EYLEA 40mg / ml solution for injection in pre-filled syringe medication leaflet

Eylea 40 mg/mL solution for injection in pre-filled syringe.

1 mL solution for injection contains 40 mg aflibercept*.

One pre-filled syringe contains an extractable volume of at least 0.09 mL, equivalent to at least 3.6 mgaflibercept. This provides a usable amount to deliver a single dose of 0.05 mL containing 2 mgaflibercept to adult patients or a single dose of 0.01 mL containing 0.4 mg aflibercept to preterminfants.

*Fusion protein consisting of portions of human VEGF (Vascular Endothelial Growth Factor)receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and produced in

Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Each ml solution for injection contains 0.3 mg polysorbate 20 (E 432).

For the full list of excipients, see section 6.1.

Solution for injection (injection)

The solution is a clear, colourless to pale yellow and iso-osmotic solution.

Eylea is indicated for adults for the treatment of

* neovascular (wet) age-related macular degeneration (AMD) (see section 5.1),

* visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO orcentral RVO) (see section 5.1),

* visual impairment due to diabetic macular oedema (DME) (see section 5.1),

* visual impairment due to myopic choroidal neovascularisation (myopic CNV) (see section 5.1).

EYLEA is indicated in preterm infants for the treatment of

* retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or

AP-ROP (aggressive posterior ROP) disease.

Eylea is for intravitreal injection only.

Eylea must only be administered by a qualified physician experienced in administering intravitrealinjections.

Posologywet AMD

The recommended dose for Eylea is 2 mg aflibercept, equivalent to 0.05 mL.

Eylea treatment is initiated with one injection per month for three consecutive doses. The treatmentinterval is then extended to two months.

Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may bemaintained at two months or further extended using a treat-and-extend dosing regimen, whereinjection intervals are increased in 2- or 4-weekly increments to maintain stable visual and/or anatomicoutcomes.

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

There is no requirement for monitoring between injections. Based on the physician’s judgement theschedule of monitoring visits may be more frequent than the injection visits.

Treatment intervals greater than four months or shorter than 4 weeks between injections have not beenstudied (see section 5.1).

Macular oedema secondary to RVO (branch RVO or central RVO)

The recommended dose for Eylea is 2 mg aflibercept equivalent to 0.05 mL.

After the initial injection, treatment is given monthly. The interval between two doses should not beshorter than one month.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment,

Eylea should be discontinued.

Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs ofdisease activity. Three or more consecutive, monthly injections may be needed.

Treatment may then be continued with a treat-and-extend regimen with gradually increased treatmentintervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data toconclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatmentinterval should be shortened accordingly.

The monitoring and treatment schedule should be determined by the treating physician based on theindividual patient’s response.

Monitoring for disease activity may include clinical examination, functional testing or imagingtechniques (e.g. optical coherence tomography or fluorescein angiography).

Diabetic macular oedema

The recommended dose for Eylea is 2 mg aflibercept equivalent to 0.05 mL.

Eylea treatment is initiated with one injection per month for five consecutive doses, followed by oneinjection every two months.

Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may bemaintained at 2 months or individualized, such as with a treat-and-extend dosing regimen, where thetreatment intervals are usually increased by 2-week increments to maintain stable visual and/oranatomic outcomes. There are limited data for treatment intervals longer than 4 months. If visualand/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

Treatment intervals shorter than 4 weeks have not been studied (see section 5.1).

The schedule for monitoring should be determined by the treating physician.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment,

Eylea should be discontinued.

Myopic choroidal neovascularisation

The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to0.05 mL.

Additional doses may be administered if visual and/or anatomic outcomes indicate that the diseasepersists. Recurrences should be treated as a new manifestation of the disease.

The schedule for monitoring should be determined by the treating physician.

The interval between two doses should not be shorter than one month.

Retinopathy of prematurity (ROP)

The recommended dose for Eylea is a single intravitreal injection of 0.4 mg aflibercept equivalent to0.01 mL.

Treatment of ROP is initiated with a single injection per eye and may be given bilaterally on the sameday. In total, up to 2 injections per eye may be administered within 6 months of treatment initiation ifthere are signs of disease activity. The treatment interval between the 2 doses injected into the sameeye should be at least 4 weeks.

No specific studies in patients with hepatic and/or renal impairment have been conducted with Eylea.

Available data do not suggest a need for a dose adjustment with Eylea in these patients (seesection 5.2).

No special considerations are needed. There is limited experience in patients older than 75 years with

The safety and efficacy of Eylea in children and adolescents below 18 years of age for indicationsother than ROP have not been established (see section 4.4). There is no relevant use of Eylea in thepaediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV.

Intravitreal injections must be carried out according to medical standards and applicable guidelines bya qualified physician experienced in administering intravitreal injections. In general, adequateanaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied tothe periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterilegloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.

Immediately following the intravitreal injection, patients should be monitored for elevation inintraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nervehead or tonometry. If required, sterile equipment for paracentesis should be available.

Following intravitreal injection, adult patients should be instructed to report any symptoms suggestiveof endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Patients with ROP should be observed by healthcare professionals for any signs suggestive ofendophthalmitis (e.g. redness/irritation of the eye, ocular discharge, lid swelling, photophobia).

Parents and caregivers should also be instructed to observe and report any signs suggestive ofendophthalmitis without delay.

Each pre-filled syringe should only be used for the treatment of a single eye. Extraction of multipledoses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to0.05 mL solution for injection). The extractable volume of the syringe is the amount that can beexpelled from the syringe and is not to be used in total. For the Eylea pre-filled syringe, the extractablevolume is at least 0.09 mL. The excess volume must be expelled before injecting the recommendeddose (see section 6.6).

Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubblesalong with excess medicinal product, slowly depress the plunger to align the base of the plungerdome (not the tip of the dome) with the dosing line on the syringe (equivalent to 0.05 mL i.e. 2 mgaflibercept) (see sections 4.9 and 6.6).

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity,avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of0.05 mL is then delivered; a different scleral site should be used for subsequent injections.

After injection any unused product must be discarded.

For treatment of preterm infants, the PICLEO paediatric dosing device in combination with the pre-filled syringe must be used for administration of a single dose of 0.4 mg aflibercept (equivalent to0.01 mL solution for injection) (see section 6.6).

The injection needle should be inserted into the eye 1.0 to 2.0 mm from the limbus with the needlepointing towards the optic nerve.

After injection any unused product must be discarded.

For handling of the medicinal product before administration, see section 6.6.

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

Active or suspected ocular or periocular infection.

Active severe intraocular inflammation.

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

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis,intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumaticcataract (see section 4.8). Proper aseptic injection techniques must always be used when administering

Eylea. In addition, patients should be monitored during the week following the injection to permitearly treatment if an infection occurs.

