are anticipated.

Effects of other medicinal products on alirocumab

Statins and other lipid-modifying therapy are known to increase production of PCSK9, the protein targeted byalirocumab. This leads to the increased target-mediated clearance and reduced systemic exposure ofalirocumab. Compared to alirocumab monotherapy, the exposure to alirocumab is about 40%, 15%, and 35%lower when used concomitantly with statins, ezetimibe, and fenofibrate, respectively. However, reduction of

LDL-C is maintained during the dosing interval when alirocumab is administered every two weeks.

There are no data from the use of Praluent in pregnant women. Alirocumab is a recombinant IgG1 antibody,therefore it is expected to cross the placental barrier (see section 5.3).

Animal studies do not indicate direct or indirect harmful effects with respect to maintenance of pregnancy orembryo-foetal development; maternal toxicity was noted in rats, but not in monkeys at doses in excess of thehuman dose, and a weaker secondary immune response to antigen challenge was observed in the offspring ofmonkeys (see section 5.3).

The use of Praluent is not recommended during pregnancy unless the clinical condition of the womanrequires treatment with alirocumab.

It is not known whether alirocumab is excreted in human milk. Human immunoglobulin G (IgG) is excretedin human milk, in particular in colostrum; the use of Praluent is not recommended in breast-feeding womenduring this period. For the remaining duration of breast-feeding, exposure is expected to be low.

Since the effects of alirocumab on the breast-fed infant are unknown, a decision should be made whether todiscontinue nursing or to discontinue Praluent during this period.

In animal studies, there were no adverse effects on surrogate markers of fertility (see section 5.3). There areno data on adverse effects on fertility in humans.

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

The most common adverse reactions, at recommended doses, are local injection site reactions (6.1%), upperrespiratory tract signs and symptoms (2.0%), and pruritus (1.1%). Most common adverse reactions leading totreatment discontinuation in patients treated with alirocumab were local injection site reactions.

The safety profile in ODYSSEY OUTCOMES was consistent with the overall safety profile described in thephase 3 controlled trials.

No difference in the safety profile was observed between the two doses (75 mg and 150 mg) used in thephase 3 program.

The following adverse reactions were reported in patients treated with alirocumab in pooled controlledstudies and/or post-marketing use (see Table 1).

Frequencies for all adverse reactions identified from clinical trials have been calculated based on theirincidence in pooled phase 3 clinical trials. Adverse reactions are presented by system organ class. Frequencycategories are defined as: 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).

The frequency of adverse reactions reported during post-marketing use cannot be determined as they arederived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as 'notknown'.

Table 1 - Adverse reactions

System organ class Common Rare Not known

Immune system disorders Hypersensitivity,hypersensitivityvasculitis

Respiratory, thoracic and Upper respiratorymediastinal disorders tract signs andsymptoms*

Skin and subcutaneous tissue Pruritus Urticaria, Angioedemadisorders eczema nummular

System organ class Common Rare Not known

General disorders and Injection site Flu-like illnessadministration site conditions reactions**

* including mainly oropharyngeal pain, rhinorrhea, sneezing

** including erythema/redness, itching, swelling, pain/tenderness

Local injection site reactions

Local injection site reactions, including erythema/redness, itching, swelling, and pain/tenderness, werereported in 6.1% of patients treated with alirocumab versus 4.1% in the control group (receiving placeboinjections). Most injection site reactions were transient and of mild intensity. The discontinuation rate due tolocal injection site reactions was comparable between the two groups (0.2% in the alirocumab group versus0.3% in the control group). In the cardiovascular outcomes study (ODYSSEY OUTCOMES), injection sitereactions also occurred more frequently in alirocumab-treated patients than in placebo-treated patients (3.8%alirocumab versus 2.1% placebo).

General allergic reactions

General allergic reactions were reported more frequently in the alirocumab group (8.1% of patients) than inthe control group (7.0% of patients), mainly due to a difference in the incidence of pruritus. The observedcases of pruritus were typically mild and transient. In addition, rare and sometimes serious allergic reactionssuch as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported incontrolled clinical studies (see section 4.4). In the cardiovascular outcomes study (ODYSSEY

OUTCOMES), general allergic reactions were similar in alirocumab-treated patients and placebo-treatedpatients (7.9% alirocumab, 7.8% placebo). No difference was seen in the incidence of pruritus.

Although no safety issues were observed in patients over 75 years of age, data are limited in this age group.

In the phase 3 primary hypercholesterolemia and mixed dyslipidaemia controlled studies, 1,158 patients(34.7%) treated with alirocumab were ≥65 years of age and 241 patients (7.2%) treated with alirocumab were≥75 years of age. In the cardiovascular outcomes controlled study, 2,505 patients (26.5%) treated withalirocumab were ≥65 years of age and 493 patients (5.2%) treated with alirocumab were ≥75 years of age.

There were no significant differences observed in safety and efficacy with increasing age.

The safety and efficacy of Praluent have been established in children and adolescents with heterozygousfamilial hypercholesterolaemia (HeFH). A clinical study to evaluate the effects of Praluent was conducted in153 patients, 8 to 17 years of age with HeFH. No new safety findings were identified and the safety data inthis population were consistent with the known safety profile of the product in adults with HeFH.

The experience of alirocumab in paediatric patients with homozygous familial hypercholesterolaemia(HoFH) is limited to 18 patients aged 8 to 17 years. No new safety finding was observed compared to theknown adult safety profile.

Every 4 week dosing study

The safety profile in patients treated with a 300 mg once every 4 week (monthly) dosing regimen was similarto the safety profile as described for the clinical studies program using a 2 week dosing regimen, except for ahigher rate of local injection site reactions. Local injection site reactions were reported overall at a frequencyof 16.6% in the 300 mg once every 4 weeks treatment group and 7.9% in the placebo group. Patients in thealirocumab 300 mg every 4 weeks treatment group received alternating placebo injections to maintainblinding in regard to injection frequency. Excluding injection site reactions (ISRs) that occurred after theseplacebo injections, the frequency of ISRs was 11.8%. The discontinuation rate due to injection site reactionswas 0.7% in the 300 mg once every 4 weeks treatment group and 0% in the placebo group.

LDL-C values <25 mg/dL (<0.65 mmol/L)

In all clinical studies background lipid lowering therapies could not be adjusted by trial design. Thepercentage of patients who reached LDL-C values <25 mg/dL (<0.65 mmol/L) depended both on thebaseline LDL-C and the dose of alirocumab.

