Leaflet OPUVIZ 40mg / ml solution for injection
Indicated for: macular degeneration; diabetic macular edema
Route of administration: injectable
Substance: aflibercept (fusion protein)
ATC: S01LA05 (Sensory organs | Ocular vascular disorder agents | Antineovascularisation agents)
This medicine may cause vision disturbances.
Aflibercept is a medication used in the treatment of certain ophthalmological and oncological conditions. In ophthalmology, it is indicated for the treatment of wet age-related macular degeneration, diabetic macular edema, macular edema secondary to retinal vein occlusion, and choroidal neovascularization. In oncology, it is used in combination with other medications to treat certain types of cancer, such as metastatic colorectal cancer.
Aflibercept acts as a vascular endothelial growth factor (VEGF) inhibitor, blocking the formation of abnormal new blood vessels and reducing fluid leakage from blood vessels. In ophthalmology, it is administered via intravitreal injections, while in oncology, it is given through intravenous infusion.
Side effects may include eye irritation, eye pain, increased intraocular pressure, or local inflammation in ophthalmological use. In oncological use, side effects may include high blood pressure, fatigue, diarrhea, or an increased risk of bleeding. Administration should be performed under strict medical supervision, and patients should inform their doctor about any other conditions or ongoing treatments.
General data about OPUVIZ 40mg / ml
- Substance: aflibercept
- Date of latest medicines list: 01-05-2026
- Product code: W71837001
- Concentration: 40mg / ml
- Pharmaceutical form: solution for injection
- Quantity: 1
- Product type: Generic medicine
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for aflibercept
Concentrations available for aflibercept
- 114.3mg/ml
- 25mg/ml
- 40mg/ml
Leaflet OPUVIZ 40mg/ml
Contents of the package leaflet for the medicine OPUVIZ 40mg / ml solution for injection
1. NAME OF THE MEDICINAL PRODUCT
Opuviz 40 mg/mL solution for injection in a vial.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 mL solution for injection contains 40 mg aflibercept*.
One vial contains an extractable volume of at least 0.1 mL, equivalent to at least 4 mg aflibercept. Thisprovides a usable amount to deliver a single dose of 0.05 mL containing 2 mg aflibercept.
*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.
Excipient with known effectEach ml solution for injection contains 0.3 mg polysorbate 20 (E 432).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection)
The solution is a clear, colourless to pale yellow and iso-osmotic solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Opuviz 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 RVOor central 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 section5.1).
4.2 Posology and method of administration
Opuviz is for intravitreal injection only.
Opuviz must only be administered by a qualified physician experienced in administering intravitrealinjections.
Posologywet AMD
The recommended dose for Opuviz is 2 mg aflibercept, equivalent to 0.05 mL.
Opuviz 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 Opuviz 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,
Opuviz 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 Opuviz is 2 mg aflibercept equivalent to 0.05 mL.
Opuviz 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,
Opuviz should be discontinued.
Myopic choroidal neovascularisation
The recommended dose for Opuviz 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.
Special populationsHepatic and/or renal impairment
No specific studies in patients with hepatic and/or renal impairment have been conducted withaflibercept..
Available data do not suggest a need for a dose adjustment with aflibercept in these patients (seesection 5.2).
Elderly populationNo special considerations are needed. There is limited experience in patients older than 75 years with
DME.Paediatric population
The safety and efficacy of aflibercept have not been established in children and adolescents. There isno relevant use of aflibercept in the paediatric population for the indications of wet AMD, CRVO,
BRVO, DME and myopic CNV.
Method of administrationIntravitreal 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.
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.
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 patients should be instructed to report any symptoms suggestive ofendophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.
Each vial should only be used for the treatment of a single eye. Extraction of multiple doses from asingle vial may increase the risk of contamination and subsequent infection.
The vial contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mLsolution for injection). The extractable volume of the vial is the amount that can be withdrawn fromthe vial and is not to be used in total. For the Opuviz vial, the extractable volume is at least 0.1 mL.
The excess volume must be expelled before injecting the recommended dose (see section 6.6).