Adult patients should be instructed to report any symptoms suggestive of endophthalmitis or any ofthe above mentioned events without delay.

Patients with ROP should be observed by healthcare professionals for any signs suggestive ofendophthalmitis (e.g. redness/irritation of the eye, ocular discharge, lid swelling, photophobia).

Parents and caregivers should also be instructed to observe and report any signs suggestive ofendophthalmitis without delay.

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to0.05 mL) for adult patients. The excess volume must be expelled prior to administration (seesections 4.2 and 6.6).

The pre-filled syringe contains more than the recommended dose of 0.4 mg (equivalent to 0.01 mL)for preterm infants (see section 6.6). The pre-filled syringe must be used in combination with the

PICLEO paediatric dosing device to avoid a higher than recommended volume that could result inincreased intraocular pressure (see sections 4.9 and 6.6).

Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, includingthose with Eylea (see section 4.8). Special precaution is needed in patients with poorly controlledglaucoma (do not inject Eylea while the intraocular pressure is ≥ 30 mmHg). In all cases, both theintraocular pressure and the perfusion of the optic nerve head must therefore be monitored andmanaged appropriately.

As this is a therapeutic protein, there is a potential for immunogenicity with Eylea (see section 4.8).

Patients should be instructed to report any signs or symptoms of intraocular inflammation, e.g. pain,photophobia, or redness, which may be a clinical sign attributable to hypersensitivity.

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events havebeen reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk thatthese may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with

CRVO, BRVO, DME or myopic CNV with a history of stroke or transient ischaemic attacks ormyocardial infarction within the last 6 months. Caution should be exercised when treating suchpatients.

As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, DME and myopic CNVthe following also applies:

* The safety and efficacy of Eylea therapy administered to both eyes concurrently have not beensystematically studied (see section 5.1). If bilateral treatment is performed at the same time thiscould lead to an increased systemic exposure, which could increase the risk of systemic adverseevents.

* Concomitant use of other anti-VEGF (vascular endothelial growth factor)

There is no data available on the concomitant use of Eylea with other anti-VEGF medicinalproducts (systemic or ocular).

* Risk factors associated with the development of a retinal pigment epithelial tear after anti-

VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment.

When initiating Eylea therapy, caution should be used in patients with these risk factors forretinal pigment epithelial tears.

* Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage 3or 4 macular holes.

* In the event of a retinal break the dose should be withheld and treatment should not be resumeduntil the break is adequately repaired.

* The dose should be withheld and treatment should not be resumed earlier than the nextscheduled treatment in the event of:

o a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with thelast assessment of visual acuity;o a subretinal haemorrhage involving the centre of the fovea, or, if the size of thehaemorrhage is ≥50%, of the total lesion area.

* The dose should be withheld within the previous or next 28 days in the event of a performed orplanned intraocular surgery.

* Eylea should not be used in pregnancy unless the potential benefit outweighs the potential riskto the foetus (see section 4.6).

* Women of childbearing potential have to use effective contraception during treatment and for atleast 3 months after the last intravitreal injection of aflibercept (see section 4.6).

* There is limited experience with treatment of patients with ischaemic CRVO and BRVO. Inpatients presenting with clinical signs of irreversible ischaemic visual function loss, thetreatment is not recommended.

The warnings and precautions for adults also apply to preterm infants with ROP. The long-term safetyprofile in preterm infants has not been established.

There is only limited experience in the treatment of subjects with DME due to type I diabetes or indiabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.

Eylea has not been studied in patients with active systemic infections or in patients with concurrenteye conditions such as retinal detachment or macular hole. There is also no experience of treatmentwith Eylea in diabetic patients with uncontrolled hypertension. This lack of information should beconsidered by the physician when treating such patients.

In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients whohave previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

This medicinal product contains

- less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ’sodium-free’

- 0.003 mg of polysorbate 20 in each 0.01 ml dose or 0.015 mg of polysorbate 20 in each 0.05 mldose which is equivalent to 0.3 mg/ml. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Adjunctive use of verteporfin photodynamic therapy (PDT) and Eylea has not been studied, therefore,a safety profile is not established.

No interaction studies have been performed.

Women of childbearing potential have to use effective contraception during treatment and for at least3 months after the last intravitreal injection of aflibercept (see section 4.4).

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

Studies in animals have shown embryo-foetal toxicity (see section 5.3).

Although the systemic exposure after ocular administration is very low, Eylea should not be usedduring pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Based on very limited human data, aflibercept may be excreted in human milk at low levels.

Aflibercept is a large protein molecule and the amount of medication absorbed by the infant isexpected to be minimal. The effects of aflibercept on a breast-fed newborn/infant are unknown.

As a precautionary measure, breast-feeding is not recommended during the use of Eylea.

Results from animal studies with high systemic exposure indicate that aflibercept can impair male andfemale fertility (see section 5.3). Such effects are not expected after ocular administration with verylow systemic exposure.

Injection with Eylea has a minor influence on the ability to drive and use machines due to possibletemporary visual disturbances associated either with the injection or the eye examination. Patientsshould not drive or use machines until their visual function has recovered sufficiently.

A total of 3,102 patients constituted the safety population in the eight phase III studies. Among those,2,501 patients were treated with the recommended dose of 2 mg.

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred inless than 1 in 1,900 intravitreal injections with Eylea and included blindness, endophthalmitis, retinaldetachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocularpressure increased (see section 4.4).

The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) wereconjunctival haemorrhage (25%), retinal haemorrhage (11%), visual acuity reduced (11%), eyepain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), andvitreous floaters (7%).

The safety data described below include all adverse reactions from the eight phase III studies in theindications wet AMD, CRVO, BRVO, DME and myopic CNV with a reasonable possibility ofcausality to the injection procedure or medicinal product.

The adverse reactions are listed by system organ class and frequency using the following convention:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (1/10,000to <1/1,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness.

Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies(pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic

CNV) or during post-marketing surveillance

System Organ Class Frequency Adverse reaction

Immune system disorders Uncommon Hypersensitivity***

Eye disorders Very common Visual acuity reduced, Retinal haemorrhage,

Conjunctival haemorrhage, Eye pain

Common Retinal pigment epithelial tear*, Detachment of theretinal pigment epithelium, Retinal degeneration,

Vitreous haemorrhage, Cataract, Cataract cortical,

Cataract nuclear, Cataract subcapsular, Cornealerosion, Corneal abrasion, Intraocular pressureincreased, Vision blurred, Vitreous floaters, Vitreousdetachment, Injection site pain, Foreign bodysensation in eyes, Lacrimation increased, Eyelidoedema, Injection site haemorrhage,

Punctate keratitis, Conjunctival hyperaemia, Ocularhyperaemia

Uncommon Endophthalmitis**, Retinal detachment, Retinaltear, Iritis, Uveitis, Iridocyclitis, Lenticularopacities, Corneal epithelium defect, Injection siteirritation, Abnormal sensation in eye, Eyelidirritation, Anterior chamber flare, Corneal oedema

Rare Blindness, Cataract traumatic, Vitritis, Hypopyon

Not known Scleritis****

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

** Culture positive and culture negative endophthalmitis

*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, andisolated cases of severe anaphylactic/anaphylactoid reactions.

