Ranibizumab (Lucentis) and aflibercept (Eylea) for ocular indications

• Ranibizumab and aflibercept are anti-vascular endothelial growth factor (anti-VEGF) antibodies
  After intravitreal injection they produce an anti-angiogenic effect, inhibiting ocular neovascularisation and improving oedema by reducing vascular permeability.
• In people with neovascular eye disease, ranibizumab and aflibercept help maintain visual acuity
  In trials, ranibizumab and aflibercept have been shown to be effective in maintaining or increasing overall visual acuity and reducing the risk of severe vision loss in people with ocular vascular disorders, including neovascular ('wet') age-related macular degeneration, diabetic macular oedema, and retinal vein occlusion.
• Monitor for adverse events
  Monitor for post-injection infections (eye pain or discomfort, abnormal degree of redness) and visual disturbances (blurred or decreased vision, or increased sensitivity to light). Driving and operating machinery should be avoided until vision has normalised post injection.
• Serious systemic adverse events are rare
  Serious systemic adverse events, including arterial thromboembolic events and non-ocular haemorrhage, have been observed in trials but are rare.

What is known about these drugs

Ranibizumab and aflibercept are anti-VEGF therapies administered initially on a monthly basis to treat:

• neovascular ('wet') age-related macular degeneration (AMD)
• visual impairment due to diabetic macular oedema (DME)
• macular oedema due to retinal vein occlusion (RVO).

They are more effective at improving overall best corrected visual acuity (BCVA) compared with other treatment methods such as verteporfin photodynamic therapy (PDT) or laser photocoagulation.

These anti-VEGF therapies have been associated with ocular and non-ocular adverse effects; however, the occurrence of adverse effects is low and the incidence is similar to that observed with other treatment methods.

Areas of uncertainty

Due to the low incidence of serious ocular and non-ocular adverse events in most studies after injection of ranibizumab and aflibercept, meta-analyses and statistical analyses of comparative harms data could not be accurately performed.

What does NPS MedicineWise say?

Ranibizumab and aflibercept are PBS listed for treatment of neovascular AMD.

The Pharmaceuticals Benefits Advisory Committee has recommended extension of the listing to include visual impairment due to DME, or macular oedema secondary to RVO. Ranibizumab and aflibercept should only be administered under aseptic conditions by a qualified ophthalmologist.

Ranibizumab and aflibercept improve the overall visual acuity of people with neovascular AMD, visual impairment due to DME, or macular oedema secondary to RVO.

While these drugs are administered by a specialist ophthalmologist, primary care health professionals should be aware of the risk of ocular and non-ocular adverse events and monitor patients accordingly. Such adverse events include:

• transient post-injection ocular pain
• cataracts
• intraocular inflammation associated with intraocular infection (endophthalmitis)
• increased intraocular pressure
• arterial thromboembolic events (ATEs)
• non-ocular haemorrhage.

Ranibizumab (Lucentis) and aflibercept (Eylea)

Authority required

Ranibizumab and aflibercept are PBS listed as Authority Required for the treatment of neovascular AMD.

In July 2014 the PBAC recommended extending the PBS listing of ranibizumab as a Section 85 Authority Required benefit to include treatment of visual impairment due to DME, and macular oedema due to central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO).¹

In November 2014 the PBAC recommended extending the PBS listing for aflibercept as a Section 85 Authority Required benefit to include treatment of patients with visual impairment due to DME or patients with macular oedema due to CRVO.¹

For both recommendations the conditions must have been diagnosed by fluorescein angiography (FA).^{1- 4}

At the time of publication, neither of these recommendations had been reflected in PBS listings for these additional indications.