In a pool of controlled studies using a 75 mg every 2 week (Q2W) starting dose and in which the dose wasincreased to 150 mg Q2W if the patient’s LDL-C was not <70 mg/dL or < 100 mg/dL (1.81 mmol/L or 2.59mmol/L), 29.3% of patients with baseline LDL-C <100 mg/dL and 5.0% of patients with baseline LDL-C≥100 mg/dL treated with alirocumab had two consecutive values of LDL-C <25 mg/dL (<0.65 mmol/L). Inthe ODYSSEY OUTCOMES study, in which the starting alirocumab dose was 75 mg Q2W and the dosewas increased to 150 mg Q2W if the patient’s LDL-C was not <50 mg/dL (1.29 mmol/L), 54.8% of patientswith baseline LDL-C <100 mg/dL and 24.2% of patients with baseline LDL-C ≥100 mg/dL treated withalirocumab had two consecutive values of LDL-C <25 mg/dL (<0.65 mmol/L).

Although adverse consequences of very low LDL-C were not identified in alirocumab trials, the long-termeffects of sustained very low levels of LDL-C are unknown.

Immunogenicity/ Anti-drug-antibodies (ADA)

In the ODYSSEY OUTCOMES trial, 5.5% of patients treated with alirocumab 75 mg and/or 150 mg every2 weeks (Q2W) had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% ofpatients treated with placebo, most of these were transient responses. Persistent ADA responses wereobserved in 0.7% of patients treated with alirocumab and 0.4% of patients treated with placebo. Neutralisingantibody (NAb) responses were observed in 0.5% of patients treated with alirocumab and in <0.1% ofpatients treated with placebo.

Anti-drug antibody responses, including NAb, were low titer and did not appear to have a clinicallymeaningful impact on the efficacy or safety of alirocumab, except for a higher rate of injection site reactionsin patients with treatment emergent ADA compared to patients who were ADA negative (7.5% vs 3.6%).

The long-term consequences of continuing alirocumab treatment in the presence of ADA are unknown.

In a pool of ten placebo-controlled and active-controlled trials of patients treated with alirocumab 75 mgand/or 150 mg Q2W as well as in a separate clinical study of patients treated with alirocumab 75 mg Q2W or300 mg every 4 weeks (including some patients with dose adjustment to 150 mg Q2W), the incidence ofdetecting ADA and NAb was similar to the results from the ODYSSEY OUTCOMES trial described above.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no specific treatment for alirocumab overdose. In the event of an overdose, the patient should betreated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents, ATC code: C10AX14.

Alirocumab is a fully human IgG1 monoclonal antibody that binds with high affinity and specificity toproprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors(LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primaryreceptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher bloodlevels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRsavailable to clear LDL, thereby lowering LDL-C levels.

The LDLR also binds triglyceride-rich VLDL remnant lipoproteins and intermediate-density lipoprotein(IDL). Therefore, alirocumab treatment can produce reductions in these remnant lipoproteins as evidencedby its reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C) andtriglycerides (TG). Alirocumab also results in reductions in lipoprotein (a) [Lp(a)], which is a form of LDLthat is bound to apolipoprotein (a). However, the LDLR has been shown to have a low affinity for Lp(a),therefore the exact mechanism by which alirocumab lowers Lp(a) is not fully understood.

In genetic studies in humans, PCSK9 variants with either loss-of-function or gain-of-function mutations havebeen identified. Individuals with single allele PCSK9 loss-of-function mutation have lower levels of LDL-C,which correlated with a significantly lower incidence of coronary heart disease. A few individuals have beenreported, who carry PCSK9 loss-of-function mutations in two alleles and have profoundly low LDL-Clevels, with HDL-C and TG levels in the normal range. Conversely, gain-of-function mutations in the

PCSK9 gene have been identified in patients with increased LDL-C levels and a clinical diagnosis of familialhypercholesterolaemia.

In a multicenter, double-blind, placebo-controlled, 14 week study, 13 patients with heterozygous familialhypercholesterolaemia (heFH) due to gain-of-function mutations in the PCSK9 gene were randomised toreceive either alirocumab 150 mg Q2W or placebo. Mean baseline LDL-C was 151.5 mg/dL (3.90 mmol/L).

At week 2, the mean reduction from baseline in LDL-C was 62.5% in the alirocumab-treated patients ascompared to 8.8% in the placebo patients. At week 8, the mean reduction in LDL-C from baseline with allpatients treated with alirocumab was 72.4%.

In in vitro assays, alirocumab did not induce Fc-mediated effector function activity (antibody-dependentcell-mediated toxicity and complement-dependent cytotoxicity) either in the presence or absence of PCSK9and no soluble immune complexes capable of binding complement proteins were observed for alirocumabwhen bound to PCSK9.

Clinical efficacy and safety in primary hypercholesterolaemia and mixed dyslipidaemia

Summary of the Phase 3 Clinical Trials Program - 75 mg and/or 150 mg every 2 weeks (Q2W) dosingregimen

The efficacy of alirocumab was investigated in ten phase 3 trials (five placebo-controlled and fiveezetimibe-controlled studies), involving 5,296 randomised patients with hypercholesterolaemia(heterozygous familial and non-familial) or mixed dyslipidaemia, with 3,188 patients randomised toalirocumab. In the phase 3 studies, 31% of patients had type 2 diabetes mellitus, and 64% of patients had ahistory of coronary heart disease. Three of the ten studies were conducted exclusively in patients withheterozygous familial hypercholesterolaemia (heFH). The majority of patients in the phase 3 program weretaking background lipid-modifying therapy consisting of a maximally tolerated dose of statin, with orwithout other lipid-modifying therapies, and were at high or very high cardiovascular (CV) risk. Two studieswere conducted in patients who were not concomitantly treated with a statin, including one study in patientswith documented statin intolerance.

Two studies (LONG TERM and HIGH FH), involving a total of 2,416 patients, were performed with a150 mg every 2 weeks (Q2W) dose only. Eight studies were performed with a dose of 75 mg Q2W, andcriteria-based up-titration to 150 mg Q2W at week 12 in patients who did not achieve their pre-defined target

LDL-C based on their level of CV risk at week 8.