**** From post-marketing reporting.

In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage inpatients receiving anti-thrombotic agents. This increased incidence was comparable between patientstreated with ranibizumab and Eylea.

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGFinhibition. There is a theoretical risk of arterial thromboembolic events, including stroke andmyocardial infarction, following intravitreal use of VEGF inhibitors.

A low incidence rate of arterial thromboembolic events was observed in the Eylea clinical trials inpatients with AMD, DME, RVO, myopic CNV and ROP. Across indications no notable differencebetween the groups treated with aflibercept and the respective comparator groups were observed.

As with all therapeutic proteins, there is a potential for immunogenicity with Eylea.

The safety of Eylea for the treatment of ROP was evaluated in a 6-month phase III study, whichincluded 75 preterm infants treated with aflibercept 0.4 mg at baseline. The long-term safety profile inpreterm infants has not been established.

Adverse reactions reported in more than one patient treated with aflibercept 0.4 mg were retinaldetachment, retinal haemorrhage, conjunctival haemorrhage, injection site haemorrhage, intraocularpressure increased and eyelid oedema.

Adverse reactions established for adult indications are considered applicable to preterm infants with

ROP, though not all were observed in the phase III study.

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

In clinical trials, doses of up to 4 mg in monthly intervals have been used and isolated cases ofoverdoses with 8 mg occurred.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case ofoverdose, intraocular pressure should be monitored and if deemed necessary by the treating physician,adequate treatment should be initiated (see section 6.6).

Pharmacotherapeutic group: Ophthalmologicals/Antineovascularisation agents

ATC code: S01LA05

Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2extracellular domains fused to the Fc portion of human IgG1.

Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity thantheir natural receptors, and thereby can inhibit the binding and activation of these cognate VEGFreceptors.

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members ofthe VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascularpermeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases; VEGFR-1 and

VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is alsopresent on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result inpathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF-

A in these processes, and is also known to promote leucocyte infiltration and vascular inflammation.

Pharmacodynamic effectswet AMD

Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood andfluid from CNV may cause retinal thickening or oedema and/or sub-/intra-retinal haemorrhage,resulting in loss of visual acuity.

In patients treated with Eylea (one injection per month for three consecutive months, followed by oneinjection every 2 months), central retinal thickness [CRT] decreased soon after treatment initiation,and the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mgevery month.

In the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (-130and -129 microns at week 52 for the Eylea 2 mg every two months and ranibizumab 0.5 mg everymonth study groups, respectively). Also at the 52 week time point, in the VIEW2 study there weremean decreases in CRT on OCT (-149 and -139 microns for the Eylea 2 mg every two months andranibizumab 0.5 mg every month study groups, respectively). The reduction of CNV size andreduction in CRT were generally maintained in the second year of the studies.

The ALTAIR study was conducted in Japanese patients with treatment naïve wet AMD, showingsimilar outcomes to the VIEW studies using 3 initial monthly Eylea 2 mg injections, followed by oneinjection after a further 2 months, and then continued with a treat-and-extend regimen with variabletreatment intervals (2- week or 4- week adjustments) up to a maximum 16 week interval according topre-specified criteria. At week 52, there were mean decreases in central retinal thickness (CRT) on

OCT of -134.4 and -126.1 microns for the 2-week adjustment group and the 4-week adjustment group,respectively. The proportion of patients without fluid on OCT at week 52 was 68.3% and 69.1% in the2- and 4-week adjustment groups, respectively. The reduction in CRT was generally maintained inboth treatment arms in the second year of the ALTAIR study.

The ARIES study was designed to explore the non-inferiority of an Eylea 2 mg treat-and-extend dosingregimen initiated immediately after administration of 3 initial monthly injections and one additionalinjection after 2 months vs. a treat-and-extend dosing regimen initiated after one year of treatment. Forpatients requiring a more frequent than Q8 dosing at least once over the course of the study, CRTremained higher, but the mean decrease in CRT from baseline to week 104 was -160.4 microns, similarto the patients treated at Q8 or less frequent intervals.

Macular oedema secondary to CRVO and BRVO

In CRVO and BRVO, retinal ischaemia occurs and signals the release of VEGF which in turndestabilises the tight junctions, and promotes endothelial cell proliferation. Up-regulation of VEGF isassociated with the breakdown of the blood retina barrier, increased vascular permeability, retinaloedema, and neovascularisation complications.

In patients treated with 6 consecutive monthly injections of Eylea 2 mg, there was a consistent, rapidand robust morphologic response (as measured by improvements in mean CRT) observed. At week 24,the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in

CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -280 vs. -128 microns). This decrease from baseline in CRT was maintained to the end of each study,week 100 in COPERNICUS, week 76 in GALILEO, and week 52 in VIBRANT.

Diabetic macular oedema

Diabetic macular oedema is a consequence of diabetic retinopathy and is characterised by increasedvasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.

In patients treated with Eylea, the majority of whom were classified as having Type II diabetes, a rapidand robust response in morphology (CRT, DRSS level) was observed.

In the VIVIDDME and the VISTADME studies, a statistically significant greater mean decrease in CRTfrom baseline to week 52 was observed in patients treated with Eylea than with the laser control, -192.4 and -183.1 microns for the 2Q8 Eylea groups and -66.2 and -73.3 microns for the controlgroups, respectively. At week 100 the decrease was maintained with -195.8 and -191.1 microns for the2Q8 Eylea groups and -85.7 and -83.9 microns for the control groups, in the VIVIDDME and

VISTADME studies, respectively.

A ≥2 step improvement in DRSS was assessed in a pre-specified manner in VIVIDDME and VISTADME.

The DRSS score was gradable in 73.7% of the patients in VIVIDDME and 98.3% of the patients in

VISTADME. At week 52, 27.7% and 29.1% of the Eylea 2Q8 groups, and 7.5% and 14.3% of thecontrol groups experienced a ≥2 step improvement in the DRSS. At week 100, the respectivepercentages were 32.6% and 37.1% of the Eylea 2Q8 groups and 8.2% and 15.6% of the controlgroups.

The VIOLET study compared three different dosing regimens of Eylea 2 mg for treatment of DMEafter at least one year of treatment at fixed intervals, where treatment was initiated with 5 consecutivemonthly doses followed by dosing every 2 months. At week 52 and week 100 of the study, i.e. secondand third year of treatment, the mean changes in CRT were clinically similar for treat-and-extend(2T&E), pro re nata (2PRN) and 2Q8, respectively, -2.1, 2.2 and -18.8 microns at week 52, and 2.3,

- 13.9 and -15.5 microns at week 100.

