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`ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
`
`1
`
`Novartis Exhibit 2222.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NAME OF THE MEDICINAL PRODUCT
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
`1.
`
`Lucentis 10 mg/ml solution for injection
`
`
`2.
`
`One ml contains 10 mg ranibizumab*. Each vial contains 2.3 mg of ranibizumab in 0.23 ml solution.
`This provides a usable amount to deliver a single dose of 0.05 ml containing 0.5 mg ranibizumab to
`adult patients and a single dose of 0.02 ml containing 0.2 mg ranibizumab to preterm infants.
`
`*Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by
`recombinant DNA technology.
`
`For the full list of excipients, see section 6.1.
`
`
`3.
`
`Solution for injection.
`
`Clear, colourless to pale yellow aqueous solution.
`
`
`4.
`
`4.1 Therapeutic indications
`
`Lucentis is indicated in adults for:
`
`The treatment of neovascular (wet) age-related macular degeneration (AMD)
`
`The treatment of visual impairment due to diabetic macular oedema (DME)
`
`The treatment of proliferative diabetic retinopathy (PDR)
`
`The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion
`(branch RVO or central RVO)
`The treatment of visual impairment due to choroidal neovascularisation (CNV)
`
`PHARMACEUTICAL FORM
`
`CLINICAL PARTICULARS
`
`
`
`Lucentis is indicated in preterm infants for:
`
`The treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II
`(stage 3+) or AP-ROP (aggressive posterior ROP) disease.
`
`
`4.2 Posology and method of administration
`
`Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections.
`
`Posology
`
`Adults
`The recommended dose for Lucentis in adults is 0.5 mg given as a single intravitreal injection. This
`corresponds to an injection volume of 0.05 ml. The interval between two doses injected into the same
`eye should be at least four weeks.
`
`Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved
`and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and
`symptoms of the disease under continued treatment. In patients with wet AMD, DME, PDR and RVO,
`initially, three or more consecutive, monthly injections may be needed.
`
`
`2
`
`Novartis Exhibit 2222.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Thereafter, monitoring and treatment intervals should be determined by the physician and should be
`based on disease activity, as assessed by visual acuity and/or anatomical parameters.
`
`If, in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefiting
`from continued treatment, Lucentis should be discontinued.
`
`Monitoring for disease activity may include clinical examination, functional testing or imaging
`techniques (e.g. optical coherence tomography or fluorescein angiography).
`
`If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is
`achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise
`until signs of disease activity or visual impairment recur. The treatment interval should be extended by
`no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for
`DME. For PDR and RVO, treatment intervals may also be gradually extended, however there are
`insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment
`interval should be shortened accordingly.
`
`The treatment of visual impairment due to CNV should be determined individually per patient based
`on disease activity. Some patients may only need one injection during the first 12 months; others may
`need more frequent treatment, including a monthly injection. For CNV secondary to pathologic
`myopia (PM), many patients may only need one or two injections during the first year (see
`section 5.1).
`
`Lucentis and laser photocoagulation in DME and in macular oedema secondary to BRVO
`There is some experience of Lucentis administered concomitantly with laser photocoagulation (see
`section 5.1). When given on the same day, Lucentis should be administered at least 30 minutes after
`laser photocoagulation. Lucentis can be administered in patients who have received previous laser
`photocoagulation.
`
`Lucentis and verteporfin photodynamic therapy in CNV secondary to PM
`There is no experience of concomitant administration of Lucentis and verteporfin.
`
`Preterm infants
`The recommended dose for Lucentis in preterm infants is 0.2 mg given as an intravitreal injection.
`This corresponds to an injection volume of 0.02 ml. In preterm infants treatment of ROP is initiated
`with a single injection per eye and may be given bilaterally on the same day. In total, up to three
`injections per eye may be administered within six months of treatment initiation if there are signs of
`disease activity. Most patients (78%) in the clinical study received one injection per eye. The
`administration of more than three injections per eye has not been studied. The interval between two
`doses injected into the same eye should be at least four weeks.
`
`Special populations
`Hepatic impairment
`Lucentis has not been studied in patients with hepatic impairment. However, no special considerations
`are needed in this population.
`
`Renal impairment
`Dose adjustment is not needed in patients with renal impairment (see section 5.2).
