OPHTHALMIC NUTRACEUTIC COMPOSITION FOR THE TREATMENT OF RETINAL PATHOLOGIES WITH A NEOVASCULAR COMPONENT

Description

FIELD OF INVENTION

[0001] The present invention relates to a nutraceutical ophthalmic composition comprising in particular resveratrol intended to be administered to a subject receiving anti-VEGF treatment, in particular in the context of the management of a retinal pathology with a neovascular component.

[0002] Surprisingly, the present application demonstrates that joint administration of such a composition and an anti-VEGF agent produces a beneficial effect on the level of VEGF produced and offers promising prospects for the treatment of these ocular pathologies. STATE OF THE ART

[0003] In Europe, the majority of cases of blindness and severe vision loss are due to age-related retinal diseases. Given current demographic trends, an increase in the prevalence and incidence of these diseases is expected. One of the direct economic consequences will be significant pressure on European healthcare systems.

[0004] To date, Age-Related Macular Degeneration (AMD) affects approximately 34 million people in Europe. The number of AMD patients is expected to increase by nearly 25% by 2050 due to population growth and aging. Furthermore, regarding diabetic eye diseases, including Diabetic Macular Edema (DME), the current and future situation is similar. More than 25% of diabetic patients are affected by diabetic eye disease (DED), representing nearly 4 million individuals in Europe. As the prevalence of diabetes increases significantly due to demographic trends and lifestyle changes, this type of condition will also increase.

[0005] More specifically, age-related macular degeneration (AMD) is the leading cause of visual impairment in people over 50. In all its forms, this disease affects approximately 8% of the French population, but its prevalence increases significantly with age: it affects 1% of people aged 50 to 55, about 10% of those aged 65 to 75, and 25 to 30% of those over 75. If we consider only late-onset forms of the disease, associated with a loss of central vision, these figures are roughly halved.

[0006] This condition selectively affects the macular region, that is, the central area of ​​the retina, leading to a progressive loss of central vision—the field of vision used for reading, recognizing faces, or driving. It is the leading cause of vision loss in older adults.

[0007] The disease begins with an early, non-degenerative phase called age-related maculopathy (AMM or "early dry"). This phase is characterized by the accumulation of small, whitish deposits (or "soft drusen") in and around the macula. These deposits are visible during a simple fundus examination. This phase is most often asymptomatic, but the patient may eventually perceive distortions of straight lines ("metamorphopsia") and blurred spots.

[0008] In more advanced stages, symptoms appear, varying according to the severity of the disease: Decreased visual acuity, requiring better lighting for reading or any precision work; Increasingly blurred central vision, altered color perception, distortion of straight lines, which appear deformed and wavy; Appearance of a dark spot in the center of the visual field called a scotoma, difficulty recognizing faces, visual hallucinations or sudden drop in visual acuity; Severe involvement of the second eye varies greatly from one subject to another: it can occur rapidly, in one year, in 10 years, or never.

[0009] AMD can remain stable throughout life. However, in about half of cases, and under the influence of several factors, AMD progresses to late-onset degenerative forms: The atrophic form is a dry form in which the macula atrophies with age and is gradually replaced by scar tissue; the wet form is an exudative form in which small, blood-filled vessels develop under the macula. These new vessels bleed easily and are responsible for exudates and hemorrhages in the fundus. If exudative AMD is present in one eye, there is a risk of developing it in the other.

[0010] These two late-onset forms have roughly equivalent incidence. They lead to irreversible macular degeneration and loss of central vision affecting one or both eyes. Mixed forms may also be observed.

[0011] From a mechanistic standpoint, the wet form of age-related macular degeneration (AMD), also known as neovascular or exudative AMD, like diabetic retinopathy, macular edema, retinal vein occlusion (RVO), or high myopia, results in the proliferation of new, abnormal blood vessels under the retina. These fragile vessels leak serum, causing retinal detachment, and / or blood, leading to retinal hemorrhages. This form progresses rapidly if left untreated, with vision loss occurring within weeks or even days. This process can be slowed by taking anti-VEGF medications.

[0012] VEGF (Vascular Endothelial Growth Factor) is a vascular endothelial growth factor that plays a role in angiogenesis, the budding of pre-existing vessels, and vasculogenesis, the formation of new vessels from endothelial progenitors. VEGF, and more specifically the VEGF-A isoform, binds to the surface of tyrosine kinase receptors, notably VEGF-R1 and VEGF-R2, which play a crucial role in angiogenesis.

[0013] Thus, starting in 2006, certain ocular pathologies such as the wet form of AMD (or "AMD wet") were treated using VEGF inhibitors. Progressively, other neovascular pathologies such as diabetic macular edema (DME), retinal vein occlusion (RVO), or myopic choroidal neovascularization (CNV) (or PM) were also treated with these agents.

