Eurotimes 19 9 supp Eylea Bayer

Bayer Satellite Symposium, Retina Day, Royal College of Ophthalmologists Annual Congress, 19 May 2014, Birmingham, UK

Supplement September 2014

Making Time for Change Using aflibercept solution for injection (Eylea® ) in a clinical setting

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Significant vision and anatomic improvements achieved in ‘real-world’ practice, shown in multiple efficacy audits

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3 6 4 5 This article has been produced on behalf of Bayer Healthcare and reports a Bayer-funded and organised symposium.

Prescribing information can be found on back cover

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Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

Chairman’s introduction

Macular degeneration and retinal disease, a major and growing worldwide health challenge

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rof Andrew Lotery, honorary consultant ophthalmologist, University Hospital Southampton and professor of ophthalmology, University of Southampton, chaired Bayer’s Satellite Symposium ‘Making time for change: using aflibercept solution for injection in a clinical setting’, Retina Day, the Royal College of Ophthalmologists Annual Congress, held 19 May 2014, Birmingham, UK.

“Age-related macular degeneration is the commonest cause of blindness in the western world,” explained Prof Lotery.1 “It affects up to 25 million people worldwide and up to 30,000 people are diagnosed with neovascular AMD each year in the United Kingdom alone.1,2 Studies evaluating age-specific prevalence of AMD show a strong rise with age, and overall prevalence rates in the age groups 65-74 years and 75-84 years of 20 and 35 per cent, respectively.3 So there’s an escalating epidemic as the population ages and AMD is a major public health problem.”

The Southampton aflibercept care pathway for wet AMD Prof Andrew Lotery, honorary consultant ophthalmologist, University Hospital Southampton, Southampton rof Lotery described his initial early experience implementing intravitreal aflibercept (Eylea®, Bayer) as a NICE-approved treatment option (National Institute for Health and Care Excellence technology appraisal guidance 294) for patients diagnosed with neovascular AMD.4 The eye unit at University Hospital Southampton manages around 80,000 patient appointments each year and provides approximately 750 intravitreal injections for neovascular AMD each month, with new patient numbers growing between 10 per cent and 20 per cent per annum. “So we need new solutions to cope with this growing AMD treatment capacity issue,” explained Prof Lotery.

Two solutions have proved beneficial at University Hospital Southampton: increased injection capacity and the introduction of an altered AMD care pathway that provides the added option of aflibercept injection as an alternative to ranibizumab (Lucentis®, Novartis) for neovascular AMD patients. “We have boosted our injection capacity by creating four dedicated injection rooms, extending our limited floor space and uplifting treatment capacity from 10 to 40 intravitreal injections per clinic,” said Prof Lotery. “New service provision innovations in development include the introduction of suitably trained nurse injectors.”

Southampton care pathway for wet AMD driven by patient preference Under the Southampton AMD care pathway, wet AMD patients who meet NICE treatment criteria for recommended anti-VEGF treatments and do not have polyps are offered the choice of ranibizumab or aflibercept therapy. “We have a discussion with each patient to determine which therapy and care pathway they would prefer,” explained Prof Lotery.

“If patients are started on ranibizumab therapy, they receive a loading dose of three intravitreal injections over 90 days followed by monthly monitoring and retreatment as required, with an average of eight intravitreal injections in the first year.

“For wet AMD, treatment with aflibercept is initiated with one injection each month for three consecutive doses, followed by one injection every two months in the first year. Importantly, there is no requirement for monitoring between treatments. Patients initiated on aflibercept therapy receive seven injections over a 12-month period. After one year of aflibercept injections, the dosing interval may be further extended based on visual and anatomic outcomes.

“Baseline clinic visit includes fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) assessment, followed by repeat OCT scans at the month five and month 11 clinic visit, the latter also including fluorescein angiography and/or indocyanine green. In total, there are three clinic visits and three OCT evaluations in year one.”

Aflibercept therapy for neovascular AMD requires substantially fewer clinic visits and OCT examinations than therapy with ranibizumab,

“We have boosted our injection capacity by creating four dedicated injection rooms...” which requires monthly review with OCT assessment from month four, explained Prof Lotery. If all 750 wet AMD patients were treated only with aflibercept, the hospital would avoid the need for 5,250 OCT examinations, 5,250 clinic visits and 750 intravitreal procedures each year.

