Vabysmo is indicated for the treatment of adult patients with:

• neovascular (wet) age-related macular degeneration (nAMD) (see section 5.1),

• visual impairment due to diabetic macular oedema (DMO) (see section 5.1)

• visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO).

Vabysmo must be administered by a qualified healthcare professional trained in intravitreal injections. Each vial should only be used for the treatment of a single eye.

Posology

nAMD

The recommended dose for Vabysmo is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks for the first 4 doses.

Thereafter, treatment may be individualised using a treat-and-extend approach following an assessment of the individual patient's anatomic and visual outcomes. The dosing interval may be extended up to every 16 weeks, and extensions in increments of up to 4 weeks should be considered, based on the physician's judgement of the individual patient's anatomic and/or visual outcomes. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reductions of up to 8 weeks may be implemented if deemed necessary (see section 5.1). Treatment intervals shorter than 21 days between injections have not been studied.

Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion, but there is no requirement for monthly monitoring between injections.

DMO

The recommended dose for Vabysmo is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks for the first 4 doses.

Thereafter, treatment may be individualised using a treat-and-extend approach following an assessment of the individual patient's anatomic and visual outcomes. The dosing interval may be extended from every 4 to every 16 weeks, with extensions in increments of up to 4 weeks, based on the physician's judgement of the individual patient's anatomic and/or visual outcomes. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reductions of up to 8 weeks may be implemented if deemed necessary (see section 5.1).

Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion, but there is no requirement for monthly monitoring between injections.

Macular oedema secondary to retinal vein occlusion (RVO)

The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks (monthly); 3 or more consecutive, monthly injections might be needed.

Thereafter, treatment may be individualised using a treat -and-extend approach. Based on the physician's judgement of the patient's anatomic and/or visual outcomes, the dosing interval may be extended in increments of up to 4 weeks. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see section 5.1). Treatment intervals shorter than 21 days and longer than 16 weeks have not been studied.

Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion but there is no requirement for monthly monitoring between injections.

Duration of treatment

Vabysmo is intended for long-term treatment.

If visual and/or anatomic outcomes indicate that the patient is not benefitting from continued treatment, Vabysmo should be discontinued.

Delayed or missed dose

If a dose is delayed or missed, the patient should return for assessment at the next available visit and continue dosing depending on physician's discretion.

Special populations

Elderly (≥ 65 years)

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

Renal impairment

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

Hepatic impairment

No specific studies in patients with hepatic impairment have been conducted with Vabysmo. No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Vabysmo in children and adolescents have not been established. No data are available.

Method of administration

Single-use vial for intravitreal use only.

Vabysmo should be inspected visually for particulate matter and discolouration prior to administration, and if present, the vial should not be used.

The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.8). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior 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 of 0.05 mL is then delivered slowly; a different scleral site should be used for subsequent injections.

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

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. Sterile equipment should be available in case paracentesis is required.

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

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

Ocular or periocular infections.

Active intraocular inflammation.

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

Traceability

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

Intravitreal injection-related reactions

Intravitreal injections, including those with Vabysmo have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (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 events without delay, to permit prompt and appropriate management.

Intraocular pressure increases

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including those with Vabysmo (see section 4.8). Sustained (present at 2 or more consecutive visits) IOP increases > 21 mm Hg have also been reported. Special precaution is needed in patients with 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.

Vabysmo has not been studied in patients with poorly controlled glaucoma. Special precaution is needed in patients with poorly controlled glaucoma.

Systemic effects

Arterial thromboembolic events (ATE's): Systemic adverse events including arterial thromboembolic events have been reported following intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors, including Vabysmo, and there is a theoretical risk that these may be related to VEGF inhibition.

There is limited data on the safety of Vabysmo in patients with history of stroke or transient ischemic attack or myocardial infarction.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with Vabysmo (see section 4.8). Patients should be instructed to inform their physician of any signs or symptoms of intraocular inflammation such as vision loss, eye pain, increased sensitivity to light, floaters or worsening eye redness, which might be a clinical sign attributable to hypersensitivity (see section 4.8).

Bilateral treatment

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

Concomitant use of other anti-VEGF

There are no data available on the concomitant use of Vabysmo with anti-VEGF medicinal products or other therapies (e.g., photodynamic therapy) for the treatment of nAMD,DMO and RVO in the same eye. Vabysmo should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).