[0014] Among the anti-VEGF agents are antibodies or antibody fragments directed against VEGF, as well as recombinant proteins capable of binding to VEGF receptors. Examples include ranibizumab (e.g., the product LUCENTIS® marketed by NOVARTIS PHARMA SAS or its biosimilars in development by SAMSUNG, INTAS, or FORMYCON), bevacizumab (e.g., the product AVASTIN® marketed by ROCHE), aflibercept (e.g., the product EYLEA® marketed by BAYER SANTE), abicipar pegol (in development by ALLERGAN), conbercept (e.g., the product in development by CHENGDU KANGHON BIOTECH INC), faricimab (e.g., the product RG7716 in development by ROCHE), and brolucizumab (NOVARTIS).

[0015] These anti-VEGF agents are usually administered by intravitreal injection, namely an injection through the conjunctiva and sclera, directly into the ocular cavity located behind the lens, i.e. the vitreous cavity containing the vitreous humor.

[0016] This involves injecting medication directly into the eye. Compared to other methods of administration, particularly topical application, this treatment offers several advantages: a reduction in the amount of active ingredient; a more effective action; effective targeting of the area to be treated; a reduction in side effects or a reduction in systemic absorption.

[0017] However, intravitreal injection remains a technical procedure, performed by specialized practitioners and requiring strict adherence to aseptic and antiseptic conditions. Furthermore, this injection can cause a number of rather problematic side effects: endophthalmitis, retinal detachment, ocular hypertension / glaucoma, cataracts, inflammation, subconjunctival hemorrhage, systemic toxicity, and the appearance of floaters. In addition, it is generally not recommended to inject both eyes on the same day to avoid total vision loss in case of problems or side effects following the injection. Indeed, these injections are usually followed by a very painful period for patients, which may require them to spend several hours in complete darkness.

[0018] The dosage, in particular the dose and frequency of administration, may depend on the active ingredient but also on the pathology to be treated, with an average of seven injections per year.

[0019] For example, treatment of age-related macular degeneration (AMD) with ranibizumab or bevacizumab begins with an induction phase of one injection per month for three consecutive months, followed by a maintenance phase during which the patient's visual acuity is checked monthly. If the patient experiences a loss of visual acuity of more than five letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale or the equivalent of one line on the Snellen scale, the drug must be administered again. The interval between doses should not be less than one month.

[0020] For DME, monthly injections of ranibizumab or bevacizumab are recommended until visual acuity stabilizes during three consecutive monthly assessments under treatment.

[0021] For VOR, monthly injections of ranibizumab or bevacizumab are recommended until visual acuity stabilizes. Failure to improve visual acuity after three consecutive monthly injections warrants discontinuation of treatment. In the presence of aflibercept, the protocol is slightly different:

[0022] For age-related macular degeneration (AMD), at the start of treatment, as with other anti-VEGF agents, aflibercept is injected once a month for three consecutive months, then once every two months, without a follow-up visit between injections. After the first 12 months of treatment, the interval between two injections may be extended depending on visual and anatomical results. In this case, the follow-up schedule should be determined by the physician administering the treatment, and follow-up visits may be more frequent than the scheduled injections.

[0023] For retinal vein occlusion (RVO), the recommended dose is 2 mg of aflibercept, corresponding to 50 µL. After the first injection, treatment is administered monthly. The interval between two injections should not be less than one month. If no improvement in visual and anatomical parameters is observed after the first three injections, continued treatment is not recommended. Monthly treatment is continued until stable visual and anatomical results are achieved during three monthly assessments. The need for continued treatment can then be reassessed. If necessary, treatment can be continued with a gradual increase in the interval between two injections to maintain the visual and anatomical response.

[0024] Alongside these treatments using anti-VEGF agents administered by intravitreal injection, other techniques are used to destroy new blood vessels, including photocoagulation (thermal destruction of abnormal vessels) and photodynamic therapy. The latter technique involves intravenously injecting a photosensitive product (for example, verteporfin) that becomes toxic under the effect of red light applied locally with a laser.

[0025] Prior to these heavy treatments, implemented at advanced stages of the pathology, studies have been carried out to try to find earlier and "lighter" treatments, with the aim of preventing the onset and delaying the progression of the disease.

[0026] Thus, studies called AREDS 1 (Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8 and 9. Arch Ophthalmol. 2001) and AREDS 2 (Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013 May 15;309(19):2005-15. doi: 10.1001 / jama.2013.4997) were conducted with the aim of demonstrating the beneficial effect of dietary supplements on eye diseases.

[0027] These studies have revealed that antioxidant-based dietary supplements are potentially beneficial in relation to eye diseases, including age-related diseases, particularly AMD.