Injecting the entire volume of the vial could result in overdose. To expel the air bubbles along withexcess medicinal product, slowly depress the plunger so that the flat plunger edge aligns with the linethat marks 0.05 mL on the syringe (equivalent to 0.05 mL i.e. 2 mg aflibercept) (see sections 4.9 and6.6).
After injection any unused product must be discarded.
For handling of the medicinal product before administration, see section 6.6.
4.3 Contraindications
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
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Intravitreal injection-related reactionsIntravitreal injections, including those with aflibercept, 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
Opuviz. In addition, patients should be monitored during the week following the injection to permitearly treatment if an infection occurs. Patients should be instructed to report any symptoms suggestiveof endophthalmitis or any of the above mentioned events without delay.
The vial contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). Theexcess volume must be discarded prior to administration (see sections 4.2 and 6.6).
Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, includingthose with aflibercept (see section 4.8). Special precaution is needed in patients with poorly controlledglaucoma (do not inject Opuviz 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.
ImmunogenicityAs this is a therapeutic protein, there is a potential for immunogenicity with aflibercept (see section4.8). 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 effectsSystemic 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.
OtherAs with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, DME and myopic CNVthe following also applies:
* The safety and efficacy of aflibercept therapy administered to both eyes concurrently havenot been systematically studied (see section 5.1). If bilateral treatment is performed at thesame time this could lead to an increased systemic exposure, which could increase the riskof systemic adverse events.
* Concomitant use of other anti-VEGF (vascular endothelial growth factor)
* There is no data available on the concomitant use of aflibercept with other anti-VEGFmedicinal products (systemic or ocular).
* Risk factors associated with the development of a retinal pigment epithelial tear afteranti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinaldetachment. When initiating aflibercept therapy, caution should be used in patients withthese risk factors for retinal pigment epithelial tears.
* Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage3 or 4 macular holes.
* In the event of a retinal break the dose should be withheld and treatment should not beresumed until 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:
- a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the lastassessment of visual acuity;
- 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 aperformed or planned intraocular surgery.
* Aflibercept should not be used in pregnancy unless the potential benefit outweighs thepotential risk to the foetus (see section 4.6).
* Women of childbearing potential have to use effective contraception during treatment andfor at least 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.
Populations with limited dataThere 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.
Aflibercept has not been studied in patients with active systemic infections or in patients withconcurrent eye conditions such as retinal detachment or macular hole. There is also no experience oftreatment with aflibercept in diabetic patients with uncontrolled hypertension. This lack of informationshould be considered by the physician when treating such patients.
In myopic CNV there is no experience with aflibercept in the treatment of non-Asian patients, patientswho have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.
Information about excipientsThis medicinal product contains
- less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.
- 0.015 mg of polysorbate 20 in each 0.05 ml dose which is equivalent to 0.3 mg/ml. Polysorbatesmay cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Adjunctive use of verteporfin photodynamic therapy (PDT) and aflibercept has not been studied,therefore, a safety profile is not established.
4.6 Fertility, pregnancy and lactation
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).
PregnancyThere 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, Opuviz should not be usedduring pregnancy unless the potential benefit outweighs the potential risk to the foetus.
Breast-feedingBased 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 Opuviz.
FertilityResults 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.
4.7 Effects on ability to drive and use machines
Injection with aflibercept has a minor influence on the ability to drive and use machines due topossible temporary visual disturbances associated either with the injection or the eye examination.
Patients should not drive or use machines until their visual function has recovered sufficiently.
4.8 Undesirable effects
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 aflibercept and included blindness, endophthalmitis,retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, andintraocular pressure increased (see section 4.4).
The most frequently observed adverse reactions (in at least 5% of patients treated with aflibercept)were conjunctival haemorrhage (25%), retinal haemorrhage (11%), visual acuity reduced (11%), eyepain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), andvitreous floaters (7%).
Tabulated list of adverse reactionsThe 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 (pooleddata of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic CNV) orduring 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,and isolated cases of severe anaphylactic/anaphylactoid reactions.
**** From post-marketing reporting.
Description of selected adverse reactionsIn 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 aflibercept.
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 aflibercept clinical trialsin patients with AMD, DME, RVO and myopic CNV. 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 aflibercept.
Reporting of suspected adverse reactionsReporting 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.