With aflibercept therapy, vision is measured at each visit. As a precaution, if at any visit visual acuity (VA) has decreased by five letters or more in either eye, the patient is reassessed in clinic. If a second eye requires treatment, both eyes are treated the same day.

Equivalent vision outcomes using every-two-month schedule vs. monthly dosing “The key question is whether an every-two-month treatment regimen using aflibercept is as effective as monthly dosing in neovascular AMD patients,” commented Prof Lotery. “Results from VIEW 1 and VIEW 2 studies show that intravitreal aflibercept given monthly or every two months after three initial monthly doses produces equivalent efficacy and safety outcomes to ranibizumab administered monthly.5,6 The VIEW studies confirm that aflibercept is a highly effective treatment for neovascular AMD. Moreover, an every-two-month dosing regimen helps avoid the burden and cost of monthly monitoring.

“There is some fluctuation in central retinal thickness when injections are spaced from four to eight weeks in the first year. But evidence shows that if you treat using the licensed bimonthly posology for aflibercept, you achieve vision stabilisation and sustained improvement in best corrected visual acuity (BCVA) that is equivalent to that attained with monthly ranibizumab through to 52 weeks.

“Fixed or scheduled monitoring of neovascular AMD patients helps free up much-needed clinic capacity and allows for accurate scheduling of injections. Randomised clinical trials repeatedly show that intravitreal anti-VEGF treatment must be given regularly and on time to obtain good clinical outcomes. Our aflibercept neovascular AMD care pathway, by replicating the dosing regimen assessed in the VIEW studies, should give similar results to that observed in these pivotal phase III clinical trials.

“The Southampton aflibercept neovascular AMD care pathway offers equivalent vision benefits to those attainable with other intravitreal anti-VEGF therapies; moreover, we found that it releases extra service capacity, simplifies appointment scheduling and is cost-effective,” concluded Prof Lotery.

Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

Highlights from a year using aflibercept in Bradford Faruque Ghanchi, consultant ophthalmologist, Bradford Royal Infirmary, Bradford r Ghanchi outlined ‘real-world’ outcomes in neovascular AMD following aflibercept as initial therapy, achieved at two large NHS macular services in West Yorkshire.7 The two-centre study, at Leeds and Bradford Teaching Hospitals, was designed as a prospective interventional consecutive case series, evaluating functional and anatomical outcomes following intravitreal aflibercept therapy in treatment-naïve neovascular AMD patients.

“Our experience is that we can replicate vision outcomes from the VIEW studies in real-world clinical practice” Outcomes assessed include change from baseline in mean Early Treatment Diabetic Retinopathy Study (ETDRS) letter score and 1mm central retinal thickness (CRT) measured by spectral-domain OCT. Patients with other significant ocular pathology, prior vitrectomy or anti-VEGF therapy in the study eye were excluded. Patients received a loading phase of three injections every four weeks followed by injections every two months for the first year.

Mean ETDRS letter score at baseline was 51.5 and mean central retinal thickness was 408 µm. The mean ETDRS letter score increase

from baseline to month six was 8.1 for 96 eyes evaluated; mean central retinal thickness decreased 133.8 µm to 274.2 µm at month six.

Combined audit data show: • a mean gain from baseline of 8.1 ETDRS letters at month six compared with an improvement of 8.4 ETDRS letters seen with aflibercept in the VIEW studies at 12 months;5 • a change from baseline in retinal thickness of -133.8µm at month six, comparable to VIEW data; • no serious ocular adverse events reported to date; and • arterial thromboembolic events (ATEs), including stroke and myocardial infarction, were rare and unrelated to study drug.

Patients presenting to NHS macular clinics have a variable duration of symptoms and are referred from a varied number of sources, which is in contrast to patients selected for research and clinical trials who have to meet strict enrollment criteria. Nonetheless, combined data from this twin-centre study represent real-world evidence that good functional and anatomic gains in wet AMD are achievable using onlabel intravitreal aflibercept in routine clinical practice, study authors concluded. “Our experience is that we can replicate vision outcomes from the VIEW studies in real-world clinical practice,” observed Dr Ghanchi. “The introduction of intravitreal aflibercept therapy has proved a highly positive addition to our medical retina service, representing a good treatment option for all wet AMD patients, whether treatmentnaïve or ‘switch’ patients.”