Ranibizumab or aflibercept treatment must be the sole PBS-subsidised therapy for each condition treated and must be prescribed and administered by an ophthalmologist experienced in administering intravitreal injections.^{5, 6}

Anti-VEGF therapies as standard care for neovascular AMD, DME, RVO

Some ocular disorders, including neovascular AMD, are characterised by growth of abnormal leaky blood vessels into the retina and macula, a process termed angiogenesis, leading to severe vision loss.^7-10

Certain retinal vascular conditions such as diabetic retinopathy and RVO may be complicated by increased vascular leakage leading to macular oedema, causing reduction in visual acuity.¹¹

An important regulator of angiogenesis is vascular endothelial growth factor (VEGF), particularly vascular endothelial growth factor-A (VEGF-A), which, when secreted, promotes the formation, and increases the permeability, of abnormal vasculature, leading to increased fluid in the retinal area and subsequent damage to the macula.^7-10

Inhibitors of VEGF have become important for treating ocular vascular disorders.

Ranibizumab

Ranibizumab is a humanised monoclonal antibody fragment that binds to all isoforms of VEGF-A with high affinity, preventing VEGF-A from binding to its receptors, VEGFR-1 and VEGFR-2.^{5, 7, 12}

Aflibercept

Aflibercept is a recombinant fusion protein mimic of VEGFR-1 and -2 and the Fc region of a human immunoglobulin G₁ (IgG₁).⁶ It acts as a soluble decoy receptor that binds VEGF-A with higher affinity than their natural receptors, thereby blocking the binding and activation of these VEGF receptors. ^{13, 14}

Bevacizumab

Bevacizumab is another monoclonal anti-VEGF therapy derived from the same parent mouse antibody as ranibizumab.^{8, 15} It has been used as a comparator in some of the clinical trials investigating safety and efficacy of ranibizumab and aflibercept.^{9, 10, 16-19} However, it is neither TGA approved nor PBS listed for ophthalmic indications.^{18, 20, 21}

Ranibizumab and aflibercept are indicated for use in adults for the treatment of neovascular AMD, visual impairment due to DME, and macular oedema secondary to RVO.^{5, 6, 22-26}

AMD is a progressive degenerative disease involving the central part of the retina (macula) that is the most common cause of irreversible vision loss in Australia.²⁷

AMD can be classified as either early stage or late stage, depending on disease progression and characteristics of the disease in the affected eye. Late-stage AMD can be classified as non-neovascular ('dry') or neovascular ('wet') AMD.

Early-stage AMD affects about 13% of the Australian population.^{28, 29} Non-neovascular AMD affects 0.65% of the Australian population and is often associated with yellow deposits, known as drusen, under the retina, which can lead to a gradual loss of central vision.^{27, 29,30}

Currently there is no effective treatment for non-neovascular AMD.^{27, 29} However, a clinical trial to determine if ranibizumab treatment will prevent progression from non-neovascular AMD to neovascular AMD (ClinicalTrials.gov ID: NCT02140151) is ongoing.³¹

Although neovascular AMD affects a small percentage of the Australian population (about 1.3% in 2010), it is responsible for up to 90% of cases of severe vision loss.^{27, 28}

Neovascular AMD is characterised by choroidal neovascularisation (CNV), in which abnormal blood vessels from the choroid grow aberrantly under the retina, leading to haemorrhage and oedema in and under the retina, subsequent loss of central vision and eventually permanent vision loss.^{9, 27}

Neovascular AMD causes painless blurred or distorted central vision and is diagnosed using slit-lamp biomicroscopy, optical coherence tomography (OCT) and fluorescein angiography (FA).^{9, 27}

Diabetic retinopathy is an ocular complication of diabetes mellitus defined as the presence of typical microvascular signs.^{11, 32} DME – swelling of the retina resulting from accumulation of extracellular fluid in the macula and increased vascular permeability – is an advanced complication of diabetes.^{10, 11, 33}

DME affects about 3.3% of people with diabetes in Australia.³⁴ When the oedema is left untreated irreversible damage can result, leading to permanent loss of vision.^{10, 35} It can be detected using ophthalmoscopy, slit lamp biomicroscopy, fundus photography, FA and OCT.¹¹