4.9 Overdose
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).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
Mechanism of actionVascular 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 vascularinflammation.
Opuviz is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency https://www.ema.europa.eu/en.
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 aflibercept (one injection per month for three consecutive months, followed byone injection every 2 months), central retinal thickness [CRT] decreased soon after treatmentinitiation, and the mean CNV lesion size was reduced, consistent with the results seen withranibizumab 0.5 mg every month.
In the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (-130and -129 microns at week 52 for the aflibercept 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 aflibercept 2 mg every two monthsand ranibizumab 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 aflibercept 2 mg injections, followed byone injection after a further 2 months, and then continued with a treat-and-extend regimen withvariable treatment intervals (2- week or 4- week adjustments) up to a maximum 16 week intervalaccording to pre-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-weekadjustment group, respectively. The proportion of patients without fluid on OCT at week 52 was68.3% and 69.1% in the 2- and 4-week adjustment groups, respectively. The reduction in CRT wasgenerally maintained in both treatment arms in the second year of the ALTAIR study.
The ARIES study was designed to explore the non-inferiority of an aflibercept 2 mg treat-and-extenddosing regimen initiated immediately after administration of 3 initial monthly injections and oneadditional injection after 2 months vs. a treat-and-extend dosing regimen initiated after one year oftreatment. For patients requiring a more frequent than Q8 dosing at least once over the course of thestudy, CRT remained higher, but the mean decrease in CRT from baseline to week 104 was -160.4microns, similar to 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 aflibercept 2 mg, there was a consistent,rapid and robust morphologic response (as measured by improvements in mean CRT) observed. Atweek 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 tothe 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 aflibercept, the majority of whom were classified as having Type II diabetes, arapid and 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 aflibercept than with the lasercontrol, -192.4 and -183.1 microns for the 2Q8 aflibercept groups and -66.2 and -73.3 microns for thecontrol groups, respectively. At week 100 the decrease was maintained with -195.8and -191.1 microns for the 2Q8 aflibercept 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 thepatients in VISTADME. At week 52, 27.7% and 29.1% of the aflibercept 2Q8 groups, and 7.5% and14.3% of the control groups experienced a ≥2 step improvement in the DRSS. At week 100, therespective percentages were 32.6% and 37.1% of the aflibercept 2Q8 groups and 8.2% and 15.6% ofthe control groups.
The VIOLET study compared three different dosing regimens of aflibercept 2 mg for treatment of
DME after at least one year of treatment at fixed intervals, where treatment was initiated with 5consecutive monthly doses followed by dosing every 2 months. At week 52 and week 100 of thestudy, i.e. second and third year of treatment, the mean changes in CRT were clinically similar fortreat-and-extend (2T&E), pro re nata (2PRN) and 2Q8, respectively, -2.1, 2.2 and -18.8 microns atweek 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 aflibercept 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 aflibercept at week 24 (-79 microns and -4 microns for the aflibercept 2mg treatment 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 aflibercept were assessed in two randomised, multi-centre, double-masked,active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of 2,412patients treated and evaluable for efficacy (1,817 with aflibercept). Patient ages ranged from 49 to 99years with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of thepatients randomised to treatment with aflibercept 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) aflibercept administered at 2 mg every 8 weeks following 3 initial monthly doses (aflibercept2Q8);2) aflibercept administered at 2 mg every 4 weeks (aflibercept 2Q4);3) aflibercept administered at 0.5 mg every 4 weeks (aflibercept 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 aprotocol-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 aflibercept 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 aflibercept 2Q8 group maintained vision compared to 94.4% patients in theranibizumab 0.5Q4 group. In both studies aflibercept was shown to be non-inferior and clinicallyequivalent to the ranibizumab 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 VIEW1and VIEW2 studiesB)
Efficacy Outcome Aflibercept 2Q8E) Ranibizumab 0.5Q4(aflibercept 2 mg every 8 weeks (ranibizumab 0.5 mg every 4following 3 initial monthly weeks)doses)(N = 595)(N = 607)
Week 52 Week 96 Week 52 Week 96
Mean number of injections 7.6 11.2 12.3 16.5from baseline
Mean number of injections 4.2 4.7from Week 52 to 96
Proportion of patients with 95.33%B) 92.42% 94.42% B) 91.60%< 15 letters loss frombaseline (PPS A))
DifferenceC) (95% CI)D) 0.9% 0.8%(-1.7, 3.5)F) (-2.3, 3.8)F)
Mean change in BCVA as 8.40 7.62 8.74 7.89measured by ETDRSA)letter score from baseline
Difference in LS A) mean -0.32 -0.25change (ETDRS letters)C) (-1.87, 1.23) (-1.98, 1.49)(95% CI)D)
Proportion of patients with 30.97% 33.44% 32.44% 31.60%≥ 15 letters gain frombaseline
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 of patients withmaintained visual acuity at week 52 which is PPS
C) The difference is the value of the aflibercept group minus the value of the ranibizumab group. A positive value favoursaflibercept.
