BEOVU 120mg / ml injection solution in pre-filled syringe medication leaflet

Beovu 120 mg/ml solution for injection in pre-filled syringe

Beovu 120 mg/ml solution for injection

One ml solution for injection contains 120 mg of brolucizumab*.

* Brolucizumab is a humanised monoclonal single-chain Fv (scFv) antibody fragment produced in

Escherichia coli cells by recombinant DNA technology.

Beovu 120 mg/ml solution for injection in pre-filled syringe

Each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 ml solution. This provides a usableamount to deliver a single dose of 0.05 ml solution containing 6 mg of brolucizumab.

Beovu 120 mg/ml solution for injection

Each vial contains 27.6 mg brolucizumab in 0.23 ml solution. This provides a usable amount to delivera single dose of 0.05 ml solution containing 6 mg of brolucizumab.

Each pre-filled syringe contains 0.03 mg polysorbate 80 in 0.165 ml solution. This corresponds to0.01 mg polysorbate 80 per dose (0.05 ml).

Each vial contains 0.05 mg polysorbate 80 in 0.23 ml solution. This corresponds to 0.01 mgpolysorbate 80 per dose (0.05 ml).

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution.

Beovu is indicated in adults for the treatment of

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

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

Beovu must be administered by a qualified ophthalmologist experienced in intravitreal injections.

Wet AMD

Treatment initiation - loading

The recommended dose is 6 mg brolucizumab (0.05 ml solution), administered by intravitrealinjection every 4 weeks (monthly) for the first 3 doses. A disease activity assessment is suggested16 weeks (4 months) after treatment start.

Alternatively, 6 mg brolucizumab (0.05 ml solution) may be administered every 6 weeks for the first2 doses. A disease activity assessment is suggested 12 weeks (3 months) after treatment start. A thirddose may be administered based on disease activity as assessed by visual acuity and/or anatomicalparameters at week 12.

After the last loading dose, the physician may individualise treatment intervals based on disease activityas assessed by visual acuity and/or anatomical parameters. In patients without disease activity,treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatmentevery 8 weeks (2 months) should be considered. If patients are being treated according to a treat-and-extend regimen and there are no signs of disease activity, the treatment intervals could be extendedstepwise until signs of disease activity recur. The treatment interval should be extended or shortenedby no more than 4 weeks (1 month) at a time (see section 5.1). There are limited data on treatmentintervals longer than 20 weeks (5 months). The treatment interval between two doses of Beovu shouldnot be less than every 8 weeks (2 months) (see section 4.4).

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

Beovu should be discontinued.

The recommended dose is 6 mg brolucizumab (0.05 ml solution) administered by intravitreal injectionevery 6 weeks for the first 5 doses.

Thereafter, the physician may individualise treatment intervals based on disease activity as assessed byvisual acuity and/or anatomical parameters. In patients without disease activity, treatment every12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks(2 months) should be considered. After 12 months of treatment, in patients without disease activity,treatment intervals up to 16 weeks (4 months) could be considered (see sections 4.4 and 5.1).

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

Beovu should be discontinued.

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

No dose adjustment is required in patients with renal impairment (see section 5.2).

Brolucizumab has not been studied in patients with hepatic impairment. No dose adjustment isrequired in patients with hepatic impairment (see section 5.2).

The safety and efficacy of brolucizumab in children and adolescents below 18 years of age have notbeen established. No data are available.

Beovu is for intravitreal use only.

The solution for injection should be inspected visually prior to administration (see section 6.6).

The intravitreal injection procedure should be carried out under aseptic conditions, which includes theuse of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (orequivalent). Sterile paracentesis equipment should be available as a precautionary measure. Thepatient’s medical history for hypersensitivity reactions should be carefully evaluated prior toperforming the intravitreal procedure (see section 4.3). Adequate anaesthesia and a broad-spectrumtopical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administeredprior to the injection.

The injection needle should be inserted 3.5 to 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 slowly; 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.

The pre-filled syringe is for single use only. Each pre-filled syringe should only be used for thetreatment of a single eye.

Since the volume contained in the pre-filled syringe (0.165 ml) is greater than the recommended dose(0.05 ml), a portion of the volume contained in the pre-filled syringe must be discarded prior toadministration.

Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubblealong with excess medicinal product, the plunger should be slowly depressed until the edge below thedome of the rubber stopper is aligned with the 0.05 ml dose mark (equivalent to 50 µl, i.e. 6 mgbrolucizumab).

Vial

The vial is for single use only. Each vial should only be used for the treatment of a single eye.

Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml), aportion of the volume contained in the vial must be discarded prior to administration.

Injecting the entire volume of the vial could result in overdose. To expel the air bubble along withexcess medicinal product, the air should be carefully expelled from the syringe and the dose adjustedto the 0.05 ml mark (equivalent to 50 µl, i.e. 6 mg brolucizumab).

For instructions on preparation of the medicinal product before administration, see section 6.6.

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

Patients with active or suspected ocular or periocular infections.

Patients with active 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.

Endophthalmitis, intraocular inflammation, traumatic cataract, retinal detachment, retinal tear, retinalvasculitis, and/or retinal vascular occlusion

Intravitreal injections, including those with Beovu, have been associated with endophthalmitis,intraocular inflammation, traumatic cataract, retinal detachment and retinal tear (see section 4.8).

Proper aseptic injection techniques must always be used when administering Beovu.

Patients should be instructed to report any symptoms suggestive of the above-mentioned eventswithout delay.

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, has beenreported with the use of Beovu (see sections 4.3 and 4.8). A higher number of intraocularinflammation events were observed among patients with treatment-emergent antibodies. Afterinvestigation, retinal vasculitis and/or retinal vascular occlusion were found to be immune-mediatedevents. Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, mayoccur following the first intravitreal injection and at any time of treatment. These events wereobserved more frequently at the beginning of the treatment.

Based on clinical studies these events were more frequent in female patients treated with Beovu thanmale patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER) and in Japanese patients.

In patients developing these events, treatment with Beovu should be discontinued and the eventsshould be promptly managed. Patients treated with Beovu with a medical history of intraocularinflammation and/or retinal vascular occlusion (within 12 months prior to the first brolucizumabinjection) should be closely monitored, since they are at increased risk of developing retinal vasculitisand/or retinal vascular occlusion.

The interval between two Beovu doses during maintenance treatment should not be less than 8 weeksconsidering that a higher incidence of intraocular inflammation (including retinal vasculitis) andretinal vascular occlusion was reported in patients with nAMD who received Beovu every 4 weekmaintenance dosing in a clinical study compared to patients who received Beovu every 8 or 12 weekmaintenance dosing in the pivotal Phase III clinical studies.

Transient increases in intraocular pressure have been seen within 30 minutes of intravitreal injectionwith vascular endothelial growth factor (VEGF) inhibitors, including brolucizumab (see section 4.8).

Special precaution is needed in patients with poorly controlled glaucoma (do not inject Beovu whilethe intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve headmust be monitored and managed appropriately.

The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied.

As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (seesection 4.8). Patients should be instructed to inform their physician if they develop symptoms such aseye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increasednumber of small particles in their vision, or increased sensitivity to light (see section 4.8).

There are no data available on the concomitant use of Beovu with other anti-VEGF medicinal productsin the same eye. Brolucizumab should not be administered concurrently with other anti-VEGFmedicinal products (systemic or ocular) (see section 4.5).

In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not beresumed earlier than the next scheduled treatment in the event of:

* a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the lastassessment of visual acuity;

* a retinal break;

* a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is≥50% of the total lesion area;

* performed or planned intraocular surgery within the previous or next 28 days.

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGFtherapy for wet AMD include a large and/or high pigment epithelial retinal detachment. Wheninitiating brolucizumab therapy, caution should be used in patients with these risk factors for retinalpigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4macular holes.

Systemic effects following intravitreal use

Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events,have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical riskthat these may relate to VEGF inhibition. There are limited data on safety in the treatment of patientswith AMD and DME with a history of stroke, transient ischaemic attacks or myocardial infarctionwithin the last 3 months. Caution should be exercised when treating such patients.

There is limited experience with Beovu treatment in diabetic patients with HbA1c greater than 10% orwith proliferative diabetic retinopathy. There is also no experience of treatment with Beovu in diabeticpatients with uncontrolled hypertension. This lack of information should be considered by thephysician when treating such patients.

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

Polysorbate 80 content

This medicinal product contains 0.01 mg polysorbate 80 per dose (0.05 ml). Polysorbates may causeallergic reactions. Patients need to be instructed to tell their doctor if they have any known allergies.