RVO occurs when either the central retinal vein or a branch retinal vein is obstructed. This may lead to macular oedema and can result in severe irreversible vision loss.^{7, 10, 36} It is diagnosed using slit-lamp biomicroscopy, OCT, and fundus fluorescein angiography (FFA).⁷

Laser therapies slow vision loss but do not improve overall vision

Laser therapies, including verteporfin photodynamic therapy (PDT) and laser photocoagulation, were historically the 'gold standard' therapies for neovascular AMD and DME.^{11, 18, 27, 35, 37}

Systematic reviews and meta-analyses concluded that, while PDT and laser photocoagulation are effective at slowing the progression of vision loss in people with these indications, these interventions did very little to improve overall vision.^{9, 10, 18, 27, 38}

PDT requires regular 3-monthly treatments, as the effect is temporary, and it can also lead to atrophy within the treated areas of the macula.²⁷

Laser photocoagulation involves application of a thermal laser to ablate leaky blood vessels; however, this can also damage the overlying retina and is therefore not appropriate for people with diffuse DME that involves the fovea.^{27, 39}

Because of their effectiveness at maintaining and improving visual acuity, anti-VEGF therapies are becoming the new standard treatment for people with neovascular AMD, DME or RVO.

Clinical trial data have shown that intravitreal injections of ranibizumab or aflibercept are more effective for treating neovascular AMD, DME, and RVO than sham injections and laser therapies (including verteporfin PDT and laser photocoagulation).^{7, 9, 35, 40}

Clinical trials reported changes in visual acuity using the Snellen and/or Early Treatment Diabetic Retinopathy Study (ETDRS) charts^a (Figure 1). Visual acuity outcome data from the clinical trials are presented here as Snellen equivalents. However, when these data were not available, visual acuity outcomes using the ETDRS chart are presented.

Figure 1. Snellen and ETDRS charts for assessing visual acuity.

How does ranibizumab compare?

Ranibizumab improves visual acuity compared with control treatments

Monthly intravitreal injections of ranibizumab improved visual acuity in people with neovascular AMD compared with sham injections or control interventions such as verteporfin PDT.^{9, 38, 41, 42}

A systematic review and meta-analysis showed that in people with neovascular AMD a greater proportion of those treated with ranibizumab had visual acuity better than a Snellen equivalent of 20/200^b compared with sham or control interventions at follow-up at 1 year (Table 1).⁹

In the MARINA and ANCHOR studies a significantly greater percentage of people with neovascular AMD treated with ranibizumab had Snellen equivalents of 20/40^c vision or better compared with control interventions at follow-up at 1 year (Table 1).^{38, 41, 42}

Additionally it was shown that a significantly smaller percentage of people with neovascular AMD treated with ranibizumab had Snellen equivalents of 20/200 or worse compared with control interventions at follow-up at 1 year (Table 1).^{38, 41, 42}

Similar beneficial effects were observed when ranibizumab was used for DME in the RISE and RIDE studies. These showed that, compared with sham injection, monthly intravitreal injections of ranibizumab in people with DME resulted in:

• a higher percentage of people with Snellen equivalent ≥ 20/40
• a lower percentage of people with Snellen equivalent ≤ 20/200 or worse.^{33, 43}

In the CRUISE study, intravitreal injection of ranibizumab in people with CRVO resulted in a greater percentage of people with vision of Snellen equivalent ≥ 20/40 at 6 months compared with sham injections (43.9–46.9% vs 20.8%, respectively, p < 0.0001).

