WO2017046140A1

WO2017046140A1 - Treatment regimens for dr and rvo in dependence of the extent of retinal ischemia

Info

Publication number: WO2017046140A1
Application number: PCT/EP2016/071658
Authority: WO
Inventors: Oliver ZEITZ; Carola METZIG; Todd Katz
Original assignee: Bayer Pharma AG; Bayer Healthcare LLC
Current assignee: Bayer Pharma AG; Bayer Healthcare LLC
Priority date: 2015-09-18
Filing date: 2016-09-14
Publication date: 2017-03-23
Anticipated expiration: 2018-03-18

Abstract

The present invention provides methods for optimizing the therapeutic efficacy of an anti-VEGF treatment applied to patents with DME or macular edema due to RVO. Additionally, present invention provides methods for the treatments of patients diagnosed with DR or RVO with Anti-VEGF therapies.

Description

Treatment regimens for DR and RVO in dependence of the extent of retinal ischemia

Diabetic retinopathy (DR) is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME) is the most frequent cause of vision impairment and represents a significant public health issue. Diabetes is characterized by increased levels of blood sugar (glucose) which can damage blood vessels. This leads to ischemia and subsequent VEGF release. Consequently, fluid leaks out of the tiny, fragile, and already damaged blood vessels in the back of the eye, and accumulates in the macula and causes swelling of the tissue. This leads to DME and hence blurred vision and reduced visual acuity. However, patients with DR suffer from various degrees of pathological changes of the retina (including ischemia), which may not yet immediately lead to an impaired visual function. Retinal vein occlusion is a blockage of the small veins that carry blood away from the retina. This blockage leads to hemorrhages (bleeding) and leakage of fluid from the blocked blood vessels. There are two types of retinal vein occlusion: Central retinal vein occlusion (CRVO) is the blockage of the main retinal vein. Branch retinal vein occlusion (BRVO) is the blockage of one of the smaller branch veins.

DME and retinal vein occlusions are vascular diseases of the retina resulting in retinal ischemia. Retinal ischemia is a condition with insufficient supply of oxygen to the retina. As a response to retinal ischemia VEGF is released to compensate for the deficient oxygen supply. This causes vascular leakage and angiogenesis. If leakage occurs into the macula, macular edema can develop secondary to the underlying condition and visual acuity may be impaired. Anti-VEGF agents have been shown to reduce macular edema and restore visual acuity partially or completely (JF Korobelnik et al., Intravitreal aflibercept for diabetic macular edema, Ophthalmology. 2014 Nov;121(l l):2247-54; QD Nguyen et al. Ranibizumab for Diabetic Macular Edema Results from 2 Phase III Randomized Trials: RISE and RIDE Ophthalmology 2012;119:789-801; P Mitchell et al, The RESTORE Study

Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema, Ophthalmology 2011;118:615-625; FG Holz 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;97:278-284; D Boyer 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: 1024-1032).

Originally, there was the assumption that anti-VEGF treatment, due to inhibition of angiogenesis and potential vasoconstriction, may enhance ischemia in these patients (Feucht et al., Clinical

Ophthalmology 2013:7 173-178; Goel et al., caser report, Int Ophthalmol (2011) 31:39^12).

However, surprisingly, some recent studies imply that anti-VEGF therapy reduces retinal ischemia. In the GALILEO/COPERNICUS study 11.1% of patients were initially considered as "non-perfused" employing the Central Retinal Vein Occlusion criteria (CVOS criteria; Central Retinal Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol 1997; 115: 486 - 491; The Central Vein Occlusion Study Group A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion: The Central Retinal Vein Occlusion Study Group N Report. Ophthalmology 1995; 102: 1434 - 44.), while after 24 weeks of aflibercept treatment the proportion of "non-perfused" subjects was reduced to 6.9% (Holz FG, 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;97:278-284; Boyen et al., Vascular Endothelial Growth Factor Trap-Eye for Macular Edema Secondary to Central Retinal Vein

Occlusion, 2012 by the American Academy of Ophthalmology). This was not observed in the untreated control arm. However, after crossing over the control arm to active treatment a similar change in the proportion of non-perfused subjects was observed.