`
`Elderly
`No dose adjustment is required in the elderly. There is limited experience in patients older than
`75 years with DME.
`
`
`3
`
`Novartis Exhibit 2222.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Paediatric population
`The safety and efficacy of Lucentis in children and adolescents below 18 years of age for indications
`other than retinopathy of prematurity have not been established. Available data in adolescent patients
`aged 12 to 17 years with visual impairment due to CNV are described in section 5.1 but no
`recommendation on a posology can be made.
`
`Method of administration
`
`Single-use vial for intravitreal use only.
`
`Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml for
`adults and 0.02 ml for preterm infants), a portion of the volume contained in the vial must be discarded
`prior to administration.
`
`Lucentis should be inspected visually for particulate matter and discoloration prior to administration.
`
`For information on preparation of Lucentis, see section 6.6.
`
`The 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)
`and the availability of sterile paracentesis (if required). The patient’s medical history for
`hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure
`(see section 4.4). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the
`periocular skin, eyelid and ocular surface should be administered prior to the injection, in accordance
`with local practice.
`
`Adults
`In adults the injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous
`cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection
`volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.
`
`Paediatric population
`For treatment of preterm infants the low volume high accuracy syringe provided together with an
`injection needle (30G x ½″) in the VISISURE kit should be used (see also section 6.6).
`
`In preterm infants, the injection needle should be inserted into the eye 1.0 to 2.0 mm posterior to the
`limbus, with the needle pointing towards the optic nerve. The injection volume of 0.02 ml is then
`delivered.
`
`4.3 Contraindications
`
`Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
`
`Patients with active or suspected ocular or periocular infections.
`
`Patients with active severe intraocular inflammation.
`
`4.4 Special warnings and precautions for use
`
`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.
`
`
`4
`
`Novartis Exhibit 2222.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Intravitreal injection-related reactions
`
`Intravitreous injections, including those with Lucentis, 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
`Lucentis. In addition, patients should be monitored during the week following the injection to permit
`early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive
`of endophthalmitis or any of the above mentioned events without delay.
`
`Intraocular pressure increases
`
`In adults transient increases in intraocular pressure (IOP) have been seen within 60 minutes of
`injection of Lucentis. Sustained IOP increases have also been identified (see section 4.8). Both
`intraocular pressure and the perfusion of the optic nerve head must be monitored and managed
`appropriately.
`
`Patients should be informed of the symptoms of these potential adverse reactions and instructed to
`inform their physician if they develop signs such as eye pain or increased discomfort, worsening eye
`redness, blurred or decreased vision, an increased number of small particles in their vision, or
`increased sensitivity to light (see section 4.8).
`
`Bilateral treatment
`
`Limited data on bilateral use of Lucentis (including same-day administration) do not suggest an
`increased risk of systemic adverse events compared with unilateral treatment.
`
`Immunogenicity
`
`There is a potential for immunogenicity with Lucentis. Since there is a potential for an increased
`systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this
`patient population cannot be excluded. Patients should also be instructed to report if an intraocular
`inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody
`formation.
`
`Concomitant use of other anti-VEGF (vascular endothelial growth factor)
`
`Lucentis should not be administered concurrently with other anti-VEGF medicinal products (systemic
`or ocular).
`
`Withholding Lucentis in adults
`
`The dose should be withheld and treatment should not be resumed earlier than the next scheduled
`treatment in the event of:
`
`a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last
`assessment of visual acuity;
`an intraocular pressure of ≥30 mmHg;
`a retinal break;
`a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is
`≥50%, of the total lesion area;
`performed or planned intraocular surgery within the previous or next 28 days.
`
`
`
`Retinal pigment epithelial tear
`
`Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF
`therapy for wet AMD and potentially also other forms of CNV, include a large and/or high pigment
`epithelial retinal detachment. When initiating ranibizumab therapy, caution should be used in patients
`with these risk factors for retinal pigment epithelial tears.
`
`
`
`
`
`5
`
`Novartis Exhibit 2222.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`Rhegmatogenous retinal detachment or macular holes in adults
`
`Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4
`macular holes.
`
`Paediatric population
`
`The warnings and precautions for adults also apply to preterm infants with ROP. Long-term safety in
`preterm infants with ROP has been studied for 2 years in the RAINBOW extension trial and showed
`no new safety signals. The safety profile in preterm infants has not been established beyond 2 years.