No interaction studies have been performed.

Women of childbearing potential should use effective contraception during treatment withbrolucizumab and for at least one month after the last dose when stopping treatment withbrolucizumab.

There are no or limited amount of data from the use of brolucizumab in pregnant women. A study inpregnant cynomolgus monkeys did not indicate any harmful effects with respect to reproductivetoxicity. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Although the systemic exposure after ocular administration is very low due to its mechanism of action,there is a potential risk to embryofoetal development. Therefore, brolucizumab should not be usedduring pregnancy unless the potential benefit outweighs the potential risk to the foetus.

It is unknown whether brolucizumab is excreted in human milk. In a reproductive toxicity study,brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys (seesection 5.3). A risk to the breast-fed newborn/infant cannot be excluded. Brolucizumab is notrecommended during breast-feeding and breast-feeding should not be started for at least one monthafter the last dose when stopping treatment with brolucizumab. A decision must be made whether todiscontinue breast-feeding or to abstain from brolucizumab therapy, taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

No reproductive or fertility studies have been conducted. VEGF inhibition has been shown to affectfollicular development, corpus luteum function and fertility. Based on the mechanism of action of

VEGF inhibitors, there is a potential risk for female reproduction.

Beovu has a minor influence on the ability to drive and use machines due to possible temporary visualdisturbances following the intravitreal injection and the associated eye examination. Patients shouldnot drive or use machines until visual function has recovered sufficiently.

Wet AMD

For wet AMD, a total of 1 088 patients treated with brolucizumab constituted the safety population intwo Phase III studies. Of these, 730 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were reduced visual acuity (7.3%), cataract (7.0%),conjunctival haemorrhage (6.3%) and vitreous floaters (5.1%).

The most serious adverse reactions were blindness (0.8%), endophthalmitis (0.7%), retinal arteryocclusion (0.8%) and retinal detachment (0.7%).

For DME, a total of 558 patients treated with brolucizumab constituted the safety population in two

Phase III studies. Of these, 368 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were cataract (9.0%), conjunctival haemorrhage(6.5%) and intraocular pressure increased (5.4%).

The most serious adverse reactions were cataract (9.0%), retinal vascular occlusion (1.1%), retinalartery occlusion (0.8%), and endophthalmitis (0.5%).

The adverse reactions experienced following administration of Beovu in clinical studies aresummarised in Table 1 below.

Adverse reactions (Table 1) are listed according to the MedDRA system organ class. Within eachsystem organ class, the adverse reactions are ranked by frequency, with the most frequent reactionsfirst. Frequency categories for each adverse reaction are based on the following convention: verycommon (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to<1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Frequencies of adverse reactions in clinical studies

MedDRA System organ class Frequency category*

Hypersensitivity (including urticaria, rash, pruritus, Commonerythema)

Visual acuity reduced Common

Retinal haemorrhage Common

Uveitis Common

Iridocyclitis Common

Iritis Common

Retinal vascular occlusion Common

Vitreous haemorrhage Common

Vitreous detachment Common

Retinal tear Common

Cataract Common

Conjunctival haemorrhage Common

Vitreous floaters Common

Eye pain Common

Intraocular pressure increase Common

Conjunctivitis Common

Retinal pigment epithelial tear Common

Vision blurred Common

Corneal abrasion Common

Punctate keratitis Common

Blindness Uncommon

Endophthalmitis Uncommon

Retinal detachment Uncommon

Conjunctival hyperaemia Uncommon

Lacrimation increased Uncommon

Abnormal sensation in eye Uncommon

Detachment of retinal pigment epithelium Uncommon

Vitritis Uncommon

Anterior chamber inflammation Uncommon

Anterior chamber flare Uncommon

Corneal oedema Uncommon

Retinal vasculitis Uncommon

Scleritis** Uncommon

*The frequency category for each adverse reaction is based on the most conservative incidence rate from eitherpooled nAMD or pooled DME Phase III pivotal studies.

**including episcleritis

There is a potential for an immune response in patients treated with Beovu.

Wet AMD

After dosing with Beovu for 88 weeks, treatment-emergent anti-brolucizumab antibodies weredetected in 23-25% of patients.

After dosing with Beovu for 96 weeks, treatment-emergent anti-brolucizumab antibodies were detectedin 16-23% of patients.