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 aflibercept to ranibizumab
Figure 1: Mean Change in Visual Acuity from Baseline to Week 96 for the Combined Data from the
View1 and View2 Studies
In combined data analysis of VIEW1 and VIEW2, aflibercept demonstrated clinically meaningfulchanges from 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 a15-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 aflibercept following twodifferent adjustment intervals (2- weeks and 4- weeks) of a treat-and-extend dosing regimen.
All patients received monthly doses of aflibercept 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)aflibercept treat-and-extend with 2-week adjustments and 2) aflibercept 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 lessthan 15 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 aflibercept 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 aflibercept).
Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately52% (112/217) of the patients randomised to treatment with aflibercept were 65 years of age or older,and approximately 18% (38/217) were 75 years of age or older. In both studies, patients wererandomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or thecontrol group receiving 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 ifpre-specified criteria were met.
In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15letters in BCVA at week 24 compared to baseline. A secondary efficacy variable was change in visualacuity at week 24 compared to baseline.
The difference between treatment groups was statistically significant in favour of aflibercept 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
Aflibercept Control Aflibercept ControlE) AfliberceptF) ControlE,F) Aflibercept Control Aflibercept Control AfliberceptG) ControlG)2 mg Q4 2 mg 2 mg 2 mg Q4 2 mg 2 mg(N = 114) (N = 73) (N = 114) (N = 73) (N = 114) (N = 73) (N = 103) (N = 68) (N = 103) (N = 68) (N = 103) (N = 68)
Proportion of patients with ≥15 letters gain 56% 12% 55% 30% 49.1% 23.3% 60% 22% 60% 32% 57.3% 29.4%from baseline
Weighted differenceA,B,E) 44.8% 25.9% 26.7% 38.3% 27.9% 28.0%(95% CI) (33.0, 56.6) (11.8, 40.1) (13.1, 40.3) (24.4, 52.1) (13.0, 42.7) (13.3, 42.6)p-value p < 0.0001 p = 0.0006 p=0.0003 p < 0.0001 p = 0.0004 p=0.0004
Mean change in BCVAC) as measured by 17.3 -4.0 16.2 3.8 13.0 1.5 18.0 3.3 16.9 3.8 13.7 6.2
ETDRSC) letter score from baseline (SD) (12.8) (18.0) (17.4) (17.1) (17.7) (17.7) (12.2) (14.1) (14.8) (18.1) (17.8) (17.7)
Difference in LS meanA,C,D,E) 21.7 12.7 11.8 14.7 13.2 7.6(95% CI) (17.4, 26.0) (7.7, 17.7) (6.7, 17.0) (10.8, 18.7) (8.2, 18.2) (2.1, 13.1)p-value p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p=0.0070
A) Difference is aflibercept 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/Pacificfor 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 aflibercept on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks.
F) In COPERNICUS study, both control group and aflibercept 2 mg patients received aflibercept 2 mg on an as-needed basis as frequently as every 4 weeks starting from week 52 to week 96; patientshad mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.
G) In GALILEO study, both control group and aflibercept 2 mg patients received aflibercept 2 mg on an as-needed basis every 8 weeks starting from week 52 to week 68; patients had mandatory visitsevery 8 weeks.