Myopic choroidal neovascularisation

Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults withpathologic myopia. It develops as a wound healing mechanism consequent to Bruch’s membraneruptures and represents the most vision-threatening event in pathologic myopia.

In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, withadditional injections given in case of disease persistence or recurrence), CRT decreased soon aftertreatment initiation favouring Eylea at week 24 (-79 microns and -4 microns for the Eylea 2 mgtreatment group and the control group, respectively), which was maintained through week 48. Inaddition, the mean CNV lesion size decreased.

Clinical efficacy and safetywet AMD

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked,active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of2,412 patients treated and evaluable for efficacy (1,817 with Eylea). Patient ages ranged from 49 to99 years with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of thepatients randomised to treatment with Eylea were 65 years of age or older, and approximately63% (1,139/1,817) were 75 years of age or older. In each study, patients were randomly assigned in a1:1:1:1 ratio to 1 of 4 dosing regimens:

1) Eylea administered at 2 mg every 8 weeks following 3 initial monthly doses (Eylea 2Q8);2) Eylea administered at 2 mg every 4 weeks (Eylea 2Q4);3) Eylea administered at 0.5 mg every 4 weeks (Eylea 0.5Q4); and4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).

In the second year of the studies, patients continued to receive the initially randomised dosage but on amodified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks.

In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Setwho maintained vision, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.

In the VIEW1 study, at week 52, 95.1% of patients in the Eylea 2Q8 group maintained visioncompared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6%of patients in the Eylea 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab0.5Q4 group. In both studies Eylea was shown to be non-inferior and clinically equivalent to theranibizumab 0.5Q4 group.

Detailed results from the combined analysis of both studies are shown in Table 2 and Figure 1 below.

Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the

VIEW1 and VIEW2 studiesB)

Efficacy Outcome Eylea 2Q8 E) Ranibizumab 0.5Q4(Eylea 2 mg every 8 weeks (ranibizumab 0.5 mg everyfollowing 3 initial monthly 4 weeks)doses)(N = 607) (N = 595)

Week 52 Week 96 Week 52 Week 96

Mean number of injections7.6 11.2 12.3 16.5from baseline

Mean number of injections4.2 4.7from Week 52 to 96

Proportion of patients with< 15 letters loss from 95.33%B) 92.42% 94.42% B) 91.60%baseline ( PPS A))

DifferenceC) 0.9% 0.8%(95% CI)D) (-1.7, 3.5)F) (-2.3, 3.8)F)

Mean change in BCVA asmeasured by ETDRSA) 8.40 7.62 8.74 7.89letter score from baseline

Difference in LS A)mean change (ETDRS -0.32 -0.25letters)C) (-1.87, 1.23) (-1.98, 1.49)(95% CI)D)

Proportion of patients with≥ 15 letters gain from 30.97% 33.44% 32.44% 31.60%baseline

DifferenceC) -1.5% 1.8%(95% CI)D) (-6.8, 3.8) (-3.5, 7.1)

A) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LS: Least square means derived from ANCOVA

PPS: Per Protocol Set

B) Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) for all analyses except proportion ofpatients with maintained visual acuity at week 52 which is PPS

C) The difference is the value of the Eylea group minus the value of the ranibizumab group. A positive valuefavours Eylea.

D) Confidence interval (CI) calculated by normal approximation

E) After treatment initiation with three monthly doses

F) A confidence interval lying entirely above -10% indicates a non-inferiority of Eylea to ranibizumab

Figure 1. Mean Change in Visual Acuityfrom Baseline to Week 96 for the Combined

Data from the View1 and View2 Studies

In combined data analysis of VIEW1 and VIEW2, Eylea demonstrated clinically meaningful changesfrom baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function

Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. Themagnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

In the second year of the studies, efficacy was generally maintained through the last assessment atweek 96, and 2-4% of patients required all injections on a monthly basis, and a third of patientsrequired at least one injection with a treatment interval of only one month.

Decreases in mean CNV area were evident in all dose groups in both studies.

Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type,lesion size) in each study and in the combined analysis were consistent with the results in the overallpopulations.

ALTAIR was a 96 week multicentre, randomised, open-label study in 247 Japanese patients withtreatment naïve wet AMD, designed to assess the efficacy and safety of Eylea following two differentadjustment intervals (2- weeks and 4- weeks) of a treat-and-extend dosing regimen.

All patients received monthly doses of Eylea 2 mg for 3 months, followed by one injection after afurther 2 month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1)

Eylea treat-and-extend with 2-week adjustments and 2) Eylea treat-and-extend with 4-weekadjustments. Extension or shortening of the treatment interval was decided based on visual and/oranatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups.

The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondaryefficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion ofpatients who gained at least 15 letters of BCVA from baseline to week 52.

At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 lettersfrom baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean differencein letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 lettersin the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustmentgroups). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-weekadjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extendedtheir treatment interval to 12 weeks or beyond was 42.3% in the 2-week adjustment group and 49.6%in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients wereextended to 16 week intervals. At the last visit up to week 52, 56.8% and 57.8% of patients in the2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of12 weeks or beyond.

In the second year of the study, efficacy was generally maintained up to and including the lastassessment at week 96, with a mean gain from baseline of 7.6 letters for the 2-week adjustment groupand 6.1 letters for the 4-week adjustment group. The proportion of patients who extended theirtreatment interval to 12 weeks or beyond was 56.9% in the 2-week adjustment group and 60.2% in the4-week adjustment group. At the last visit prior to week 96, 64.9% and 61.2% of patients in the2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of12 weeks or beyond. During the second year of treatment patients in both the 2-week and 4-weekadjustment groups received an average of 3.6 and 3.7 injections, respectively. Over the 2 yeartreatment period patients received an average of 10.4 injections.

Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW 1and VIEW 2.

ARIES was a 104-week multicentre, randomised, open-label, active-controlled study in 269 patientswith treatment naïve wet AMD, designed to assess the non-inferiority in terms of efficacy as well asthe safety of a treat-and-extend dosing regimen initiated after 3 consecutive monthly doses followedby extension to a 2 monthly treatment interval vs. a treat-and-extend dosing regimen initiated after thefirst year of treatment.