The primary efficacy endpoint in all of the phase 3 studies was the mean percent reduction from baseline in

LDL-C at week 24 as compared to placebo or ezetimibe. All of the studies met their primary endpoint. Ingeneral, administration of alirocumab also resulted in a statistically significant greater percent reduction intotal cholesterol (Total-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo

B), and lipoprotein (a) [Lp(a)] as compared to placebo/ ezetimibe, whether or not patients wereconcomitantly being treated with a statin. Alirocumab also reduced triglycerides (TG), and increasedhigh-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo A-1) as compared to placebo.

For detailed results see Table 2 below. Reduction in LDL-C was seen across age, gender, body mass index(BMI), race, baseline LDL-C levels, patients with heFH and non-heFH, patients with mixed dyslipidaemia,and diabetic patients. Although similar efficacy was observed in patients over 75 years, data are limited inthis age group. LDL-C reduction was consistent regardless of concomitantly used statins and doses. Asignificantly higher proportion of patients achieved an LDL-C of ˂70 mg/dL (˂1.81 mmol/L) in thealirocumab group as compared to placebo or ezetimibe at week 12 and week 24. In studies using the criteria-based up-titration regimen, a majority of patients achieved the pre-defined target LDL-C (based on theirlevel of CV risk) on the 75 mg Q2W dose, and a majority of patients maintained treatment on the 75 mg

Q2W dose. The lipid-lowering effect of alirocumab was observed within 15 days after the first dose reachingmaximum effect at approximately 4 weeks. With long-term treatment, efficacy was sustained over theduration of the studies (up to 2 years). Following discontinuation of alirocumab, no rebound in LDL-C wasobserved, and LDL-C levels gradually returned to baseline levels.

In pre-specified analyses before possible up-titration at week 12 in the 8 studies in which patients startedwith the 75 mg every 2 weeks dosing regimen, mean reductions in LDL-C ranging from 44.5% to 49.2%were achieved. In the 2 studies in which patients were started and maintained on 150 mg every 2 weeks, theachieved mean reduction of LDL-C at week 12 was 62.6%. In analyses of pooled phase 3 studies thatallowed up-titration, among the subgroup of patients up-titrated, an increase from 75 mg Q2W to 150 mg

Q2W alirocumab at week 12 resulted in an additional 14% mean reduction in LDL-C in patients on abackground statin. In patients not on a background statin, up-titration of alirocumab resulted in an additional3% mean reduction in LDL-C, with the majority of the effect seen in approximately 25% of patients whoachieved at least an additional 10% LDL-C lowering after up-titration. Patients up-titrated to 150 mg Q2Whad a higher mean baseline LDL-C.

Evaluation of cardiovascular (CV) events

In pre-specified analyses of pooled phase 3 studies, treatment-emergent CV events confirmed byadjudication, consisting of coronary heart disease (CHD) death, myocardial infarction, ischemic stroke,unstable angina requiring hospitalisation, congestive heart failure hospitalisation, and revascularisation, werereported in 110 (3.5%) patients in the alirocumab group and 53 (3.0%) patients in the control group (placeboor active control) with HR=1.08 (95% CI, 0.78 to 1.50). Major adverse cardiovascular events (“MACE-plus”, i.e.: CHD death, myocardial infarction, ischemic stroke, and unstable angina requiring hospitalisation)confirmed by adjudication were reported in 52 of 3,182 (1.6%) patients in the alirocumab group and 33 of1,792 (1.8%) patients in the control group (placebo or active control); HR=0.81 (95% CI, 0.52 to 1.25).

In pre-specified final analyses of the LONG TERM study, treatment-emergent CV events confirmed byadjudication occurred in 72 of 1,550 (4.6%) patients in the alirocumab group and in 40 of 788 (5.1%)patients in the placebo group; MACE-plus confirmed by adjudication were reported in 27 of 1,550 (1.7%)patients in the alirocumab group and 26 of 788 (3.3%) patients in the placebo group. Hazard ratios werecalculated post-hoc; for all CV events, HR=0.91 (95% CI, 0.62 to 1.34); for MACE-plus, HR=0.52 (95% CI,0.31 to 0.90).

All-cause mortality

All-cause mortality in phase 3 studies was 0.6% (20 of 3,182 patients) in the alirocumab group and 0.9% (17of 1,792 patients) in the control group. The primary cause of death in the majority of these patients was CVevents.

Combination therapy with a statin

Placebo-controlled phase 3 studies (on background statin) in patients with primary hypercholesterolaemiaor mixed dyslipidaemia

LONG TERM study

This multicenter, double-blind, placebo-controlled, 18-month study included 2,310 patients with primaryhypercholesterolaemia at high or very high CV risk and on a maximally tolerated dose of statin, with orwithout other lipid-modifying therapy. Patients received either alirocumab at a dose of 150 mg Q2W orplacebo in addition to their existing lipid-modifying therapy. The LONG TERM study included 17.7% heFHpatients, 34.6% with type 2 diabetes mellitus, and 68.6% with a history of coronary heart disease. At week24, the mean treatment difference from placebo in LDL-C percent change from baseline was -61.9% (95%

CI: -64.3%, -59.4%; p-value: ˂0.0001). For detailed results see Table 2. At week 12, 82.1% of patients in thealirocumab group reached an LDL-C ˂70 mg/dL (˂1.81 mmol/L) compared to 7.2% of patients in theplacebo group. Difference versus placebo was statistically significant at week 24 for all lipids/lipoproteins.

COMBO I study

A multicenter, double-blind, placebo-controlled, 52 week study included 311 patients categorised as veryhigh CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin, with orwithout other lipid-modifying therapy. Patients received either 75 mg alirocumab Q2W or placebo inaddition to their existing lipid-modifying therapy. Dose up-titration of alirocumab to 150 mg Q2W occurredat week 12 in patients with LDL-C ≥70 mg/dL (≥1.81 mmol/L). At week 24, the mean treatment differencefrom placebo in LDL-C percent change from baseline was -45.9% (95% CI: -52.5%, -39.3%; p-value:

˂0.0001). For detailed results see Table 4. At week 12 (before up-titration), 76.0% of patients in thealirocumab group reached an LDL-C of ˂70 mg/dL (˂ 1.81 mmol/L) as compared to 11.3% in the placebogroup. The dose was up-titrated to 150 mg Q2W in 32 (16.8%) patients treated beyond 12 weeks. Among thesubgroup of patients up-titrated at week 12, an additional 22.8% mean reduction in LDL-C was achieved atweek 24. The difference versus placebo was statistically significant at week 24 for all lipids/ lipoproteinsexcept TG and Apo A-1.