So far there is no consensus whether RVO, DR or DME require ongoing anti-VEGF therapy or whether therapy can be ceased at some point in time. Effective treatment requires repeated injections, although recent data suggest that the treatment burden diminishes after 1 year and less frequent injections are required as follow-up of initial improvements (GE Lang et al., Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema: Interim Analysis of the RESTORE Extension Study,. Ophthalmology 2013;120 (10): 2004-2012; The Diabetic Retinopathy Clinical Research Network Elman MJ et al., Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema

Ophthalmology; 117(6): 1064-1077; Heier JS et al., Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study, Ophthalmology. 2014 121(7): 1414-1420; Ogura Y et al., Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study, Am J Ophthalmol. 2014 Nov;158(5): 1032-8; Brown DM et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100- Week Results From the VISTA and VIVID Studies, Ophthalmology. 2015 18 S0161-6420). The GALILEO/COPERNICUS study data on the treatment of macular edema secondary to CRVO imply that a subset of patients is well treated with no or a very limited number of injections, while others require ongoing therapy to maintain the initial vision gains achieved after the start of anti-VEGF therapy. While relevant studies across RVO and DME/DR suggest a reduced treatment need beyond year 1 on average, it appears the treatment need is individually variable.

Summary of invention

The present invention provides methods for optimizing the therapeutic efficacy of an anti-VEGF treatment applied to patents with DME or macular edema due to RVO. Additionally, present invention provides methods for the treatments of patients diagnosed with DR or RVO with Anti-VEGF therapies. According to the invention the individual treatment need correlates with the extent of retinal ischemia. An increase in retinal ischemia indicates an increased treatment need whereas a decrease

in/disappearance of retinal ischemia indicates a reduced treatment need.

One embodiment of the invention is a method of optimizing the therapeutic efficacy of an anti-VEGF treatment of a subject having DME or a macular edema due to RVO wherein the method comprises i.) determining the extent of ischemia in the retina of the subject at two consecutive time points which are at least 4 weeks apart,

ii) identifying the subject as one with decreased, increased, or stable extent of retinal ischemia between the two determinations and

iii) adapting the treatment interval.

A further embodiment of the invention is a method for treating a patient diagnosed with DR or RVO, wherein it is first determined whether a retinal ischemia is present and then in case the retinal ischemia is present the patient is treated with an anti-VEGF treatment.

Detailed description of the invention

Patients

Optimization of the therapeutic efficacy of an anti-VEGF treatment

In one embodiment of the invention the optimization of the therapeutic efficacy of an anti-VEGF treatment is done in patients diagnosed with DME or with a macular edema due to RVO. These patients can be either treatment naive patients or be pre-treated with one or more of the following treatments: a. Intravitreal anti-VEGF monotherapy as used for the treatment of DME or of macular edema due to RVO, whereas anti-VEGF therapy refers to all approved and non-approved treatments aiming to attenuate free VEGF in the eye. This includes particularly aflibercept, ranibizumab, bevacizumab, KH-902, and pegaptanib, or VEGF receptor blockers, but is not limited to these compounds. Anti-VEGF treatment may be applied according to the treatment regimens used for DME patients or patients with macular edema due to RVO. In a preferred embodiment patients are pretreated with five monthly intravitreal injections of aflibercept or five intravitreal injections of aflibercept each 4 weeks apart followed by dosing every other two month or every 8 weeks. In another preferred embodiment the patients diagnosed with RVO are pretreated with monthly intravitreally injection of 0.5 mg ranibizumab (0.05 mL of 10 mg/mL ranibizumab solution) or patients diagnosed with DME are pretreated with monthly intravitreally injection with 0.3 mg ranibizumab (0.05 mL of 6 mg/mL ranibizumab solution). b. repeated applications of photodynamic therapy with Visudyne^® (V^®-PDT) c. Single or repeated applications of steroids (all available local or systemic application routes) including slow-release or depot formulations (e.g. Ozurdex, triamcinolone, dexamethasone, Iluvien, etc.)