[0028] In practice, the AREDS 1 study recommends the daily intake of antioxidants such as trace elements and vitamins, as follows: Zinc 80 mg Vitamin C 500 mg Vitamin E 267 mg Copper 2 mg Beta-carotene (= Vitamin A) 15 mg

[0029] These supplements could decrease the risk of vision loss among patients with advanced AMD.

[0030] The AREDS 2 study was conducted to highlight the effects of lutein, zeaxanthin (as a replacement for beta-carotene), and omega-3 fatty acid supplementation. This study recommended the elimination of vitamin A and reported the benefit of additional daily intake of the following: Lutein 10 mg Zeaxanthin 2 mg docosahexaenoic acid (DHA) 350 mg eicosapentaenoic acid (EPA) 650 mg

[0031] Based on the results of the AREDS studies, daily intake of such dietary supplements was recommended for individuals at high risk of developing age-related macular degeneration (AMD), particularly those with AMD affecting one or both eyes, as well as patients with advanced AMD still affecting only one eye. However, these studies did not demonstrate a positive effect of these formulas on disease progression in patients with advanced AMD, nor on vision loss.

[0032] The NAT 2 study (Merle et al., Invest Ophthalmol Vis Sci. 2014 Mar 28;55(3):2010-9. doi: 10.1167 / iovs.14-13916), which included 300 patients over three years, demonstrated a 68% reduction in the risk of developing neovascular AMD after a significant increase in DHA in cells. Thus, this study is the first to explore the potential of long-term oral DHA supplementation to prevent the development of AMD.

[0033] Finally, document WO 2016 / 151269 describes a food supplement combining vitamins, trace elements, carotenoids, omega-3 fatty acids, and resveratrol, and its use for the treatment and / or prevention of eye diseases. In particular, this document reports that the combination of the various listed compounds has a differential and beneficial effect on the expression and activity of VEGF or its receptors (VEGF-R).

[0034] However, there is a clear need to develop new solutions to improve the management of eye diseases, particularly retinal diseases with a neovascular component, specifically addressing the following expectations: spacing out intravitreal anti-VEGF injections, reducing the side effects associated with them, reducing public health costs and improving the quality of life of patients. DESCRIPTION OF THE INVENTION

[0035] Surprisingly, the Applicant highlighted that the administration of a dietary supplement would increase, prolong or even improve the effects of current anti-VEGF treatments, including intravitreal injection treatments, in patients receiving such treatments.

[0036] According to a first aspect, the invention relates to a nutraceutical ophthalmic composition comprising resveratrol and the administration of such a composition to a subject receiving anti-VEGF treatment, in particular undergoing treatment with an anti-VEGF agent.

[0037] In the context of this invention, a "nutraceutical composition" is defined as a composition intended to supplement the normal diet and constituting a concentrated source of nutrients or other substances having a nutritional or physiological effect, alone or in combination. It is advantageously a dietary supplement.

[0038] In the context of this invention, an "ophthalmic composition" is defined as a composition possessing properties beneficial to eye health. However, this does not preclude the possibility that such a composition may have a beneficial effect on other organs of humans or animals.

[0039] Resveratrol is a polyphenolic compound, derived from stilbene, of which there are two isomers, but the form trans is predominantly active. In the rest of the description, the term "resveratrol" can therefore be used instead of trans-resveratrol.

[0040] Resveratrol is a polyphenol found in abundant quantities in certain fruits, particularly grapes and oilseeds, and in wine. Several commercial sources of resveratrol are currently available that can be used to prepare a composition implemented within the scope of the invention: Vitis vinifera: ∘ Grape skin ∘ Grape seed Polygonum Cuspidatum Produced by fermentation

[0041] Key sources include: Resveratrol source Vitis vinifera, Grape skin: for example a concentrated natural extract at 5%; Synthetic Resveratrol 99% (CAS Number: 501-36-0).

[0042] Resveratrol is advantageously present in an amount (daily dose) greater than or equal to 1 mg, or even 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, or even 100 mg or 200 mg. According to a particular embodiment, its daily amount is greater than or equal to 20 mg, or even greater than 20 mg, greater than or equal to 30 mg, or even greater than or equal to 50 mg, or even greater than or equal to 60 mg, or even greater than or equal to 100 mg. Advantageously, it is less than or equal to 1 g, preferably less than or equal to 500 mg, and particularly preferably less than or equal to 200 mg. According to a particular embodiment, a composition implemented within the framework of the invention comprises a daily dose of resveratrol equal to 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg or 200 mg.

[0043] According to an advantageous embodiment, the composition further includes vitamins, trace elements, carotenoids, and omega-3 fatty acids. Even more advantageously, the ingredients vitamins, trace elements, omega-3 fatty acids, and carotenoids, known for their antioxidant properties, are chosen as recommended by the AREDS studies.

[0044] According to a particular embodiment, the composition comprises at least one vitamin, advantageously a combination of vitamins. This is advantageously vitamin C and / or vitamin E.