`
`Populations with limited data
`
`There is only limited experience in the treatment of subjects with DME due to type I diabetes.
`Lucentis has not been studied in patients who have previously received intravitreal injections, in
`patients with active systemic infections, or in patients with concurrent eye conditions such as retinal
`detachment or macular hole. There is limited experience of treatment with Lucentis in diabetic patients
`with an HbA1c over 108 mmol/mol (12%) and no experience in patients with uncontrolled
`hypertension. This lack of information should be considered by the physician when treating such
`patients.
`
`There are insufficient data to conclude on the effect of Lucentis in patients with RVO presenting
`irreversible ischaemic visual function loss.
`
`In patients with PM, there are limited data on the effect of Lucentis in patients who have previously
`undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while a consistent
`effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data to
`conclude on the effect of Lucentis in PM subjects with extrafoveal lesions.
`
`Systemic effects following intravitreal use
`
`Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have
`been reported following intravitreal injection of VEGF inhibitors.
`
`There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNV
`secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be
`exercised when treating such patients (see section 4.8).
`
`4.5
`
`No formal interaction studies have been performed.
`
`For the adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in wet AMD and PM,
`see section 5.1.
`
`For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see sections 4.2
`and 5.1.
`
`In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to
`visual acuity or central retinal subfield thickness (CSFT) in patients treated with Lucentis was not
`affected by concomitant treatment with thiazolidinediones.
`
`Paediatric population
`
`No interaction studies have been performed.
`
`
`Interaction with other medicinal products and other forms of interaction
`
`6
`
`Novartis Exhibit 2222.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`4.6 Fertility, pregnancy and lactation
`
`Women of childbearing potential/contraception in females
`
`Women of childbearing potential should use effective contraception during treatment.
`
`Pregnancy
`
`For ranibizumab no clinical data on exposed pregnancies are available. Studies in cynomolgus
`monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or
`embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is low after
`ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially
`teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during pregnancy
`unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become
`pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the
`last dose of ranibizumab before conceiving a child.
`
`Breast-feeding
`
`It is unknown whether Lucentis is excreted in human milk. Breast-feeding is not recommended during
`the use of Lucentis.
`
`Fertility
`
`There are no data available on fertility.
`
`4.7 Effects on ability to drive and use machines
`
`The treatment procedure may induce temporary visual disturbances, which may affect the ability to
`drive or use machines (see section 4.8). Patients who experience these signs must not drive or use
`machines until these temporary visual disturbances subside.
`
`4.8 Undesirable effects
`
`Summary of the safety profile
`
`The majority of adverse reactions reported following administration of Lucentis are related to the
`intravitreal injection procedure.
`
`The most frequently reported ocular adverse reactions following injection of Lucentis are: eye pain,
`ocular hyperaemia, increased intraocular pressure, vitritis, vitreous detachment, retinal haemorrhage,
`visual disturbance, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation
`in eyes, increased lacrimation, blepharitis, dry eye and eye pruritus.
`
`The most frequently reported non-ocular adverse reactions are headache, nasopharyngitis and
`arthralgia.
`
`Less frequently reported, but more serious, adverse reactions include endophthalmitis, blindness,
`retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).
`
`The adverse reactions experienced following administration of Lucentis in clinical trials are
`summarised in the table below.
`
`
`7
`
`Novartis Exhibit 2222.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Tabulated list of adverse reactions#
`
`The adverse reactions are listed by system organ class and frequency using the following convention:
`very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000
`to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within
`each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
`
`
`Common
`
`Infections and infestations
`
`Very common
`Nasopharyngitis
`Common
`Urinary tract infection*
`
`
`Blood and lymphatic system disorders
`Common
`Anaemia
`
`
`Immune system disorders
`
`Common
`Hypersensitivity
`
`
`Psychiatric disorders
`
`Common
`Anxiety
`
`
`Nervous system disorders
`
`Very common
`Headache
`
`
`Eye disorders
`
`Very common
`Vitritis, vitreous detachment, retinal haemorrhage, visual
`disturbance, eye pain, vitreous floaters, conjunctival
`haemorrhage, eye irritation, foreign body sensation in eyes,
`lacrimation increased, blepharitis, dry eye, ocular hyperaemia,
`eye pruritus.