Among AMD and DME patients with treatment-emergent antibodies, a higher number of intraocularinflammation adverse reactions were observed. After investigation, retinal vasculitis and/or retinalvascular occlusion, typically in the presence of intraocular inflammation, were found to be immune-mediated adverse events related to exposure to Beovu (see section 4.4). Anti-brolucizumab antibodieswere not associated with an impact on clinical efficacy.

There is a theoretical risk of arterial thromboembolic events, including stroke and myocardialinfarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterialthromboembolic events was observed in the brolucizumab clinical studies in patients with AMD and

DME. There were no major notable differences between the groups treated with brolucizumab andcomparator.

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.

Overdosing with greater than recommended injection volume may increase intraocular pressure. In theevent of overdose, intraocular pressure should therefore be monitored and, if deemed necessary by thetreating physician, appropriate treatment should be initiated.

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA06

Brolucizumab is a humanised monoclonal single chain Fv (scFv) antibody fragment with a molecularweight of ~26 kDa.

Increased levels of signalling through the vascular endothelial growth factor A (VEGF-A) pathway areassociated with pathological ocular angiogenesis and retinal oedema. Brolucizumab binds with highaffinity to VEGF-A isoforms (e.g. VEGF110, VEGF121, and VEGF165), thereby preventing binding of

VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding, brolucizumabsuppresses endothelial cell proliferation, thereby reducing pathological neovascularisation anddecreasing vascular permeability.

Wet AMD

In the HAWK and HARRIER studies, anatomical parameters related to leakage of blood and fluid thatcharacterise choroidal neovascularisation (CNV) were part of the disease activity assessments guidingtreatment decisions. Reductions in central subfield thickness (CST) and in presence ofintraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid wereobserved in patients treated with Beovu as early as 4 weeks after treatment initiation and up toweek 48 and week 96.

At week 16, the reduction in CST was statistically significant on Beovu versus aflibercept in bothstudies (HAWK: -161 vs. -134 microns; HARRIER: -174 vs. -134 microns). This decrease frombaseline in CST was also statistically significant at week 48 (HAWK: -173 vs. -144 microns;

HARRIER: -194 vs. -144 microns), and maintained to the end of each study at week 96 (HAWK: -175vs. -149 microns; HARRIER: -198 vs. -155 microns).

At week 16, the percentage difference in patients with IRF and/or SRF fluid was statisticallysignificant on Beovu versus aflibercept in both studies (HAWK: 34% vs. 52%; HARRIER: 29% vs.

45%). This difference was also statistically significant at week 48 (HAWK: 31% vs. 45%; HARRIER:

26% vs. 44%), and maintained to the end of each study at week 96 (HAWK: 24% vs. 37%;

HARRIER: 24% vs. 39%).

At week 16, the percentage difference in patients with sub-RPE fluid was statistically significant on

Beovu versus aflibercept in both studies (HAWK: 19% vs. 27%; HARRIER: 16% vs. 24%). Thisdifference was also statistically significant at week 48 (HAWK: 14% vs. 22%; HARRIER: 13% vs.

22%), and maintained to the end of each study at week 96 (HAWK: 11% vs. 15%; HARRIER: 17%vs. 22%).

In these studies, for patients treated with Beovu, reductions in CNV lesion size were observed as earlyas 12 weeks, and at weeks 48 and 96 after treatment initiation.

In the KESTREL and KITE studies, related anatomical parameters were part of the disease activityassessments guiding treatment decisions. Reductions in CST and in presence of IRF/SRF wereobserved in patients treated with Beovu as early as 4 weeks after treatment initiation and up toweek 52. These reductions were maintained up to week 100.

Wet AMD

The efficacy and safety of Beovu were assessed in two randomised, multicentre, double-masked,active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD.

A total of 1,817 patients were treated in these studies for two years (1 088 on Beovu and 729 oncomparator aflibercept). Patient ages ranged from 50 to 97 years, with a mean age of 76 years.

In both studies, after the first three monthly doses (weeks 0, 4 and 8), brolucizumab patients weretreated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based ondisease activity. Disease activity was assessed by a physician during the first 12-week interval (atweeks 16 and 20) and at each subsequent scheduled 12-weekly treatment visit. Patients who showeddisease activity (e.g. decreased visual acuity, increased CST and/or presence of IRF/SRF or sub-RPEfluid) at any of these visits were adjusted to an 8-weekly treatment interval. The comparatoraflibercept was administered every 8 weeks after the first 3 monthly doses.