[0045] It could also include the following vitamins: nicotinamide or niacinamide or vitamin B3 or PP; pyridoxine, for example in the form of pyridoxine HCl, or vitamin B6; riboflavin or vitamin B2; thiamine, for example in the form of thiamine nitrate, or vitamin B1; cyanocobalamin or vitamin B12; folic acid or vitamin B9; Vitamin B5; Vitamin B8; Vitamin D.

[0046] Vitamin C, available as ascorbic acid or calcium ascorbate, is advantageously present in an amount (daily dose) between 50 and 500 mg, for example equal to 240 mg or 120 mg.

[0047] Vitamin E or alpha-tocopherol, for example available as 67% oil, is advantageously present in a quantity (daily dose) between 10 and 500 mg, for example equal to 30 mg.

[0048] According to another embodiment, the following daily amounts, expressed in mg, may be considered for the following vitamins: Vitamin B3 or PP: 1 to 100, for example 18; Vitamin B6: 1 to 10, for example 2; Vitamin B2: 1 to 10, for example 1.6; Vitamin B1: 1 to 10, for example 1.4; Vitamin B12: 0.0005 to 0.01, for example 0.001; Vitamin B9: 0.1 to 1, for example 0.2.

[0049] According to a particular embodiment, the composition does not include vitamin A or beta-carotene.

[0050] According to a particular embodiment, the composition comprises at least one trace element, advantageously a combination of trace elements. This is advantageously zinc (Zn) and / or copper (Cu). It may also include the following trace elements: manganese, for example anhydrous manganese sulfate; selenium, for example sodium selenite; magnesium, for example magnesium oxide.

[0051] Zinc (Zn), available as zinc oxide or zinc sulfate (monohydrate), is advantageously present in quantities (daily dose) between 5 and 100 mg, for example equal to 12.5 mg.

[0052] Copper (Cu), available in the form of copper sulfate, monohydrate or anhydrous, is advantageously present in quantities (daily dose) between 0.2 and 10 mg, for example equal to 1 mg.

[0053] According to another embodiment, the following daily quantities, expressed in mg, may be considered for the following trace elements: manganese: between 1 and 10 mg, for example 1 mg; selenium: between 0.01 and 0.1 mg, for example 0.025 mg; magnesium: between 1 and 50 mg, for example 10 mg.

[0054] According to a particular embodiment, the composition comprises at least one carotenoid, advantageously a combination of carotenoids. This is advantageously lutein and / or zeaxanthin. It may also comprise the following carotenoids: meso-zeaxanthin; lycopene; astaxanthin.

[0055] Lutein, available in the form of 20% lutein by weight, is advantageously present in a quantity (daily dose) between 2 and 50 mg, for example equal to 10 mg or 20 mg.

[0056] Zeaxanthin, available as zeaxanthin at 5 or 14% by weight, is advantageously present in an amount (daily dose) between 0.5 and 10 mg, for example equal to 2 mg or 4 mg.

[0057] In a particular embodiment, the composition comprises at least one omega-3 polyunsaturated fatty acid, advantageously a combination of omega-3 fatty acids. This is advantageously eicosapentaenoic acid (EPA) and / or docosahexaenoic acid (DHA). It may also include the following omega-3 fatty acids: of alpha-linolenic acid (ALA); of docosapentaenoic acid (DPA).

[0058] The omega-3 fatty acids used in such a formula can be derived from fish oil rich in omega-3 fatty acids, or from vegetable oil, such as flaxseed oil. These fatty acids are advantageously present in quantities (daily intake) between 100 and 1000 mg. More generally, fish oil can be present in daily quantities between 400 and 1000 mg, or even between 800 and 1000 mg.

[0059] In this context, EPA is advantageously present in a quantity (daily dose) between 100 and 1000 mg, for example equal to 172 mg.

[0060] In this context, DHA is advantageously present in a quantity (daily dose) between 100 and 1000 mg, for example equal to 366 mg.

[0061] According to specific embodiments, the composition implemented within the framework of the invention may contain other active ingredients such as: one or more polyphenols, such as epigallocatechin-3-gallate (EGCG); glutathione, for example at a dose of 1 to 10 mg per day, or even 2 mg per day; one or more anthocyanosides; hydroxythyrosol.

[0062] The content of each of these ingredients is easily determined and adjusted by a person skilled in the art.

[0063] Thus, and according to one variant, the composition includes or is made up of the following ingredients: vitamin C; vitamin E; possibly vitamin D; zinc; copper; lutein; zeaxanthin; omega 3 fatty acids from fish oil, including EPA and DHA; resveratrol.