Withholding treatment

Treatment should be withheld in patients with:

• Rhegmatogenous retinal detachment, stage 3 or 4 macular holes, retinal break; treatment should not be resumed until an adequate repair has been performed.

• Treatment related decrease in Best Corrected Visual Acuity (BCVA) of ≥ 30 letters compared with the last assessment of visual acuity; treatment should not be resumed earlier than the next scheduled treatment.

• Performed or planned intraocular surgery within the previous or next 28 days; treatment should not be resumed earlier than the next scheduled treatment.

Retinal pigment epithelial tear

Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) in patients with nAMD. Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for nAMD, include a large and/or high pigment epithelial detachment. When initiating Vabysmo therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Populations with limited data

In nAMD clinical trials, there is limited data on patients with a total lesion size > 9 disc areas on fundus fluorescein angiography. There is only limited experience in the treatment of DMO patients with HbA1c over 10%, patients with high-risk proliferative diabetic retinopathy (DR), or nAMD,DMO and RVO patients with active systemic infections. There is also no experience of treatment with Vabysmo in diabetic or RVO patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

Sodium content

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

No studies evaluating the drug interaction potential of Vabysmo have been performed.

Women of childbearing potential

Female patients of childbearing potential should use effective contraception during treatment with Vabysmo and for at least 3 months following the last intravitreal injection of Vabysmo.

Pregnancy

There are no or limited amount of data from the use of faricimab in pregnant women. Systemic exposure after ocular administration of Vabysmo is very low. Animal studies in pregnant cynomolgus monkeys did not indicate direct or indirect harmful effects with respect to reproductive toxicity including embryo-foetal development (see section 5.3).

As a precautionary measure it is preferable to avoid the use of Vabysmo during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast-feeding

It is unknown whether faricimab is excreted in human milk. A risk to the breast-fed newborn/infant cannot be excluded. Vabysmo is not recommended during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Vabysmo therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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

Vabysmo may have a minor influence on the ability to drive and use machines due to possible temporary visual disturbances following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently.

Summary of the safety profile

Based on Phase III studies, the most frequently reported adverse reactions were cataract (10%), conjunctival haemorrhage (7.%), vitreous detachment (4%), IOP increased (4%), vitreous floaters (4%), retinal pigment epithelial tear (nAMD only) (3%), and eye pain (3%).

The most serious adverse reactions were uveitis (0.5%), endophthalmitis (0.4%), vitritis (0.4%), retinal tear (0.2%), rhegmatogenous retinal detachment (0.1%) and traumatic cataract (< 0.1%) (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions reported in clinical studies or during post-marketing surveillance are listed according to the MedDRA system organ class and ranked by frequency using the following convention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or not known (frequency cannot be estimated from the available data). Due to the widely varying conditions between studies, the adverse reaction profiles and frequencies reported from the development studies of Vabysmo cannot be directly compared to those reported in other development programs. Within each frequency grouping, adverse drug reactions are presented in order of decreasing frequency.

Table 1: Frequencies of adverse reactions in phase III clinical studies

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 of uncertain size, it is not always possible to reliably estimate their frequency.

Description of selected adverse reactions

Retinal Vasculitis and Retinal Occlusive Vasculitis

Rare cases of retinal vasculitis and/or retinal occlusive vasculitis have been spontaneously reported in the post-marketing setting. Retinal vasculitis and retinal occlusive vasculitis have also been reported in patients treated with IVT therapies.

Product-class-related adverse reactions

There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the Vabysmo clinical trials in patients with nAMD, DMO and RVO. Across indications, no notable difference between the groups treated with Vabysmo and the comparator were observed.

Immunogenicity

There is a potential for an immune response in patients treated with Vabysmo (see section 4.4). After dosing with Vabysmo for up to 112 (nAMD), 100 (DMO) and 72 (RVO) weeks, treatment-emergent anti-faricimab antibodies were detected in approximately 13.8%,9.6% and 14.4% of patients with nAMD, DMO and RVO randomized to faricimab respectively. The clinical significance of anti-faricimab antibodies on safety is unclear at this time. The incidence of intraocular inflammation in anti-faricimab antibody positive patients was 12/98 (12.2%; nAMD),15/128 (11.7%; DMO), and 9/95 (9.5%; RVO) and in anti-faricimab antibody negative patients was 8/562 (1.4%; nAMD), 5/1124 (0.4%; DMO) 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%; DMO) and 7/95 (7.4%; RVO) and in anti-faricimab antibody negative patients was 23/562 (4.1%; nAMD),45/1124 (4.0%; DMO) and 34/543 (6.3%; RVO). Anti-faricimab antibodies were not associated with an impact on clinical efficacy or systemic pharmacokinetics.