The ARIES study also explored the percentage of patients that required more frequent treatment thanevery 8 weeks based on the investigator’s decision. Out of the 269 patients 62 patients received morefrequent dosing at least once during the course of the study. Such patients remained in the study andreceived treatment according to the investigator’s best clinical judgement but not more frequently thanevery 4 weeks and their treatment intervals could be extended again afterwards. The average treatmentinterval after the decision to treat more frequently was 6.1 weeks. Week 104 BCVA was lower inpatients requiring more intensive treatment at least once over the course of the study compared withpatients who did not and the mean change in BCVA from baseline to end of the study was+2.3 ± 15.6 letters. Among the patients treated more frequently, 85.5% maintained vision, i.e. lost lessthan15 letters, and 19.4% gained 15 letters or more. The safety profile of patients treated morefrequently than every 8 weeks was comparable to the safety data in VIEW 1 and VIEW 2.

Macular oedema secondary to CRVO

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked,sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and

GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with Eylea). Patientages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52%(112/217) of the patients randomised to treatment with Eylea were 65 years of age or older, andapproximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomlyassigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4), or the control groupreceiving sham injections every 4 weeks for a total of 6 injections.

After 6 consecutive monthly injections, patients received treatment only if they met pre-specifiedretreatment criteria, except for patients in the control group in the GALILEO study who continued toreceive sham (control to control) until week 52. From this timepoint all patients were treated if pre-specified criteria were met.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least15 letters in BCVA at week 24 compared to baseline. A secondary efficacy variable was change invisual acuity at week 24 compared to baseline.

The difference between treatment groups was statistically significant in favour of Eylea in bothstudies. The maximal improvement in visual acuity was achieved at month 3 with subsequentstabilisation of visual acuity and CRT until month 6. The statistically significant difference wasmaintained through week 52.

Detailed results from the analysis of both studies are shown in Table 3 and Figure 2 below.

Table 3: Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCFC)) in COPERNICUS and GALILEO studies

COPERNICUS GALILEO

Efficacy Outcomes24 Weeks 52 Weeks 100 Weeks 24 Weeks 52 Weeks 76 Weeks

Eylea Control Eylea Eylea F) Control E,F) Eylea Control Eylea Eylea G) Control

ControlE) G)2 mg 2 mg 2 mg (N=73) 2 mg 2 mg Control 2 mg

Q4 (N =73) Q4(N= 73) (N = (N= (N = 68) (N = (N = 68) (N = 103)(N = 114) 114) (N = 103) (N = 68)114) 103)

Proportion of patients with ≥1556% 12% 55% 30% 49.1% 23.3% 60% 22% 60% 32% 57.3% 29.4%letters gain from baseline

Weighted differenceA,B,E) 44.8% 25.9% 38.3% 27.9%26.7% 28.0%(95% CI) (33.0, 56.6) (11.8, 40.1) (24.4, 52.1) (13.0, 42.7)(13.1, 40.3) (13.3, 42.6)p-value p < p =p=0.0003 p < 0.0001 p = 0.0004 p=0.00040.0001 0.0006

Mean change in BCVAC) as17.3 -4.0 16.2 3.8 13.0 1.5 18.0 3.3 16.9 3.8 13.7 6.2measured by ETDRSC) letter(12.8) (18.0) (17.4) (17.1) (17.7) (17.7) (12.2) (14.1) (14.8) (18.1) (17.8) (17.7)score from baseline (SD)

Difference in LS meanA,C,D,E) 14.721.7 12.7 11.8 13.2 7.6(95% CI) (10.8,(17.4, 26.0) (7.7, 17.7) (6.7, 17.0) (8.2, 18.2) (2.1, 13.1)18.7)p < 0.0001 p=0.0070p-value p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001

A) Difference is Eylea 2 mg Q4 weeks minus control

B) Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for region (America vs. rest of the world for COPERNICUS and

Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

C) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LOCF: Last Observation Carried Forward

SD: Standard deviation

LS: Least square means derived from ANCOVA

D) LS mean difference and confidence interval based on an ANCOVA model with factors treatment group, region (America vs. rest of the world for COPERNICUS and Europe vs.

Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

E) In COPERNICUS study, control group patients could receive Eylea on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every4 weeks.

F) In COPERNICUS study, both control group and Eylea 2 mg patients received Eylea 2 mg on an as-needed basis as frequently as every 4 weeks starting from week 52 to week 96;patients had mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.

G) In GALILEO study, both control group and Eylea 2 mg patients received Eylea 2 mg on an as-needed basis every 8 weeks starting from week 52 to week 68; patients hadmandatory visits every 8 weeks.

Figure 2: Mean Change from Baseline to Week 76/100 in Visual Acuity by Treatment Groupfor the COPERNICUS and GALILEO Studies (Full Analysis Set)

In GALILEO, 86.4% (n=89) of the Eylea group and 79.4% (n=54) of the sham group had perfused

CRVO at baseline. At week 24, this was 91.8% (n=89) in the Eylea group and 85.5% (n=47) in thesham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Eylea groupand 84.0% (n=42) in the sham group.

In COPERNICUS, 67.5% (n = 77) of the Eylea group and 68.5% (n = 50) of the sham group hadperfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Eylea group and 58.6%(n = 34) in the sham group. These proportions were maintained at week 100 with 76.8% (n = 76) in the

Eylea group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive

Eylea from week 24.

The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups ofperfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender,race, baseline visual acuity, CRVO duration) in each study were in general consistent with the resultsin the overall populations.

In combined data analysis of GALILEO and COPERNICUS, Eylea demonstrated clinicallymeaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute

Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to thatseen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity(BCVA).

Macular oedema secondary to BRVO

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included

Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with

Eylea). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study,approximately 58% (53/91) of the patients randomised to treatment with Eylea were 65 years of age orolder, and approximately 23% (21/91) were 75 years of age or older. In the study, patients wererandomly assigned in a 1:1 ratio to either 2 mg Eylea administered every 8 weeks following 6 initialmonthly injections or laser photocoagulation administered at baseline (laser control group). Patients inthe laser control group could receive additional laser photocoagulation (called ‘rescue laser treatment’)beginning at week 12 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients inthe laser group could receive rescue treatment with Eylea 2 mg from week 24, administered every4 weeks for 3 months followed by every 8 weeks.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained atleast 15 letters in BCVA at week 24 compared to baseline and the Eylea group was superior to lasercontrol.

A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, whichwas statistically significant in favour of Eylea in the VIBRANT study. The course of visualimprovement was rapid and peaked at 3 months with maintenance of the effect until month 12.

In the laser group 67 patients received rescue treatment with Eylea beginning at week 24 (Active

Control/ Eylea 2 mg group), which resulted in improvement of visual acuity by about 5 letters fromweek 24 to 52.

Detailed results from the analysis of the VIBRANT study are shown in Table 4 and Figure 3 below.