Aflibercept injection for treatmentnaîve wet AMD at Leeds and Bradford Teaching Hospitals

MO

M1

M2

M4

M6

Number of subjects

217

212

202

135

96

Mean VA ETDRS letter score

51.5

56.4

58.1

59.3

59.6

Mean 1mm central retinal thickness (µm)

408

292

247.5

281.9

274.2

Month

Aflibercept dosing in year two: what did year one tell us? Experience in London Sobha Sivaprasad, consultant ophthalmologist, King’s College Hospital and Moorfields Eye Hospital, London esults from our clinical experience show that a majority of patients (~75 per cent) switched from ranibizumab pro re nata (PRN) dosing to aflibercept therapy can be treated effectively on an inject-and-extend basis, the treatment interval extended to between eight and 12 weeks in the second year,” explained Dr Sivaprasad.8 An aflibercept treatment service for wet AMD was introduced at King’s College Hospital in April 2013. Switching anti-VEGF treatment from ranibizumab to aflibercept was initially planned for so-called ‘frequent flyers’ (those requiring six or more treatments in the previous year) but subsequently treatment selection became a matter of patient choice.

The approved treatment posology for aflibercept in neovascular AMD involves an initial loading phase of three consecutive monthly treatments, followed by an every-two-month injection maintenance

“Seventy-seven per cent of participants showed a change from baseline of ±1 ETDRS letters at six months’ follow-up” phase through to month 12, thereafter by treat-and-extend dosing in year two, the treatment interval extended based on visual and anatomic results.9 Patients are assessed using ETDRS BCVA and OCT at each clinic visit. If both eyes show lesion activity, treatment is synchronised to same day.

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Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

Improved macular anatomy seen in eyes ‘switched’ to aflibercept from ranibizumab Switching to aflibercept is considered for neovascular AMD patients who are never completely inactive despite repeat ranibizumab therapy, or for patients who opt for aflibercept or experience an adverse reaction on ranibizumab treatment. Several different dosing regimens have been used depending on patient response, and include a three-dose loading phase and then monthly PRN dosing, treat-and-extend from the start or monthly as-needed treatment.

“We undertook a retrospective audit to evaluate anatomical outcomes on OCT in a small series of 45 neovascular AMD patients who were switched to aflibercept from initial ranibizumab therapy.8 Good anatomical responses together with stable visual acuity were observed, with a mean nine-weekly injections (range 8-12 weekly). Seventy-seven per cent of participants showed a change from baseline of ±1 ETDRS letters at six months’ follow-up.”

At last follow-up, six months after the initial aflibercept injection and following an average of 3.3±1.38 injections, average central retinal thickness decreased from 372±96 at time of switch to 325±95 (P<0.0001).

There were significant responses in reduction of intraretinal and subretinal fluid, demonstrating a pronounced anti-permeability or drying effect on macular fluid, despite the use of varying dosing schedules.

Approximately one in five patients (22 per cent) were still ‘wet’ and

required ongoing monthly follow-up and frequent retreatment. Two of 45 patients asked to be switched back to ranibizumab therapy.

Majority suitable for treat-and-extend dosing in year two “No clear discernible pattern was identified that might help predict the required retreatment regimen,” noted Dr Sivaprasad. “However, high-risk cases may be those who remain wet after three loading injections or three consecutive monthly doses or those patients with persistent fluid on OCT at eight-weekly follow-up but who are dry at four weeks. In the latter case, it’s recommended to shorten follow-up weekly until the threshold week is obtained.

“I can comfortably say that, for switch patients showing no retinal fluid on OCT, around three-quarters can be managed successfully on a treat-and-extend basis in the second year. But while a majority of neovascular AMD patients switched to aflibercept treatment can be extended to retreatment on an 8-12 week injection regime, it is crucial to identify ‘frequent flyers’ that may require more frequent monitoring and retreatment.

“The key message is that, for those with stable vision and who are dry following intravitreal aflibercept injection, treat first and then extend the treatment interval,” concluded Dr Sivaprasad. “Our experience to date is that aflibercept has a highly potent drying effect in switch patients and can help stabilise their visual acuity.”

The benefits of aflibercept in the VIEW 1 and VIEW 2 trials have been achieved in clinical practice at Newcastle James Talks, consultant ophthalmologist, Royal Victoria Infirmary, Newcastle upon Tyne Results from the VIEW studies demonstrate that aflibercept treatment, dosed every other month following three consecutive monthly injections, maintained vision (loss of ≤15 letters) in a similar proportion of patients to those treated with ranibizumab injected monthly,” explained James Talks.5,6 “As these two anti-VEGF agents appear equally effective, having a treatment option that requires fewer visits is beneficial for patients and service providers alike.”

