VABYSMO 120mg / ml injectible solution medication leaflet

Vabysmo 120 mg/mL solution for injection

Vabysmo 120 mg/mL solution for injection in pre-filled syringe

One mL of solution contains 120 mg of faricimab.

Each pre-filled syringe contains 21 mg faricimab in 0.175 mL solution. This provides a usable amountto deliver a single dose of 0.05 mL solution containing 6 mg of faricimab.

Vial

Each vial contains 28.8 mg faricimab in 0.24 mL solution. This provides a usable amount to deliver asingle dose of 0.05 mL solution containing 6 mg of faricimab.

Faricimab is a humanised antibody produced in mammalian Chinese Hamster Ovary (CHO) cellculture by recombinant DNA technology.

Each 0.05 mL solution contains 0.02 mg polysorbate and 0.07 mg sodium.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colourless to brownish-yellow solution, with a pH of 5.5 and an osmolality of270-370 mOsm/kg.

Vabysmo is indicated for the treatment of adult patients with:

* neovascular (wet) age-related macular degeneration (nAMD),

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

* visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO orcentral RVO).

This medicinal product must be administered by a qualified physician experienced in intravitrealinjections.

The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every4 weeks (monthly) for the first 3 doses.

Thereafter, an assessment of disease activity based on anatomic and/or visual outcomes isrecommended 16 and/or 20 weeks after treatment initiation so that treatment can be individualised. Inpatients without disease activity, administration of faricimab every 16 weeks (4 months) should beconsidered. In patients with disease activity, treatment every 8 weeks (2 months) or 12 weeks(3 months) should be considered. If anatomic and/or visual outcomes change, the treatment intervalshould be adjusted accordingly, and interval reduction should be implemented if anatomic and/orvisual outcomes deteriorate (see section 5.1). There is limited safety data on treatment intervals of8 weeks or less between injections (see section 4.4). Monitoring between the dosing visits should bescheduled based on the patient's status and at the physician's discretion, but there is no requirement formonthly monitoring between injections.

Visual impairment due to diabetic macular oedema (DME) and macular oedema secondary to retinalvein occlusion (RVO)

The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every4 weeks (monthly); 3 or more consecutive, monthly injections may be needed.

Thereafter, treatment is individualised using a treat -and-extend approach. Based on the physician’sjudgement of the patient’s anatomic and/or visual outcomes, the dosing interval may be extended inincrements of up to 4 weeks. If anatomic and/or visual outcomes change, the treatment interval shouldbe adjusted accordingly, and interval reduction should be implemented if anatomic and/or visualoutcomes deteriorate (see section 5.1). Treatment intervals shorter than 4 weeks and longer than4 months between injections have not been studied. Monitoring between the dosing visits should bescheduled based on the patient’s status and at the physician’s discretion but there is no requirement formonthly monitoring between injections.

This medicinal product is intended for long-term treatment. If visual and/or anatomic outcomesindicate that the patient is not benefitting from continued treatment, treatment should be discontinued.

If a dose is delayed or missed, the patient should return to be assessed by physician at the nextavailable visit and continue dosing depending on physician’s discretion.

No dose adjustment is required in patients aged 65 years or above (see section 5.2). Safety data innAMD and RVO patients ≥ 85 years is limited (see section 4.4).

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

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

There is no relevant use of this medicinal product in the paediatric population for the indications ofnAMD, DME, and RVO.

For intravitreal use only. Each pre-filled syringe or vial should only be used for the treatment of asingle eye.

Vabysmo should be inspected visually for particulate matter and discoloration prior to administration,and if present, the pre-filled syringe or vial should not be used.

The intravitreal injection procedure should be carried out under aseptic conditions, which includes theuse of surgical hand disinfection, a sterile drape and a sterile eyelid speculum (or equivalent). Thepatient’s medical history for hypersensitivity reactions should be carefully evaluated prior toperforming the intravitreal procedure (see section 4.8). Adequate anaesthesia and a broad-spectrumtopical microbicide to disinfect the periocular skin, eyelid, and ocular surface should be administeredprior to the injection.

The pre-filled syringe contains an excess of volume. The excess volume must be expelled beforeinjecting the recommended dose. Injecting the entire volume of the pre-filled syringe could result inoverdose.

To expel the air bubbles along with excess medicinal product, slowly push the plunger rod until thelower edge of the rubber stopper’s dome is aligned with the 0.05 mL dose mark (see sections 4.9 and6.6).

The injection filter needle (included in the package) should be inserted 3.5 to 4.0 mm posterior to thelimbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of theglobe. The injection volume of 0.05 mL is then delivered slowly; a different scleral site should be usedfor subsequent injections.

Vial

The injection needle (30-gauge x ½ inch, not included in the package) should be inserted 3.5 to4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aimingtowards the centre of the globe. The injection volume of 0.05 mL is then delivered slowly; a differentscleral site should be used for subsequent injections.

Post-injection monitoring

After injection, any unused medicinal product or waste material should be disposed of in accordancewith local requirements.

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. vision loss, eye pain, redness of the eye, photophobia, blurring of vision) withoutdelay.

For instructions on handling 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.

Active or suspected ocular or periocular infections.

Active intraocular inflammation.

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

Intravitreal injections, including those with faricimab, 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

Vabysmo. Patients should be instructed to report any symptoms, such as pain, loss of vision,photophobia, blurred vision, floaters, or redness, suggestive of endophthalmitis or any of the above-mentioned adverse reactions without delay, to permit prompt and appropriate management. Patientswith increased frequency of injections may be at increased risk of procedural complications.

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitrealinjection, including those with faricimab (see section 4.8). Special precaution is needed in patientswith poorly controlled glaucoma (do not inject Vabysmo while the IOP is ≥ 30 mmHg). In all cases,both the IOP and perfusion of the optic nerve head must be monitored and managed appropriately.

Systemic adverse events including arterial thromboembolic events have been reported followingintravitreal injection of vascular endothelial growth factor (VEGF) inhibitors and there is a theoreticalrisk that these may be related to VEGF inhibition. A low incidence rate of arterial thromboembolicevents was observed in the faricimab clinical trials in patients with nAMD, DME, and RVO. There arelimited data on the safety of faricimab treatment in DME patients with high blood pressure(≥ 140/90 mmHg) and vascular disease, and in nAMD and RVO patients ≥ 85 years of age.

As this is a therapeutic protein, there is a potential for immunogenicity with faricimab (see section4.8). Patients should be instructed to inform their physician of any signs or symptoms of intraocularinflammation such as vision loss, eye pain, increased sensitivity to light, floaters or worsening eyeredness, which might be a clinical sign attributable to hypersensitivity against faricimab (see section4.8).