There were also fewer patients with vision of 20/200 or worse in the ranibizumab group compared with the sham injection group (11.5–15.2% vs 27.7%, respectively, p < 0.005).³⁶

Ranibizumab with and without laser therapy is superior to laser therapy alone

In the RESTORE study, treatment with ranibizumab with or without laser therapy resulted in a significantly greater proportion of DME patients with a BCVA letter score of > 72 on the ETDRS scale (equal to 20/40 Snellen equivalent) compared with laser treatment alone (44.9% and 53% versus 23.6%, respectively). ⁴⁴

In addition, people with DME treated with ranibizumab (with or without laser therapy) reported an overall improvement in visual functioning based on increased National Eye Institute Visual Functioning questionnaire-25 (NEI VFQ-25)^d scores.^44-47

Ranibizumab is non-inferior to bevacizumab

It is important to note that, while bevacizumab has been used as a comparator for ranibizumab for investigating safety and efficacy,^{9, 10, 18, 19, 27, 48} bevacizumab is currently neither TGA approved nor PBS listed for ocular indications.^{18, 20, 21}

Intravitreal injection of ranibizumab has been shown to be non-inferior to bevacizumab for treating neovascular AMD.^{9, 16, 17} Systematic review and meta-analysis concluded that the proportion of people with neovascular AMD with visual acuity better than the Snellen equivalent of 20/200 was comparable in ranibizumab and bevacizumab groups at follow-up at 1 year (RR 0.98; 95% CI 0.96 to 1.01) and 2 years (RR 1.00, 95% CI 0.95 to 1.06).⁹

One direct comparison between ranibizumab and bevacizumab made in people with DME demonstrated a significantly greater mean improvement in BCVA after ranibizumab treatment compared with bevacizumab treatment at follow-up at 8 weeks (p = 0.0318) and 32 weeks (p = 0.0415).¹⁹

However, there was no difference in the proportion of eyes gaining (RR 0.81, 95% CI 0.44 to 1.47) or losing (RR 2.64; 95% CI 0.11 to 62.23) three or more lines of visual acuity on the ETDRS chart^e.^{10, 19}

Due to the small cohort size, low statistical power of the study and short follow-up, these effects in people with DME should be interpreted with caution.

A head-to-head trial comparing the safety and efficacy of aflibercept, bevacizumab and ranibizumab for treating DME (ClinicalTrials.gov ID: NCT01627249) is ongoing and due to be completed in September 2015.⁴⁹

This study will report on changes in visual acuity from baseline and the proportions of eyes with two and three line gains or losses in visual acuity.⁴⁹

How does aflibercept compare?

Aflibercept is superior to sham injection for RVO

For CRVO, a systematic review of trials revealed there was a significantly higher mean change in BCVA from baseline in aflibercept-treated groups compared with sham groups at 6-month follow-up (RR 21.30, 95% CI 16.55 to 26.05).⁷

This significant difference was maintained to 1-year follow-up (GALILEO: 16.9 vs 3.8 letters on the ETDRS chart at week 52, p < 0.0001; COPERNICUS: 16.2 vs 3.8 letters at week 52, p < 0.001).^{7, 50, 51}

In addition, at 6-month follow-up aflibercept treatment resulted in a greater proportion of patients who gained ≥ 15 ETDRS letters in BCVA (RR 3.37, 95% CI 2.04 to 5.57) and a lower proportion of patients who lost ≥ 15 ETDRS letters in BCVA (RR 0.06, 95% CI 0.02 to 0.27). ⁷

These improvements in visual acuity at 6-month follow-up were accompanied by significant reductions in central retinal thickness (CRT) from baseline in aflibercept-treated people with CRVO compared with sham groups (GALILEO: –448.6 vs –169.3 micrometres; COPERNICUS: –457.2 vs –144.8 micrometres).^{7, 50, 51}

Aflibercept is non-inferior to ranibizumab for neovascular AMD

The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW1 and 2) studies were large, randomised controlled trials comparing aflibercept with ranibizumab,⁵² after ranibizumab was previously shown to be superior to sham or verteporfin PDT in the MARINA and ANCHOR studies.^{38, 41, 42}

In patients with neovascular AMD, intravitreal aflibercept was non-inferior to monthly intravitreal ranibizumab injections, with comparable efficacy in improving visual acuity (measured by loss of < 15 ETDRS letters), retinal thickness and CNV.⁵²

Visual acuity gains in DME greater with aflibercept than with laser photocoagulation

The VISTA and VIVID studies compared the efficacy of aflibercept injections with laser photocoagulation for the treatment of DME.