Table 4: Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) in

VIBRANT study

Efficacy Outcomes VIBRANT24 Weeks 52 Weeks

Eylea 2mg Q4 Active Control Eylea 2mg Q8 Active Control(laser)

D) (laser)/Eylea 2mgE)(N = 91) (N = 91)(N = 90) (N = 90)

Proportion of patients 52.7% 26.7% 57.1% 41.1%with ≥15 letters gainfrom Baseline (%)

Weighted Difference 16.2%26.6%

A,B) (%)(2.0, 30.5)(95% CI) (13.0, 40.1)p=0.0296p-value p=0.0003

Mean change in BCVA 6.9 17.1 12.2 (11.9)17.0as measured by ETDRS(12.9) (13.1)letter score from (11.9)

Baseline (SD)

Difference in LS mean 10.5 5.2

A,C)(7.1, 14.0) (1.7, 8.7)(95% CI)p<0.0001 p=0.0035F)p-value

A) Difference is Eylea 2 mg Q4 weeks minus Laser Control

B) Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North

America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200)

C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVAcategory (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline

BCVA as covariate.

D) From week 24 on the treatment interval in the Eylea treatment group was extended for all subjects from4 weeks to 8 weeks through week 48.

E) Beginning at week 24 subjects in the Laser Group could receive rescue treatment with Eylea, if they met atleast one pre-specified eligibility criterion. At total of 67 subjects in this group received Eylea rescuetreatment. The fixed regimen for Eylea rescue was three times Eylea 2 mg every 4 weeks followed byinjections every 8 weeks.

F) Nominal p-value

Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to

Week 52 in VIBRANT Study

At baseline, the proportion of perfused patients in the Eylea and laser groups was 60% and 68%,respectively. At week 24 these proportions were 80% and 67%, respectively. In the Eylea group theproportion of perfused patients was maintained through week 52. In the laser group, where patientswere eligible for rescue treatment with Eylea from week 24, the proportion of perfused patientsincreased to 78% by week 52.

Diabetic macular oedema

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked,active-controlled studies in patients with DME (VIVIDDME and VISTADME). A total of 862 patientswere treated and evaluable for efficacy, 576 with Eylea. Patient ages ranged from 23 to 87 years with amean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised totreatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years ofage or older. The majority of patients in both studies had Type II diabetes.

In both studies, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:

1) Eylea administered 2 mg every 8 weeks following 5 initial monthly injections (Eylea 2Q8);2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); and3) macular laser photocoagulation (active control).

Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receiveadditional treatment: patients in the Eylea groups could receive laser and patients in the control groupcould receive Eylea.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA atweek 52 and both Eylea 2Q8 and Eylea 2Q4 groups demonstrated statistical significance and weresuperior to the control group. This benefit was maintained through week 100.

Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 5 and

Figure 4 below.

Table 5: Efficacy outcomes at week 52 and week 100 (Full Analysis Set with LOCF) in VIVIDDME and VISTADME studies

Efficacy VIVIDDME VISTADME

Outcomes52 Weeks 100 Weeks 52 Weeks 100 Weeks

Eylea Eylea Active Eylea Eylea Active Eylea Eylea Active Eylea Eylea Active

Control Control Control Control2 mg Q8 A 2 mg Q4 2 mg Q8 A 2mg Q4 2 mg Q8 A 2 mg Q4 2 mg Q8 A 2 mg Q4(laser) (laser) (laser) (laser)(N = 135) (N = 136) (N = 135) (N=136) (N = 151) (N = 154) (N = 151) (N=154)(N = 132) (N = 132) (N = 154) (N = 154)

Mean change in

BCVA asmeasured by10.7 10.5 1.2 9.4 11.4 0.7 10.7 12.5 0.2 11.1 11.5 0.9

ETDRS E letterscore from

Baseline

Difference in LS9.1 9.3 8.2 10.7 10.45 12.19 10.1 10.6mean B,C,E(6.3, 11.8) (6.5, 12.0) (5.2, 11.3) (7.6, 13.8) (7.7, 13.2) (9.4, 15.0) (7.0, 13.3) (7.1, 14.2)(97.5% CI)

Proportion ofpatients with ≥ 15letters gain from 33% 32% 9% 31.1% 38.2% 12.1% 31% 42% 8% 33.1% 38.3% 13.0%

Baseline

Adjusted24% 23% 19.0% 26.1% 23% 34% 20.1% 25.8%

Difference D,C,E(13.5, 34.9) (12.6, 33.9) (8.0, 29.9) (14.8, 37.5) (13.5, 33.1) (24.1, 44.4) (9.6, 30.6) (15.1, 36.6)(97.5% CI)

A After treatment initiation with 5 monthly injections

B LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, region (Europe/Australia vs. Japan) had beenincluded as factor for VIVIDDME, and history of MI and/or CVA as a factor for VISTADME

C Difference is Eylea group minus active control (laser) group

D Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by region (Europe/Australia vs. Japan) for VIVIDDME andmedical history of MI or CVA for VISTADME

E BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LOCF: Last Observation Carried Forward

LS: Least square means derived from ANCOVA

CI: Confidence interval

Figure 4: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to

Week 100 in VIVIDDME and VISTADME Studies

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visualacuity, prior anti-VEGF therapy) in each study and in the combined analysis were generally consistentwith the results in the overall populations.

In the VIVIDDME and VISTADME studies, 36 (9%) and 197 (43%) patients received prior anti-VEGFtherapy, respectively, with a 3-month or longer washout period. Treatment effects in the subgroup ofpatients who had previously been treated with a VEGF inhibitor were similar to those seen in patientswho were VEGF inhibitor naïve.

Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye ifassessed necessary by the physician. In the VISTADME study, 217 (70.7%) of Eylea patients receivedbilateral Eylea injections until week 100; in the VIVIDDME study, 97 (35.8%) of Eylea patientsreceived a different anti-VEGF treatment in their fellow eye.

An independent comparative trial (DRCR.net Protocol T) utilised a flexible dosing regimen based onstrict OCT and vision re-treatment criteria. In the aflibercept treatment group (n = 224) at week 52,this treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to theadministered number of doses in the Eylea 2Q8 group in VIVIDDME and VISTADME, while overallefficacy of the aflibercept treatment group in Protocol T was comparable to the Eylea 2Q8 group in

VIVIDDME and VISTADME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters invision from baseline was observed in Protocol T. Safety outcomes demonstrated that overall incidenceof ocular and non-ocular adverse events (including ATEs) were comparable across all treatmentgroups in each of the studies and between the studies.

VIOLET, a 100-week multicentre, randomised, open-label, active controlled study in patients with

DME compared three different dosing regimens of Eylea 2 mg for treatment of DME after at least oneyear of treatment at fixed intervals, where treatment was initiated with 5 consecutive monthly dosesfollowed by dosing every 2 months. The study evaluated non-inferiority of Eylea 2 mg dosedaccording to a treat-and-extend regimen (2T&E where injections intervals were kept at a minimum of8 weeks and gradually extended based onclinical and anatomical outcomes) and Eylea 2 mg dosed asneeded (2PRN where patients were observed every 4 weeks and injected when needed based onclinical and anatomical outcomes), compared to Eylea 2 mg dosed every 8 weeks (2Q8) for the secondand third year of treatment.