Combined data from the VIEW 1 and VIEW 2 trials show that aflibercept treatment significantly improves BCVA from baseline, with a mean gain of 8.4 ETDRS letters at week 52.5 The mean number of injections from baseline to week 96 was 16.5 with ranibizumab and 11.2 with aflibercept.6 Real-world outcomes sometimes fail to match those seen in randomised trials Phase III ANCHOR (predominantly classic CNV lesions) and MARINA (minimally classic or occult CNV lesions) clinical trials evaluating monthly 0.5mg ranibizumab treatment in patients with wet AMD

reported mean VA gains at one year of 11.3 and 7.2 ETDRS letters, respectively.10,11 “Real-world outcomes often do not match the vision improvements seen in randomised controlled trials,” observed Dr Talks.

Results from real-world evaluations of intravitreal ranibizumab in wet AMD include: • The international AURA study group, which retrospectively evaluated vision outcomes in ranibizumab-treated wet AMD patients across eight countries, found a mean VA change from baseline of 2.4 ETDRS letters at one year.12 In the UK cohort (n=410 included in the effectiveness analysis set), mean VA change from baseline to month 12 was 5.9 letters, the majority (87 per cent) receiving an initial loading phase of three consecutive monthly injections.12 • A multicentre, national neovascular AMD database study of 11,135 treatment-naïve wet AMD patients treated in the UK with ranibizumab injections reported a mean VA change from baseline at one year of two letters.13

Efficacy outcomes at one year in treatment- naîve wet AMD series treated with intravitreal aflibercept at Royal Victoria Infirmary, Newcastle-upon-Tyne (mean number of injections per patient: 7n) Proportion (%) who maintained vision (loss of <15 letters)

Proportion (%) who lost <5 letters

96 (95/99)

85 (83/98)

Mean improvement from baseline in ETDRS VA

Proportion (%) with ETDRS VA >70 letters

Proportion (%) with ETDRS VA >61 letters

Proportion (%) with no retinal fluid on OCT

Proportion (%) suitable for flexible treatand-extend dosing

10.1

41 (18)

61 (40)

58

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Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

A retrospective case series review assessing the benefit of intravitreal ranibizumab for treatment-naïve patients with neovascular AMD (n=892 at one year) treated at the Newcastle Eye Centre recorded a mean VA change from baseline to one year of 3.8.14 Good efficacy outcomes evaluating aflibercept in neovascular AMD at one year follow-up “Similar vision stabilisation and BCVA results are achievable with aflibercept or ranibizumab monotherapy, but therapy with aflibercept does not require ongoing monthly monitoring,” Dr Talks observed.

Dr Talks reviewed results at one year from an audit evaluating outcomes using aflibercept injection in 99 treatment-naïve neovascular AMD patients treated at Newcastle, 90 patients completing 12 months’ follow-up. Of the nine patients without full follow-up data, seven had not lost significant vision when last seen and two patients were discontinued on aflibercept treatment due to decreased vision associated with retinal pigment epithelium rip. There were 10 second

eyes at baseline in this case series, and 10 patients subsequently developed second eye involvement during the study period.

Ninety-one per cent (90/99) continued aflibercept treatment through to the end of year one, with a mean of seven injections through 12 months.

Efficacy outcomes at one-year follow-up are shown in the table below.

“From our initial clinical experience, real-life gains in visual acuity at 12 months replicated those seen in the VIEW clinical trials,” observed Dr Talks. “Mean VA at year one was 60.7 ETDRS letters, representing a mean gain over baseline of 10.1 letters, compared with a gain of 8.4 letters in the VIEW studies.5 The mean starting vision in our study population was slightly lower than that of the VIEW studies.

“Close to half of the 98 patients assessed for mean change in VA from baseline lost or gained less than five ETDRS letters at one year. Outcomes for the 90 patients with complete follow-up data at one year showed marked vision improvements from baseline, some patients reaching good 6/6 vision (80+ letters), and 96 per cent of the full patient series (last observation carried forward) had maintained vision at one year (vs. 95 per cent at one year in the combined analysis from the VIEW studies).”5

Implementing an effective aflibercept treatment service for central retinal vein occlusion Ian Pearce, consultant ophthalmologist, St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool r Pearce reviewed clinical trial results evaluating intravitreal aflibercept injection in patients with macular oedema following central retinal vein occlusion (CRVO). He also provided practical tips on securing a successful and appropriately resourced service provision for extended treatment indications in medical retina.