`Retinal degeneration, retinal disorder, retinal detachment,
`retinal tear, detachment of the retinal pigment epithelium,
`retinal pigment epithelium tear, visual acuity reduced, vitreous
`haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis,
`cataract, cataract subcapsular, posterior capsule opacification,
`punctuate keratitis, corneal abrasion, anterior chamber flare,
`vision blurred, injection site haemorrhage, eye haemorrhage,
`conjunctivitis, conjunctivitis allergic, eye discharge, photopsia,
`photophobia, ocular discomfort, eyelid oedema, eyelid pain,
`conjunctival hyperaemia.
`Blindness, endophthalmitis, hypopyon, hyphaema,
`keratopathy, iris adhesion, corneal deposits, corneal oedema,
`corneal striae, injection site pain, injection site irritation,
`abnormal sensation in eye, eyelid irritation.
`
`
`Respiratory, thoracic and mediastinal disorders
`Common
`Cough
`
`
`Gastrointestinal disorders
`
`Common
`Nausea
`
`
`Skin and subcutaneous tissue disorders
`Common
`Allergic reactions (rash, urticaria, pruritus, erythema)
`
`
`
`Uncommon
`
`8
`
`Novartis Exhibit 2222.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Musculoskeletal and connective tissue disorders
`Very common
`Arthralgia
`
`
`Investigations
`
`Very common
`Intraocular pressure increased
`# Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients)
`which occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with
`Lucentis 0.5 mg than in those receiving control treatment (sham or verteporfin PDT).
`* observed only in DME population
`
`
`Product-class-related adverse reactions
`
`In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event
`potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly
`increased in ranibizumab-treated patients. However, there was no consistent pattern among the
`different haemorrhages. 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 Lucentis clinical trials in patients with AMD,
`DME, PDR, RVO and CNV and there were no major differences between the groups treated with
`ranibizumab compared to control.
`
`Paediatric population
`
`The safety of Lucentis 0.2 mg was studied in a 6month clinical trial (RAINBOW), which included
`73 preterm infants with ROP treated with ranibizumab 0.2 mg (see section 5.1). Ocular adverse
`reactions reported in more than one patient treated with ranibizumab 0.2 mg were retinal haemorrhage
`and conjunctival haemorrhage. Non-ocular adverse reactions reported in more than one patient treated
`with ranibizumab 0.2 mg were nasopharyngitis, anaemia, cough, urinary tract infection and allergic
`reactions. Adverse reactions established for adult indications are considered applicable to preterm
`infants with ROP, though not all were observed in the RAINBOW trial. Long-term safety in preterm
`infants with ROP has been studied for 2 years in the RAINBOW extension trial and showed no new
`safety signals. The safety profile in preterm infants has not been established beyond 2 years.
`
`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
`listed in Appendix V.
`
`4.9 Overdose
`
`Cases of accidental overdose have been reported from the clinical studies in wet AMD and post-
`marketing data. Adverse reactions associated with these reported cases were intraocular pressure
`increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an
`overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the
`attending physician.
`
`
`
`
`
`
`9
`
`Novartis Exhibit 2222.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`PHARMACOLOGICAL PROPERTIES
`
`5.
`
`5.1 Pharmacodynamic properties
`
`Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA04
`
`Mechanism of action
`
`Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human
`vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms
`(e.g. VEGF110, VEGF121 and VEGF165), thereby preventing binding of VEGF-A to its receptors
`VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation
`and neovascularisation, as well as vascular leakage, all of which are thought to contribute to the
`progression of the neovascular form of age-related macular degeneration, pathologic myopia and CNV
`or to visual impairment caused by either diabetic macular oedema or macular oedema secondary to
`RVO in adults and retinopathy of prematurity in preterm infants.
`
`Clinical efficacy and safety
`
`Treatment of wet AMD
`In wet AMD, the clinical safety and efficacy of Lucentis have been assessed in three randomised,
`double-masked, sham- or active-controlled studies of 24 months duration in patients with neovascular
`AMD. A total of 1,323 patients (879 active and 444 control) were enrolled in these studies.
`
`In study FVF2598g (MARINA), 716 patients with minimally classic or occult with no classic lesions
`were randomised in a 1:1:1 ratio to receive monthly injections of Lucentis 0.3 mg, Lucentis 0.5 mg or
`sham.