Retinal pigment epithelial tear

Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) in patients with nAMD. RPE tears are common in nAMD patients with PED, treated with IVT anti-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 were mild to moderate, without impact to vision and occurred during the loading phase.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system; Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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

Pharmacotherapeutic group: Ophthalmologicals, other ocular vascular disorder agents, ATC code: S01LA09

Mechanism of action

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

Ang-2 causes vascular instability by promoting endothelial destabilisation, pericyte loss, and pathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitises blood 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.

Pharmacodynamic effects

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

nAMD

nAMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening with sub and/or intraretinal fluid accumulation (SRF, IRF) and haemorrhages, which can result in vision loss.

In TENAYA and LUCERNE, objective, pre-specified visual and anatomic criteria, as well as treating physician clinical assessment, were used to guide treatment decisions at the disease activity assessment 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 µ m and -137 µ m in patients treated with Vabysmo dosed up to every 16 weeks (Q16W) as compared to -129 µ m and -131 µ m 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 Vabysmo and aflibercept on the reduction of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). These effects in IRF, SRF, and PED were maintained at year 2. There were also comparable changes in total CNV lesion area and reductions in CNV leakage area from baseline for patients in the Vabysmo and aflibercept treatment arms.

DMO

DMO is a consequence of DR and is characterised by increased vasopermeability and damage to the retinal capillaries, mediated in part due to VEGF and Ang2, which may result in vision loss.

In YOSEMITE and RHINE, anatomic parameters related to macular oedema were part of the disease activity assessments guiding treatment decisions in the Vabysmo up to Q16W adjustable dosing arm.

The mean CST reduction from baseline at the primary endpoint visits (averaged at weeks 48-56) were numerically greater than those observed with aflibercept, with -207 µ m and -197 µ m in patients treated with Vabysmo Q8W and Vabysmo up to Q16W adjustable dosing as compared to -170 µ m in aflibercept Q8W patients in YOSEMITE; results were 196 µ m, 188 µ m and 170 µ m, respectively in RHINE. Consistent reductions in CST were observed through Year 2.

Greater proportions of patients in both Vabysmo arms achieved absence of IRF and absence of DMO (defined as reaching CST below 325 µ m) over time through year 2 as compared to aflibercept in both studies.

RVO

RVO is characterised by an increase in intraluminal pressure due to vascular obstruction, which causes areas of reduced perfusion and ischaemia. The subsequent break down of the blood retinal barrier and a pathological increase of retinal vessel permeability leads to macular oedema and vision loss.

In Phase III studies in patients with branch retinal vein occlusion (BRVO; BALATON) and central/hemiretinal vein occlusion (C/HRVO; COMINO), reductions in mean CST were observed from baseline to week 24 with Vabysmo Q4W and were comparable to those seen with aflibercept Q4W. The mean CST reduction from baseline to week 24 was 311.4 μ m for Vabysmo Q4W versus 304.4 μ m for aflibercept Q4W, in BALATON, and 461.6 μ m versus 448.8 μ m in COMINO for Vabysmo and aflibercept, respectively. CST reductions were maintained through week 72 when patients moved to a Vabysmo up to Q16W adjustable dosing regimen.

Comparable proportions of patients in both Vabysmo Q4W and afliberceptQ4W arms achieved absence of IRF, absence of SRF, and absence of macular oedema (defined as reaching CST below 325 µ m) over time through week 24, in both studies. These results were maintained through week 72 when patients moved to a Vabysmo up to Q16W adjustable dosing regimen.

Clinical efficacy and safety

nAMD

The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, active comparator-controlled, 2-year studies in patients with nAMD, TENAYA and LUCERNE. A total of 1,329 treatment-naï ve patients were enrolled with 1,135 (85%) patients completing the studies through week 112. A total of 1,326 patients received at least one dose (664 with Vabysmo). Patient ages ranged from 50 to 99 years with a mean of 75.9 years.