Results demonstrate that intravitreal injections of aflibercept (2 mg) given monthly or 2-monthly were superior to laser photocoagulation, resulting in significant gains in visual acuity and prevention of severe visual acuity loss.^{10, 53}

Specifically, the study showed that monthly and 2-monthly injections of aflibercept exhibited significantly greater BCVA gains from baseline compared with the laser photocoagulation group.^{10, 53}

Aflibercept treatment resulted in a greater proportion of eyes that gained ≥ 10 or ≥ 15 letters and a lower proportion of eyes that lost ≥ 15 letters from baseline compared with laser photocoagulation groups.

Systematic review and meta-analyses showed that a small number of people treated with intravitreal ranibizumab or aflibercept (< 1%) experienced ocular adverse events and non-ocular adverse events.^{7, 9, 10, 38, 41, 53}

For information about reporting adverse reactions to the Therapeutic Goods Administration, or to report suspected adverse reactions online, see the TGA website.

For more information on adverse events associated with intravitreal ranibizumab or aflibercept refer to the TGA approved product information.

Transient post-injection ocular pain

Transient post-injection ocular pain is commonly associated with intravitreal injection of ranibizumab and aflibercept in the clinical setting, affecting 10–15% of people.^{5- 7, 9, 44, 45}

Serious ocular adverse events

Clinical studies have shown a varying number of participants (ranging from zero to 17%) experienced serious ocular adverse events after intravitreal injection of ranibizumab or aflibercept.^{5- 7, 9, 10, 27, 52} Serious ocular adverse events observed across the trials included:^{5, 6}

• cataract
• intraocular inflammation with or without intraocular infection (endophthalmitis)
• increased intraocular pressure
• retinal or vitreous detachment
• vitreous haemorrhage.

Higher incidence of cataracts

Compared with sham injections or control interventions (such as PDT), intravitreal injections of ranibizumab or aflibercept were associated with a higher incidence of cataracts when administered in people with neovascular AMD, DME or RVO.^{7, 9, 36, 38, 45}

In people with neovascular AMD, cataract was reported in 9–17% of people treated with anti-VEGF compared with zero to 13% in the control group (sham or laser) at 1- and 2-year follow-up.^{9, 38}

Meta-analyses indicated that the risk of developing cataracts was four times higher in people with CRVO who received anti-VEGF therapies compared with control groups.⁷

Low occurrence of endophthalmitis

Intravitreal injections in general have been associated with intraocular inflammation (endophthalmitis, uveitis), although their rate of occurrence is low.^{7, 9, 10, 38}

Endophthalmitis is classified as severe intraocular inflammation typically resulting from intraocular infection.⁵⁴

Systematic review and meta-analyses indicated that endophthalmitis occurred more often in people with AMD treated with ranibizumab compared with those treated with sham or control interventions at follow-up at 1 year (RR 2.71, 95% CI 1.36 to 5.42) and 2 years (RR 3.91, 95% CI 1.89 to 8.09).^{9, 42}

Currently no published data are available comparing the rate of occurrence of endophthalmitis in people with neovascular AMD treated with aflibercept or control interventions.

The occurrence of endophthalmitis was low to none in patients with DME who were treated with ranibizumab or aflibercept.^{7, 19, 33, 43, 45, 53}

Meta-analyses in patients with RVO revealed that anti-VEGF therapies may be associated with a fivefold higher chance of endophthalmitis compared with sham or no injection, although the CI reflects considerable uncertainty (Peto OR 5.20, 95% CI 0.09 to 287.41).⁷

Non-ocular adverse events

Non-ocular adverse events observed across trials of both drugs included ATEs and non-ocular haemorrhage.^{5, 6}

Arterial thromboembolic events

In clinical trials it has been reported that across all treatment groups a small percentage of participants, ranging from zero to 8.8%, experienced ATEs, including non-fatal stroke, non-fatal MI, or deaths owing to vascular or unknown causes.^{7, 9, 10, 33, 38, 41-43, 52, 53}

