Australian Doctor 14th July Issue 14JULY2023 issue | Page 31

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Box 1 . Complications of intravitreal procedures

• Perioperative : — Ocular pain . — Subconjunctival haemorrhage . — Corneal abrasion . — Lens contact . — Temporary raised intraocular pressure . — Central retinal artery occlusion . — Hypotony . — Vitreous floaters . — Vision loss .

• Postoperative : — Endophthalmitis . — Retinal detachment . — Vitreous haemorrhage . — Vitreous floaters . — Cataract . — Intraocular inflammation . — Persistent raised intraocular pressure . — Vision loss . — Occlusive vasculitis ( reported with brolucizumab ). Source : Azarbod P et al 2020 33

characterisation of the choroidal circulation , which can be helpful for conditions like idiopathic polypoidal choroidal vasculopathy , a subtype of neovascular AMD . Idiopathic polypoidal choroidal vasculopathy sometimes requires additional intervention beyond intravitreal anti- VEGF therapy to close the active polyps . Again , non-invasive OCT criteria are increasingly helping with the diagnosis of idiopathic polypoidal

18 , 19 choroidal vasculopathy .

MANAGEMENT

Prevention of late-stage AMD

THE natural history is the eventual development of late-stage AMD with either atrophic ( dry ) or neovascular ( wet ) changes . While this transition is influenced by non-modifiable genetic factors , the correction of modifiable environmental factors can help slow disease progression . A Mediterranean diet rich in antioxidants , together with increased physical activity and smoking cessation , has been reported to be protective . 8-10 Additionally , micronutrients — such as lutein , zeaxanthin , zinc and vitamins C and E — reduced the rate of AMD progression by a small degree in the Age-Related Eye Disease 2 Study ( AREDS2 ). 20

Treatment of neovascular ( wet ) AMD

The treatment of neovascular AMD is primarily aimed at reducing activity of VEGF-A , which inhibits angiogenesis and vascular permeability . This is achieved by administering drug molecules ( anti-VEGF ) that bind to VEGF-A with greater affinity than natural receptors ( see table 1 ).

The ground-breaking MARINA clinical trial randomised patients to monthly ranibizumab 0.3mg , 0.5mg and sham injections . 21 After one year , about 95 % of the groups treated with ranibizumab lost fewer than 15 letters from baseline compared with 62 % receiving sham injections . The ranibizumab 0.3mg and 0.5mg treatment groups were also more likely to have at least a 15-letter visual acuity gain ( 25 % and 34 %, respectively ) compared with sham injections ( 5 %).

Table 1 . Mechanism of action of available intravitreal drugs for neovascular AMD Available intravitreal drugs Dose Mechanism of action Aflibercept 2mg in 0.05mL Inhibits VEGF-A , VEGF-B and placental growth factor 28 Bevacizumab ( off-label ) 1.25mg in 0.05mL Inhibits all isoforms of VEGF-A 29 Brolucizumab 6mg in 0.05mL Inhibits all isoforms of VEGF-A 30 Faricimab 6mg in 0.05mL Inhibits VEGF-A and angiopoietin 2 ( Ang-2 ) 31

Ranibizumab 0.5mg in 0.05mL Inhibits all isoforms of VEGF-A 32

Table 2 . Key recent and ongoing neovascular AMD clinical trials Study

Gene therapy

Study phase

The VIEW 1 and 2 clinical trials used fixed interval dosing of aflibercept every eight weeks after an initial loading phase , with similarly impressive visual outcomes . 22

The introduction of intravitreal anti-VEGF injections as a gold standard in many developed countries has led to a significant 50 % decline in legal blindness caused by wet AMD . 23 Real-world studies have identified the importance of early diagnosis and treatment , with baseline visual acuity the strongest predictor of long-term visual outcomes . 24 Furthermore , in eyes with good visual potential , more proactive rather than reactive treatment regimens have been associated with better longterm visual prognosis . 25

With the existing treatments of aflibercept , ranibizumab or off-label bevacizumab , it is difficult to extend the treatment intervals in many eyes beyond 12 weeks . For a condition requiring long-term treatment ,

Investigational product

Route of administration

there is an unmet need for treatment that can be administered at longer intervals .

Brolucizumab potentially offers longer duration of effect , but it is mainly a second-line agent because of reported higher rates of intraocular inflammation and occlusive vasculitis , which can sometimes be sight-threatening . 26 Faricimab is a newer drug that targets both VEGF and angiopoietin 2 ; the 2022 phase III trials reported that more than 75 % of patients were on a treatment interval of 12 weeks or longer by two years . 27 Faricimab is TGA approved and awaiting PBS listing .