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

• Vabysmo 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 Vabysmo arm received Q16W, every 12 weeks (Q12W) or Q8W dosing based on an assessment of disease activity at weeks 20 and 24, using objective pre-specified ETDRS-measured BCVA and SD-OCT CST criteria as well as treating physician clinical assessment of the presence/absence of macular haemorrhage. Patients remained on these fixed dosing intervals until week 60 without supplemental therapy.

From week 60 onwards, patients in the Vabysmo arm moved to an adjustable dosing regimen, where their treatment interval could be modified by up to 4 week interval extensions (up to Q16W) or reduced by up to 8 week intervals (up to Q8W) based on an automated objective assessment of pre-specified visual and anatomic disease activity criteria. Patients in the aflibercept arm remained on Q8W dosing throughout the study period. Both studies were 112 weeks in duration.

Results

Both studies demonstrated 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, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1. Vision gains remained comparable between both treatment arms through Week 112. Improvements from baseline BCVA at week 112 are shown in Figure 1 and Figure 2.

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 visits^a and at year 2^b in TENAYA.

^aAverage of weeks 40, 44 and 48; ^b Average of weeks 104,108,112

^* Median number of injections received for Year 1 corresponds to the period of baseline through week 48, and for Year 2 corresponds to the period after Week 60 until End of Study

Q1: 1st quartile

Q3: 3rd quartile

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 binary outcome and is used for assessment of categorical variables.

Table 3: Efficacy outcomes at the primary endpoint visits^a and at year 2^b in LUCERNE

^aAverage of weeks 40, 44 and 48; ^bAverage of weeks 104, 108, 112

* Median number of injections received for Year 1 corresponds to the period of baseline through week 48, and for Year 2 corresponds to the period after Week 60 until End of Study,

Q1: 1st quartile

Q3: 3rd quartile

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 binary 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 were comparable 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 ≥ Q12W interval (Q16W or Q12W). Of these, 67% and 75% of patients, respectively, maintained a ≥ Q12W interval 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 through week 112.

At week 60, 20% and 22% of patients in TENAYA and LUCERNE, respectively, were on a Q8W interval. 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 overall populations.

In both studies, Vabysmo up to Q16W demonstrated clinically meaningful improvements from baseline to week 48 in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score that was comparable to aflibercept Q8W. Patients in Vabysmo arms in TENAYA and LUCERNE achieved a ≥ 4 point improvement from baseline in the NEI VFQ -25 composite score at week 48. These results were maintained at week 112.

DMO

The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, active comparator-controlled 2-year studies (YOSEMITE and RHINE) in patients with DMO. A total of 1,891 patients were enrolled in the two studies with 1622 (85.8%) patients completing the studies through week 100. A total of 1,887 were treated with at least one dose through week 56 (1,262 with Vabysmo). Patient ages ranged from 24 to 91 with a mean of 62.2 years. The overall population included both anti-VEGF naive patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%). In both studies, patients were randomised in a 1:1:1 ratio to one of the three treatment regimens:

• Vabysmo 6 mg Q8W after the first 6 monthly doses.

• Vabysmo 6 mg up to Q16W adjustable dosing administered in 4, 8, 12 or 16-week intervals after the first 4 monthly doses.

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

In the up to 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 based on CST change as measured on OCT and/or BCVA change as measured by ETDRS letters, using data obtained only at study drug dosing visits.

Results

Both studies demonstrated 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. In both studies, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintained through year 2.

After 4 initial monthly doses, the patients in the Vabysmo up to Q16W adjustable dosing arm could have received between the minimum of 6 and the maximum of 21 total injections through week 96. At week 52, 74% and 71% of patients in the Vabysmo 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 an interval 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 YOSEMITE and RHINE, respectively. At week 96, 78% of patients in the Vabysmo up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in both studies (60% and 64% on Q16W, 18% and 14% on Q12W). 4% and 6% of patients were extended to Q8W and stayed on ≤ Q8W dosing intervals through week 96; 3% and 5% received only Q4W dosing in YOSEMITE and RHINE, respectively. The proportion of patients in YOSEMITE and RHINE, respectively, who received >15 injections in the PTI arms through week 96 was 13% and 18%.