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

Bilateral treatment could cause bilateral ocular adverse reactions and/or potentially lead to an increasein systemic exposure, which could increase the risk of systemic adverse reactions. Until data forbilateral use become available, this is a theoretical risk for faricimab.

There are no data available on the concomitant use of faricimab with anti-VEGF medicinal products inthe same eye. Faricimab should not be administered concurrently with other anti-VEGF medicinalproducts (systemic or ocular).

Use of other injection needles with the pre-filled syringe

Only use the pre-filled syringe with the co-packaged injection filter needle. There are no clinical dataavailable on the use of other injection needles with the pre-filled syringe.

Treatment should be withheld in patients with:

* Rhegmatogenous retinal detachment, stage 3 or 4 macular holes, retinal break; treatment shouldnot be resumed until an adequate repair has been performed.

* Treatment related decrease in Best Corrected Visual Acuity (BCVA) of ≥ 30 letters comparedwith the last assessment of visual acuity; treatment should not be resumed earlier than the nextscheduled treatment.

* An intraocular pressure of ≥ 30 mmHg.

* 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; treatment shouldnot be resumed earlier than the next scheduled treatment.

Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) inpatients with nAMD. Risk factors associated with the development of a retinal pigment epithelial tearafter anti-VEGF therapy for nAMD, include a large and/or high pigment epithelial detachment. Wheninitiating faricimab therapy, caution should be used in patients with these risk factors for retinalpigment epithelial tears. RPE tears are common in nAMD patients with PED, treated with intravitrealanti-VEGF agents including faricimab. There was a higher rate of RPE tear in the faricimab group(2.9%) compared to aflibercept group (1.5%). The majority of events occurred during the loadingphase, and were mild to moderate, without impact on vision.

There is only limited experience in the treatment of nAMD and RVO patients ≥ 85 years, and DMEpatients with type I diabetes, patients with HbA1c over 10%, patients with high-risk proliferativediabetic retinopathy (DR), high blood pressure (≥ 140/90 mmHg) and vascular disease, sustaineddosing intervals shorter than every 8 weeks (Q8W), or nAMD, DME, and RVO patients with activesystemic infections. There is limited safety information on sustained dosing intervals of 8 weeks orless and these may be associated with a higher risk of ocular and systemic adverse reactions, includingserious adverse reactions. There is also no experience of treatment with faricimab in diabetic or RVOpatients with uncontrolled hypertension and patients with RVO who have failed previous therapy. Thislack of information should be considered by the physician 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 content

This medicinal product contains 0.02 mg of polysorbate per 0.05 mL dose. Patients withhypersensitivity to polysorbate should not take this medicine.

No interaction studies have been performed. Based on the biotransformation and elimination offaricimab (see section 5.2), no interactions are expected. However, faricimab should not beadministered concurrently with other systemic or ocular anti-VEGF medicinal products (see section4.4).

Women of childbearing potential should use effective contraception during treatment and for at least3 months following the last intravitreal injection of faricimab.

There are no or limited amount of data from the use of faricimab in pregnant women. The systemicexposure to faricimab is low after ocular administration, but due to its mechanism of action (i.e. VEGFinhibition), faricimab must be regarded as potentially teratogenic and embryo-/foetotoxic (see section5.3).

Faricimab should not be used during pregnancy unless the potential benefit outweighs the potentialrisk to the foetus.

It is unknown whether faricimab is excreted in human milk. A risk to the breast-fed newborn/infantcannot be excluded. Vabysmo should not be used during breast-feeding. A decision must be madewhether to discontinue breast-feeding or to discontinue/abstain from faricimab therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

No effects on reproductive organs or fertility were observed in a 6-month cynomolgus monkey studywith faricimab (see section 5.3).

Vabysmo has a minor influence on the ability to drive and use machines. Temporary visualdisturbances may occur following the intravitreal injection and the associated eye examination.

Patients should not drive or use machines until visual function has recovered sufficiently.

The most frequently reported adverse reactions were cataract (10%), conjunctival haemorrhage (7%),vitreous detachment (4%), IOP increased (4%), vitreous floaters (4%), eye pain (3%), and retinalpigment epithelial tear (nAMD only) (3%).

The most serious adverse reactions were uveitis (0.5%), endophthalmitis (0.4%), vitritis (0.4%), retinaltear (0.2%), rhegmatogenous retinal detachment (0.1%), and traumatic cataract (< 0.1%) (see section4.4).

The adverse reactions reported in clinical studies or during post-marketing surveillance are listedaccording to the MedDRA system organ class and ranked by frequency using the followingconvention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100),rare (≥ 1/10 000 to < 1/1 000) or not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Frequencies of adverse reactions

MedDRA System organ class Frequency category

Cataract Common

Conjunctival haemorrhage Common

Vitreous detachment Common

Increased intraocular pressure Common

Vitreous floaters Common

Retinal pigment epithelial tear (nAMD only) Common

Eye pain Common

Corneal abrasion Uncommon

Eye irritation Uncommon

Increased lacrimation Uncommon

Blurred vision Uncommon

Eye pruritus Uncommon

Ocular discomfort Uncommon

Ocular hyperaemia Uncommon

Iritis Uncommon

Reduced visual acuity Uncommon

Uveitis Uncommon

Endophthalmitis Uncommon

Sensation of foreign body Uncommon

Vitreous haemorrhage Uncommon

Vitritis Uncommon

Iridocyclitis Uncommon

Conjunctival hyperaemia Uncommon

Procedural pain Uncommon

Retinal tear Uncommon

Rhegmatogenous retinal detachment Uncommon

Transiently reduced visual acuity Rare

Traumatic cataract Rare

Retinal vasculitis* Not known

Retinal occlusive vasculitis* Not known

Terms marked with asterisk (*) are adverse reactions which have been identified based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequency.

Retinal Vasculitis and Retinal Occlusive Vasculitis

Rare cases of retinal vasculitis and/or retinal occlusive vasculitis have been spontaneously reported inthe post-marketing setting (see section 4.4). Retinal vasculitis and retinal occlusive vasculitis have alsobeen reported in patients treated with IVT therapies.

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 faricimab clinical trials in patients with nAMD, DME,and RVO (see section 4.4). Across indications, no notable difference between the groups treated withfaricimab and the comparator were observed.