[0064] According to another variant, the composition includes or consists of the following ingredients, based on a daily dose: 50 mg to 500 mg of vitamin C, advantageously 240 mg, particularly advantageously 120 mg; 10 mg to 500 mg of vitamin E, advantageously 30 mg; 5 mg to 100 mg of zinc, advantageously 12.5 mg; 0.2 mg to 10 mg of copper, advantageously 1 mg; 2 mg to 50 mg of lutein, advantageously 20 mg; 0.5 mg to 10 mg of zeaxanthin, advantageously 4 mg; 400 mg to 1000 mg of fish oil, particularly advantageously 800 to 1000 mg; resveratrol, advantageously in an amount greater than or equal to 20 mg, preferably greater than 30 mg, particularly preferably greater than 50 mg, most advantageously in an amount greater than or equal to 60 mg; possibly vitamin D, advantageously 5 µg.

[0065] According to a preferred embodiment, the composition comprises or is made up of the following ingredients, on a daily dose basis: 120 mg of vitamin C; 30 mg of vitamin E; 12.5 mg of zinc; 1 mg of copper; 20 mg of lutein; 4 mg of zeaxanthin; 950 mg of fish oil advantageously containing 366 mg of DHA and 172 mg of EPA; resveratrol, advantageously in an amount greater than or equal to 50 mg, very advantageously in an amount greater than or equal to 60 mg.

[0066] Alternatively, the composition includes or consists of: 240 mg of vitamin C; 30 mg of vitamin E; 12.5 mg of zinc; 1 mg of copper; 10 mg of lutein; 2 mg of zeaxanthin; 950 mg of fish oil; resveratrol, advantageously in an amount greater than or equal to 20 mg, very advantageously in an amount greater than or equal to 30 mg.

[0067] According to a particular embodiment, such a composition is devoid of at least one of the ingredients in the following list: saffron; a metal-chelating agent, such as EDTA or phytic acid; a nucleotide; pycnogenol; an extract of ginkgo biloba.

[0068] According to this embodiment, the composition used does not combine resveratrol with saffron, or resveratrol with a metal-chelating agent and one or more nucleotides, or resveratrol and pycnogenol and / or an extract of ginkgo biloba.

[0069] A composition implemented within the framework of the invention may be in the form of a liquid, solution, suspension, paste or gel.

[0070] Advantageously, it is available in solid form, such as powder, tablets (including effervescent tablets), capsules, softgels, tablets, or lozenges, prepared conventionally using acceptable additives such as binding agents, fillers, lubricants, disintegrating agents, or wetting agents. The tablets may optionally be coated in a manner known to those skilled in the art using sugars, films, or enteric coatings.

[0071] Alternatively, other delivery systems can be implemented, such as preparations in soft gelatin or gelatin-based capsules or formulations prepared using nanotechnologies, such as nano-dispersions, nano-emulsions or nano-encapsulations.

[0072] Such a composition may also contain one or more additives such as colorings, pigments, flavorings, ...

[0073] In a particular embodiment, the composition is presented in the form of capsules, defining a given volume in which the composition is contained. The capsule breaks down in the digestive system to release the active ingredients and allow their assimilation by the body.

[0074] In this context, common additives include: glycerol, for example glycerol monostearate; and / or soybean oil; and / or beeswax; and / or soy lecithin.

[0075] Appropriately, these additives are added to the composition because of their ability to improve, for example, the flow properties or the homogenization of the mixture.

[0076] Furthermore, and as is known to those skilled in the art, the capsule shell can be made from the following ingredients: gelatin; and / or red iron oxide; and / or black iron oxide; and / or sorbitol; and / or glycerol.

[0077] As is known to those skilled in the art, the distribution in this type of packaging involves a compromise between: a limited number of doses, to ensure good adherence to the treatment; an appropriate volume of doses, allowing the formulation of all ingredients and easy ingestion.

[0078] Advantageously, such a composition is administered daily, that is to say, on a daily basis.

[0079] According to an advantageous embodiment, this composition is formulated in 2 capsules, each containing the ingredients listed above in half the quantity.

[0080] According to one alternative, all these ingredients are mixed and administered in a single composition. Alternatively, these ingredients can be combined in different ways to be formulated and / or administered simultaneously or at different times.

[0081] Typically, the composition implemented within the framework of the invention is administered orally, advantageously in the form of two daily doses. According to a particular embodiment, the composition is presented in the form of two capsules that can be taken with a little water. They can be taken simultaneously, for example, at the beginning or during the main meal.

[0082] In view of the effect highlighted in the examples, such a composition is intended for administration to a subject receiving anti-VEGF treatment.

[0083] According to another aspect, an anti-VEGF treatment as detailed below is intended for administration in a subject taking a composition as defined above, advantageously by oral intake, even more advantageously by daily oral intake.

[0084] According to a particular embodiment and within the framework of the invention, an anti-VEGF treatment corresponds to taking an anti-VEGF agent, more precisely an inhibitor of the VEGF signaling pathway.