`
`In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions were
`randomised in a 1:1:1 ratio to receive Lucentis 0.3 mg monthly, Lucentis 0.5 mg monthly or
`verteporfin PDT (at baseline and every 3 months thereafter if fluorescein angiography showed
`persistence or recurrence of vascular leakage).
`
`Key outcome measures are summarised in Table 1 and Figure 1.
`
`Table 1
`
`Outcomes at Month 12 and Month 24 in study FVF2598g (MARINA) and FVF2587g
`(ANCHOR)
`
`
`Outcome measure
`
`
`Month
`
`FVF2598g (MARINA)
`Lucentis
`Sham
`(n=238)
`0.5 mg
`(n=240)
`95%
`90%
`
`62%
`53%
`
`FVF2587g (ANCHOR)
`Verteporfin
`Lucentis
`PDT (n=143)
`0.5 mg
`(n=140)
`96%
`90%
`
`64%
`66%
`
`Month 12
`Month 24
`
`
`
`
`
`Loss of <15 letters in
`visual acuity (%)a
`(maintenance of
`vision, primary
`endpoint)
`Gain of ≥15 letters in
`visual acuity (%)a
`Mean change in
`visual acuity (letters)
`(SD)a
`a p<0.01
`
`Month 12
`Month 24
`Month 12
`Month 24
`
`34%
`5%
`33%
`4%
`-10.5 (16.6) +7.2 (14.4)
`-14.9 (18.7) +6.6 (16.5)
`
`6%
`6%
`-9.5 (16.4)
`-9.8 (17.6)
`
`40%
`41%
`+11.3 (14.6)
`+10.7 (16.5)
`
`
`
`
`
`
`
`
`
`
`
`10
`
`Novartis Exhibit 2222.010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Figure 1 Mean change in visual acuity from baseline to Month 24 in study FVF2598g
`(MARINA) and study FVF2587g (ANCHOR)
`
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`Results from both trials indicated that continued ranibizumab treatment may also be of benefit in
`patients who lost ≥15 letters of best-corrected visual acuity (BCVA) in the first year of treatment.
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`Statistically significant patient-reported visual functioning benefits were observed in both MARINA
`and ANCHOR with ranibizumab treatment over the control group as measured by the NEI VFQ-25.
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`In study FVF3192g (PIER), 184 patients with all forms of neovascular AMD were randomised in a
`1:1:1 ratio to receive Lucentis 0.3 mg, Lucentis 0.5 mg or sham injections once a month for
`3 consecutive doses, followed by a dose administered once every 3 months. From Month 14 of the
`study, sham-treated patients were allowed to receive ranibizumab and from Month 19, more frequent
`treatments were possible. Patients treated with Lucentis in PIER received a mean of 10 total
`treatments.
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`After an initial increase in visual acuity (following monthly dosing), on average, patients’ visual acuity
`declined with quarterly dosing, returning to baseline at Month 12 and this effect was maintained in
`most ranibizumab-treated patients (82%) at Month 24. Limited data from sham subjects who later
`received ranibizumab suggested that early initiation of treatment may be associated with better
`preservation of visual acuity.
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`Data from two studies (MONT BLANC, BPD952A2308 and DENALI, BPD952A2309) conducted
`post approval confirmed the efficacy of Lucentis but did not demonstrate additional effect of the
`combined administration of verteporfin (Visudyne PDT) and Lucentis compared to Lucentis
`monotherapy.
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`Treatment of visual impairment due to CNV secondary to PM
`The clinical safety and efficacy of Lucentis in patients with visual impairment due to CNV in PM have
`been assessed based on the 12-month data of the double-masked, controlled pivotal study F2301
`(RADIANCE). In this study 277 patients were randomised in a 2:2:1 ratio to the following arms:
`
`Group I (ranibizumab 0.5 mg, dosing regimen driven by “stability” criteria defined as no change
`in BCVA compared to two preceding monthly evaluations).
`Group II (ranibizumab 0.5 mg, dosing regimen driven by “disease activity” criteria defined as
`vision impairment attributable to intra- or subretinal fluid or active leakage due to the CNV
`lesion as assessed by optical coherence tomography and/or fluorescence angiography).
`
`Group III (vPDT - patients were allowed to receive ranibizumab treatment as of Month 3).