Significant vision gains with initial monthly aflibercept The phase III COPERNICUS and GALILEO studies assessed the efficacy of aflibercept compared with sham in patients with macular oedema secondary to central retinal vein occlusion.15-18 A combined total of 307 CRVO patients completed 52 weeks of aflibercept treatment.

Summary efficacy results show: • In COPERNICUS, 56.1 per cent of aflibercept-treated patients vs. 12.3 per cent of patients receiving sham injections gained 15 or more letters at 24 weeks (P<0.001 vs. sham); at week 52, 55.3 per cent of aflibercepttreated patients vs. 30.1 per cent in the control group (who received aflibercept PRN dosing in the extension period from week 24 to week 52) gained ≥15 letters.15,16 • In GALILEO, 60.2 per cent of aflibercept-treated patients vs. 22.1 per cent of sham patients gained 15 or more letters at week 24 (P<0.0001 vs. sham), compared with 60.2 per cent vs. 32.4 per cent, respectively, at week 52.17,18 “The data demonstrate rapid vision gains with monthly aflibercept injection, with over half of subjects gaining three or more lines of VA (≥15 letters), representing clinically significant vision improvement,” noted Dr Pearce.

“Gains in visual acuity were maintained with less frequent treatment during a six-month extension period following the initial 24-week study period (n=139). Some 70 per cent of patients received ≤3 aflibercept injections during the six-month treatment extension. Twenty-four per cent of enrolled subjects were non-perfused or of indeterminate perfusion at baseline. Treatment was well tolerated; the most common adverse event was conjunctival haemorrhage.”19 Substantial benefit of intravitreal anti-VEGF therapy over previous treatment approaches NICE technology appraisal guidance 305, issued February 2014, recommended aflibercept as an option for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion.20 The recommended posology for aflibercept in treating macular oedema following CRVO involves initial fixed monthly dosing until visual and/or

anatomical outcomes are stable for three monthly assessments, thereafter, during stable disease, a flexible approach based on treat-and-extend or PRN dosing regimens.9 Treatment should be discontinued if there is no visual or anatomic improvement after three consecutive injections.

Dr Pearce commented: “Aflibercept is an effective first-line treatment option for CRVO, even in patients with poor perfusion or poor visual acuity. Retina specialists are advised to treat monthly until there is a plateau in patient response, followed thereafter by as-needed treatment or a treat-and-extend dosing regimen. Analyses show that the treatment interval can be successfully extended after an initiation phase of monthly aflibercept injections.19 “It’s important when developing service proposals for the introduction of aflibercept as a treatment option for CRVO to decide on a clear care pathway,” explained Dr Pearce. “Clinical commissioning groups will often demand to see a care pathway before approving a new or extended service provision. In my experience, a dedicated CRVO service is ideal.

The care pathway must include provision for refracted BCVA, fluorescein angiography, an option to switch to alternative treatments in case of poor response and also incorporate recommended futility criteria, i.e., when to stop treatment.

“For maximum benefit, we need to treat CRVO early following initial detection. A dedicated CRVO care pathway is a service that works and aflibercept therapy can provide CRVO patients with good visual improvement and treatment frequency decreases over time.”

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Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

PANEL DISCUSSIONS

Q.

Following speaker presentations, the symposium closed with a Q & A session involving congress delegates and panel speakers. Summary highlights below.

Regular OCT examination can help detect early second eye involvement and ‘frequent flyers’ with persistent fluid despite repeat treatment, so there are concerns about reducing the number of regular OCT scans when monitoring AMD patients.

“The aflibercept care pathway for wet AMD is very much a pragmatic solution in that we do not have capacity to see all patients every month. We do greater good by creating greater capacity and being able to quickly assess and treat many more new patients. In an ideal world, it probably would be better to monitor some wet AMD patients monthly.

We were very careful when we designed our aflibercept AMD care pathway to ensure that clinicians retain the freedom to exercise clinical judgment on how best to manage individual patients.” [Andrew Lotery]

Q.

When a patient is on a bimonthly aflibercept treatment regimen and you detect aggressive intraretinal or subretinal fluid, do you rethink your treatment approach or maintain everytwo-month injections?