d. Radiation therapy

e. Thermal laser therapy or laser photocoagulation including sub-threshold treatments f. Surgical therapy

g. Pharmacological vitreolysis (e.g. with Jetria or other approved or non-approved drugs) h. Systemically or locally applied inhibitors of tyrosine kinases

i. Systemically or locally applied inhibitors of the VEGF receptor

Anti-VEGF treatment of patients diagnosed with DR or RVO

In another embodiment of the invention the patients are diagnosed with DR or RVO but still do not suffer from vision impairment. Usually, they are treatment-naive patients. However, in rare cases the patients are treated with one or more of the above mentioned treatments. According to the invention it is determined whether an ischemia is present in the retina of the patient and in case the retinal ischemia is present the patient is treated with an anti-VEGF treatment.

Determination of retinal ischemia

According to the invention the ischemia is determined in the retina including the central and peripheral part of the retina. The extent of retinal ischemia is determined by a method where one or more images of the retina are obtained. These methods may require application of a dye to visualize perfusion (angiographic methods). Other methods may determine perfusion without a dye, e.g. by detecting the blood flow. Methods which can be used for the determination of retinal ischemia have to be able to make a distinction between sufficiently and insufficiently perfused parts of the retina. This distinction can be achieved by one or combinations of the following methods or further development of these methods but are not limited to these methods:

• Digital color fundus photography with or without specific image processing including ultra- wide-field fundus angiography

• Angiographic techniques using dyes

• Optical coherence tomography (OCT) techniques

• Doppler-OCT techniques

• Technologies, which visualize or otherwise measure the perfusion of the retina.

• Technologies, which visualize or otherwise measure metabolic activity of the retina.

The best characterized technique currently available for the determination of retinal ischemia is fluorescin angiography (FA). FA is a technique for examining the circulation of the retina and choroid. An area of the retina which is non-perfused is considered to be ischemic. FA uses a fluorescent dye and a specialized camera for the visualization of non-perfused areas of the retina. It involves injection of sodium fluorescein into the systemic circulation, and then an angiogram is obtained by photographing the fluorescence emitted after illumination of the retina with blue light at a wavelength of 490 nanometers. Non-perfused areas of the retina appear as hypo-fluorescent areas on the obtained image. For example some studies define the retinal ischemia as angiographically visually significant hypo-fluorescence of an area of at least one disc diameter (representing retinal non-perfusion or capillary dropout) or areas of microvascular pathology (multiple microaneurysms, intra-retinal microvascular anomalies and significant perivascular leakage) with associated capillary pruning of at least one disc diameter (Peripheral retinal ischaemia, as evaluated by ultra- wide-field fluorescein angiography, is associated with diabetic macular oedema., Br J Ophthalmol 2012;96:694e698).

Retinal ischemia may be assessed categorically (absent/present; absent/small/medium/large; etc.) or with a continuous variable like area of retinal ischemia or ischemic index. For example the ischemic index is calculated by the ratio between the ischemic area and the total visible area. The size of total visible area depends on the photography technique which is used for the angiography. Traditionally used retinal photography techniques are able to view approximately 30° of the retina. The Early

Treatment Diabetic Retinopathy Study (ETDRS) developed the 7-standard fields (7SF) protocol in which seven photographed areas of the retina were combined to view nearly 75° of the retina ETDRS Research Group 1991). The most recent technique is ultra- wide field fluorescein angiography which is able to view 200° of the retina in a single photograph (Peripheral retinal ischaemia, as evaluated by ultra- widefield fluorescin angiography, is associated with diabetic macular oedema., Br J Ophthalmol 2012;96:694e698).