[0085] Advantageously, the anti-VEGF agent is chosen from an antibody, an antibody fragment, a recombinant protein, a fusion protein, and a mixture thereof.

[0086] According to a particular embodiment, the anti-VEGF agent is chosen from the group consisting of: ranibizumab, bevacizumab, aflibercept, abicipar pegol, conbercept, faricimab, brolucizumab, their biosimilars and mixtures thereof.

[0087] For the purposes of this invention, a biosimilar is understood in its common meaning, namely a medicinal product similar to a biological substance produced from a living cell or organism, referred to as the reference medicinal product. This biosimilar medicinal product must have similar physicochemical and biological properties, the same pharmaceutical substance and pharmaceutical form as the reference medicinal product, as well as equivalent efficacy and safety.

[0088] Ranibizumab is an antibody fragment derived from a humanized monoclonal antibody directed against VEGF-A.

[0089] Bevacizumab is a recombinant humanized monoclonal antibody directed against VEGF.

[0090] Aflibercept is a recombinant fusion protein corresponding to the extracellular domains of human VEGF type 1 and 2 receptors (VEGF-R1 and VEGF-R2) fused to the crystallizable fragment (Fc) of a human IgG1 immunoglobulin.

[0091] Abicipar pegol is a protein designed by repeating ankyrin that binds to all VEGF-A isoforms. Its small size (34 kDa) suggests a short intraocular half-life, but pegylation, i.e. the addition of polyethylene glycol molecules, allows it to acquire the pharmacokinetic characteristics of a larger protein, including a longer half-life.

[0092] Conbercept is similar to aflibercept in that it is a recombinant fusion protein corresponding to the key extracellular domains of human VEGF type 1 and 2 receptors and IgG Fc. However, conbercept also contains the fourth domain of the VEGF 2 receptor.

[0093] Faricimab is a bispecific monoclonal antibody against angiopoietin 2 and VEGF.

[0094] Brolucizumab (or RTH258, Novartis) is a single-chain antibody that achieves much higher antibody concentrations in the eye than currently approved treatments. This antibody has a very high affinity for all VEGF-A isoforms and should allow for less frequent intravitreal injections.

[0095] Typically, these anti-VEGF agents are administered by intravitreal injection. However, given the potentiation of their effect in the presence of a composition such as that described above, topical administration, advantageously to the ocular surface, can be considered.

[0096] The combination of these two treatments (oral ophthalmic nutraceutical composition and anti-VEGF treatment by intravitreal injection or topical application) is advantageous in the treatment of ocular pathologies, particularly retinal pathologies with a neovascular component, and even more advantageously chosen in the group consisting of: age-related macular degeneration, advantageously the wet form of AMD; diabetic macular edema (DME); retinal vein occlusion (RVO); myopic choroidal neovascularization; neovascular glaucoma; and proliferative diabetic retinopathy.

[0097] According to another aspect, the present invention relates to a combination product or a combination preparation containing the nutraceutical composition and the anti-VEGF treatment as described above for simultaneous, separate, or sequential use in the treatment of an ocular pathology, advantageously a retinal pathology with a neovascular component, even more advantageously selected from the group consisting of: age-related macular degeneration, advantageously the wet form of AMD; diabetic macular edema (DME); retinal vein occlusion (RVO); myopic choroidal neovascularization; neovascular glaucoma; and proliferative diabetic retinopathy.

[0098] As already mentioned and in this context, the nutraceutical composition is advantageously administered orally, even more advantageously on a daily basis, for example in the form of 2 capsules taken at the beginning or in the middle of the main meal.

[0099] Anti-VEGF treatment is administered by intravitreal injection or topically. Intravitreal injection remains the preferred route of administration, but ongoing developments suggest the possibility of topical administration, advantageously via application to the ocular surface.

[0100] Indeed, as demonstrated, this combination allows for a reduction in dosage, particularly of anti-VEGF treatment. Thus, it is possible to decrease the administered doses, or advantageously, to space out the administrations (or decrease the frequency of administration), which are typically spaced 1 to 3 months apart.

[0101] In other words, this combination product allows the dose and / or frequency of anti-VEGF treatment to be reduced compared to the dose and / or frequency applied to a subject not receiving the nutraceutical composition.

[0102] According to another aspect, the interval between two anti-VEGF treatments can be 30 days longer, advantageously 45 days longer, preferably 60 days longer or even 75 days longer, more advantageously 90 days longer compared to the current dosage.

[0103] Thus, and according to another aspect, the interval between two anti-VEGF treatments is greater than 30 days, advantageously greater than 45 days, preferably greater than 60 days or even 75 days, more advantageously greater than 90 days.