Placebo-controlled phase 3 studies (on background statin) in patients with heterozygous familialhypercholesterolaemia (heFH)

FH I and FH II studies

Two multicenter, placebo-controlled, double-blind 18-month studies included 732 patients with heFHreceiving a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patientsreceived either alirocumab 75 mg Q2W or placebo in addition to their existing lipid-modifying therapy. Doseup-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C≥70 mg/dL (≥1.81 mmol/L). At week 24, the mean treatment difference from placebo in LDL-C percentchange from baseline was -55.8% (95% CI: -60.0%, -51.6%; p-value: ˂ 0.0001). For detailed results see

Table 2. At week 12 (before up-titration), 50.2% of patients reached an LDL-C of˂70 mg/dL (˂1.81 mmol/L) as compared to 0.6% in the placebo group. Among the subgroup of patientsup-titrated at week 12, an additional 15.7% mean reduction in LDL-C was achieved at week 24. Differenceversus placebo was statistically significant at week 24 for all lipids/ lipoproteins.

HIGH FH study

A third multicenter, double-blind, placebo-controlled 18-month study included 106 heFH patients on amaximally tolerated dose of statin, with or without other lipid-modifying therapies, and a baseline LDL-C≥160 mg/dL (≥4.14 mmol/L). Patients received either alirocumab at a dose of 150 mg Q2W or placebo inaddition to their existing lipid-modifying therapy. At week 24, the mean treatment difference from placebo in

LDL-C percent change from baseline was -39.1% (95% CI: -51.1%, -27.1%; p-value: ˂0.0001). For detailedresults see Table 2. Mean changes for all other lipids/ lipoproteins were similar to the FH I and FH II studies,however statistical significance was not reached for TG, HDL-C and Apo A-1.

Ezetimibe-controlled phase 3 study (on background statin) in patients with primary hypercholesterolaemiaor mixed dyslipidaemia

COMBO II study

A multicenter, double-blind, ezetimibe-controlled 2 year study included 707 patients categorised as very high

CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin. Patients receivedeither alirocumab 75 mg Q2W or ezetimibe 10 mg once daily in addition to their existing statin therapy.

Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C≥70 mg/dL (≥1.81 mmol/L). At week 24, the mean treatment difference from ezetimibe in LDL-C percentchange from baseline was -29.8% (95% CI: -34.4%, -25.3%; p-value: ˂0.0001). For detailed results see

Table 2. At week 12 (before up-titration), 77.2% of patients reached an LDL-C of˂70 mg/dL (˂1.81 mmol/L) as compared to 46.2% in the ezetimibe group. Among the subgroup of patientsup-titrated at week 12, an additional 10.5% mean reduction in LDL-C was achieved at week 24. Differenceversus ezetimibe was statistically significant at week 24 for all lipids/ lipoproteins except for TG, and Apo

A-1.

Monotherapy or as add-on to non-statin lipid-modifying therapy

Ezetimibe-controlled phase 3 trials in patients with primary hypercholesterolaemia (without a backgroundstatin)

ALTERNATIVE study

A multicentre, double-blind, ezetimibe-controlled, 24 week study included 248 patients with documentedstatin intolerance due to skeletal muscle-related symptoms. Patients received either alirocumab 75 mg Q2Wor ezetimibe 10 mg once daily, or atorvastatin 20 mg once daily (as a re-challenge arm). Dose up-titration ofalirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C ≥70 mg/dL (≥1.81 mmol/L) or≥100 mg/dL (≥2.59 mmol/L), depending on their level of CV risk. At week 24, the mean treatmentdifference from ezetimibe in LDL-C percent change from baseline was -30.4% (95% CI: -36.6%, -24.2%; p-value: ˂0.0001). For detailed results see Table 2. At week 12 (before up-titration), 34.9% of patients reachedan LDL-C of ˂70 mg/dL (˂1.81 mmol/L) as compared to 0% in the ezetimibe group. Among the subgroup ofpatients up-titrated at week 12, an additional 3.6% mean reduction in LDL-C was achieved at week 24.

Difference versus ezetimibe was statistically significant at week 24 for LDL-C, Total-C, Non-HDL-C, Apo

B, and Lp(a).

This trial evaluated patients who did not tolerate at least two statins (at least one at the lowest approveddose), In these patients, musculo-skeletal adverse events occurred at a lower rate in the alirocumab group(32.5%) as compared to the atorvastatin group (46.0%) (HR= 0.61 [95% CI, 0.38 to 0.99]), and a lowerpercentage of patients in the alirocumab group (15.9%) discontinued study treatment due to musculo-skeletaladverse events as compared to the atorvastatin group (22.2%). In the five placebo-controlled trials in patientson a maximally tolerated dose of statin (n=3752), the discontinuation rate due to musculo-skeletal adverseevents was 0.4% in the alirocumab group and 0.5% in the placebo group.

MONO study

A multicenter, double-blind, ezetimibe-controlled, 24-week study included 103 patients with a moderate CVrisk, not taking statins or other lipid-modifying therapies, and a baseline LDL-C between100 mg/dL (2.59 mmol/L) to 190 mg/dL (4.91 mmol/L). Patients received either alirocumab 75 mg Q2W orezetimibe 10 mg once daily. Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patientswith LDL-C ≥70 mg/dL (≥1.81 mmol/L). At week 24, the mean treatment difference from ezetimibe in

LDL-C percent change from baseline was -31.6% (95% CI: -40.2%, -23.0%; p-value: ˂0.0001). For detailedresults see Table 2. At week 12 (before up-titration), 57.7% of patients reached an LDL-C of˂70 mg/dL (˂1.81 mmol/L) as compared to 0% in the ezetimibe group. The dose was up-titrated to 150 mg

Q2W in 14 (30.4%) patients treated beyond 12 weeks. Among the subgroup of patients up-titrated at week12, an additional 1.4 % mean reduction in LDL-C was achieved at week 24. The difference versus ezetimibewas statistically significant at week 24 for LDL-C, Total-C, Non-HDL-C and Apo B.