According to the invention stable retinal ischemia is defined as a change (increase or decrease) of retinal ischemia that is less than 10% compared to the previous determination which is at least 4 weeks apart. An increase or decrease of retinal ischemia is defined as a change (increase or decrease) of retinal ischemia that is more than or equal tol0% compared to the previous determination which is at least 4 weeks apart.

Treatment regimens

Optimization of the therapeutic efficacy of an anti-VEGF treatment

The treatment of patients diagnosed with DME or macular edema due to RVO in dependence of the extent, increase or reduction of retinal ischemia allows adaptation of spacing between administrations which results in an individualized therapy linked to the disease extend. In addition, better patient compliance is likely achievable with projectable, less frequent intravitreal injections. In some cases, a single anti VEGF treatment may be sufficient to ameliorate the disease or prevent disease progression for many years. In other cases more frequent injections may be required. Anti-VEGF treatment of patients diagnosed with DR or RVO

In the first stage of DR there are no symptoms and the patient has a normal vision. The main reason for rapid vision loss is DME due to the development of an edema in the macular. However, also DME may not have any warning signs for some time and anti-VEGF treatment is only applied after the patient suffers loss of vision. On embodiment of the invention is to treat patients with anti-VEGF treatment when a retinal ischemia is detected in the retina of the patient in order to prevent vision loss.

According to the invention all described treatment regimens can be applied for both: (i) Optimization of the therapeutic efficacy of an anti-VEGF treatment in patients diagnosed with DME or with macular edema due to RVO or (ii) anti-VEGF treatment of patients diagnosed with DR or RVO and additionally diagnosed with a retinal ischemia.

According to the invention the treatment regimen comprises

i.) determining the extent of ischemia in the retina of the subject at two consecutive time points which are at least 4 weeks apart,

iii) adapting the treatment interval.

Furthermore according to the invention the treatment regimen comprises adapting the treatment interval in a patient

- who is diagnosed with DME or macular edema due to RVO

- in whom the extent of retinal ischemia has been determined at two consecutive time points which are at least 4 weeks apart and

- who has decreased, increased, or stable extent of retinal ischemia between the two determinations.

Anti-VEGF treatment is applied when ischemia has been determined in the retina. Once a stable retinal ischemia is achieved the treatment intervals can be extended stepwise until increase of retinal ischemia reoccurs. The treatment interval is extended by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In a preferred embodiment the treatment interval is extended by 1, 2, 4, 8, or 16 weeks. Treatment intervals can also be gradually extended. In case an increase of retinal ischemia reoccurs, the treatment interval will be shortened by 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In a preferred embodiment the treatment interval is set back to the previous treatment interval.

Possible treatment regimen 1

In one embodiment of the invention the adaptation of the time interval between administrations of anti-VEGF treatment is driven by the ischemic index (ratio between ischemic area to total visible retinal area as determined for example by ultra- wide-field angiography). In case the ischemic index is between 0.1 - 1.0 (e.g. 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0) anti-VEGF treatment is applied every four weeks or every month. Once the area of retinal ischemia has stabilized, meaning the change (increase or decrease) of the ischemic index is less than 0,1 or less than 10% between two anti-VEGF treatments the time interval for the next administration is gradually extended by increments of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20weeks until the ischemic index increases again by more than 0,1 or by more than 10% between two anti-VEGF- treatments. The treatment interval is then set back to the last interval length, with which stable extent of retinal ischemia was observed.

Possible treatment regimen 2

In another embodiment of the invention the adaptation of the time interval between administrations of anti-VEGF treatment is driven by the ischemic index (ratio between ischemic area to total visible retinal area as determined for example by ultra- wide-field angiography). In case the ischemic index is between 0.1 - 1.0(e.g. 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0) anti-VEGF treatment is applied every four weeks or every month. Once the area of retinal ischemia is stabilized, meaning the change (increase or decrease) of the ischemic index is less than 0,1 or less than 10% between two anti-VEGF treatments the next anti-VEGF treatment is deferred by 4 weeks until the ischemic index increases by at least 0.1 or at least 10% compared to the previous determination. When the ischemic index increased by at least 0.1 or at least 10% compared to the previous determination, anti-VEGF-treatment is applied. In other words the ischemic index is determined every 4 weeks and treatment is deferred by 4 weeks when the retinal ischemia is stabilized compared to the previous determination (change of ischemic index of less than 0.1 or less than 10%). When the ischemic index increased by at least 0.1 or by at least 10% compared to the previous determination then the anti-VEGF treatment is administered.