“If a patient exhibited significant change in macular anatomy, evident clinically or on OCT, you ought to reconsider the monitoring regimen and perhaps reschedule an earlier clinic visit.” [Faruque Ghanchi]

Q.

“You also need to consider the evidence base. The combined VIEW trial data show that the mean visual change from baseline to week 96 with a two-monthly injection regimen is as good as a monthly injection regimen. So it is reasonable to initiate treatment with three consecutive monthly doses and then treat every two months thereafter for the first year, with no need for monthly OCT scans. Following starting treatment on aflibercept, we then assess patients using OCT at the time of the fourth injection and repeat OCT examinations at month six and month 12.” [James Talks]

Do you still offer patients a choice of intravitreal anti-VEGF agent for second eye involvement or do you encourage the patient to continue with the same anti-VEGF drug that is being used in the first affected eye?

“We have a principle in place of only using the same intravitreal anti-VEGF agent in one patient, to avoid the risks associated with using different anti-VEGF agents. If a patient is doing well on the initial intravitreal anti-VEGF agent in their first eye, we would offer the same agent for second eye involvement.” [Andrew Lotery]

“We monitor vision regularly and if visual acuity drops in either eye, we bring the patient back for review – so there is an escape clause if you like. There are pros and cons with any AMD care pathway – we believe the benefits outweigh the risks and we have evidence from the VIEW 2 study and real-world audit data, albeit early, which shows good vision outcomes for patients treated with aflibercept on a 2mg q8 basis. If you have capacity to monitor patients each month, that’s a valid approach that will work too.” [Andrew Lotery]

Q.

Do you run separate clinics for aflibercept- and ranibizumabtreated wet AMD patients or do you combine patients into a single clinic with appropriate verification checks?

“At University Hospital Southampton, the eye clinic combines all wet AMD patients irrespective of intravitreal drug used, although for simplicity there are moves to separate patients by treatment choice as numbers increase.” [Andrew Lotery]

“Vision assessment can be a good indicator of the need for an OCT scan.” [Sobha Sivaprasad]

“The AMD clinics in Newcastle combine patients irrespective of drug selection. Capacity remains a central challenge, even with bimonthly treatment regimens, particularly with extended retinal indications that can be treated with anti-VEGF therapy. Documentation is very important and noting which eye you are going to inject is crucial. In addition to clinical records, we always mark the affected eye prior to treatment.” [James Talks]

Q.

If you individualise treatment dosing, rather than give all patients a fixed number of intravitreal injections in one year, you’d probably provide fewer injections overall.

“Medical retina specialists often take different views on how best to manage and monitor patients. We have huge capacity issues and we have successfully implemented the aflibercept for neovascular AMD service model – the treatment regimen replicates that used in pivotal phase III neovascular AMD trials and this allows us to treat more people.

It works in Southampton and we get very effective results with this approach. We struggle with capacity in implementing a treat as-needed regimen for neovascular AMD.” [Andrew Lotery]

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“Ranibizumab is a good treatment option and with monthly review, PRN dosing can work well. However, we were increasingly struggling to actually do monthly review – we have achieved a significant increase in our capacity but we were still struggling. At best we were treating on a six-weekly basis. With aflibercept treatment, we dose with bimonthly injections after an initial loading phase of three consecutive doses once a month. Now this might mean under- or over-treatment in some cases, but we are much closer in practice to the treatment regimen shown to be effective in pivotal clinical trials. We have increased our capacity as a result. We still have capacity issues, for example with extended indications for anti-VEGF therapy, but at least it’s a step in the right direction. I also believe that patient compliance is better with fewer hospital and clinic visits.” [James Talks] “Additional studies are needed to better understand if there are any significant benefits from utilising modified monitoring and dosing schedules in neovascular AMD.” [Andrew Lotery]

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Making Time For Change| Using aflibercept solution for injection (Eylea) in a clinical setting

References

1. Chopdar A, Chakravarthy U, Verma D. Age related macular degeneration.

BMJ. 2003;326(7387):485-8.

2. Owen CG, Jarrar Z, Wormald R, et al. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol.

2012;96(5):752-6.

3. Klaver CCW. PhD thesis. Genetic epidemiologic studies on age-related maculopathy. Erasmus University Amsterdam. Netherlands 2000.

4. National Institute for Health and Care Excellence. NICE technology appraisal guidance 294 (2013).

5. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups.

Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-48.

6. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.

7. Kaye M, Suter C, McKibbon M, et al. Real-world outcomes with intravitreal aflibercept for newly diagnosed neovascular AMD. Poster presentation at the Royal College of Ophthalmologists Annual Congress; Birmingham, UK: May 20-22, 2014.

8. Fernández-Ledo N, Tathew R, Kiousis G, et al. Initial experience of neovascular AMD unresponsive to ranibizumab treated with aflibercept.

Poster presentation at the Royal College of Ophthalmologists Annual Congress; Birmingham, UK: May 20-22, 2014.

9. Bayer plc. Eylea 40 mg/ml solution for injection summary of product characteristics. Bayer plc, Newbury, Berkshire.

10. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-44.

11. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 5;355(14):1419-31.

12. Hykin P, Sivaprasad S, Chakravarthy U, et al, on behalf of the AURA Study Group. AURA study: real-world utilisation of anti-VEGF therapy for neovascular (wet) age-related macular degeneration (wAMD) in the UK. Poster presentation at the Royal College of Ophthalmologists Annual Congress; Birmingham, UK: May 20-22, 2014.

13. Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab Injections: report 1: visual acuity.

Ophthalmology. 2014;121(5):1092-101.

14. Pushpoth S, Sykakis E, Merchant K, et al. Measuring the benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Br J Ophthalmol. 2012;96(12):1469-73.

15. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology.

2012 ;119(5):1024-32.

16. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-37.

17. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278-84.

18. Korobelnik JF, Holz FG, Rider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology. 2014;121(1):202-8.

19. Lorenz K. Intravitreal aflibercept in CRVO: treatment interval extension based on visual and anatomic outcomes. Presentation at the 5th World Congress on Controversies in Ophthalmology (COPHy); Lisbon, Portugal: March 20-23, 2014.

20. National Institute for Health and Care Excellence. NICE technology appraisal guidance 305 (2014).

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Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment of neovascular (wet) age-related macular degeneration (AMD) and macular oedema secondary to central retinal vein occlusion (CRVO) in adults.

Posology & method of administration: For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults: The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections. After the first 12 months of treatment, treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring may be more frequent than the schedule of injections.

For CRVO, after the initial injection, treatment is given monthly at intervals not shorter than one month, and continues until visual and anatomic outcomes are stable for three monthly assessments. Thereafter the need for continued treatment should be reconsidered. Treatment may be continued with gradually increasing treatment intervals to maintain a stable visual and anatomic outcome. Continued treatment is not recommended if no improvement in visual and anatomic outcomes over the first three injections. If treatment is discontinued, monitor visual and anatomic outcomes and resume treatment if these deteriorate. Usually, monitoring should be done at the injection visits.

During treatment interval extension until therapy completion, the monitoring schedule should be determined by the treating physician based on the individual patient’s response and may be more frequent than the schedule of injections. Hepatic and/or renal impairment: No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population: No special considerations are needed. Paediatric population: No data available. Contra-indications: Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: Endophthalmitis has been reported, as with other intravitreal therapies. Aseptic injection technique essential. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is ≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation. Theoretical risk of systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events. Safety and efficacy of concurrent use in both eyes have not been studied. Caution in patients with risk factors for development of retinal pigment epithelial tears including large and/or high pigment epithelial retinal detachment. Withhold treatment in patients: with rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. Withhold treatment

and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of ≥30 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection. There is limited experience with treatment of patients with ischaemic, chronic CRVO. Treatment in patients presenting with clinical signs of irreversible ischaemic visual function loss is not recommended. There is limited clinical data with Eylea in patients with diabetic retinopathy. Interactions: No available data. Fertility, pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women.

Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding.

Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), eye pain. Common: retinal pigment epithelium tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, eyelid irritation. Serious: cf. CI/W&P - in addition: endophthalmitis, traumatic cataract, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare. Consult the SmPC in relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Incompatibilities: Do not mix with other medicinal products.

Special Precautions for Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic NHS Costs: Single vial pack £816.00. MA Number(s): EU/1/12/797/002.

Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000.

Date of preparation: February 2014 Eylea® is a trademark of the Bayer Group

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Bayer plc.

Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk

Cited comment and opinion reflect the views of speakers and participants and do not necessarily reflect those of Bayer HealthCare.

L.GB.07.2014.7068 Date of preparation: July 2014

Supplement September 2014