DRUG MECHANISM OF ACTION Table 1 outlines the currently available drugs and their mechanisms of action . Box 1 lists the potential complications of the intravitreal procedures . Note that the more severe complications are rare .

Target

OPTIC ( Adverum Biotechnologies )

Slow-release and slow clearance

ALTISSIMO ( Graybug Vision )

CLN-0046 ( Ocular Therapeutix )

I

OTX-TKI ( Axitinib )

Intravitreal Tyrosine kinase inhibiton , targeting VEGF-A , VEGF-B and VEGF-C

Combination therapy

TENAYA / LUCERNE ( Roche ) III Faricimab Intravitreal VEGF-A and Ang-2 antibody COAST / ShORe ( Opthea ) IIb OPT-302 Intravitreal VEGF-C and VEGF-D Continuous delivery drug-device technology

LADDER / ARCHWAY ( Roche )

III

Ranibizumab PDS

Table 3 . Key recent and ongoing atrophic AMD clinical trials Study

OAKS / DERBY ( Apellis )

Study phase

III

Investigational product

Pegcetacoplan ( APL-2 )

Pars plana

Route of administration

Intravitreal

Refillable drug implant device with sustained release

Target

Complement factor C3

GATHER 1 / 2 ( Iveric Bio ) II / III Avacincaptad pegol Intravitreal Complement factor C5 OnwarD ( Alexion ) II Danicopan Oral tablet Complement factor D

GOLDEN ( Ionis Pharmaceuticals )

HORIZON ( Gyroscope Therapeutics )

JNJ-81201887 ( Janssen and Janssen )

Complement factor B

I AAVCAGsCD59 Intravitreal Antiviral injection inhibiting MAC formation

Treatment of atrophic AMD

In contrast to neovascular AMD , atrophic AMD progresses relatively slowly . However , there is currently no effective licensed pharmacological treatment . Lifestyle interventions include AREDS2 vitamin supplements and smoking cessation .

The reality for many patients with atrophic ( dry ) AMD is a slow evolution of significant central vision impairment . Initially , changes to vision may be subtle as patients begin to lose contrast sensitivity and the ability to adapt to the dark . In more advanced disease , the ability to drive , read and avoid hazards will be significantly affected . 3 There are supportive measures available to assist patients to maintain their independence and quality of life . Aids — such as magnifying devices , technological adjuncts and lighting apparatus — can help with reading , cooking and other activities of daily living . Another

Box 2 . Criteria for definition of complete retinal pigment epithelial and outer retinal atrophy

• A region of hyper transmission of at least 250μm in diameter ; and

• A zone of attenuation or disruption of the RPE of at least 250μm in diameter ; and

• Evidence of overlying photoreceptor degeneration — all occurring in the absence of signs of an RPE tear .

aspect of managing advanced AMD is access to support services .

Nascent geographic atrophy describes the subsidence of the inner nuclear layer and outer plexiform layer : a hyporeflective wedgeshaped band within the Henle fibre layer — often accompanied by RPE disturbance and increased signal hyper-transmission into the choroid .

In 2020 , the term complete retinal pigment epithelial and outer retinal atrophy ( cRORA ) was proposed as an end point for atrophy that occurred in the presence of drusen ; this is defined in box 2 . The term incomplete RORA ( iRORA ) was also introduced in 2020 to describe a stage of AMD where these OCT signs were present but not extensive enough to fulfil all the criteria for cRORA . 34

THE FUTURE

Home monitoring AS the technology advances , there has been interest in whether OCT monitoring of AMD could partly be transitioned from the clinical arena to a patient ’ s home . Results have been mixed in initial pilot studies , and barriers will have to be overcome to facilitate real-world implementation . 24-27

New treatments for neovascular AMD Research into longer-duration therapies is ongoing ; clinical trials ( see table 2 ) are assessing the efficacy and safety of slow clearance and release of medication or , alternatively , creating a reservoir as a means of providing continuous drug delivery .

In addition , there are efforts being made in the field of gene therapy ; however , these potential improvements in duration of therapy need to be balanced against the potential risks of the intervention . Retinal pigment epithelium atrophy was reported at the edge of bleb sites when treated with voretigene neparvovec-rzyl : a gene therapy subretinal injection for treatment of RPE65-inherited retinal dystrophy . 39 Therefore , longer-term follow-up is needed to gain a more thorough understanding of whether new neovascular AMD treatments will have a detrimental impact on central vision in the future .

New treatments for atrophic AMD While current treatment options are limited , modulation of the innate immune system is a promising area of research for the prevention of geographic atrophy , with the potential to offer treatment options in the next few years , subject to regulatory approval . 40 The complement system is being targeted through both specific molecular inhibitors and gene therapy ( see table 3 ). Intravitreal pegcetacoplan