Possible treatment regimen 3

In a further embodiment of the invention the adaptation of the time interval between administrations of anti-VEGF treatment is driven by the absolute area of ischemic retina. The ischemic area may, for example, be determined by ultra-wide-field angiography. The ischemic area of the retina can be quantified in number of disk areas (DA). In case the ischemic area is at least of an size of 1 DA anti- VEGF treatment is applied every four weeks or every month. Once the area of ischemic retina has stabilized, meaning the change (increase or decrease) of the area of ischemic retina is less than 1 DA or less than 10% between two anti-VEGF treatments, the time interval for the next administration is extend by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20weeks until the area of ischemic retina increases again by more than 1 DA or more than 10% between two anti-VEGF- treatments. The treatment interval is then set back to the last interval length, with which stable extent of retinal ischemia was observed.

Possible treatment regimen 4 In a further embodiment of the invention the adaptation of the time interval between administrations of anti-VEGF treatment is driven by the absolute area of ischemic retina. The ischemic area may, for example, be determined by ultra-wide-field angiography. The ischemic area of the retina can be quantified in number of disk areas (DA). In case the ischemic area is at least of an size of 1 DA anti- VEGF treatment is applied every four weeks or every month. Once the area of retinal ischemia is stabilized, meaning the change (increase or decrease) of the area of ischemic retina is less than 1 DA or less than 10% between two anti-VEGF treatments the next anti-VEGF treatment is deferred by 4 weeks. In case the area of ischemic retina increases by at least 1 DA or by at least 10% compared to the previous determination, anti-VEGF-treatment is applied. In other words the area of ischemic retina is determined every 4 weeks and anti-VEGF treatment is deferred by 4 weeks in case the retinal ischemia is stabilized (change of area of ischemic retina of less than 1 DA or less than 10%) compared to the previous determination. In case the area of ischemic retina increased by at least 1 DA or at least 10% compared to the previous determination, anti-VEGF treatment is applied.

In any of the described treatment regimens the anti-VEGF treatment can be combined with treatment of the retinal ischemic area by the use of laser photocoagulation including Modified Grid Laser photocoagulation and Panretinal photocoagulation. In case of Modified Grid Laser photocoagulation a 'C shaped area around the macula is treated with low intensity small burns. This helps in clearing the macular edema. The goal of panretinal photocoagulation or PRP (also called scatter laser treatment) is to create 1,600 - 2,000 burns in the retina to reduce the retina's oxygen demand, and hence the possibility of retinal ischemia. It is done in multiple sessions.

Anti-VEGF treatment

Anti-VEGF treatment include but are not limited to anti-VEGF antibodies or antibody fragments such as Bevacizumab (Avastin ®; WO 9845331), Ranibizumab (Lucentis^® W09845331), non-antibody VEGF antagonists such as Aflibercept (Eylea^®; WO2000/75319; also known as VEGF-Trap), Pegaptanib (Macugen^®; W09818480), KH-902 (WO2007112675), and Tyrosine kinase inhibitors.