There is a potential for an immune response in patients treated with faricimab (see section 4.4). Afterdosing with faricimab for up to 112 (nAMD), 100 (DME), and 72 (RVO) weeks, treatment-emergentanti-faricimab antibodies were detected in approximately 13.8%, 9.6%, and 14.4% of patients withnAMD, DME, and RVO randomised to faricimab, respectively. The clinical significance of anti-faricimab antibodies on safety is unclear at this time. The incidence of intraocular inflammation inanti-faricimab antibody positive patients was 12/98 (12.2%; nAMD), 15/128 (11.7%; DME), and 9/95(9.5%; RVO), and in anti-faricimab antibody negative patients was 8/562 (1.4%; nAMD), 5/1124(0.4%; DME), and 10/543 (1.8%; RVO). The incidence of serious ocular adverse reactions in anti-faricimab antibody positive patients was 6/98 (6.1%; nAMD), 14/128 (10.9%; DME), and 7/95 (7.4%;

RVO), and in anti-faricimab antibody negative patients was 23/562 (4.1%; nAMD), 45/1124 (4.0%;

DME), and 34/543 (6.3%; RVO). Anti-faricimab antibodies were not associated with an impact onclinical efficacy or systemic pharmacokinetics.

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, IOP should be monitored and, if deemed necessary by the treating physician,appropriate treatment should be initiated.

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA09

Faricimab is a humanised bispecific immunoglobulin G1 (IgG1) antibody that acts through inhibitionof two distinct pathways by neutralisation of both angiopoietin-2 (Ang-2) and vascular endothelialgrowth factor A (VEGF-A).

Ang-2 causes vascular instability by promoting endothelial destabilisation, pericyte loss, andpathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitisesblood vessels to the activity of VEGF-A resulting in further vascular destabilisation. Ang-2 and

VEGF-A synergistically increase vascular permeability and stimulate neovascularisation.

By dual inhibition of Ang-2 and VEGF-A, faricimab reduces vascular permeability and inflammation,inhibits pathological angiogenesis and restores vascular stability.

A suppression from baseline of median ocular free Ang-2 and free VEGF-A concentrations wasobserved from day 7 onwards in the six Phase III studies described hereafter.

In TENAYA and LUCERNE, objective, pre-specified visual and anatomic criteria, as well as treatingphysician clinical assessment, were used to guide treatment decisions at the disease activityassessment time points (week 20 and week 24).

The mean central subfield thickness (CST) reduction from baseline at the primary endpoint visits(averaged at weeks 40-48) was comparable to those observed with aflibercept, with -137 µmand -137 µm in patients treated with faricimab dosed up to every 16 weeks (Q16W) as comparedto -129 µm and -131 µm with aflibercept, in TENAYA and LUCERNE, respectively. These mean

CST reductions were maintained through year 2.

At week 48, in both studies there was a comparable effect of faricimab and aflibercept on thereduction of intraretinal fluid (IRF), subretinal fluid (SRF), and PED. These effects in IRF, SRF, and

PED were maintained at year 2. There were also comparable changes in total CNV lesion area andreductions in CNV leakage area from baseline for patients in the faricimab and aflibercept treatmentarms.

In YOSEMITE and RHINE, anatomic parameters related to macular oedema were part of the diseaseactivity assessments guiding treatment decisions.

The mean CST reduction from baseline at the primary endpoint visits (averaged at weeks 48-56) wasnumerically greater than those observed with aflibercept, with -207 µm and -197 µm in patientstreated with faricimab Q8W and faricimab up to Q16W adjustable dosing as compared to -170 µm inaflibercept Q8W patients in YOSEMITE; results were 196 µm, 188 µm, and 170 µm, respectively in

RHINE. Consistent reductions in CST were observed through year 2. Greater proportions of patientsin both faricimab arms achieved absence of IRF and absence of DME (defined as reaching CST below325 µm) over time through year 2 as compared to aflibercept in both studies.

RVO

In Phase III studies in patients with branch retinal vein occlusion (BRVO; BALATON) andcentral/hemiretinal vein occlusion (C/HRVO; COMINO), reductions in mean CST were observedfrom baseline to week 24 with faricimab Q4W and were comparable to those seen with aflibercept

Q4W. The mean CST reduction from baseline to week 24 was 311.4 μm for faricimab Q4W versus304.4 μm for aflibercept Q4W, in BALATON, and 461.6 μm versus 448.8 μm in COMINO forfaricimab and aflibercept, respectively. CST reductions were maintained through week 72 whenpatients moved to a faricimab up to Q16W adjustable dosing regimen.

Comparable proportions of patients in both faricimab Q4W and aflibercept Q4W arms achievedabsence of IRF, absence of SRF, and absence of macular edema (defined as reaching CST below325 µm) over time through week 24, in both studies. These results were maintained through week 72when patients moved to a faricimab up to Q16W adjustable dosing regimen.

Clinical efficacy and safetynAMD

The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked,active comparator-controlled, 2-year non-inferiority studies in patients with nAMD, TENAYA and

LUCERNE. A total of 1 329 patients were enrolled, with 1 135 (85%) patients completing the studiesthrough week 112. A total of 1 326 patients received at least one dose (664 with faricimab). Patientages ranged from 50 to 99 years with a mean [standard deviation; SD] of 75.9 [8.6] years.

In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms:

* Faricimab 6 mg up to Q16W after four initial monthly doses

* Aflibercept 2 mg Q8W after three initial monthly doses

After the first four monthly doses (weeks 0, 4, 8, and 12) patients randomised to the faricimab armreceived Q16W, every 12 weeks (Q12W) or Q8W dosing based on an assessment of disease activity atweeks 20 and 24. Disease activity was assessed using objective pre-specified visual (BCVA) andanatomic (CST) criteria, as well as treating physician clinical assessment of the presence of macularhaemorrhage or nAMD disease activity requiring treatment (week 24 only). Patients remained on thesefixed dosing intervals until week 60 without supplemental therapy. From week 60 onwards, patients inthe faricimab arm moved to an adjustable dosing regimen, where their treatment interval could bemodified by up to 4 week interval extensions (up to Q16W) or reduced by up to 8 week intervals (upto Q8W) based on an automated objective assessment of pre-specified visual (BCVA) and anatomic(CST and macular haemorrhage) disease activity criteria. Patients in the aflibercept arm remained on

Q8W dosing throughout the study period. Both studies were 112 weeks in duration.

Both studies showed efficacy in the primary endpoint, defined as the mean change from baseline in

BCVA when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment

Diabetic Retinopathy Study (ETDRS) letter score (Table 2 and Table 3). In both studies, faricimab upto Q16W treated patients had a non-inferior mean change from baseline in BCVA, as the patientstreated with aflibercept Q8W at year 1, and these vision gains were maintained through week 112.

Improvements from baseline BCVA at week 112 are shown in Figure 1.