The primary efficacy endpoint (change in BCVA from baseline to week 52) was 0.5 ± 6.7 letters in the2T&E group and 1.7 ± 6.8 letters in the 2PRN group compared to 0.4 ± 6.7 letters in the 2Q8 group,achieving statistical non-inferiority (p<0.0001 for both comparisons; NI margin 4 letters). The changesin BCVA from baseline to week 100 were consistent with the week 52 results: -0.1 ± 9.1 letters in the2T&E group and 1.8 ± 9.0 letters in the 2PRN group compared to 0.1 ± 7.2 letters in the 2Q8 group.

The mean number of injections over 100 weeks were 12.3, 10.0 and 11.5 for 2Q8fix, 2T&E and2PRN, respectively.

Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in thepivotal studies VIVID and VISTA.

In the 2T&E group, the increments and decrements for the injection intervals were at the investigator’sdiscretion; increments of 2 weeks were recommended in the study.

Myopic choroidal neovascularisation

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV. A total of 121 patients weretreated and evaluable for efficacy (90 with Eylea). Patient ages ranged from 27 to 83 years with amean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised totreatment with Eylea were 65 years of age or older, and approximately 10% (9/91) were 75 years ofage or older.

Patients were randomly assigned in a 3:1 ratio to receive either 2 mg Eylea intravitreally or shaminjections administered once at study start with additional injections given monthly in case of diseasepersistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patientsinitially randomised to sham were eligible to receive the first dose of Eylea. Following this, patients inboth groups continued to be eligible for additional injections in case of disease persistence orrecurrence.

The difference between treatment groups was statistically significant in favour of Eylea for theprimary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion ofpatients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for bothendpoints were maintained through week 48.

Detailed results from the analysis of the MYRROR study are shown in Table 6 and Figure 5 below.

Table 6: Efficacy outcomes at week 24 (primary analysis) and week 48 in MYRROR study(Full Analysis Set with LOCFA))

Efficacy Outcomes MYRROR24 Weeks 48 Weeks

Eylea 2mg Sham Eylea 2mg Sham/(N = 90) (N = 31) (N = 90) Eylea 2mg(N = 31)

Mean change in BCVA B) as measured by 12.1 -2.0 13.5 3.9

ETDRS letter score from baseline (SD) B) (8.3) (9.7) (8.8) (14.3)

Difference in LS mean C,D,E) 14.1 9.5(95% CI) (10.8, 17.4) (5.4, 13.7)

Proportion of patients with ≥15 letters gain38.9% 9.7% 50.0% 29.0%from baseline

Weighted difference D,F) 29.2% 21.0%(95% CI) (14.4, 44.0) (1.9, 40.1)

A) LOCF: Last Observation Carried Forward

B) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

SD: Standard Deviation

C) LS mean: Least square means derived from ANCOVA model

D) CI: Confidence Interval

E) LS mean difference and 95% CI based on an ANCOVA model with treatment group and country (countrydesignations) as fixed effects, and baseline BCVA as covariant.

F) Difference and 95% CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for country(country designations)

Figure 5: Mean Change from Baseline to Week 48 in Visual Acuity by Treatment Group for the

MYRROR Study (Full Analysis Set, LOCF)

Retinopathy of prematurity (ROP)

The efficacy, safety and tolerability of Eylea 0.4 mg for the treatment of ROP in preterm infants wereassessed based on the 6-month data from the multicentre, randomised, 2-arm, open-label parallel-group study FIREFLEYE, which was designed to evaluate Eylea 0.4 mg given as intravitreal injectionin comparison to laser photocoagulation therapy (laser). Eligible patients had treatment-naïve ROPclassified according to the International Classification for Retinopathy of Prematurity in at least oneeye with one of the following retinal findings:

* ROP Zone I Stage 1+, 2+, 3 or 3+, or

* ROP Zone II Stage 2+ or 3+, or

* AP-ROP (aggressive posterior ROP)

Eligible patients had a maximum gestational age at birth of 32 weeks or a maximum birth weight of1500 g. The patients weighed >800 g at the day of treatment.

Patients were randomised in a 2:1 ratio to receive intravitreal Eylea 0.4 mg or laser therapy. All113 patients treated at baseline (Eylea 0.4 mg n=75; laser n=38) were evaluated for the primaryefficacy analysis.

Treatment success was defined as absence of active ROP and unfavourable structural outcomes in botheyes at 24 weeks after the start of study treatment. The success criterion (non-inferiority of Eylea 0.4mg therapy to conventional laser therapy) was statistically not met, although treatment success wasnumerically slightly higher with Eylea 0.4 mg (85.5%) compared to laser (82.1%) at 24 weeks.

However, available data from infants at 2 years of age in the extension study FIREFLEYE NEXT (54infants: 36 Eylea 0.4 mg group and 18 laser group) tend to confirm long term efficacy of Eylea 0.4mg.

The majority of patients treated with Eylea 0.4 mg received a single injection per eye (78.7%) andwere treated bilaterally (94.7%). No patient received more than 2 injections per eye.

Table 7: Outcomes at week 24 (FIREFLEYE)

Treatment success

Treatment Estimated 90% CI2 Comparison Treatment 90% CI2, 3response difference1probability1

Eylea 0.4 mg 85.5% (78.0%, Eylea 0.4 mg 3.4% (-8%, 16.2%)(N=75) 91.3%) vs laser

Laser 82.1% (70.5%,(N=38) 90.8%)

Results based on a Bayesian analysis using non-informative prior distributions.

1 Median of posterior distribution2 CI: Credible interval3 Success criterion: Lower limit of 90% CI above -5%

During the 24 weeks of the study, a lower proportion of patients in the Eylea 0.4 mg group switched toanother treatment modality due to lack of response compared with the laser group (10.7% vs. 13.2%).

Unfavourable structural outcomes were reported in a similar proportion of patients in the Eylea 0.4 mggroup (6 patients, 8%) compared with laser (3 patients, 7.9%).

The European Medicines Agency has waived the obligation to submit the results of studies with Eyleain all subsets of the paediatric population in wet AMD, CRVO, BRVO, DME and myopic CNVpopulations (see section 4.2 for information on paediatric use). In addition, the European Medicines

Agency has waived the obligation to submit the results of studies with Eylea in the following subsetsof the paediatric population in ROP: term newborn infants, infants, children and adolescents.

Eylea is administered directly into the vitreous to exert local effects in the eye.

Absorption/Distribution

Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitrealadministration and is predominately observed in the systemic circulation as an inactive, stablecomplex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.