Table 2: Mean percent change from baseline in LDL-C and other lipids/ lipoproteins in placebo-controlled and ezetimibe-controlled studies - 75 mg and/or 150 mg Q2W dosing regimen

Mean Percent Change from Baseline in Placebo-Controlled Studies on Background Statin

LONG TERM FHI and FHII High FH (N=106) COMBO I (N=311)(N=2310) (N=732)

Placeb Alirocuma Placeb Alirocuma Placeb Alirocuma Placeb Alirocumao b o b o b o b

Number 780 1530 244 488 35 71 106 205ofpatients

Mean 122.0 122.8 140.9 141.3 201.0 196.3 104.6 100.3

Baseline (3.16) (3.18) (3.65) (3.66) (5.21) (5.10) (2.71) (2.60)

LDL-C inmg/dL(mmol/L)

Week 12

LDL-C 1.5 -63.3 5.4 -43.6 -6.6 -46.9 1.1 -46.3(ITT)a

LDL-C 1.4 -64.2 5.3 -44.0 -6.6 -46.9 1.7 -47.6(ontreatment)b

Week 24

LDL-C 0.8 -61.0c 7.1 -48.8d -6.6 -45.7e -2.3 -48.2f(ITT)a

LDL-C 0.7 -62.8 6.8 -49.3 -6.6 -45.5 -0.8 -50.7(ontreatment)b

Non- 0.7 -51.6 7.4 -42.8 -6.2 -41.9 -1.6 -39.1

HDL-C

Apo B 1.2 -52.8 1.9 -41.7 -8.7 -39.0 -0.9 -36.7

Total-C -0.3 -37.8 5.5 -31.2 -4.8 -33.2 -2.9 -27.9

Lp(a) -3.7 -29.3 -8.5 -26.9 -8.7 -23.5 -5.9 -20.5

TG 1.8 -15.6 4.3 -9.8 -1.9 -10.5 -5.4 -6.0

HDL-C -0.6 4.0 0.2 7.8 3.9 7.5 -3.8 3.5

Apo A-1 1.2 4.0 -0.4 4.2 2.0 5.6 -2.5 3.3

Mean percent change from baseline in ezetimibe-controlled studies

On background statin Without background statin

COMBO II (N=707) ALTERNATIVE (N=248) MONO (N=103)

Ezetimibe Alirocumab Ezetimibe Alirocumab Ezetimibe Alirocumab

Number of 240 467 122 126 51 52patients

Mean baseline 104.5 108.3 194.2 191.1 138.3 141.1

LDL-C in mg/dL (2.71) (2.81) (5.03) (5.0) (3.58) (3.65)(mmol/L)

Week 12

LDL-C (ITT )a -21.8 -51.2 -15.6 -47.0 -19.6 -48.1

LDL-C (on -22.7 -52.4 -18.0 -51.2 -20.4 -53.2treatment)b

Week24

LDL-C (ITT)a -20.7 -50.6g -14.6 -45.0h -15.6 -47.2i

LDL-C (on -21.8 -52.4 -17.1 -52.2 -17.2 -54.1treatment)b

Non-HDL-C -19.2 -42.1 -14.6 -40.2 -15.1 -40.6

Apo B -18.3 -40.7 -11.2 -36.3 -11.0 -36.7

Total-C -14.6 -29.3 -10.9 -31.8 -10.9 -29.6

Lp(a) -6.1 -27.8 -7.3 -25.9 -12.3 -16.7

TG -12.8 -13.0 -3.6 -9.3 -10.8 -11.9

HDL-C 0.5 8.6 6.8 7.7 1.6 6.0

Apo A-1 -1.3 5.0 2.9 4.8 -0.6 4.7a ITT analysis - intent-to-treat population, includes all lipid data throughout the duration of the study irrespective ofadherence to the study treatment.b On-treatment analysis - analysis restricted to the time period that patients actually received treatment.

The % LDL-C reduction at week 24 corresponds to a mean absolute change of:c -74.2 mg/dL (-1.92 mmol/L); d -71.1 mg/dL (-1.84 mmol/L); e -90.8 mg/dL (-2.35 mmol/L); f -50.3 mg/dL (-1.30 mmol/L); g -55.4 mg/dL (1.44 mmol/L); h -84.2 mg/dL (-2.18 mmol/L); i -66.9 mg/dL (-1.73 mmol/L)

Every 4 week (Q4W) dosing regimen

CHOICE I study

A multicenter, double-blind, placebo-controlled, 48 week study included 540 patients on a maximallytolerated dose of a statin, with or without other lipid-modifying therapy (308 in the alirocumab 300 mg Q4Wgroup, 76 in the alirocumab 75 mg Q2W group, and 156 in the placebo group), and 252 patients not treatedwith a statin (144 in the alirocumab 300 mg Q4W group, 37 in the alirocumab 75 mg Q2W group, and 71 inthe placebo group). Patients received either alirocumab 300 mg Q4W, alirocumab 75 mg Q2W, or placebo inaddition to their existing lipid-modifying therapy (statin, non-statin therapy or diet alone). Patients in thealirocumab 300 mg every 4 weeks treatment group received alternating placebo injections to maintainblinding in regard to injection frequency. Overall, 71.6% of patients were categorized at high or very high

CV risk and not at their LDL-C target. Dose adjustment in the alirocumab groups to 150 mg Q2W occurredat week 12 in patients with LDL-C ≥70 mg/dL or ≥100 mg/dL, depending on their level of CV risk, or inpatients who did not have at least a 30% reduction of LDL-C from baseline.

In the cohort of patients on background statin, the mean baseline LDL-C was 112.7 mg/dL. At week 12, themean percent change from baseline with alirocumab 300 mg Q4W in LDL-C (ITT analysis) was -55.3%compared to +1.1% for placebo. At week 12 (before dose adjustment), 77.3% of patients treated withalirocumab 300 mg Q4W reached an LDL-C of ˂70 mg/dL as compared to 9.3% in the placebo group. Atweek 24, the mean percent change from baseline with alirocumab 300 mg Q4W/150 mg Q2W in LDL-C(ITT analysis) was -58.8% compared to -0.1% for placebo. At week 24, the mean treatment difference foralirocumab 300 mg Q4W/150 mg Q2W from placebo in LDL-C percent change from baseline was -58.7%(97.5% CI: -65.0%, -52.4%; p-value: ˂ 0.0001). In patients treated beyond 12 weeks, the dose was adjustedto 150 mg Q2W in 56 (19.3%) of 290 patients in the alirocumab 300 mg Q4W arm. Among the subgroup ofpatients dose adjusted to 150 mg Q2W at week 12, an additional 25.4% reduction in LDL-C was achieved atweek 24.