The proportion of patients on each of the different treatment intervals at week 112 in TENAYA and

LUCERNE, respectively was:

* Q16W: 59% and 67%

* Q12W: 15% and 14%

* Q8W: 26% and 19%

Table 2: Efficacy outcomes at the primary endpoint visitsa and at year 2b in TENAYA

Efficacy Outcomes TENAYA

Year 1 Year 2

Faricimab up to Aflibercept Faricimab up to Aflibercept

Q16W Q8W Q16W Q8W

N = 334 N = 337 N = 334 N = 337

Mean change in BCVA as 5.8 5.1 3.7 3.3measured by ETDRS letter (4.6, 7.1) (3.9, 6.4) (2.1, 5.4) (1.7, 4.9)score from baseline (95% CI)

Difference in LS mean 0.7 0.4(95% CI) (-1.1, 2.5) (-1.9, 2.8)

Proportion of patients with 20.0% 15.7% 22.5% 16.9%≥ 15 letter gain from baseline (15.6%, 24.4%) (11.9%, 19.6%) (17.8%, 27.2%) (12.7%, 21.1%)(CMH weighted proportion,95% CI)

Difference in CMH 4.3% 5.6%weighted % (95% CI) (-1.6%, 10.1%) (-0.7%,11.9%)

Proportion of patients 95.4% 94.1% 92.1% 88.6%avoiding ≥ 15 letter loss from (93.0%, 97.7%) (91.5%, 96.7 %) (89.1%, 95.1%) (85.1%, 92.2%)baseline (CMH weightedproportion, 95% CI)

Difference in CMH 1.3% 3.4%weighted % (95% CI) (-2.2%, pct. 4.8%) (-1.2%, 8.1%)aAverage of weeks 40, 44, and 48; bAverage of weeks 104, 108, 112

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

CI: Confidence Interval

LS: Least Square

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with abinary outcome and is used for assessment of categorical variables.

Table 3: Efficacy outcomes at the primary endpoint visitsa and at year 2b in LUCERNE

Efficacy Outcomes LUCERNE

Year 1 Year 2

Faricimab up to Aflibercept Faricimab up to Aflibercept

Q16W Q8W Q16W Q8W

N = 331 N = 327 N = 331 N = 327

Mean change in BCVA as 6.6 6.6 5.0 5.2measured by ETDRS letter (5.3, 7.8) (5.3, 7.8) (3.4, 6.6) (3.6, 6.8)score from baseline (95% CI)

Difference in LS mean 0.0 -0.2(95% CI) (-1.7, 1.8) (-2.4, 2.1)

Proportion of patients with 20.2% 22.2% 22.4% 21.3%≥ 15 letter gain from baseline (15.9%, 24.6%) (17.7%, 26.8%) (17.8%, 27.1% (16.8%, 25.9%)(CMH weighted proportion,95% CI)

Difference in CMH -2.0% 1.1%weighted % (95% CI) (-8.3%, pct. 4.3%) (-5.4%, 7.6%)

Proportion of patients 95.8% 97.3% 92.9% 93.2%avoiding ≥ 15 letter loss from (93.6%, 98.0%) (95.5%, 99.1%) (90.1%, 95.8%) (90.2%, 96.2%)baseline (CMH weightedproportion, 95% CI)

Difference in CMH -1.5% -0.2%weighted % (95% CI) (-4.4%, 1.3%) (-4.4%, 3.9%)aAverage of weeks 40, 44, and 48; bAverage of weeks 104, 108, 112

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

CI: Confidence Interval

LS: Least Square

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with abinary outcome and is used for assessment of categorical variables.

Figure 1: Mean change in visual acuity from baseline to year 2 (week 112); combined data from

TENAYA and LUCERNE studies

In both TENAYA and LUCERNE, improvements from baseline in BCVA and CST at week 60 werecomparable across the two treatment arms and consistent with those seen at week 48.

At week 60, 46% of patients in both TENAYA and LUCERNE were on a Q16W interval. Of these,69% of patients in both studies maintained Q16W through week 112 without interval reduction.

At week 60, 80% and 78% of patients in TENAYA and LUCERNE, respectively, were on a ≥ Q12Winterval (Q16W or Q12W). Of these, 67% and 75% of patients, respectively, maintained a ≥ Q12Winterval through week 112 without an interval reduction below Q12W.

At week 60, 33% of patients in both TENAYA and LUCERNE were on a Q12W interval. Of these,3.2% and 0% of patients in TENAYA and LUCERNE, respectively, maintained Q12W throughweek 112.

At week 60, 20% and 22% of patients in TENAYA and LUCERNE, respectively, were on a Q8Winterval. Of these, 34% and 30% of patients in TENAYA and LUCERNE, respectively, maintained

Q8W therapy through week 112.

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

Across studies, faricimab up to Q16W showed improvement in pre-specified efficacy endpoint ofmean change from baseline to week 48 in the National Eye Institute Visual Function Questionnaire(NEI VFQ-25) composite score that was comparable to aflibercept Q8W, and exceeded the thresholdof 4 points. The magnitude of these changes corresponds to a 15-letter gain in BCVA.

The incidence of ocular adverse events in the study eye was 53.9% and 52.1% and non-ocular adverseevents was 73.3% and 74.3%, through week 112 in the faricimab and aflibercept arms, respectively(see section 4.4 and 4.8).

The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked,active comparator-controlled 2-year non-inferiority studies (YOSEMITE and RHINE) in patients with

DME. A total of 1 891 patients were enrolled in the two studies with 1 622 (86%) patients completingthe studies through week 100. A total of 1 887 patients were treated with at least one dose throughweek 56 (1 262 with faricimab). Patient ages ranged from 24 to 91 with a mean [SD] of62.2 [9.9] years. The overall population included both anti-VEGF naive patients (78%) and patientswho had been previously treated with a VEGF inhibitor prior to study participation (22%). In bothstudies, patients were randomised in a 1:1:1 ratio to one of the three treatment regimens:

* Faricimab 6 mg Q8W after the first 6 monthly doses.

* Faricimab 6 mg up to Q16W adjustable dosing administered in 4, 8, 12 or 16-week intervalsafter the first 4 monthly doses.

* Aflibercept 2 mg Q8W after the first 5 monthly doses.

In the Q16W adjustable dosing arm, the dosing followed a standardised treat-and-extend approach.

The interval could be increased in 4-week increments or decreased in 4- or 8-week increments basedon anatomic and/or visual outcomes, using data obtained only at study drug dosing visits.

Both studies showed efficacy in the primary endpoint, defined as the mean change from baseline in

BCVA at year 1 (average of the week 48, 52, and 56 visits), measured by the ETDRS Letter Score. Inboth studies, faricimab up to Q16W treated patients had a non-inferior mean change from baseline in

BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintainedthrough year 2.