Detailed results from the analyses of YOSEMITE and RHINE studies are listed in Table 4, Table 5 and Figures 2 and 3 below.

.

Table 4: Efficacy outcomes at the year 1 primary endpoint visits^a and at year 2^b in YOSEMITE and RHINE

^aAverage of weeks 48, 52, 56, ^bAverage of weeks 92, 96, 100

^* Median number of injections received for Year 1 corresponds to the period of baseline through Year 1, and for Year 2 corresponds to the period from Year 1 to Year 2

Q1: 1st quartile

Q3: 3rd quartile

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 a binary outcome and is used for assessment of categorical variables.

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

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

Figure 3: Mean change in visual acuity from baseline to year 2 (week 100) in RHINE

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

An additional key efficacy outcome in DMO studies was the change in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline to week 52. Of the 1,891 patients enrolled in Studies YOSEMITE and RHINE, 708 and 720 patients were evaluable for 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 (DRSS 43/47/53) at baseline.

At week 52, the proportion of patients improving by ≥ 2 steps on the ETDRS-DRSS was 43% to 46% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 36% and 47% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively. The results at week 96 were 43% to 54% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 42% and 44% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively. Comparable results across the treatment arms were observed in both studies in the proportions of patients improving by ≥ 3 steps on the ETDRS-DRSS from baseline at week 52, and these results were maintained at week 96.

The results from the ≥ 2-step and ≥ 3-step ETDRS-DRSS improvement analyses from baseline at week 52 and at week 96 are shown in Table 4 below. Clinically meaningful proportions of patients achieved ≥ 2-step DRSS improvement from baseline at Week 52 in all three treatment arms (Vabysmo Q8W, Vabysmo PTI and aflibercept Q8W), and these outcomes were maintained at Week 96.

Table 5: Proportion of patients who achieved ≥ 2-step and ≥ 3-step improvement from baseline in ETDRS-DRSS score at week 52 and at week 96 in YOSEMITE and RHINE (DR evaluable population)

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 outcome and is used for assessment of categorical variables.

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

Across studies, Vabysmo 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 composite score that were comparable to aflibercept Q8W and exceeded the threshold of 4 points. Vabysmo Q8W and 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 of these changes corresponds to a 15-letter gain in BCVA. Comparable proportions of patients treated with Vabysmo Q8W, Vabysmo up to Q16W adjustable dosing, and aflibercept Q8W experienced a clinically meaningful improvement of ≥ 4-points from baseline to week 52 in the NEI VFQ-25 composite score, a pre-specified efficacy endpoint. These results were maintained at week 100.

DR treatment effects in the subgroup of patients who were anti-VEGF naive prior to study participation were comparable to those observed in the overall DR evaluable population. Treatment effects in evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, and baseline visual acuity) in each study were generally consistent with the results in the overall population.

RVO

The safety and efficacy of Vabysmo 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 Vabysmo). Patient ages ranged from 28 to 93 with a mean [SD] of 64 [10.7] years, and 22 to 100 with a mean [SD] of 65 [13.2] years in BALATON and COMINO, respectively.

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

• Vabysmo 6 mg Q4W for 6 consecutive monthly doses

• Aflibercept 2 mg Q4W for 6 consecutive monthly doses

After 6 initial monthly doses, patients initially randomized to the aflibercept 2 mg arm moved to 6 mg Vabysmo Vabysmo, and could have received Vabysmo6 mg Vabysmo according to an up to Q16W adjustable dosing regimen, where the dosing interval could be increased in 4-week increments or decreased by 4-, 8- or 12-weeks based on an automated objective assessment of pre-specified visual and anatomic disease activity criteria.

Results

Both studies showed efficacy in the primary endpoint, defined as the change from baseline in BCVA at week 24, measured by the ETDRS Letter Score. In both studies, Vabysmo Q4W treated patients had a 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 Vabysmo up to Q16W adjustable dosing regimen.

Between week 24 and week 68, 81.5% and 74.0% of the patients receiving Vabysmo 6 mg up to Q16W adjustable 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 Q12W and 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 dosing through week 68 in BALATON and COMINO, respectively.