Anti-VEGF therapies of the invention will generally be administered to the patient via intravitreal injection, though other routes of administration may be used, such as a slow-release depot or eye drops. For example, aflibercept is generally administered via intravitreal injection at a dose of 2 mg (suspended in 0.05 mL buffer comprising 40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2). As another example ranibizumab is generally administered via intravitreal injection at a dose of 0.5 mg ranibizumab (0.05 mL of 10 mg/mL ranibizumab solution) or in case of the treatment of DME with a dose of 0.3 mg ranibizumab (0.05 mL of 6 mg/mL ranibizumab solution). However, the normal dose may be reduced for the treatment of patients with a small area of peripheral retinal ischemia. Anti-VEGF treatment can be combined with one of the following therapies: a. Single or repeated applications of photodynamic therapy with Visudyne^® (V^®-PDT) b. Single or repeated applications of steroids (all available local or systemic application routes) including slow-release or depot formulations (e.g. Ozurdex, triamcinolone, dexamethasone, Iluvien, etc.)

c. Radiation therapy

d. Thermal laser therapy or laser photocoagulation including sub-threshold treatments e. Thermal laser therapy or laser photocoagulation of the ischemic area of the retina f. Surgical therapy

i. Systemically or locally applied inhibitors of the VEGF receptor

j. Systemically or locally applied inhibitors of the PDGF-beta receptor or ligands k. Systemically or locally applied inhibitors of the Angiopoetin-2 receptor or ligands

Example 1:

Study design: a randomized, controlled, two-arm clinical study in patients with DME involving the center of the macula (defined as the area of the center subfield of OCT) plus retinal non-perfusion (i.e. retinal ischemia) at one month after a first aflibercept intravitreal treatment. The perfusion status will be determined by ultra wide-field fluorescence angiography (UWFA) or 7 standard fields FA. The key inclusion criteria are as follows:

• Adult subjects with DME secondary to diabetes mellitus Type 1 or 2 involving the center of the macula (defined as the area of the center subfield of OCT) in the study eye

• Decrease in vision determined to be primarily the result of DME in the study eye

• Central retinal thickness (CRT) as assessed by OCT of >300 μιη in the study eye

• BCVA ETDRS letter score of 73 to 24 (20/40 to 20/320) in the study eye

• Retinal Non-perfusion on UWFA or 7SF FA 1 month following a single IVT Eylea

The key exclusion data are as follows:

• Any history of laser photocoagulation (panretinal or macular) in the study eye

• Active proliferative diabetic retinopathy (PDR) in the study eye

• Any surgery in the study eye in the prior 6 months

• Pre-retinal fibrosis or any structural damage or disease of the center of the macula (other than DME) in the study eye which is likely to limit/reduce vision

The study objective is to compare the number of injections applied in flexible treatment regimens (Treat-and-extend regimen) of 2 mg aflibercept with or without additional laser photocoagulation. The flexible dosing regimen will take into account the perfusion status of the individual patient for the treatment decision.

Treatment arms to be studied:

• Fixed dosing regimen: Five consecutive monthly intravitreal injections of 2mg aflibercept followed by dosing of aflibercept 2mg every other month (reference arm)

• Flexible dosing regimen: Treat- and-Extent (T&E) from baseline without extension limit intravitreal injections of 2mg aflibercept.

The primary endpoint, ie number of injections will be determined after 2 years.

Additionally the following secondary endpoints will assessed at year 2:

• mean change in BCVA (best corrected visual acuity) from baseline according to the standard protocol of the ETDRS (Early Treatment Diabetic Retinopathy Study)

• mean change central retinal thickness (CRT) from baseline

• proportion of subjects gaining 3 lines of vision as determined by BCVA according to the ETDRS standard protocol

• proportion of subjects with proliferative diabetic retinopathy (PDR)

The study may continue beyond the primary endpoint.

Determination of perfusion status using UWFA

Perfusion/ retinal ischemia is determined by the use of ultra- wide-field FA according to Wessel et al (Peripheral retinal ischaemia, as evaluated by ultra-widefield angiography, is associated with diabetic macular oedema., Br J Ophthalmol 2012;96:694e698). Retinal ischemia is defined as angiographically visually hypofluorescence of an area of at least one disc diameter (representing retinal non-perfusion or capillary dropout) or areas of microvascular pathology (multiple microaneurysms, intraretinal microvascular anomalies and significant perivascular leakage) with associated capillary pruning of at least one disc diameter. The total retinal surface area, as well as the area of retinal ischaemia is measured in pixels.