After 4 initial monthly doses, the patients in the faricimab up to Q16W adjustable dosing arm couldhave received between the minimum of 6 and the maximum of 21 total injections through week 96. Atweek 52, 74% and 71% of patients in the faricimab up to Q16W adjustable dosing arm achieved a

Q16W or Q12W dosing interval in YOSEMITE and RHINE, respectively (53% and 51% on Q16W,21% and 20% on Q12W). Of these patients, 75% and 84% maintained ≥ Q12W dosing without aninterval reduction below Q12W through week 96; of the patients on Q16W at week 52, 70% and 82%of patients maintained Q16W dosing without an interval reduction through week 96 in YOSEMITEand RHINE, respectively. At week 96, 78% of patients in the faricimab up to Q16W adjustable dosingarm achieved a Q16W or Q12W dosing interval in both studies (60% and 64% on Q16W, 18% and14% on Q12W). 4% and 6% of patients were extended to Q8W and stayed on ≤ Q8W dosing intervalsthrough week 96; 3% and 5% received only Q4W dosing in YOSEMITE and RHINE throughweek 96, respectively.

Detailed results from the analyses of YOSEMITE and RHINE studies are listed in Table 4, Table 5,and Figure 2 below.

Table 4: Efficacy outcomes at the year 1 primary endpoint visitsa and at year 2b in YOSEMITE

Efficacy Outcomes YOSEMITE

Year 1 Year 2

Faricimab Faricimab Aflibercept Faricimab Faricimab up Aflibercept

Q8W up to Q16W Q8W Q8W to Q16W Q8W

N = 315 adjustable N = 312 N = 315 adjustable N = 312dosing dosing

N = 313 N = 313

Mean change in BCVA as 10.7 11.6 10.9 10.7 10.7 11.4measured by ETDRS (9.4, 12.0) (10.3, 12.9) (9.6, 12.2) (9.4, 12.1) (9.4, 12.1) (10.0, 12.7)letter score from baseline(97.5% CI year 1 and95% CI year 2)

Difference in LS mean -0.2 0.7 -0.7 -0.7(97.5% CI year 1, 95% CI (-2.0, 1.6) (-1.1, 2.5) (-2.6, 1.2) (-2.5, 1.2)year 2)

Proportion of patients who 29.2% 35.5% 31.8% 37.2% 38.2% 37.4%gained at least 15 letters in (23.9%, (30.1%, (26.6%, (31.4%, (32.8%, (31.7%,

BCVA from baseline 34.5%) 40.9%) 37.0%) 42.9%) 43.7%) 43.0%)(CMH weightedproportion, 95% CI year 1and year 2)

Difference in CMH -2.6% 3.5% -0.2% 0.2%weighted % (95% CI (-10.0%, (-4.0%, (-8.2%, (-7.6%,year 1 and year 2) 4.9%) 11.1%) 7.8%) 8.1%)

Proportion of patients who 98.1% 98.6% 98.9% 97.6% 97.8% 98.0%avoided loss of at least (96.5%, (97.2%, (97.6%, (95.7%, (96.1%, (96.2%,15 letters in BCVA from 99.7%) 100.0%) 100.0%) 99.5%) 99.5%) 99.7%)baseline (CMH weightedproportion, 95% CI year 1and year 2)

Difference in CMH -0.8% -0.3% -0.4% -0.2%weighted % (95% CI (-2.8%, (-2.2%, (-2.9%, (-2.6%, 2.2%)year 1 and year 2) 1.3%) 1.5%) 2.2%)aAverage of weeks 48, 52, 56; bAverage of weeks 92, 96, 100

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LS: Least Square

CI: Confidence Interval

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with abinary outcome and is used for assessment of categorical variables.

Note: CMH weighted % for aflibercept arm presented for faricimab Q8W vs. aflibercept comparison, howeverthe corresponding CMH weighted % for faricimab adjustable vs. aflibercept comparison is similar to the oneshown above.

Table 5: Efficacy outcomes at the year 1 primary endpoint visitsa and at year 2b in RHINE

Efficacy Outcomes RHINE

Year 1 Year 2

Faricimab Faricimab Aflibercept Faricimab Faricimab up Aflibercept

Q8W up to Q16W Q8W Q8W to Q16W Q8W

N = 317 adjustable N = 315 N = 317 adjustable N = 315dosing dosing

N = 319 N = 319

Mean change in BCVA 11.8 10.8 10.3 10.9 10.1 9.4as measured by ETDRS (10.6, (9.6, 11.9) (9.1, 11.4) (9.5, 12.3) (8.7, 11.5) (7.9, 10.8)letter score from baseline 13.0)(97.5% CI year 1 and95% CI year 2)

Difference in LS mean 1.5 0.5 1.5 0.7(97.5% CI year 1, (-0.1, 3.2) (-1.1, 2.1) (-0.5, 3.6) (-1.3, 2.7)95% CI year 2)

Proportion of patients 33.8% 28.5% 30.3% 39.8% 31.1% 39.0%who gained at least (28.4%, (23.6%, (25.0%, (34.0%, (26.1%, (33.2%,15 letters in BCVA from 39.2%) 33.3%) 35.5%) 45.6%) 36.1%) 44.8%)baseline (CMH weightedproportion, 95% CIyear 1 and year 2)

Difference in CMH 3.5% -2.0% 0.8% -8%weighted % (95% CI (-4.0%, (-9.1%, (-7.4%, (-15.7%, -year 1 and year 2) 11.1%) 5.2%) 9.0%) 0.3%)

Proportion of patients 98.9% 98.7% 98.6% 96.6% 96.8% 97.6%who avoided loss of at (97.6%, (97.4%, (97.2%, (94.4%, (94.8%, (95.7%,least 15 letters in BCVA 100.0%) 100.0%) 99.9%) 98.8%) 98.9%) 99.5%)from baseline (CMHweighted proportion,95% CI year 1 andyear 2)

Difference in CMH 0.3% 0.0% -1.0% -0.7%weighted % (95% CI (-1.6%, (-1.8%, (-3.9%, (-3.5%, 2.0%)year 1 and year 2) 2.1%) 1.9%) 1.9%)aAverage of weeks 48, 52, 56; bAverage of weeks 92, 96, 100

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LS: Least Square

CI: Confidence Interval

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with abinary outcome and is used for assessment of categorical variables.

Note: CMH weighted % for aflibercept arm presented for faricimab Q8W vs. aflibercept comparison, howeverthe corresponding CMH weighted % for faricimab adjustable vs. aflibercept comparison is similar to the oneshown above.