The overall incidence of ATEs was comparable between the anti-VEGF-treated and control groups in people with neovascular AMD, with zero to 3.8% of people experiencing ATEs.^{9, 41, 52}

Among patients with DME, a recent meta-analysis suggests the incidence of ATEs is comparable between anti-VEGF treatments and controls (RR 0.89, 95% CI 0.63 to 1.25).¹⁰

In a systematic review of anti-VEGF studies for CRVO macular oedema, the reported incidence of ATE is low; however, short follow-up periods and small numbers of treated patients limit the findings of the review.⁷

Non-ocular haemorrhage

Non-ocular haemorrhage, an adverse event associated with systemic VEGF inhibition, has been observed in a greater proportion of people with neovascular AMD treated with ranibizumab compared with sham or control intervention groups at follow-up at both 1 year (RR 1.90, 95% CI 0.78 to 4.62) and 2 years (RR 1.64, 95% CI 1.05 to 2.55).⁹

Currently no published data are available comparing the rate of occurrence of endophthalmitis in people with neovascular AMD treated with aflibercept or control interventions.

Non-ocular haemorrhage adverse events reported were:³⁸

• nose bleeds (~0.7–1.5%)
• bruising (zero to 2.1%)
• GI haemorrhage (zero to 0.7%)
• blood in the urine or stools (zero to 0.7%)
• bleeding in the joints (zero to 0.7%)
• haemothorax (zero to 0.7%)
• haematomas (zero to 1.5%).

Contraindications for aflibercept and ranibizumab

Ranibizumab and aflibercept should not be prescribed for people who:^{5, 6, 24-26}

• have a known hypersensitivity or allergy to ranibizumab or aflibercept or any of the excipients
• have active or suspected ocular or periocular infection
• have active severe intraocular inflammation
• are pregnant or breastfeeding.

Effects on ability to drive or use machinery

Intravitreal injections of ranibizumab or aflibercept may result in temporary worsening of vision in the treated eye. Therefore it is recommended that driving and operating machinery should be avoided until visual function has recovered.^{5, 6}

Ranibizumab and aflibercept are approved for PBS listing for the indication of neovascular ('wet') AMD.^{55, 56}

In July 2014 the PBAC recommended extending the PBS listing of ranibizumab as an Authority Required benefit to include treatment of visual impairment due to DME and macular oedema due to BRVO and CRVO.¹ At the time of publication this recommendation had not been reflected in a PBS listing for these indications.

This recommendation was made on the basis that additional clinical evidence provided demonstrated greater gain of visual acuity and reductions in vision loss after treatment of DME and RVO (BRVO or CRVO) with ranibizumab compared with sham injection or laser photocoagulation.¹

In November 2014 the PBAC recommended extending the PBS listing for aflibercept as a Section 85 Authority Required benefit to include treatment of patients with visual impairment due to DME or patients with macular oedema due to CRVO.² At the time of publication this recommendation had not been reflected in a PBS listing for these indications.

This recommendation was made on a cost-minimisation basis compared with ranibizumab. In addition the PBAC determined that aflibercept 2 mg injection was equi-effective to ranibizumab 0.5 mg injection and to 1.25 mg and 1.5 mg bevacizumab injection (for DME and CRVO, respectively).²

Intravitreal injections of ranibizumab and aflibercept can result in temporary worsening of visual disturbances, including blurred vision or dark spots. Driving and operating machinery should be avoided until vision has returned to baseline levels post injection.^{5, 6}

Most patients will experience transient eye redness. Advise them to contact their treating ophthalmologist or their GP if they are experiencing any of the following symptoms:

• eye pain or increased discomfort
• worsening eye redness
• blurred or decreased vision
• increased sensitivity to light.

Advise patients to contact Vision Australia or the Macular Disease Foundation to find out more on how to manage low vision.

Discuss the Lucentis or Eylea Consumer Medicine Information (CMI) leaflet with the patient.