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

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

Table 6: Efficacy outcomes at the week 24 primary endpoint visit and at the end of the study in BALATON

^aAverage of weeks 64, 68, 72

* Median number of injections received for Week 24 corresponds to the period from baseline through Week 24, and for Week 72 corresponds to the period between Week 24 until the end of study

Q1: 1st quartile; Q3: 3rd quartile

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 binary outcome and is used for assessment of categorical variables.

Table 7: Efficacy outcomes at the week 24 primary endpoint visit and at the end of the study^a in COMINO

^aAverage of weeks 64, 68, 72

* Median number of injections received for Week 24 corresponds to the period from baseline through Week 24, and for Week 72 corresponds to the period between Week 24 until the end of study

Q1: 1st quartile; Q3: 3rd quartile

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 binary outcome and is used for assessment of categorical variables.

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

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

Figure 5: Mean change in visual acuity from baseline to week 72 in COMINO

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

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Vabysmo in all subsets of the paediatric population in nAMD, DMO and RVO (see section 4.2 for information on paediatric use).

Vabysmo is administered intravitreally (IVT) to exert local effects in the eye.

Absorption and Distribution

Based on a population pharmacokinetic analysis (including nAMD and DMO N = 2,246), maximum free (unbound to VEGF-A and Ang-2) faricimab plasma concentrations (Cmax) are estimated to occur approximately 2 days post-dose. Mean (± SD [standard deviation]) plasma Cmax are estimated 0.23 (0.07) µ g/mL and 0.22 (0.07) µ g/mL respectively in nAMD and in DMO patients. After repeated administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 µ g/mL for Q8W dosing.

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

Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6000-fold lower than in aqueous and vitreous humour respectively and below the binding affinity for VEGF and Ang-2. Therefore, systemic pharmacodynamic effects are unlikely, further supported by the absence of significant changes in free VEGF and Ang-2 concentration in plasma upon faricimab treatment in clinical studies.

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

Biotransformation and Elimination

Faricimab is a protein-based therapeutic hence its metabolism and elimination have not been fully characterised. Faricimab is expected to be catabolized 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 aqueous concentration-time profiles. The estimated mean ocular half-life and apparent systemic half-life of faricimab is approximately 7.5 days.

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

Special populations

Elderly

In the six Phase III clinical studies, approximately 58% (1,496/2,571) of patients randomised to treatment with Vabysmo were ≥ 65 years of age. Population pharmacokinetic analysis has shown an effect of age on ocular pharmacokinetics of faricimab, which was not considered clinically meaningful. No dose adjustment is required in patients 65 years and above.

Renal impairment

No specific studies in patients with renal impairment have been conducted with Vabysmo. Pharmacokinetic analysis of patients in all clinical studies of which 63% had renal impairment (mild 38%, moderate 23%, and severe 2%), revealed no differences with respect to systemic pharmacokinetics of faricimab after intravitreal administration of Vabysmo. No dose adjustment is required in patients with renal impairment.

Hepatic impairment

No specific studies in patients with hepatic impairment have been conducted with Vabysmo. However, no special considerations are needed in this population because metabolism occurs via proteolysis and does not depend on hepatic function. No dose adjustment is required in patients with hepatic impairment.

Other special populations

The systemic pharmacokinetics of faricimab are not influenced by race. Gender was not shown to have a clinically relevant influence on systemic pharmacokinetics of faricimab. No dose adjustment is needed.

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

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

Systemic exposure after ocular administration of Vabysmo 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 medicinal products.

30 months

Store Vabysmo in the refrigerator between 2° C to 8° C.

Do not freeze.

Keep the vial in the original carton to protect from light.

Prior to use, the unopened vial may be kept at room temperature, 20° C to 25° C, for up to 24 hours.

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

0.24 mL sterile, preservative-free solution in a glass vial with a coated rubber stopper sealed with an aluminium cap with a yellow plastic flip-off disk.

Pack size of 1 vial and 1 blunt transfer filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm).

Do not shake.

The vial contains more than the recommended dose of 6 mg. The fill volume of the vial (0.24 mL) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the vial results in overdose. The injection dose must be set to the 0.05 mL dose mark, i.e. 6 mg faricimab.

Vabysmo should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used.

The contents of the vial and the transfer filter needle are sterile and for single use only. Do not use if the packaging, vial and/or transfer filter needle 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 local requirements.