Figure 2: Mean change in visual acuity from baseline to year 2 (week 100); combined data from

YOSEMITE and RHINE studies

Efficacy results in patients who were anti-VEGF treatment naive prior to study participation and in allthe other evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, baseline visual acuity) ineach study were consistent with the results in the overall populations.

Across studies, faricimab Q8W and up to Q16W adjustable dosing showed improvements in the pre-specified efficacy endpoint of mean change from baseline to week 52 in the NEI VFQ-25 compositescore that was comparable to aflibercept Q8W and exceeded the threshold of 4 points. Faricimab Q8Wand up to Q16W adjustable dosing also demonstrated clinically meaningful improvements in the pre-specified efficacy endpoint of change from baseline to week 52 in the NEI VFQ-25 near activities,distance activities, and driving scores, that were comparable to aflibercept Q8W. The magnitude ofthese changes corresponds to a 15-letter gain in BCVA. Comparable proportions of patients treatedwith faricimab Q8W, faricimab up to Q16W adjustable dosing, and aflibercept Q8W experienced aclinically meaningful improvement of ≥ 4-points from baseline to week 52 in the NEI VFQ-25composite score, a pre-specified efficacy endpoint. These results were maintained at week 100.

An additional key efficacy outcome in DME studies was the change in the Early Treatment Diabetic

Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline to week 52. Ofthe 1 891 patients enrolled in Studies YOSEMITE and RHINE, 708 and 720 patients were evaluablefor DR endpoints, respectively.

The ETDRS-DRSS scores ranged from 10 to 71 at baseline.

The majority of patients, approximately 60%, had moderate to severe non-proliferative DR (DRSS43/47/53) at baseline.

The proportion of patients who achieved ≥ 2-step and ≥ 3-step improvement from baseline in ETDRS-

DRSS at week 52 and at week 96 are shown in Table 6 and Table 7 below.

Table 6: Proportion of patients who achieved ≥ 2-step and ≥ 3-step improvement from baselinein ETDRS-DRSS score at week 52 and at week 96 in YOSEMITE (DR evaluable population)

YOSEMITE52 Weeks 96 Weeks

Faricimab Faricimab Aflibercept Faricimab Faricimab up Aflibercept

Q8W up to Q16W Q8W Q8W to Q16W Q8Wn = 237 adjustable n = 229 n = 220 adjustable n = 221dosing dosingn = 242 n = 234

Proportion of patients 46.0% 42.5% 35.8% 51.4% 42.8% 42.2%with ≥ 2-step ETDRS-

DRSS improvementfrom baseline(CMH weightedproportion)

Weighted Difference 10.2% 6.1% 9.1% 0.0%(97.5% CI year 1, 95% (0.3%, (-3.6%, (0.0%, (-8.9%, 8.9%)year 2) 20.0% ) 15.8% ) 18.2%)

Proportion of patients 16.8% 15.5% 14.7% 22.4% 14.6% 20.9%with ≥ 3-step ETDRS-

DRSS improvementfrom baseline (CMHweighted proportion)

Weighted Difference 2.1% 0.6% 1.5% -6.7%(95% CI year 1 and (-4.3%, (-5.8%, (-6.0%, (-13.6%,year 2) 8.6%) 6.9%) 9.0%) 0.1%)

ETDRS-DRSS: Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale

CI: Confidence Interval

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with a binary outcomeand is used for assessment of categorical variables.

Note: CMH weighted % for aflibercept arm presented for faricimab Q8W vs. aflibercept comparison, however thecorresponding CMH weighted % for faricimab adjustable vs. aflibercept comparison is similar to the one shown above.

Table 7: Proportion of patients who achieved ≥ 2-step and ≥ 3-step improvement from baselinein ETDRS-DRSS score at week 52 and at week 96 in RHINE (DR evaluable population)

RHINE52 Weeks 96 Weeks

Faricimab Faricimab Aflibercept Faricimab Faricimab up Aflibercept

Q8W up to Q16W Q8W Q8W to Q16W Q8Wn = 231 adjustable n = 238 n = 214 adjustable n = 203dosing dosingn = 251 n = 228

Proportion of patients 44.2% 43.7% 46.8% 53.5% 44.3% 43.8%with ≥ 2-step ETDRS-

DRSS improvementfrom baseline (CMHweighted proportion)

Weighted Difference -2.6% -3.5% 9.7% 0.3%(97.5% CI year 1, 95% (-12.6%, (-13.4%, (0.4%, (-8.9%, 9.5%)year 2) 7.4%) 6.3%) 19.1%)

Proportion of patients 16.7% 18.9% 19.4% 25.1% 19.3% 21.8%with ≥ 3-step ETDRS-

DRSS improvementfrom baseline (CMHweighted proportion)

Weighted Difference -0.2% -1.1% 3.3% -2.7%(95% CI year 1 and (-5.8%, (-8.0%, (-4.6%, (-10.2%,year 2) 5.3%) 5.9%) 11.3%) 4.8%)

ETDRS-DRSS: Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale

CI: Confidence Interval

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with a binaryoutcome and is used for assessment of categorical variables.

Note: CMH weighted % for aflibercept arm presented for faricimab Q8W vs. aflibercept comparison, however thecorresponding CMH weighted % for faricimab adjustable vs. aflibercept comparison is similar to the one shown above.

Treatment effects in evaluable subgroups (e.g. by previous anti-VEGF treatment, age, gender, race,baseline HbA1c, and baseline visual acuity) in each study were generally consistent with the results inthe overall population.

Treatment effects in subgroups by DR severity at baseline were different and showed the greatest ≥ 2-step DRSS improvements among patients with moderately severe and severe non-proliferative DRwith approximately 90% of patients achieving improvements consistently across all treatment arms inboth studies.

The incidence of ocular adverse events in the study eye was 49.7%, 49.2%, and 45.4% and non-ocularadverse events was 73.0%, 74.2%, and 75.7% through week 100, in the faricimab Q8W, faricimab upto Q16W, and aflibercept Q8W arms, respectively (see section 4.4 and 4.8).

RVO

The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked,72-week long studies in patients with macular oedema secondary to BRVO (BALATON) or

CRVO/HRVO (COMINO). Active comparator-controlled data are available through month 6.

A total of 1 282 patients (553 in BALATON and 729 in COMINO) were enrolled in the two studies,with 1 276 patients treated with at least one dose through week 24 (641 with faricimab). Patient agesranged from 28 to 93 with a mean [SD] of 64 [10.7] years, and 22 to 100 with a mean [SD] of65 [13.2] years in BALATON and COMINO, respectively.

A total of 489 out of 553 patients randomised in BALATON completed the study at week 72;263 patients initially randomised to faricimab (‘prior faricimab’) and 267 patients initially randomisedto aflibercept (‘prior aflibercept’) received at least one dose of faricimab during the faricimabadjustable dosing phase.