In the cohort of patients not treated with a concomitant statin, the mean baseline LDL-C was 142.1 mg/dL.

At week 12, the mean percent change from baseline with alirocumab 300 mg Q4W in LDL-C (ITT analysis)was -58.4% compared to +0.3% for placebo. At week 12 (before dose adjustment), 65.2% of patients treatedwith alirocumab 300 mg Q4W reached an LDL-C of ˂70 mg/dL as compared to 2.8% in the placebo group.

At week 24, the mean percent change from baseline with alirocumab 300 mg Q4W/150 mg Q2W in LDL-C(ITT analysis) was -52.7% compared to -0.3% for placebo. At week 24, the mean treatment difference foralirocumab 300 mg Q4W/150 mg Q2W from placebo in LDL-C percent change from baseline was -52.4%(97.5% CI: -59.8%, -45.0%; p-value: ˂ 0.0001). In patients treated beyond 12 weeks, the dose was adjustedto 150 mg Q2W in 19 (14.7%) of 129 patients in the alirocumab 300 mg Q4W arm. Among the subgroup ofpatients dose adjusted to 150 mg Q2W at week 12, an additional 7.3% mean reduction in LDL-C wasachieved at week 24.

In both cohorts, the difference vs placebo was statistically significant at week 24 for all lipid parameters,except for Apo A-1 in the subgroup of patients on background statin.

Clinical efficacy and safety in prevention of cardiovascular events

ODYSSEY OUTCOMES study

A multicentre, double-blind, placebo-controlled trial included 18,924 adult patients (9,462 alirocumab; 9,462placebo) followed for up to 5 years. Patients had experienced an acute coronary syndrome (ACS) event 4 to52 weeks prior to randomization and were treated with a lipid-modifying-therapy (LMT) regimen that wasstatin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally tolerateddose of those statins, with or without other LMT. Patients were randomized 1:1 to receive either alirocumab75 mg once every two weeks (Q2W) or placebo Q2W. At month 2, if additional LDL-C lowering wasrequired based on pre-specified LDL-C criteria (LDL-C ≥50 mg/dL or 1.29 mmol/L), alirocumab wasadjusted to 150 mg Q2W. For patients who had their dose adjusted to 150 mg Q2W and who had twoconsecutive LDL-C values below 25 mg/dL (0.65 mmol/L), down-titration from 150 mg Q2W to 75 mg

Q2W was performed. Patients on 75 mg Q2W who had two consecutive LDL-C values below 15 mg/dL(0.39 mmol/L) were switched to placebo in a blinded fashion. Approximately 2,615 (27.7%) of 9,451patients treated with alirocumab required dose adjustment to 150 mg Q2W. Of these 2615 patients, 805(30.8%) were down-titrated to 75 mg Q2W. Overall, 730 (7.7%) of 9,451 patients switched to placebo. Atotal of 99.5% of patients were followed for survival until the end of the trial. The median follow-up durationwas 33 months.

The index ACS event was a myocardial infarction in 83.2% of patients (34.6% STEMI, 48.6% NSTEMI)and an episode of unstable angina in 16.8% of patients. Most patients (88.8%) were receiving high intensitystatin therapy with or without other LMT at randomization. The mean LDL-C value at baseline was 92.4mg/dL (2.39 mmol/L).

Alirocumab significantly reduced the risk for the primary composite endpoint of the time to first occurrenceof Major Adverse Cardiovascular Events (MACE-plus) consisting of coronary heart disease (CHD) death,non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, or unstable angina (UA) requiringhospitalization (HR 0.85, 95% CI: 0.78, 0.93; p-value=0.0003). Alirocumab also significantly reduced thefollowing composite endpoints: risk of CHD event; major CHD event; cardiovascular event; and thecomposite of all-cause mortality, non-fatal MI, and non-fatal ischemic stroke. A reduction of all-causemortality was also observed, with only nominal statistical significance by hierarchical testing (HR 0.85, 95%

CI: 0.73, 0.98). The results are presented in Table 3.

Table 3: Efficacy of alirocumab in ODYSSEY OUTCOMES (overall population)

Endpoint Number of events

Alirocumab Placebo Hazard ratio

N=9,462 N=9,462 (95% CI)n (%) n (%) p-value

Primary endpoint (MACE- 0.85 (0.78, 0.93)a 903 (9.5%) 1052 (11.1%)plus ) 0.00030.92 (0.76, 1.11)

CHD death 205 (2.2%) 222 (2.3%)0.380.86 (0.77, 0.96)

Non-fatal MI 626 (6.6%) 722 (7.6%)0.006f0.73 (0.57, 0.93)

Ischemic stroke 111 (1.2%) 152 (1.6%)0.01f0.61 (0.41, 0.92)

Unstable anginab 37 (0.4%) 60 (0.6%)0.02f

Secondary endpointsc 0.88 (0.81, 0.95)

CHD event 1199 (12.7%) 1349 (14.3%)0.00130.88 (0.80, 0.96)

Major CHD eventd 793 (8.4%) 899 (9.5%)0.00600.87 (0.81, 0.94)

Cardiovascular evente 1301 (13.7%) 1474 (15.6%)0.0003

All-cause mortality, non-fatal 0.86 (0.79, 0.93)973 (10.3%) 1126 (11.9%)

MI, non-fatal ischemic stroke 0.00030.92 (0.76, 1.11)

CHD death 205 (2.2%) 222 (2.3%)0.38240.88 (0.74, 1.05)

CV death 240 (2.5%) 271 (2.9%)0.15280.85 (0.73, 0.98)

All-cause mortality 334 (3.5%) 392 (4.1%)0.0261f

Favours Alirocumab Favours Placeboa MACE-plus defined as a composite of: coronary heart disease (CHD) death, non-fatal myocardial infarction (MI),fatal and non-fatal ischemic stroke, or unstable angina (UA) requiring hospitalizationb Unstable angina requiring hospitalizationc CHD event defined as: major CHD eventd, unstable angina requiring hospitalization, ischemia-driven coronaryrevascularization procedured Major CHD event defined as: CHD death, non-fatal MIe Cardiovascular event defined as follows: CV death, any non-fatal CHD event, and non-fatal ischemic strokef Nominal significance

The Kaplan-Meier estimates of the cumulative incidence of the primary endpoint for the overall patientpopulation over time are presented in Figure 1.