In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximumplasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately0.02 microgram/mL (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and wereundetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate inthe plasma when administered intravitreally every 4 weeks.

The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times belowthe aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% inanimal models, in which blood pressure changes were observed after circulating levels of freeaflibercept attained approximately 10 microgram/mL and returned to baseline when levels fell belowapproximately 1 microgram/mL. It is estimated that after intravitreal administration of 2 mg topatients, the mean maximum plasma concentration of free aflibercept is more than 100-fold lower thanthe concentration of aflibercept required to half-maximally bind systemic VEGF (2.91 microgram/mL)in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressurechanges are unlikely.

In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean Cmax offree aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/mL andindividual values not exceeding 0.14 microgram/mL. Thereafter, plasma concentrations of freeaflibercept declined to values below or close to the lower limit of quantitation generally within oneweek; undetectable concentrations were reached before the next administration after 4 weeks in allpatients.

As Eylea is a protein-based therapeutic, no metabolism studies have been conducted.

Free aflibercept binds VEGF to form a stable, inert complex. As with other large proteins, both freeand bound aflibercept are expected to be cleared by proteolytic catabolism.

No special studies in patients with renal impairment have been conducted with Eylea.

Pharmacokinetic analysis of patients in the VIEW2 study, of which 40% had renal impairment(24% mild, 15% moderate, and 1% severe), revealed no differences with respect to plasmaconcentrations of active drug after intravitreal administration every 4 or 8 weeks.

Similar results were seen in patients with CRVO in the GALILEO study, in patients with DME in the

VIVIDDME study, and in patients with myopic CNV in the MYRROR study.

Pharmacokinetic properties of aflibercept were evaluated in preterm infants with ROP at a dose of0.4 mg aflibercept (per eye). Following intravitreal injection, concentrations of free and boundaflibercept were higher than those observed in wet AMD adult patients receiving 2 mg (in one eye) butlower than after i.v. administration of the maximum tolerated dose of 1 mg/kg in adult patients. Meanconcentrations of free aflibercept declined to approximately 0.13 microgram/mL at week 4 afterdosing. Plasma concentrations of free aflibercept declined to values below or close to the lower limitof quantitation within approximately 8 weeks. Mean concentrations of adjusted bound afliberceptincreased up to 1.34 microgram/mL at week 4 and declined thereafter.

An exploratory PK/PD analysis showed no relationship between systemic aflibercept concentrations andpharmacodynamic effects such as blood pressure changes.

Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposuresconsidered substantially in excess of the maximum human exposure after intravitreal administration atthe intended clinical dose indicating little relevance to clinical use.

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated withaflibercept intravitreally were observed at systemic exposures in excess of the maximum humanexposure. At the No Observed Adverse Effect Level (NOAEL) of 0.5mg/eye in monkeys the systemicexposure for free aflibercept was 42- and 56-fold higher based on Cmax and AUC when compared tocorresponding values observed in adult patients, and 2-fold higher based on Cmax when compared tocorresponding values observed in preterm infants.

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.

An effect of aflibercept on intrauterine development was shown in embryo-foetal development studiesin pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg)administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. Adevelopmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on

Cmax and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher,respectively, when compared to corresponding values observed in humans after an intravitreal dose of2 mg.

Effects on male and female fertility were assessed as part of a 6-month study in monkeys withintravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregularmenses associated with alterations in female reproductive hormone levels and changes in spermmorphology and motility were observed at all dose levels. Based on Cmax and AUC for free afliberceptobserved at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and1,500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of2 mg. All changes were reversible.

Polysorbate 20 (E 432)

Sodium dihydrogen phosphate, monohydrate (for pH adjustment)

Disodium hydrogen phosphate, heptahydrate (for pH adjustment)

Sodium chloride

Sucrose

Water for injections

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

2 years

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

Do not freeze.

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

The unopened blister may be stored outside the refrigerator below 25 °C for up to 24 hours. Afteropening the blister, proceed under aseptic conditions.

Solution in pre-filled syringe (type I glass) marked with a dosing line, with a plunger stopper(elastomeric rubber) and a Luer lock adaptor with a tip cap (elastomeric rubber). Each pre-filledsyringe contains an extractable volume of at least 0.09 mL. Pack size of 1 pre-filled syringe.

The pre-filled syringe is for single use in one eye only. Extraction of multiple doses from a pre-filledsyringe may increase the risk of contamination and subsequent infection.

Do not open the sterile pre-filled syringe blister outside the clean administration room. Any unusedmedicinal product or waste material should be disposed of in accordance with local requirements

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to0.05 mL) for adult patients and 0.4 mg aflibercept (equivalent to 0.01 mL) for preterm infants. Seefollowing sections “Use in the adult population” and “Use in the paediatric population”.

The solution should be inspected visually for any foreign particulate matter and/or discolouration orany variation in physical appearance prior to administration. In the event of either being observed,discard the medicinal product.

For the intravitreal injection, a 30 G x ½ inch injection needle should be used.

Instructions for use of pre-filled syringe:

Use in the paediatric population

To prepare the pre-filled syringe for administration to preterm infants, follow the steps 1 and 2 belowand then adhere to the instructions for use included in the package of the PICLEO paediatric dosingdevice.

Use in the adult population

To prepare the pre-filled syringe for administration to adults, follow all steps below.

1. When ready to administer Eylea, open the carton and remove the sterilised blister. Carefully peel openthe blister ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are readyfor assembly.

2. Using aseptic technique, remove the syringe from the sterilised blister.

3. To remove the syringe cap, hold the syringe in one hand whileusing the other hand to grasp the syringe cap with the thumband fore finger. Please note: You should twist off (do not snapoff) the syringe cap.

4. To avoid compromising the sterility of the product, do not pull back on the plunger5. Using aseptic technique, firmly twist the injection needle ontothe Luer-lock syringe tip.

6. Holding the syringe with the needle pointing up, check thesyringe for bubbles. If there are bubbles, gently tap the syringewith your finger until the bubbles rise to the top.

The excess volume must be discarded prior to administration. Eliminate all bubbles and expel excess7. medicinal product by slowly depressing the plunger to align the base of the plunger dome (notthe tip of the dome) with the dosing line on the syringe (equivalent to 0.05 mL i.e. 2 mgaflibercept).

Note: This accurate positioning of the plunger is very important, because incorrect plungerpositioning can lead to delivering more or less than the labelled dose.

8. Inject while pressing the plunger carefully and with constant pressure. Do not apply additionalpressure once the plunger has reached the bottom of the syringe. Do not administer any residualsolution observed in the syringe.

9. The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe mayincrease the risk of contamination and subsequent infection.

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

Bayer AG51368 Leverkusen

Germany

EU/1/12/797/001

Date of first authorisation: 22 November 2012

Date of latest renewal: 13 July 2017

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

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