A total of 656 out of 729 patients randomised in COMINO completed the study at week 72; 353 priorfaricimab and 342 prior aflibercept patients received at least one dose of faricimab during thefaricimab adjustable dosing phase.

In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms until week 24:

* Faricimab 6 mg Q4W for 6 consecutive monthly doses

* Aflibercept 2 mg Q4W for 6 consecutive monthly doses

After 6 initial monthly doses, patients initially randomised to the aflibercept 2 mg arm moved tofaricimab 6 mg, and could have received faricimab 6 mg up to Q16W adjustable dosing, where thedosing interval could be increased in 4-week increments or decreased by 4-, 8- or 12-weeks based onan automated objective assessment of pre-specified visual and anatomic disease activity criteria.

Both studies showed efficacy in the primary endpoint, defined as the change from baseline in BCVAat week 24, measured by the ETDRS Letter Score. In both studies, faricimab Q4W treated patients hada non-inferior mean change from baseline in BCVA, compared to patients treated with aflibercept

Q4W, and these vision gains were maintained through week 72 when patients moved to a faricimab upto Q16W adjustable dosing regimen.

Between week 24 and week 68, 81.5% and 74.0% of the patients receiving faricimab up to Q16Wadjustable dosing regimen achieved a ≥ Q12W (Q16W or Q12W) dosing interval in BALATON and

COMINO, respectively. Of these patients, 72.1% and 61.6% completed at least one cycle of Q12Wand maintained ≥ Q12W dosing without an interval reduction below Q12W through week 68 in

BALATON and COMINO, respectively; 1.2% and 2.5% of the patients received only Q4W dosingthrough week 68 in BALATON and COMINO, respectively.

Across studies, at week 24 patients in the faricimab Q4W arm showed improvement in the pre-specified efficacy endpoint of change from baseline to week 24 in the NEI VFQ-25 composite scorethat was comparable to aflibercept Q4W. Faricimab Q4W also demonstrated improvement in the pre-specified efficacy endpoint of change from baseline to week 24 in the NEI VFQ-25 near activities anddistance activities, that were comparable to aflibercept Q4W. These results were maintained throughweek 72 when all patients were on faricimab up to Q16W adjustable dosing regimen.

Table 8: Efficacy outcomes at the week 24 primary endpoint visit and at the end of the studya in

BALATON

Efficacy Outcomes BALATON24 Weeks 72 Weeksa

Faricimab Q4W Aflibercept Q4W Faricimab Q4W Aflibercept Q4W

N = 276 N = 277 to Faricimab to Faricimab

Adjustable Adjustable

N = 276 N = 277

Mean change in BCVA as 16.9 17.5 18.1 18.8measured by ETDRS letter (15.7, 18.1) (16.3, 18.6) (16.9, 19.4) (17.5, 20.0)score from baseline (95% CI)

Difference in LS mean -0.6(95% CI) (-2.2, 1.1)

Proportion of patients with 56.1% 60.4% 61.5% 65.8%≥ 15 letter gain from baseline (50.4%, 61.9%) (54.7%, 66.0%) (56.0%, 67.0%) (60.3%, 71.2%)(CMH weighted proportion,95% CI)

Difference in CMH weighted -4.3%% (95% CI) (-12.3%, 3.8%)aAverage of weeks 64, 68, 72

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

CI: Confidence Interval

LS: Least Square

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with a binaryoutcome and is used for assessment of categorical variables.

Table 9: Efficacy outcomes at the week 24 primary endpoint visit and at the end of the studya in

COMINO

Efficacy Outcomes COMINO24 Weeks 72 Weeksa

Faricimab Q4W Aflibercept Q4W Faricimab Q4W Aflibercept Q4W

N = 366 N = 363 to Faricimab to Faricimab

Adjustable Adjustable

N = 366 N = 363

Mean change in BCVA as 16.9 17.3 16.9 17.1measured by ETDRS letter (15.4, 18.3) (15.9, 18.8) (15.2, 18.6) (15.4, 18.8)score from baseline (95% CI)

Difference in LS mean -0.4(95% CI) (-2.5, 1.6)

Proportion of patients with 56.6% 58.1% 57.6% 59.5%≥ 15 letter gain from baseline (51.7%, 61.5%) (53.3%, 62.9%) (52.8%, 62.5%) (54.7%, 64.3%)(CMH weighted proportion,95% CI)

Difference in CMH weighted -1.5%% (95% CI) (-8.4%, 5.3%)aAverage of weeks 64, 68, 72

BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

CI: Confidence Interval

LS: Least Square

CMH: Cochran-Mantel-Haenszel method; a statistical test that generates an estimate of an association with a binaryoutcome and is used for assessment of categorical variables.

Figure 3: Mean change in visual acuity from baseline to week 72 in BALATON

Faricimab 6 mg up to Q16W adjustable dosing started at week 24 but not all patients received faricimab at week 24.

Figure 4: Mean change in visual acuity from baseline to week 72 in COMINO

Faricimab 6 mg up to Q16W adjustable dosing started at week 24 but not all patients received faricimab at week 24.

The incidence of ocular adverse events in the study eye was 20.1% and 24.6%, and non-ocular adverseevents was 32.9% and 36.4%, through week 24 in the faricimab Q4W and aflibercept Q4W arms,respectively (see section 4.8).

The European Medicines Agency has waived the obligation to submit the results of studies withfaricimab in all subsets of the paediatric population in nAMD, DME, and RVO (see section 4.2 forinformation on paediatric use).

Faricimab is administered intravitreally to exert local effects in the eye.

Based on a population pharmacokinetic analysis (including nAMD and DME N = 2 246), maximumfree (unbound to VEGF-A and Ang-2) faricimab plasma concentrations (Cmax) are estimated to occurapproximately 2 days post-dose. Mean (±SD [standard deviation]) plasma Cmax are estimated0.23 (0.07) µg/mL and 0.22 (0.07) µg/mL respectively in nAMD and in DME patients. After repeatedadministrations, mean plasma free faricimab trough concentrations are predicted to be0.002-0.003 µg/mL for Q8W dosing.

Faricimab exhibited dose-proportional pharmacokinetics (based on Cmax and AUC) over the doserange 0.5 mg-6 mg. No accumulation of faricimab was apparent in the vitreous or in plasma followingmonthly dosing.

Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6 000-foldlower than in aqueous and vitreous humour respectively. Therefore, systemic pharmacodynamiceffects are unlikely, further supported by the absence of significant changes in free VEGF and Ang-2concentration in plasma upon faricimab treatment in clinical studies.