The primary efficacy endpoint for the studies was the change from baseline in best corrected visualacuity (BCVA) to week 48, as measured by the early treatment diabetic retinopathy study (ETDRS)letter score, with the primary objective being to demonstrate non-inferiority of Beovu versusaflibercept. In both studies, Beovu (administered in an every 12 weeks or an every 8 weeks regimen)demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks). The visual acuitygains observed in the first year were maintained in the second year.

Detailed results of both studies are shown in Table 2 and in Figure 1 below.

Table 2 Visual acuity outcomes at weeks 48 and 96 in Phase III - HAWK and HARRIERstudies

HAWK HARRIER

Efficacy outcome Week Beovu Aflibercept Difference Beovu Aflibercept Difference(n=360) 2 mg (95% CI) (n=370) 2 mg (95% CI)(n=360) brolucizumab (n=369) brolucizumab- aflibercept - aflibercept

Mean change from 48 6.6 6.8 -0.2 6.9 7.6 -0.7baseline in BCVA (SE=0.71) (SE=0.71) (-2.1, 1.8) (SE=0.61) (SE=0.61) (-2.4, 1.0)(measured by P<0.0001 a) P <0.0001 a)

ETDRS letters score) 36 - 6.7 6.7 0.0 6.5 7.7 -1.248 b) (SE=0.68) (SE=0.68) (-1.9, 1.9) (SE=0.58) (SE=0.58) (-2.8, 0.4)

P<0.0001 a) P=0.0003 a)96 5.9 5.3 0.5 6.1 6.6 -0.4(SE=0.78) (SE=0.78) (-1.6, 2.7) (SE=0.73) (SE=0.73) (-2.5,1.6)% of patients who 48 33.6 25.4 8.2 29.3 29.9 -0.6gained at least (2.2, 15.0) (-7.1, 5.8)15 letters of vision 96 34.2 27.0 7.2 29.1 31.5 -2.4(1.4, 13.8) (-8.8, 4.1)% of patients who 48 6.4 5.5 0.9 3.8 4.8 -1.0lost visual acuity (%) (-2.7, pct. 4.3) (-3.9, 2.2)(≥15 letters of BCVA 96 8.1 7.4 0.7 7.1 7.5 -0.4loss) (-3.6, pct. 4.6) (-3.8, 3.3)

BCVA: best corrected visual acuity; missing data are imputed using last observation carried forward (LOCF) method

ETDRS: early treatment diabetic retinopathy study

SE: standard errora) P-value referring to the non-inferiority hypothesis with a non-interiority margin of 4.0 letters.b) Key secondary endpoint, accounting for differences in timing of Beovu and aflibercept treatments.

Figure 1 Mean change in visual acuity from baseline to week 96 in HAWK and HARRIERstudies

HAWK0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96

Time (weeks)

Beovu 6 mg (n=360) aflibercept 2 mg (n=360)

HARRIER0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96

Time (weeks)

Beovu 6 mg (n=370) aflibercept 2 mg (n=369)

These visual acuity gains were achieved with 56% and 51% of patients treated with Beovu on a 12-weekly dosing interval at week 48, and with 45% and 39% of patients at week 96 in HAWK and

HARRIER, respectively. Among patients identified as eligible for the 12-weekly regimen during thefirst 12-week interval, 85% and 82% remained on the 12-weekly dosing interval up to week 48. Ofpatients on the 12-weekly interval at week 48, 82% and 75% remained on the 12-weekly dosinginterval up to week 96.

VA change from baseline (letters) VA change from baseline (letters)

Treatment effects in evaluable subgroups (e.g. age, gender, race, baseline visual acuity, baselineretinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with theresults in the overall populations.

Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including

CST and/or presence of IRF/SRF or sub-RPE. Disease activity was assessed throughout the studies.

Anatomical parameters of disease activity were decreased at week 48 and at week 96 for Beovucompared to aflibercept (see “Pharmacodynamic effects”).

The percentage difference in patients with disease activity at week 16 was statistically significant on

Beovu versus aflibercept (24% vs 35% in HAWK, p=0.0013; 23% vs 32% in HARRIER, p=0.0021).

In both studies, Beovu demonstrated clinically meaningful increases from baseline in the pre-specifiedsecondary efficacy endpoint of patient-reported outcomes, reported through the 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 BCVA. Patient-reported outcomebenefits were maintained in the second year.