Figure 2: Mean Change from Baseline to Week 76/100 in Visual Acuity by Treatment Group for the
COPERNICUS and GALILEO Studies (Full Analysis Set)
In GALILEO, 86.4% (n=89) of the aflibercept group and 79.4% (n=54) of the sham group hadperfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the aflibercept group and 85.5%(n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in theaflibercept group and 84.0% (n=42) in the sham group.
In COPERNICUS, 67.5% (n = 77) of the aflibercept 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 aflibercept group and 58.6%(n = 34) in the sham group. These proportions were maintained at week 100 with 76.8% (n = 76) in theaflibercept group and 78% (n = 39) in the sham group. Patients in the sham group were eligible toreceive aflibercept from week 24.
The beneficial effect of aflibercept treatment on visual function was similar in the baseline subgroupsof perfused 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 theresults in the overall populations.
In combined data analysis of GALILEO and COPERNICUS, aflibercept 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 aflibercept were assessed in a randomised, multi-centre, double-masked,active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) whichincluded Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy(91 with aflibercept). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVOstudy, approximately 58% (53/91) of the patients randomised to treatment with aflibercept were 65years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study,patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 8 weeksfollowing 6 initial monthly injections or laser photocoagulation administered at baseline (laser controlgroup). Patients in the laser control group could receive additional laser photocoagulation (called‘rescue laser treatment’) beginning at week 12 with a minimum interval of 12 weeks. Based onpre-specified criteria, patients in the laser group could receive rescue treatment with aflibercept 2 mgfrom week 24, administered every 4 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 aflibercept group was superior tolaser control.
A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, whichwas statistically significant in favour of aflibercept 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 aflibercept beginning at week 24 (Active
Control/ aflibercept 2 mg group), which resulted in improvement of visual acuity by about 5 lettersfrom week 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
Aflibercept Active Control Aflibercept Active Control2mg Q4 (laser) 2mg Q8 (laser)/Aflibercept2mgE)(N = 91) (N = 90) (N = 91) D) (N = 90)
Proportion of patients 52.7% 26.7% 57.1% 41.1%with ≥15 letters gain from
Baseline (%)
Weighted Difference 26.6% 16.2%
A,B)(%) (95% CI) (13.0, 40.1) (2.0, 30.5)p-value p=0.0003 p=0.0296
Mean change in BCVA 17.0 6.9 17.1 12.2as measured by ETDRS (11.9) (12.9) (13.1) (11.9)letter score from Baseline(SD)
Difference in LS meanA,C) 10.5 5.2(95% CI) (7.1, 14.0) (1.7, 8.7)p-value p<0.0001 p=0.0035F)
A) Difference is aflibercept 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 BCVA category (> 20/200and ≤ 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 aflibercept treatment group was extended for all subjects from 4 weeks to 8weeks through week 48.
E) Beginning at week 24 subjects in the Laser Group could receive rescue treatment with aflibercept, if they met at least onepre-specified eligibility criterion. At total of 67 subjects in this group received aflibercept rescue treatment. The fixedregimen for aflibercept rescue was three times aflibercept 2 mg every 4 weeks followed by injections 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 aflibercept and laser groups was 60% and 68%,respectively. At week 24 these proportions were 80% and 67%, respectively. In the aflibercept groupthe proportion of perfused patients was maintained through week 52. In the laser group, where patientswere eligible for rescue treatment with aflibercept from week 24, the proportion of perfused patientsincreased to 78% by week 52.
Diabetic macular oedema
The safety and efficacy of aflibercept 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 aflibercept. Patient ages ranged from 23 to 87 yearswith a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patientsrandomised to treatment with aflibercept were 65 years of age or older, and approximately 9%(52/576) were 75 years of age 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) Aflibercept administered 2 mg every 8 weeks following 5 initial monthly injections (aflibercept2Q8);2) Aflibercept administered 2 mg every 4 weeks (aflibercept 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 aflibercept groups could receive laser and patients in the controlgroup could receive aflibercept.