Population pharmacokinetic analysis has shown an effect of age and body weight on ocular orsystemic pharmacokinetics of faricimab respectively. Both effects were considered not clinicallymeaningful; no dose adjustment is needed.

Faricimab is a protein-based therapeutic hence its metabolism and elimination have not been fullycharacterised. Faricimab is expected to be catabolised in lysosomes to small peptides and amino acids,which may be excreted renally, in a similar manner to the elimination of endogenous IgG.

The faricimab plasma concentration-time profile declined in parallel with the vitreous and aqueousconcentration-time profiles. The estimated mean ocular half-life and apparent systemic half-life offaricimab is approximately 7.5 days.

Pharmacokinetic analysis of patients with nAMD, DME, and RVO (N=2 977) has shown that thepharmacokinetics of faricimab are comparable in nAMD, DME, and RVO patients.

In the six Phase III clinical studies, approximately 58% (1,496/2,571) of patients randomised totreatment with faricimab were ≥ 65 years of age. Population pharmacokinetic analysis has shown aneffect of age on ocular pharmacokinetics of faricimab. The effect was considered not clinicallymeaningful. No dose adjustment is required in patients 65 years and above (see section 4.2).

No specific studies in patients with renal impairment have been conducted with faricimab.

Pharmacokinetic analysis of patients in all clinical studies of which 63% had renal impairment (mild38%, moderate 23%, and severe 2%), revealed no differences with respect to systemicpharmacokinetics of faricimab after intravitreal administration of faricimab. No dose adjustment isrequired in patients with renal impairment (see section 4.2).

No specific studies in patients with hepatic impairment have been conducted with faricimab. However,no special considerations are needed in this population because metabolism occurs via proteolysis anddoes not depend on hepatic function. No dose adjustment is required in patients with hepaticimpairment (see section 4.2).

The systemic pharmacokinetics of faricimab are not influenced by race. Gender was not shown to havea clinically relevant influence on systemic pharmacokinetics of faricimab. No dose adjustment isneeded.

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

In pregnant cynomolgus monkeys, intravenous injections of faricimab resulting in serum exposure(Cmax) more than 500-times the maximum human exposure did not elicit developmental toxicity orteratogenicity, and had no effect on weight or structure of the placenta, although, based on itspharmacological effect faricimab should be regarded as potentially teratogenic and embryo-/foetotoxic.

Systemic exposure after ocular administration of faricimab is very low.

L-histidine

Acetic acid 30% (for pH adjustment) (E 260)

L-methionine

Polysorbate 20 (E 432)

Sodium chloride

D-sucrose

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: 30 months

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

Do not freeze.

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

Keep the pre-filled syringe in the sealed tray in the original carton in order to protect from light.

Prior to use, the unopened pre-filled syringe or vial may be kept at room temperature, 20 °C to 25 °C,in the original carton, for up to 24 hours.

Ensure that the injection is given immediately after preparation of the dose.

Solution for injection in a pre-filled syringe consisting of a glass barrel (type I) with a dose mark, abutyl rubber stopper, and a tamper-evident closure cap (including a rigid tip cap, a butyl rubber tip capand a luer lock adapter). The container is assembled with a plunger rod and an extended finger grip.

Each pre-filled syringe contains 21 mg faricimab in 0.175 mL solution.

Pack size of one sterile Extra Thin Wall injection filter needle (30-gauge × ½ inch, 0.30 mm x 12.7mm, 5 µm), co-packed with one pre-filled syringe.

The rubber tip cap, the rubber stopper, the glass barrel and the injection filter needle are in contactwith the medicinal product.

Vial0.24 mL sterile, solution in a glass vial with a coated rubber stopper sealed with an aluminum cap witha yellow plastic flip-off disk.

Pack size of one vial and one blunt transfer filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm,5 µm).

Do not shake.

Vabysmo should be inspected visually upon removal from the refrigerator and prior to administration.

If particulates or cloudiness are visible, Vabysmo must not be used.

The pre-filled syringe is for single use in one eye only. Open the sterile pre-filled syringe under asepticconditions only. The solution should be inspected visually prior to administration. If particulates orcloudiness are visible, the pre-filled syringe must not be used.

The pre-filled syringe contains more than the recommended dose of 6 mg faricimab (equivalent to0.05 mL). Each pre-filled syringe contains 21 mg faricimab in 0.175 mL solution. The excess volumemust be expelled prior to injection.

Do not use if the packaging, pre-filled syringe and/or injection filter needle are damaged or expired.

Detailed instructions for use are provided in the package leaflet.

Vial

The vial contains more than the recommended dose of 6 mg. The fill volume of the vial (0.24 mL) isnot to be used in total. The excess volume should be expelled prior to injection. Injecting the entirevolume of the vial results in overdose. The injection dose must be set to the 0.05 mL dose mark, i.e.6 mg faricimab.

The contents of the vial and the transfer filter needle are sterile and for single use only. Do not use ifthe packaging, vial and/or transfer filter needle are damaged or expired. Detailed instructions for useare provided in the package leaflet.

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

Instructions for use of pre-filled syringe:

Removal of the syringe from the syringe tray (step 1) and all subsequent steps should be done usingaseptic technique.

Note: the dose must be set to the 0.05 mL dose mark.

Open tray and remove syringe cap1 Peel the lid off the syringe tray and aseptically remove the pre-filled syringe.

2 Hold the syringe by the white collar; snap off the syringe cap (see Figure C).

Do not twist off the cap.

Figure C

Attach injection filter needle3 Aseptically remove the injection filter needle from its packaging.

4 Aseptically and firmly attach the injection filter needle onto the syringe Luer lock (see Figure

D).

Only use the providedinjection filter needle

Figure D for the administration5 Carefully remove the needle cap by pulling it straight off.

Dislodge air bubbles6 Hold the syringe with the injection filter needle pointing up. Check the syringe for airbubbles.

7 If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to thetop (see Figure E).

Figure E

Adjust medicinal product dose and expel air8 Hold the syringe at eye level and slowly push the plunger rod until the lower edge of therubber stopper’s dome is aligned with the 0.05 mL dose mark (see Figure F). This willexpel the air and the excess solution and set the dose to 0.05 mL.

Ensure that the injection is given immediately after preparation of the dose.

Figure F

Injection procedure9 The injection procedure should be carried out under aseptic conditions.

Inject slowly until the rubber stopper reaches the bottom of the syringe to deliver thevolume of 0.05 mL.

Do not recap or detach the injection filter needle from the syringe.

Any unused medicinal product or waste material should be disposed of in accordance withlocal regulations.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/22/1683/001

EU/1/22/1683/002

Date of first authorisation: 15 September 2022

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

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