No clinically meaningful differences were found between Beovu and aflibercept in changes frombaseline to week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, nearactivities, distance activities, social functioning, mental health, role difficulties, dependency, driving,colour vision and peripheral vision).

The results of the Beovu arms of the HAWK and HARRIER studies, where Beovu was administeredevery 4 weeks (monthly) for the first 3 doses (loading) followed by maintenance dosing every 12 or8 weeks, were replicated in a population pharmacokinetic/pharmacodynamic model simulation studywhere Beovu was administered every 6 weeks for the first 2 or 3 doses (loading) followed bymaintenance dosing every 12 or 8 weeks.

A treat-and-extend dosing regimen for the maintenance phase was examined in the TALON study,which was a 64-week, two-arm, randomised, double-masked, multicentre, Phase IIIb study assessingthe efficacy and safety of Beovu compared to aflibercept 2 mg in patients with nAMD.

737 patients were randomised in a 1:1 ratio to one of the two treatment arms, either brolucizumab6 mg or aflibercept 2 mg. Patients in both treatment arms were dosed once every 4 weeks for the first3 injections and then one injection after 8 weeks. Thereafter, treatment intervals were either every8 weeks, every 12 weeks, or every 16 weeks up to week 60 or 62.

The average change in BCVA from baseline at week 64 was +4.7 ETDRS letters vs. +4.9 ETDRSletters for Beovu and aflibercept 2 mg, respectively.

Results of treatment intervals at week 64 are presented in Table 3.

Table 3 Last treatment interval with no disease activity: proportion of patients at week 64

Study arm

Interval Brolucizumab 6 mg Aflibercept 2 mg(weeks) n=366 n=3684 23.2% 41.8%8 26.0% 22.0%12 22.4% 23.9%16 28.4% 12.2%255 subjects who completed the TALON study were enrolled into a 56-week open-label, one-armextension study of TALON and treated with a brolucizumab treat-and-extend dosing regimen withouta loading phase and with a maximum treatment interval of up to 20 weeks.

At week 56, more than 50% of 237 subjects who had received at least 2 injections were on a treatmentinterval of 16 weeks (24.9%) or 20 weeks (28.7%) and had no disease activity, while visual acuity wasmaintained throughout the study.

The efficacy and safety of Beovu were assessed in two randomised, multicentre, double-masked,activecontrolled Phase III studies (KESTREL and KITE) in patients with visual impairment due todiabetic macular oedema. A total of 926 patients were treated in these studies for two years (558 onbrolucizumab and 368 on aflibercept 2 mg). Patient ages ranged from 23 to 87 years, with a mean ageof 63 years.

In both studies, after the first five doses (weeks 0, 6, 12, 18 and 24), brolucizumab patients weretreated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based ondisease activity. Disease activity was assessed by a physician during the first 12-week interval (atweeks 32 and 36) and at each subsequent scheduled treatment visit. Patients who showed diseaseactivity (e.g. decreased visual acuity, increased CST) at any of these visits were adjusted to an every8 weeks treatment interval. In year 2 of KITE, patients who showed no disease activity could beextended to a 16-week treatment interval. The comparator aflibercept was administered every 8 weeksafter the first 5 monthly doses.

The primary efficacy endpoint for the studies was the change from baseline in BCVA to week 52, asmeasured by the ETDRS letter score, with the primary objective being to demonstrate non-inferiorityof Beovu versus aflibercept 2 mg. In both studies, Beovu (administered in an every 12 weeks or anevery 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every8 weeks).

The results of KESTREL and KITE also demonstrated non-inferiority of Beovu versus aflibercept2 mg for the key secondary endpoint (average change from baseline in BVCA over the period week 40to week 52).

The visual acuity gains observed in the first year were maintained in the second year.

Detailed results of both studies are shown in Table 4 and in Figure 2 below.