Determination of perfusion status using 7SF FA:

Fluorescein angiography is done. Images are taken according to the ETDRS 7-field protocol. Ischemic areas are hypo-fluorescent areas with no or reduced staining of retinal vessels and capillaries. The area of retinal ischemia can be determined in Disk Areas or converted into mm².

Determination of central retinal thickness (CRT)

An OCT scan of the macula is obtained and thickness in the center point or central ETDRS subfield is determined. Determination of proliferative diabetic retinopathy PDR:

PDR is diagnosed according to ETDRS criteria or classifications derived from that. PDR is defined as 61on the ETDRS DRSS (ETDRS Research Group 1991).

Claims

A method of optimizing the therapeutic efficacy of an anti-VEGF treatment of a subject having DME or macular edema due to RVO wherein the method comprises

i.) determining the extent of ischemia in the retina of the subject at two consecutive time points, which are at least 4 weeks apart

iii) adapting the treatment interval.

A method of optimizing the therapeutic efficacy of an anti-VEGF treatment comprising adapting the treatment interval in a subject

- who is diagnosed with DME or macular edema due to RVO

A method according to claim 1 or 2, wherein the determination of the extent of retinal ischemia in the retina is performed at two treatments, which are 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23 or 24 weeks apart.

A method according to claim 1 or 2, wherein the determination of the extent of retinal ischemia in the retina is performed by the use of ultra-wide-field fluorescence angiography or 7SF fluorescence angiography.

A method according to claim 1 or 2, wherein in case the extent of retinal ischemia is stable between the two determinations the time interval between two treatments is gradually extended by increments of 1,

2,

3,

4,

5,

6,

7,

8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.

A method according to claim 1 or 2, wherein in case the extent of retinal ischemia is increased between the two determinations by at least 10% the treatment interval is set back to the pervious treatment interval.

A method according to claim 1 or 2, wherein in case the extent of retinal ischemia is stable between the two determinations the next anti-VEGF treatment is deferred by 4 weeks until the ischemia increases by at least 10% compared to the previous determination.

A method according to claim 1 or 2, wherein an VEGF-antagonist selected from an anti- VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment. A method according to claim 8, wherein the VEGF-antagonist is selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

10. A method according to claim 1 or 2, wherein the anti-VEGF treatment is combined with laser photocoagulation treatment of the retinal ischemic area.

11. A method according to claim 1 or 2, wherein the subject has been pretreated with an anti- VEGF treatment.

12. Use of a VEGF- antagonist for the preparation of a composition for optimizing the therapeutic efficacy of an anti-VEGF treatment of a subject having DME or macular edema due to RVO wherein the method comprises

iii) adapting the treatment interval.

13. Use of a VEGF- antagonist for the preparation of a composition for optimizing the therapeutic efficacy of an anti-VEGF treatment comprising adapting the treatment interval in a subject - who is diagnosed with DME or macular edema due to RVO

14. Use according to claim 12 or 13, wherein the determination of the extent of retinal ischemia in the retina is performed at two treatments, which are 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23 or 24 weeks apart.

15. Use according to claim 12 or 13, wherein the determination of the extent of retinal ischemia in the retina is performed by the use of ultra-wide-field fluorescence angiography or 7SF fluorescence angiography.

16. Use according to claim 12 or 13, wherein in case the extent of retinal ischemia is stable

between the two determinations the time interval between two treatments is gradually extended by increments of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.

17. Use according to claim 12 or 13, wherein in case the extent of retinal ischemia is increased between the two determinations by at least 10% the treatment interval is set back to the pervious treatment interval.

18. Use according to claim 12 or 13, wherein in case the extent of retinal ischemia is stable

between the two determinations the next anti-VEGF treatment is deferred by 4 weeks until the ischemia increases by at least 10% compared to the previous determination.

19. Use according to claim 12 or 13, wherein an VEGF-antagonist selected from an anti-VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment.