[0104] This makes it possible to reduce the potential toxicity of anti-VEGF treatments, particularly their side effects. Spacing out their administration, which requires specialist intervention, is also advantageous from an economic standpoint. EXAMPLES OF THE INVENTION'S IMPLEMENTATION

[0105] The invention and the benefits arising therefrom will be more clearly shown in the following figures and examples given to illustrate the invention and not in a limiting manner. DESCRIPTION OF THE FIGURES

[0106] There figure 1 compare, in undifferentiated (pathological) retinal cells incubated (A) in the presence (lower curve) and in the absence (upper curve) of formulation A, or (B) in the presence (lower curve) and in the absence (upper curve) of formulation B, the evolution of the VEGF level after administration of AVASTIN ®< . A / Protocol: Cell Culture

[0107] In vitroARPE-19 human undifferentiated retinal cells (ATCC®< CRL-2302™< ) are cultured in DMEM medium (Dulbecco's modified eagle medium / nutrition mix F12 (1:1 Gibco, Paisley, UK)) enriched with 10% fetal bovine serum (FBS, Dominique Dutscher, South American origin, lot no. S15197S1810), 1% PSA (antibiotic cocktail: Penicillin, Streptomycin, and Amphotericin B at 10,000 U / mL, 10 mg / mL, and 25 µg / mL, respectively, PAN Biotech), and 15 mM HEPES (pH 7.4, Gibco). The cells are cultured in an atmosphere at 37°C and 5% CO2. These cells can be considered as damaged or pathological retinal cells. Treatments

[0108] The cells are cultured and inoculated in 24-well culture dishes at a density of 60,000 cells per well in DMEM / F12 medium containing 10% FBS and 1% PSA. Twenty-four hours after inoculation, the culture medium is replaced with a restrictive DMEM / F12 medium containing 1% FBS and 1% PSA without phenol red. After another 24 hours, the cells are exposed to either formulation A (with resveratrol) or formulation B (without resveratrol).

[0109] The composition of formulations A and B is described below: Table 1: Composition of formulation A (with resveratrol) Ingredient Amounts in mg / capsule Concentrations in mg / g Amounts in mg / day Fish oil ∗< of which 475 688 950 DHA 183 265 366 EPA 86 125 172 Vitamin C 60 87 120 Vitamin E 15 22 30 Zinc 6.25 9.1 12.5 Copper 0.5 0.7 1 Lutein 10 14.5 20 Zeaxanthin 2 2.9 4 Resveratrol 30 43 60 ∗<: Omegavie ®< TG Quality Silver Oil

[0110] Note that one capsule contains 690 mg of the preparation and that a daily dose of 2 capsules is recommended. Table 2: composition of formulation B (without resveratrol) Ingredients Amounts in mg / capsule Concentrations in mg / g Amounts in mg / day Fish oil ∗< of which 512.3 674 512.3 DHA 250 329 250 EPA ( ≥ ) 56 74 56 Vitamin B1 1.4 1.8 1.4 Vitamin B2 1.6 2.1 1.6 Vitamin B3 18 24 18 Vitamin B6 2 3 2 Vitamin B9 0.2 0.3 0.2 Vitamin B12 0.001 0.001 0.001 Vitamin C 60 79 60 Vitamin E 10 13 10 Zinc 7.5 9.9 7.5 Manganese 1 1 1 Selenium 0.025 0.03 0.025 Copper 1 1 1 Lutein 10 13 10 Zeaxanthin 2 2.6 2 Glutathione 1 1 1 *< : TG Oil

[0111] Note that one capsule contains 760 mg of the preparation and that a daily dose of 1 capsule is recommended.

[0112] Formulations A and B were reconstituted at a mass of 0.115 g in 1 mL of DMSO (Dimethyl Sulfoxide) to obtain a resveratrol equivalent of 10 mM for formulation A and 0 mM for formulation B. The concentrations of fish oil, vitamins C and E, zinc, copper, lutein, and zeaxanthin were considered equivalent in both preparations. From this solution, dilutions were made directly in the DMEM / F12 1% SVF, 1% PSA culture medium without phenol red to achieve the concentrations of 10 and 20 µM required for the experiment.

[0113] After 24 hours of pre-incubation, the cells are treated with AVASTIN ® < 100ng / mL (± formulation A or B). ELISA (Enzyme-linked immunosorbent assay)

[0114] At the time of treatment (t0) with Avastin® < 100 ng / mL, and again 24, 48, and 72 hours later, the cell supernatant is collected to analyze the amount of VEGF-A released. Each ELISA is performed according to the manufacturer's precise instructions (eBioscience Human VEGF-A ELISA Kit BMS277 affymetrix). Purple Crystal

[0115] The cell mat is analyzed by crystal violet to determine cell viability. A ratio between the VEGF-A level from the supernatant and the corresponding cell mat can be calculated.