Table 4 Visual acuity outcomes at weeks 52 and 100 in Phase III - KESTREL and KITEstudies

KESTREL KITE

Efficacy outcome Week Beovu Aflibercept Difference Beovu Aflibercept Difference(n=189) 2 mg (95% CI) (n=179) 2 mg (95% CI)(n=187) brolucizumab (n=181) brolucizumab-- aflibercept aflibercept52 9.2 10.5 -1.3 10.6 9.4 1.2(0.57) (0.57) (-2.9, 0.3) (0.66) (0.66) (-0.6, 3.1)a a

Change from baseline P <0.001 P <0.001in BCVA (measured 40-52 9.0 10.5 -1.5 10.3 9.4 0.9by ETDRS letters (0.53) (0.53) (-3.0, 0.0) (0.62) (0.62) (-0.9, 2.6)score) - LS mean (SE) P <0.001a P <0.001a100 8.8 10.6 -1.7 10.9 8.4 2.6(0.75) (0.75) (-3.8, 0.4) (0.85) (0.85) (0.2, 4.9)

Gain of at least 52 36.0 40.1 -4.1 46.8 37.2 9.615 letters in BCVA (-13.3, 5.9) (-0.4, 20.2)from baseline or 100 39.2 42.2 -3.0 50.4 36.9 13.6

BCVA ≥84 letters (%) (-12.5, 6.3) (3.3, 23.5)

BCVA: best corrected visual acuity; BCVA assessments after start of alternative DME treatment in the study eye were censoredand replaced by the last value prior to start of this alternative treatment.

ETDRS: early treatment diabetic retinopathy study

LS: least-square

SE: standard errora P-value referring to the non-inferiority hypothesis with a non-inferiority margin of 4.0 letters

Figure 2 Mean change in visual acuity from baseline to week 100 in KESTREL and KITEstudies

KESTREL0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

Time (weeks)

Beovu 6mg (N=189) Aflibercept 2mg (N=187)

KITE0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

Time (weeks)

Beovu 6mg (N=179) Aflibercept 2mg (N=181)

VA change from baseline (letters) VA change from baseline (letters)

These visual acuity gains were achieved with 55% and 50% of patients treated with Beovu on a 12-weekly dosing interval at week 52, and 44% and 37% of patients treated with Beovu on a 12-weeklyor 12-weekly/16-weekly dosing interval at week 100 in KESTREL and KITE, respectively. Amongpatients identified as eligible for the 12-weekly regimen during the first 12-week interval,approximately 70% remained on at least the 12-weekly interval at week 100 in both studies. In KITE,25% of patients were treated with Beovu on a 16-weekly dosing interval at week 100.

Treatment effects in evaluable subgroups (e.g. age, gender, baseline HbA1c, baseline visual acuity,baseline central subfield thickness, DME lesion type, duration of DME since diagnosis, retinal fluidstatus) in each study were generally consistent with the results in the overall populations.

In KESTREL and KITE, disease activity was assessed throughout the studies by changes in visualacuity and/or anatomical parameters, including CST and/or presence of IRF/SRF. The reduction in

CST from baseline was maintained up to week 100. At week 100, the proportion of patients with

IRF/SRF was lower in patients treated with Beovu (42% KESTREL and 41% KITE) compared topatients treated with aflibercept 2 mg (54% KESTREL and 57% KITE).

Diabetic retinopathy severity score (DRSS) was assessed in the KESTREL and KITE studies. Atbaseline, 98.1% of patients in both KESTREL and KITE had gradable DRSS scores. Based on thepooled analysis, Beovu showed non-inferiority to aflibercept 2 mg in the proportion of subjects with atleast a 2-step improvement from baseline in DRSS at week 52, using a non-inferiority margin of 10%.

Estimated proportions were 28.9% and 24.9% in Beovu and aflibercept 2 mg, respectively, resulting ina treatment difference of 4.0% (95% CI: [-0.6, 8.6]). At week 100, the proportion of patients with a≥2-step improvement from baseline to week 100 in the DRSS score was 32.8% with Beovu and 29.3%with aflibercept 2 mg in KESTREL and 35.8% with Beovu and 31.1% with aflibercept 2 mg in KITE.

The European Medicines Agency has waived the obligation to submit the results of studies with

Beovu in all subsets of the paediatric population in neovascular AMD and DME (see section 4.2 forinformation on paediatric use).

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

After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the geometircmean Cmax of free brolucizumab in the plasma was 49.0 ng/ml (range: 8.97 to 548 ng/ml) and wasattained in 1 day.

Brolucizumab is a monoclonal antibody fragment and no metabolism studies have been conducted. Asa single-chain antibody fragment, free brolucizumab is expected to undergo elimination through bothtarget-mediated disposition via binding to free endogenous VEGF, passive renal elimination andmetabolism via proteolysis.