`In Group II, which is the recommended posology (see section 4.2), 50.9% of patients required 1 or
`2 injections, 34.5% required 3 to 5 injections and 14.7% required 6 to 12 injections over the 12-month
`study period. 62.9% of Group II patients did not require injections in the second 6 months of the study.
`
`The key outcomes from RADIANCE are summarised in Table 2 and Figure 2.
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`Table 2
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`Outcomes at Month 3 and 12 (RADIANCE)
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`
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`
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`Group I
`Ranibizumab
`0.5 mg
`“vision stability”
`(n=105)
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`Group II
`Ranibizumab
`0.5 mg
`“disease activity”
`(n=116)
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`Group III
`vPDTb
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`(n=55)
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`Month 3
`Mean average BCVA change from Month 1
`to Month 3 compared to baselinea (letters)
`Proportion of patients who gained:
`≥15 letters, or reached ≥84 letters in BCVA
`Month 12
`Number of injections up to Month 12:
`Mean
`Median
`Mean average BCVA change from Month 1
`to Month 12 compared to baseline (letters)
`Proportion of patients who gained:
`≥15 letters, or reached ≥84 letters in BCVA
`a p<0.00001 comparison with vPDT control
`b Comparative control up to Month 3. Patients randomised to vPDT were allowed to receive
`ranibizumab treatment as of Month 3 (in Group III, 38 patients received ranibizumab as of Month 3)
`
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`+10.5
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`38.1%
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`4.6
`4.0
`+12.8
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`53.3%
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`+10.6
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`43.1%
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`3.5
`2.5
`+12.5
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`51.7%
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`+2.2
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`14.5%
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`
`N/A
`N/A
`N/A
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`
`N/A
`
`12
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`Figure 2 Mean change from baseline BCVA over time to Month 12 (RADIANCE)
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`The improvement of vision was accompanied by a reduction in central retinal thickness.
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`Patient-reported benefits were observed with ranibizumab treatment arms over vPDT (p-value <0.05)
`in terms of improvement in the composite score and several subscales (general vision, near activities,
`mental health and dependency) of the NEI VFQ-25.
`
`Treatment of visual impairment due to CNV (other than secondary to PM and wet AMD)
`The clinical safety and efficacy of Lucentis in patients with visual impairment due to CNV have been
`assessed based on the 12-month data of the double-masked, sham-controlled pivotal study G2301
`(MINERVA). In this study 178 adult patients were randomised in a 2:1 ratio to receive:
`
`
`ranibizumab 0.5 mg at baseline, followed by an individualised dosing regimen driven by disease
`activity as assessed by visual acuity and/or anatomical parameters (e.g. VA impairment,
`intra/sub-retinal fluid, haemorrhage or leakage);
`
`
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`sham injection at baseline, followed by an individualised treatment regimen driven by disease
`activity.
`At Month 2, all patients received open-label treatment with ranibizumab as needed.
`
`Key outcome measures from MINERVA are summarised in Table 3 and Figure 3. An improvement of
`vision was observed and was accompanied by a reduction in central subfield thickness over the
`12-month period.
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`The mean number of injections given over 12 months was 5.8 in the ranibizumab arm versus 5.4 in
`those patients in the sham arm who were eligible to receive ranibizumab from Month 2 onwards. In
`the sham arm 7 out of 59 patients did not receive any treatment with ranibizumab in the study eye
`during the 12-month period.
`
`Table 3
`
`
`Outcomes at Month 2 (MINERVA)
`
`Ranibizumab
`0.5 mg (n=119)
`9.5 letters
`31.4%
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`99.2%
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`77 µm
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`Sham (n=59)
`
`-0.4 letters
`12.3%
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`94.7%
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`-9.8 µm
`
`Mean BCVA change from baseline to Month 2 a
`Patients gaining ≥15 letters from baseline or reaching
`84 letters at Month 2
`Patients not losing >15 letters from baseline at
`Month 2
`Reduction in CSFTb from baseline to Month 2 a
`a One-sided p<0.001 comparison with sham control
`b CSFT - central retinal subfield thickness
`
`Figure 3 Mean change from baseline BCVA over time to Month 12 (MINERVA)
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`

`

`When comparing ranibizumab versus sham control at Month 2, a consistent treatment effect both
`overall and across baseline aetiology subgroups was observed:
`
`Table 4
`
`
`Treatment effect overall