[0116] The cell mat is gently rinsed twice with 1X PBS buffer. Once the excess liquid is removed, the cell mat is fixed to its support with absolute ethanol. After an incubation of at least 30 minutes, the absolute ethanol is removed. The cells are then incubated with crystal violet staining solution for 20 minutes at room temperature under oscillation (25 oscillations per minute).

[0117] The crystal violet solution is discarded, and the wells are rinsed four times with water to remove excess staining. The plates are then dried at room temperature (for 16 to 24 hours). The cell staining is then resuspended in a 33% acetic acid solution, the plates are oscillated, and the optical density can be read by spectrometry at a wavelength of 570 nm (OD 570). B / Results:

[0118] It can be observed that the presence of A helps to limit the amount of VEGF produced but also to significantly delay the rise in this level after treatment with an anti-VEGF, which would allow for spacing out the injections of anti-VEGF.

[0119] Formulation B, on the other hand, leads to a decrease in the amount of VEGF produced but does not cause a delay in the resumption of VEGF production in retinal cells treated with anti-VEGF.

[0120] This unexpected difference is related to the presence of high concentration resveratrol in formulation A.

Claims

1. An ophthalmic nutraceutical composition comprising resveratrol, advantageously in an amount greater than 20 mg, for use in the treatment of an eye disease in a subject receiving anti-VEGF treatment.

2. The composition for its use according to claim 1, characterised in that the composition comprises an amount greater than or equal to 30 mg of resveratrol, advantageously greater than 30 mg, even more advantageously greater than or equal to 50 mg.

3. The composition for its use according to one of the preceding claims, characterised in that the composition further comprises: - vitamins, advantageously selected from the group consisting of vitamin C and vitamin E; - trace elements, advantageously selected from the group consisting of zinc and copper; - carotenoids, advantageously selected from the group consisting of zeaxanthin and lutein; - omega-3 fatty acids, advantageously from fish oil, even more advantageously selected from the group consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

4. The composition for its use according to any one of the preceding claims, characterised in that the composition comprises: - vitamin C, advantageously from 50 mg to 500 mg, even more advantageously 120 mg; - vitamin E, advantageously from 10 mg to 500 mg, even more advantageously 30 mg - zinc, advantageously from 5 mg to 100 mg, even more advantageously 12.5 mg; - copper, advantageously from 0.2 mg to 10 mg, even more advantageously 1 mg; - lutein, advantageously from 2 mg to 50 mg, even more advantageously 20 mg; - zeaxanthin, advantageously from 0.5 mg to 10 mg, even more advantageously 4 mg; - omega-3 fatty acids from fish oil, advantageously from 100 mg to 1000 mg, even more advantageously from 800 mg to 1000 mg.

5. A composition for its use according to one of the preceding claims, characterised in that the composition is administered orally.

6. The composition for its use according to one of the preceding claims, characterised in that the composition is administered on a daily basis.

7. The composition for its use according to one of the preceding claims, characterised in that the anti-VEGF treatment corresponds to the administration of an inhibitor of the VEGF signalling pathway, advantageously chosen from the following group: an antibody, an antibody fragment, a recombinant protein, a fusion protein and mixtures thereof.

8. The composition for its use according to one of the preceding claims, characterised in that the inhibitor is selected from the following group: ranibizumab, bevacizumab, aflibercept, abicipar pegol, conbercept, faricimab, brolucizumab and mixtures thereof.

9. The composition for its use according to one of the preceding claims, characterised in that the anti-VEGF treatment is administered by intravitreal injection or topically.

10. The composition for its use according to one of the preceding claims, characterised in that the eye disease is selected from the group consisting of age-related macular degeneration, diabetic macular oedema, retinal vein occlusion, myopic choroidal neovascularisation, neovascular glaucoma and proliferative diabetic retinopathy.

11. The composition as defined in any of claims 1 to 4 for simultaneous, separate or sequential use with an anti-VEGF agent, advantageously as defined in claims 7 and 8, in the treatment of an eye disease, advantageously selected from the group consisting of age-related macular degeneration, diabetic macular oedema, retinal vein occlusion, myopic choroidal neovascularisation, neovascular glaucoma and proliferative diabetic retinopathy.

12. The composition for its use according to claim 11, characterised in that the composition is administered orally, advantageously on a daily basis.

13. The composition for its use according to either claim 11 or 12, characterised in that the anti-VEGF agent is administered by intravitreal injection or topically.

14. The composition for its use according to any one of claims 11 to 13, characterised in that the dose and / or frequency of the administration of the anti-VEGF agent is reduced in comparison with the dose and / or frequency applied to a subject who is not receiving the composition.

15. The composition for its use according to claim 14, characterised in that the interval between two administrations of the anti-VEGF agent is greater than 30 days, advantageously greater than 45 days, preferably greater than 60 days or even greater than 75 days, more advantageously greater than 90 days, compared with the interval between two administrations of the anti-VEGF agent in a subject not receiving the composition.