After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of4.3 ± 1.9 days. Concentrations were generally near or below the quantitation limit (<0.5 ng/ml)approximately 4 weeks after dosing in most patients. Brolucizumab did not accumulate in the serumwhen administered intravitreally every 4 weeks.

There were no relevant differences in systemic pharmacokinetics following intravitreal injection in astudy with 22 patients aged 65 to 74 years, 18 patients aged 75 to 84 years and 3 patients aged≥85 years.

The systemic pharmacokinetics of brolucizumab was evaluated in nAMD patients with normal renalfunction (≥90 ml/min [n=21]), with mild (60 to <90 ml/min [n=22]) or moderate (30 to <60 ml/min[n=7]) renal impairment. While the mean systemic clearance values for patients with mild or moderaterenal impairment were generally lower than patients with normal renal function, no significant impactof mild and moderate renal impairment on the overall systemic exposure to brolucizumab wasobserved. No patients with severe (<30 ml/min) renal impairment were studied.

Brolucizumab has not been studied in patients with hepatic impairment. Mild to severe hepaticimpairment should have no impact on the overall systemic exposure to brolucizumab, becausemetabolism occurs via proteolysis and does not depend on hepatic function.

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

In pregnant cynomolgus monkeys, brolucizumab was administered once every 4 weeks by intravitrealinjection at dose levels resulting in maximal systemic exposures 6-fold higher than those in humans atthe maximum recommended dose (based on serum Cmax). There was no impact on embryofoetaldevelopment, pregnancy or parturition, or on the survival, growth or postnatal development ofoffspring. Nevertheless, based on its pharmacological effect, brolucizumab should be regarded aspotentially teratogenic and embryo-foetotoxic.

Sodium citrate

Sucrose

Polysorbate 80

Sodium hydroxide (for pH adjustment)

Water for injections

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

Pre-filled syringe: 2 years

Vial: 2 years

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled syringe in its sealed blister and in the outer carton in order to protect from light.

Prior to use, the unopened blister may be kept at room temperature (below 25°C) for up to 24 hours.

Vial

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Prior to use, the unopened vial may be kept at room temperature (below 25°C) for up to 24 hours.

Pre-filled syringe0.165 ml sterile solution in a pre-filled syringe (type I glass) with a bromobutyl rubber plunger stopperand a syringe cap consisting of a white, tamper-evident rigid seal with a grey bromobutyl rubber tipcap including a Luer lock adapter. The pre-filled syringe has a plunger rod and a purple finger grip,and is packed in a sealed blister.

Pack size of 1 pre-filled syringe.

Vial0.23 ml sterile solution in a 2 ml glass vial with a coated rubber stopper sealed with an aluminium capwith a purple plastic flip-off disk.

Pack size of 1 vial and 1 blunt filter needle (18G x 1½″, 1.2 mm x 40 mm, 5 μm).

Not all pack sizes may be marketed.

The pre-filled syringe contains more than the recommended dose of 6 mg. The extractable volume ofthe pre-filled syringe (0.165 ml) is not to be used in total. The excess volume should be expelled priorto injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel theair bubble along with the excess medicinal product, slowly push the plunger until the edge below thedome of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml,i.e., 6 mg brolucizumab).

The solution should be inspected visually upon removal from the refrigerator and prior toadministration. If particulates or cloudiness are visible, the pre-filled syringe must not be used andappropriate replacement procedures followed.

The pre-filled syringe is sterile and for single use only. Do not use if the packaging, or pre-filledsyringe are damaged or expired. Detailed instructions for use are provided in the package leaflet.

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

Vial

The vial contains more than the recommended dose of 6 mg. The extractable volume of the vial(0.23 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injectingthe entire volume of the vial could result in overdose. The injection dose must be set to the 0.05 mldose mark, i.e. 6 mg brolucizumab.

The solution should be inspected visually upon removal from the refrigerator and prior toadministration. If particulates or cloudiness are visible, the vial must not be used, and appropriatereplacement procedures must be followed.

The content of the vial and the filter needle are sterile and for single use only. Do not use if thepackaging, vial and/or filter needle are damaged or expired. Detailed instructions for use are providedin the package leaflet.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/19/1417/001-002

Date of first authorisation: 13 February 2020

Date of latest renewal: 19 September 2024

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

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