Figure 1 Primary composite endpoint cumulative incidence over 4 years in ODYSSEY OUTCOMES

Overall population

Hazard Ratio: 0.8595% CI (0.78, 0.93)

Cumu

Placebolati

Alirocumabveincidenceofevent

Time (months)

Neurocognitive function

A 96 week, randomized, double-blinded, placebo‑controlled trial evaluated the effect of alirocumab onneurocognitive function after 96 weeks of treatment (~2 years) in patients with heterozygous familialhypercholesterolemia (HeFH) or non-familial hypercholesterolemia at high or very high cardiovascular risk.

Neurocognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery(CANTAB). A total of 2171 patients were randomized; 1087 patients were treated with alirocumab 75 mgand/or 150 mg every 2 weeks and 1084 patients were treated with placebo. A majority (>80%) of patients ineach group completed the 96-week, double-blind treatment period.

Over the 96 weeks of treatment, alirocumab showed no effect on neurocognitive function. The percentage ofpatients who experienced neurocognitive disorders was low in the alirocumab (1.3%) treatment groups andcomparable to placebo (1.7%). No safety concerns related to neurocognitive function were observed inpatients treated with alirocumab who experienced either 2 consecutive LDL-C values <25 mg/dL (<0.65mmol/L) or <15 mg/dL (<0.39 mmol/L) during the treatment period.

Treatment of homozygous familial hypercholesterolaemia (HoFH) in paediatric patients

A 48-week, open-label study was conducted to evaluate the efficacy and safety of alirocumab 75 mg Q2W(if body weight (BW) < 50 kg) or 150 mg Q2W (if BW ≥ 50 kg) in 18 paediatric patients (8 to 17 years ofage) with HoFH on top of background treatments. Patients received alirocumab 75 or 150 mg Q2W withoutdose adjustment up to week 12.

The mean baseline LDL-C was 9.6 mmol/l (373 mg/dL). The mean percent change from baseline in LDL-Cto week 12 was -4.1% (95% CI: -23.1% to 14.9%) in the ITT population (N=18) and was associated with ahigh variability in the response with regard to the decrease in LDL-C. Responders achieving ≥15% reductionfrom baseline at weeks 12, 24, and 48 were 50%, 50% and 39% respectively.

Treatment of heterozygous familial hypercholesterolaemia (HeFH) in paediatric patients

The efficacy and safety of alirocumab was evaluated in 153 patients 8 - ≤17 years of age with HeFH in a

Phase-3 multicentre study. This study consisted of a 24-week randomized, double blind (DB) treatmentwhere patients received placebo or alirocumab. This was followed by an 80-week open-label (OL) treatmentwith alirocumab. Patients had to be on a low-fat diet and receiving background lipid-lowering therapy.

Enrolled patients were randomised in a 2:1 ratio to receive alirocumab Q2W or Q4W regimen and placebo.

In the Q4W dosing regimen, 79 patients received a dose of 150 mg for body weight (BW) <50 kg or 300 mgfor BW ≥50 kg. Dose up-titration of alirocumab to 75 mg Q2W for BW <50 kg or 150 mg Q2W for BW ≥50kg occurred at week 12 in patients with LDL-C ≥110 mg/dL.

Double-blind treatment period:

The primary efficacy endpoint in this study was the percent change from baseline to week 24 in LDL-C.

Data is further detailed in Table 4. Mean absolute LDL-C values at week 24 were 2.847 mmol/L in thealirocumab group and 4.177 mmol/L in the placebo group in the Q4W cohort. Reductions in LDL-C wereobserved through the first post-baseline assessment at week 8 and maintained throughout the 24 weeks of

DB treatment period.

Table 4: Treatment effects of alirocumab and placebo in paediatric patients with HeFH

Mean percent change from baseline at week 24 (in %)

Q4W Dose Regimen

Placebo Alirocumab

Number of patients N= 27 N= 52

LDL-C -4.4 -38.2

Non-HDL-C -3.7 -35.6

TC -3.6 -34.6

Apo B -3.6 -34.3

LDL-= low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; TC = total cholesterol;

ApoB = apolipoprotein B. All adjusted p-values <0.0001.

Open-label treatment period:

A total of 74 patients from the Q4W cohort participated in an 80-week open-label single arm study. Theinitial dose was the alirocumab dose selected for the DB period, according to body weight and dosingregimen. Dose could be up- and down-titrated by the investigators based on their medical assessment. Themean (SE) percent change in LDL-C from baseline (randomisation in DB period) was -23.4% (4.7) at week104. The mean (SE) percent change from baseline to week 104 in other lipid endpoints were: -21.5% (26.2)non-HDL-C, -17.8% (21.7) ApoB, -17.4% (19.9) TC.

After subcutaneous administration of 50 mg to 300 mg alirocumab, median times to maximum serumconcentration (tmax) were 3-7 days. The pharmacokinetics of alirocumab after single subcutaneousadministration of 75 mg into the abdomen, upper arm or thigh were similar. The absolute bioavailability ofalirocumab after subcutaneous administration was about 85% as determined by population pharmacokineticanalysis. Monthly exposure with 300 mg every 4 weeks treatment was similar to that of 150 mg every2 weeks. The fluctuations between Cmax and Ctrough were higher for the every 4 weeks dosage regimen. Steadystate was reached after 2 to 3 doses with an accumulation ratio up to a maximum of about 2-fold.

Following intravenous administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating thatalirocumab is distributed primarily in the circulatory system.

Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected todegrade to small peptides and individual amino acids.

Two elimination phases were observed for alirocumab. At low concentrations, the elimination ispredominately through saturable binding to target (PCSK9), while at higher concentrations the elimination ofalirocumab is largely through a non-saturable proteolytic pathway.

Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady statewas 17 to 20 days in patients receiving alirocumab as monotherapy at subcutaneous doses of either 75 mg

Q2W or 150 mg Q2W. When co-administered with a statin, the median apparent half-life of alirocumab was12 days.

A slightly greater than dose proportional increase was observed, with a 2.1- to 2.7-fold increase in totalalirocumab concentrations for a 2-fold increase in dose from 75 mg to 150 mg Q2W.