20. Use according to claim 19, wherein the VEGF-antagonist is selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

21. Use according to claim 12 or 13, wherein the anti-VEGF treatment is combined with laser photocoagulation treatment of the retinal ischemic area.

22. Use according to claim 12 or 13, wherein the subject has been pretreated with an anti-VEGF treatment.

23. Anti-VEGF-antagonist for the use in a method of optimizing the therapeutic efficacy of an anti-VEGF treatment of a subject having DME or macular edema due to RVO wherein the method comprises

iii) adapting the treatment interval.

24. Anti-VEGF-antagonist for the use in a method of optimizing t he therapeutic efficacy of an anti-VEGF treatment comprising adapting the treatment interval in a subject

- who is diagnosed with DME or macular edema due to RVO

25. Anti-VEGF-antagonist according to claim 23 or 24, wherein the determination of the extent of retinal ischemia in the retina is performed at two treatments, which are 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23 or 24 weeks apart.

26. Anti-VEGF-antagonist according to claim 23 or 24, wherein the determination of the extent of retinal ischemia in the retina is performed by the use of ultra-wide-field fluorescence angiography or 7SF fluorescence angiography.

27. Anti-VEGF-antagonist according to claim 23 or 24, wherein in case the extent of retinal ischemia is stable between the two determinations the time interval between two treatments is gradually extended by increments of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20weeks.

28. Anti-VEGF-antagonist according to claim 23 or 24, wherein in case the extent of retinal ischemia is increased between the two determinations by at least 10% the treatment interval is set back to the pervious treatment interval.

29. Anti-VEGF-antagonist according to claim 23 or 24, wherein in case the extent of retinal ischemia is stable between the two determinations the next anti-VEGF treatment is deferred by 4 weeks until the ischemia increases by at least 10% compared to the previous determination.

30. Anti-VEGF-antagonist according to claim 23 or 24, wherein a VEGF-antagonist selected from an anti-VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment.

31. Anti-VEGF-antagonist according to claim 30, wherein the VEGF-antagonist is selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

32. Anti-VEGF-antagonist according to claim 23 or 24, wherein the anti-VEGF treatment is combined with laser photocoagulation treatment of the retinal ischemic area.

33. Anti-VEGF-antagonist according to claim 23 or 24, wherein the subject has been pretreated with an anti-VEGF treatment.

34. A method for treating DR or RVO in a patient, in whom retinal ischemia has been determined and wherein in case the ischemia is present the patient is treated according to claim 1 or 2.

35. A method according to claim 34, wherein a VEGF-antagonist selected from an anti-VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment.

36. A method according to claim 35, wherein the VEGF-antagonist is selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

37. A method according to claim 34, wherein the anti-VEGF treatment is combined with laser photocoagulation treatment of the retinal ischemic area.

38. Use of a VEGF-antagonist for the preparation of a composition for treating DR or RVO in a patient, in whom retinal ischemia has been determined and wherein in case the ischemia is present the patient is treated according to claim 1 or 2.

39. Use according to claim 38, wherein a VEGF-antagonist selected from an anti-VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment.

40. Use according to claim 39, wherein the VEGF-antagonist is selected from aflibercept,

ranibizumab, bevacizumab, KH-902, or pegaptanip.

41. Use according to claim 38, wherein the anti-VEGF treatment is combined with laser

photocoagulation treatment of the retinal ischemic area.

42. Anti-VEGF-antagonist for the use in a method for treating DR or RVO in a patient, in whom retinal ischemia has been determined and wherein in case the ischemia is present the patient is treated according to claim 1 or 2.

43. Anti-VEGF-antagonist according to claim 42, wherein a VEGF-antagonist selected from an anti-VEGF antibody or a non-antibody anti-VEGF antagonist is used for the anti-VEGF treatment.

44. Anti-VEGF-antagonist according to claim 43, wherein the VEGF-antagonist is selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

45. Anti-VEGF-antagonist according to claim 42, wherein the anti-VEGF treatment is combined with laser photocoagulation treatment of the retinal ischemic area.