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week52 and both aflibercept 2Q8 and aflibercept 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
Aflibercept Aflibercept Active Aflibercept Aflibercept Active Aflibercept Aflibercept Active Aflibercept Aflibercept Active2 mg Q8A 2 mg Q4 Control 2 mg Q8 A 2mg Q4 Control 2 mg Q8A 2 mg Q4 Control 2 mg Q8A 2 mg Q4 Control(laser) (laser) (laser) (laser)(N = 135) (N = 136) (N = 132) (N = 135) (N = 136) (N = 132) (N = 151) (N = 154) (N = 154) (N = 151) (N = 154) (N = 154)
Mean change 10.7 10.5 1.2 9.4 11.4 0.7 10.7 12.5 0.2 11.1 11.5 0.9in BCVA asmeasured by
ETDRSE letterscore from
Baseline
Difference in 9.1 9.3 8.2 10.7 10.45 12.19 10.1 10.6
LS mean 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 of 33% 32% 9% 31.1% 38.2% 12.1% 31% 42% 8% 33.1% 38.3% 13.0%patients with≥ 15 lettersgain from
Baseline
Adjusted 24% 23% 19.0% 26.1% 23% 34% 20.1% 25.8%
DifferenceD,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 been includedas factor for VIVIDDME, and history of MI and/or CVA as a factor for VISTADME
C Difference is aflibercept 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 and medical 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 visual acuity,prior anti-VEGF therapy) in each study and in the combined analysis were generally consistent with theresults 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 if assessednecessary by the physician. In the VISTADME study, 217 (70.7%) of aflibercept patients received bilateralaflibercept injections until week 100; in the VIVIDDME study, 97 (35.8%) of aflibercept patients receiveda 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, thistreatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to theadministered number of doses in the aflibercept 2Q8 group in VIVIDDME and VISTADME, while overallefficacy of the aflibercept treatment group in Protocol T was comparable to the aflibercept 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 incidences ofocular and non-ocular adverse events (including ATEs) were comparable across all treatment groups ineach of the studies and between the studies.
VIOLET, a 100-week multicentre, randomised, open-label, active controlled study in patients with DMEcompared three different dosing regimens of aflibercept 2 mg for treatment of DME after at least one yearof treatment at fixed intervals, where treatment was initiated with 5 consecutive monthly doses followedby dosing every 2 months. The study evaluated non-inferiority of aflibercept 2 mg dosed according to atreat-and-extend regimen (2T&E where injections intervals were kept at a minimum of 8 weeks andgradually extended based on clinical and anatomical outcomes) and aflibercept 2 mg dosed as needed(2PRN where patients were observed every 4 weeks and injected when needed based on clinical andanatomical outcomes), compared to aflibercept 2 mg dosed every 8 weeks (2Q8) for the second and thirdyear 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 changes in
BCVA from baseline to week 100 were consistent with the week 52 results: -0.1 ± 9.1 letters in the 2T&Egroup 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 and 2PRN,respectively.
Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in the pivotalstudies 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 aflibercept 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 aflibercept). 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 aflibercept 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 aflibercept 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 aflibercept. Following this, patientsin both 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 aflibercept 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 both endpointswere 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 Setwith LOCFA))
Efficacy Outcomes MYRROR24 Weeks 48 Weeks
Aflibercept 2mg Sham Aflibercept 2mg Sham/Aflibercept2mg(N = 90) (N = 31) (N = 90) (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 gain 38.9% 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 (country designations) as fixedeffects, 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 Groupfor the MYRROR Study (Full Analysis Set, LOCF)
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies withaflibercept in all subsets of the paediatric population in wet AMD, CRVO, BRVO, DME and myopic
CNV populations (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Aflibercept 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, stable complexwith 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 in theplasma when administered intravitreally every 4 weeks.
The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below theaflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animalmodels, in which blood pressure changes were observed after circulating levels of free aflibercept attainedapproximately 10 microgram/mL and returned to baseline when levels fell below approximately 1microgram/mL. It is estimated that after intravitreal administration of 2 mg to patients, the meanmaximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration ofaflibercept required to half-maximally bind systemic VEGF (2.91 microgram/mL) in a study of healthyvolunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.
In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean Cmax of freeaflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/mL and individualvalues not exceeding 0.14 microgram/mL. Thereafter, plasma concentrations of free aflibercept declinedto values below or close to the lower limit of quantitation generally within one week; undetectableconcentrations were reached before the next administration after 4 weeks in all patients.