Based on a population pharmacokinetic analysis, age was associated with a small difference in alirocumabexposure at steady state, with no impact on efficacy or safety.

Based on a population pharmacokinetic analysis, gender has no impact on alirocumab pharmacokinetics.

Based on a population pharmacokinetic analysis, race had no impact on alirocumab pharmacokinetics.

Following single-dose subcutaneous administration of 100 mg to 300 mg alirocumab, there was nomeaningful difference in exposure between Japanese and Caucasian healthy subjects.

Body weight was identified as one significant covariate in the final population PK model impactingalirocumab pharmacokinetics. Alirocumab exposure (AUC0-14d) at steady state at both the 75 and 150 mg

Q2W dosing regimen was decreased by 29% and 36% in patients weighing more than 100 kg as compared topatients weighing between 50 kg and 100 kg. This did not translate into a clinically meaningful difference in

LDL-C lowering.

In a phase 1 study, after administration of a single 75 mg subcutaneous dose, alirocumab pharmacokineticprofiles in subjects with mild and moderate hepatic impairment were similar as compared to subjects withnormal hepatic function. No data are available in patients with severe hepatic impairment.

Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is notexpected to impact the pharmacokinetics of alirocumab. Population pharmacokinetic analyses showed thatalirocumab exposure (AUC0-14d) at steady state at both the 75 and 150 mg Q2W dosing regimen wasincreased by 22%-35%, and 49%-50% in patients with mild and moderate renal impairment, respectively,compared to patients with normal renal function. The distribution of body weight and age, two covariatesimpacting alirocumab exposure, were different among renal function categories and most likely explain theobserved pharmacokinetic differences. Limited data are available in patients with severe renal impairment; inthese patients the exposure to alirocumab was approximately 2-fold higher compared with subjects withnormal renal function.

The pharmacokinetics of Praluent were evaluated in 140 paediatric patients 8 to 17 years of age withheterozygous familial hypercholesterolaemia (HeFH). The steady state mean Ctrough was reached at or before

Week 8 (first PK sampling during repeated dosing) with the recommended dosing regimen (see Section 4.2).

Limited pharmacokinetic data are available in 18 paediatric patients (8 to 17 years of age) with HoFH. Thesteady-state mean Ctrough alirocumab concentrations was reached at or before Week 12 in both alirocumab75 mg Q2W and 150 mg Q2W groups. No studies with alirocumab have been performed in paediatricpatients less than 8 years of age (see section 5.1).

The pharmacodynamic effect of alirocumab in lowering LDL-C is indirect, and mediated through the bindingto PCSK9. A concentration-dependent reduction in free PCSK9 and LDL-C is observed until targetsaturation is achieved. Upon saturation of PCSK9 binding, further increases in alirocumab concentrations donot result in a further LDL-C reduction, however an extended duration of the LDL-C lowering effect isobserved.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacologyand repeated dose toxicity.

Reproductive toxicology studies in rats and monkeys indicated that alirocumab, like other IgG antibodies,crosses the placental barrier.

There were no adverse effects on surrogate markers of fertility (e.g. estrous cyclicity, testicular volume,ejaculate volume, sperm motility, or total sperm count per ejaculate) in monkeys, and no alirocumab-relatedanatomic pathology or histopathology findings in reproductive tissues in any rat or monkey toxicology study.

There were no adverse effects on foetal growth or development in rats or monkeys. Maternal toxicity was notevident in pregnant monkeys at systemic exposures that were 81 times the human exposure at the 150 mg

Q2W dose. However, maternal toxicity was noted in pregnant rats at systemic exposures estimated to beapproximately 5.3 times greater than the human exposure at the 150 mg Q2W dose (based on exposuremeasured in non-pregnant rats during a 5-week toxicology study).

The offspring of monkeys that received high doses of alirocumab weekly throughout pregnancy had aweaker secondary immune response to antigen challenge than did the offspring of control animals. There wasno other evidence of alirocumab-related immune dysfunction in the offspring.

Histidine

Sucrose

Polysorbate 20

Water for injections

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

Praluent 75 mg solution for injection in pre-filled pen3 years.

Praluent 75 mg solution for injection in pre-filled syringe3 years.

Praluent 150 mg solution for injection in pre-filled pen2 years.

Praluent 150 mg solution for injection in pre-filled syringe2 years.

Praluent 300 mg solution for injection in pre-filled pen2 years.

Store in a refrigerator (2°C to 8°C). Do not freeze.

Praluent can be stored outside the refrigerator (below 25 °C) protected from light for a single period notexceeding 30 days. After removal from the refrigerator, the medicinal product must be used within 30 daysor discarded.

Keep the pen or syringe in the outer carton in order to protect from light.

1 ml or 2 ml solution in a siliconised Type 1 clear glass syringe, equipped with a stainless steel stakedneedle, a styrene-butadiene rubber needle shield, and an ethylene tetrafluoroethylene -coated bromobutylrubber plunger stopper.

75 mg solution for injection in pre-filled pen

The syringe components are assembled into a single-use pre-filled pen with a blue cap and a light greenactivation button.

1, 2 or 6 pre-filled pens.

Or

The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activationbutton.

1, 2, 3 pre-filled pens without activation button or multipack containing 6 (2 packs of 3) pre-filled penswithout activation button.

150 mg solution for injection in pre-filled pen

The syringe components are assembled into a single-use pre-filled pen with a blue cap and a dark greyactivation button.

1, 2 or 6 pre-filled pens.

Or

The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activationbutton.

1, 2, 3 pre-filled pens without activation button or multipack containing 6 (2 packs of 3) pre-filled penswithout activation button.

300 mg solution for injection in pre-filled pen

The syringe components are assembled into a single-use pre-filled pen with a blue cap and without activationbutton.

1 or 3 pre-filled pens without activation button.

75 mg solution for injection in pre-filled syringe

The syringe is equipped with a light green polypropylene plunger rod.

1, 2 or 6 pre-filled syringes.

150 mg solution for injection in pre-filled syringe

The syringe is equipped with a dark grey polypropylene plunger rod.

1, 2 or 6 pre-filled syringes.

Not all presentations and pack sizes may be marketed.

After use, the pre-filled pen/ pre-filled syringe should be placed into a puncture resistant container. Thecontainer should not be recycled.

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

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EU/1/15/1031/023

EU/1/15/1031/024

Date of first authorisation: 23 September 2015

Date of latest renewal: 2 June 2020

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

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