EliminationAs Opuviz 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 free andbound aflibercept are expected to be cleared by proteolytic catabolism.
Renal impairmentNo special studies in patients with renal impairment have been conducted with aflibercept.
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 plasma concentrations of activedrug 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.
5.3 Preclinical safety data
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 at theintended 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 human exposure.
The systemic exposure based on Cmax and AUC for free aflibercept were approximately 200 and 700-foldhigher, respectively, when compared to corresponding values observed in humans after an intravitrealdose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemicexposure was 42- and 56-fold higher based on Cmax and AUC, respectively.
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 studies inpregnant 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 Cmaxand cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, whencompared to corresponding values observed in humans after an intravitreal dose of 2 mg.
Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenousadministration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregular menses associatedwith alterations in female reproductive hormone levels and changes in sperm morphology and motilitywere observed at all dose levels. Based on Cmax and AUC for free aflibercept observed at the 3 mg/kgintravenous dose, the systemic exposures were approximately 4,900-fold and 1,500-fold higher,respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes werereversible.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium dihydrogen phosphate dihydratedi-sodium hydrogen phosphate dihydrate
Sucrose
Polysorbate 20
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
3 years
6.4 Special precautions for storage
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 vial may be stored outside the refrigerator at room temperature up to 30°C for a period ofup to 3 days. After opening the vial, proceed under aseptic conditions.
6.5 Nature and contents of container
Vial-only pack
Solution in a vial (type I glass) with a stopper (butyl rubber). Each vial contains an extractable volume ofat least 0.1 mL. Pack size of 1 vial.
Vial + filter needle pack
Solution in a vial (type I glass) with a stopper (butyl rubber), and an 18-G × 1 ½ inch, 5-micron filterneedle. Each vial contains an extractable volume of at least 0.1 mL. Pack size of 1 vial + 1 filter needle.
6.6 Special precautions for disposal and other handling
The vial is for single use in one eye only.
The vial contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). Theexcess volume must be discarded prior to administration.
The solution should be inspected visually for any foreign particulate matter and/or discolouration or anyvariation in physical appearance prior to administration. In the event of either being observed, discard themedicinal product.
Vial-only pack
For preparation and intravitreal injection, the following medical devices for single use are needed:
- a 5 µm filter needle (18-G x 1½″)
- an injection needle (30-G x ½″)
- a 1 ml sterile syringe (including a 0.05 ml mark)
These medical devices are not included within this pack.
Vial + filter needle pack
For preparation and intravitreal injection, the following medical devices for single use are needed:
- a 5 µm filter needle (18-G x 1½″, 1.2 mm x 40 mm, provided)
- an injection needle (30-G x ½″, not included within this pack)
- a 1 ml sterile syringe (including a 0.05 ml mark, not included within this pack)
Filter needle:
Filter needle, not for skin injection. Do not autoclave the filter needle.
Do not use it if individual packaging is damaged. Discard the used filter needle in approved sharpscollector.
Caution: Re use of the filter needle may lead to infection or other illness/injury. For the intravitrealinjection, a 30 G x ½ inch injection needle should be used.
Instructions for use of vial:1. Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial.
2. Attach the 18-G × 1 ½ inch, 5-micron filter needle to a 1-mL sterile syringe.
3. Push the filter needle into the centre of the vial stopper until the needle is completely inserted into thevial and the tip touches the bottom or bottom edge of the vial.
4. Using aseptic technique withdraw all of the Opuviz vial contents into the syringe, keeping the vial in anupright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure thebevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keepingthe bevel of the filter needle submerged in the liquid.
5. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completelyempty the filter needle.
6. Remove the filter needle and properly dispose of it.
Note: Filter needle is not to be used for intravitreal injection.
7. Using aseptic technique, firmly twist a 30 G x ½ inch injection needle onto the syringe tip.
8. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles,gently tap the syringe with your finger until the bubbles rise to the top.
9. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger so that theflat plunger edge aligns with the line that marks 0.05 mL on the syringe.
10. The vial is for single use only. Extraction of multiple doses from a single vial may increase the riskof contamination and subsequent infection. Any unused medicinal product or waste material should bedisposed of in accordance with local requirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.