Use of lecanemab in ophthalmological conditions

Abstract

This disclosure related to a method of preventing or treating an amyloid- associated retinal disease in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of an antibody with high affinity and specificity for amyloid beta (Abeta) oligomers, Abeta protofibrils or combination thereof.

Description

P-634033-PC USE OF LECANEMAB IN OPHTHALMOLOGICAL CONDITIONS BACKGROUND OF THE INVENTION

[0001] Glaucoma and age-related macular degeneration (AMD) are leading causes of progressive vision loss and blindness worldwide with the incidence and prevalence of each disease increasing substantially with the ageing population. As with Alzheimer’s disease (AD), both conditions have a strong age-related incidence and chronic neurodegenerative changes seen in the eyes of glaucoma and AMD patients are similar to changes characteristic of the brains of the AD patient. AMD and glaucoma have a common link in that the presence of toxic amyloid beta (Abeta) oligomers is associated with disease progression.

[0002] Amyloid beta (Abeta)-associated diseases and conditions include diseases and conditions wherein neuronal and non-neuronal cell function is affected by the presence of toxic Abeta oligomers, which are formed from misfolded Abeta monomers by aggregation. Abeta-associated diseases and conditions include ophthalmic and neurological diseases and conditions for example but not limited to Alzheimer’s disease (AD), glaucoma, and age- related macular degeneration of the retina.

[0003] Studies have shown that glaucoma is the second leading cause of blindness in the United States and is a neurodegenerative disease, with increasing evidence that Abeta toxicity plays an important role in its pathogenesis. The pathologic correlation of glaucoma is the progressive degeneration of retinal ganglion cells (RGC) and their axons which form the optic nerve. The different types of glaucoma include primary and secondary angle- closure glaucoma, primary and secondary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, glaucoma from pigmentary dispersion syndrome, glaucoma from pseudoexfoliation syndrome, neovascular glaucoma, normotension glaucoma, glaucoma from uveitis and other non-further specified eye pathologies.P-634033-PC

[0004] Recently, Abeta has been found to co-localize with dying retinal ganglion cells. Animal studies also demonstrate that the soluble Abeta1-42oligomers, in particular, are very potent toxins for retinal ganglion cells (RCG). Thus, as with AD, Abeta toxicity is thought to play a pivotal role in glaucoma and its associated conditions.

[0005] Ontogenetically, the retina is part of the central nervous system and therefore, patho- mechanisms in retina and brain can be similar. A neurodegenerative process associated with amyloid beta (Abeta) is postulated as a common cause of degenerative retinal disease, e.g. age-related macular degeneration (AMD), as well as of degenerative brain disease, e.g. Alzheimer's dementia.

[0006] Similarly, age-related macular degeneration (AMD) is a condition involving a pathology of the retina which has also been closely associated with the occurrence of Abeta toxicity in photoreceptors and retinal pigment epithelium, and which leads to a progressive loss of vision, leading finally to blindness.

[0007] In 2005, a deposition of Abeta in the retina was reported in a study with aged APOE4-HFC mice, which was suggested as an animal model of AMD. It was postulated incorrectly that Abeta deposits could serve as a drug target for treatment of AMD. At that time, non-specific antibodies against Abeta (e.g. 4G8 or de-2HG) were commonly used in Alzheimer research. In therapeutic animal studies such antibodies indeed lowered the amount of deposited Abeta in the mouse brain (cortex) and in the retina. However, treatments for humans could not successfully been developed with these models, neither for Alzheimer's nor for AMD. An approach with the anti-Abeta antibody GSK933776 reached clinical Phase 2, however, didn't show any treatment potential in humans and was abandoned. Over 18 months, GSK933776 did not reduce the rate of geographic atrophy (GA) growth in age-related macular degeneration (AMD) relative to placebo. Overall, thereP-634033-PC were no consistent meaningful differences relative to placebo in any of the visual function measures.

[0008] After many failures in Alzheimer's disease, it was finally understood that the removal of Abeta deposits from the brain with antibodies isn't an effective mechanism of action for treating Alzheimer's disease. The breakthrough in Alzheimer's therapy was achieved with anti-Abeta antibodies that are specific for soluble Abeta oligomers and Abeta protofibrils. A similar breakthrough in the therapy of retinal neurodegenerative disease has not yet happened. The failure of the anti-Abeta antibody GSK933776 in Ph2 is still considered proof of anti-Abeta antibodies in general being not efficacious for retinal diseases.

[0009] There is still a great need for affective treatments for retinal diseases. SUMMARY OF THE INVENTION

[0010] In some aspects, disclosed herein is a method of preventing or treating an amyloid-associated retinal disease in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of an antibody with high affinity and specificity for amyloid beta (Abeta) oligomers, protofibrils or combination thereof.

[0011] In some related aspects, the high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises lecanemab, aducanumab, and donanemab.

[0012] In some further related aspects, the high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises lecanemab.

[0013] In some related aspects, the amyloid-associated retinal disease comprises all forms of age-related macular degeneration (AMD), all forms of glaucoma, or combination thereof.

[0014] In some related aspects, the administration comprises ocular administration.P-634033-PC

[0015] In some related aspects, the administration is systemic administration.

[0016] In some related aspects, the antibody is administered once a day, two times a week, three times a week, every other day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every nine months or once a year.

[0017] In some related aspects, the lecanemab is administered intravenously (IV) at a 10 mg / kg dose.

[0018] In some related aspects, the lecanemab is administered by intraocular injection (intravitreal, IVT) at a 0.01-5 mg per eye per application dose.

[0019] In some related aspects, the method further comprised administering an additional compound for preventing or treating an amyloid-associated retinal disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which: Fig. 1 is a graphic illustration of Western blot analysis of the pro-apoptotic Bax protein in retina preparations of rats. The different treatments of the groups are illustrated by the three lines below the bar graph. The density of the blots was determined automatically. Shown are means of 5-7 experiments ± standard deviations. Differences between groups were marked with * for p<0.5 and ** for p<0.01; andP-634033-PC

[0021] Fig.2 is a graphic illustration of Western blot analysis of the apoptosis preventive Bcl-2 proteins in retina preparations of rats. The different treatments of the groups are illustrated by the three lines below the bar graph. The density of the blots was determined automatically. Shown are means of 5-7 experiments ± standard deviations. Differences between groups were marked with * for p<0.5.

[0022] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0023] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0024] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0025] A skilled artisan would appreciate that the term “comprising” encompasses inclusion of the recited elements, but not excluding others which may be optional.P-634033-PC

[0026] A skilled artisan would understand that when a range of values is expressed, another embodiment includes one limit value and / or the other limit value of the range. Additionally, all ranges are inclusive and combinable. Method of treatment

[0027] In some embodiments, disclosed herein is a method of preventing or treating an amyloid-associated retinal disease in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of an antibody with high affinity and specificity for amyloid beta (Abeta) oligomers, protofibrils or combination thereof.

[0028] In one embodiment, the term “treatment” refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly. In another embodiment, the term “treating” refers to reducing incidence, or alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis, slowing down of the progression (incremental worsening of the symptoms) of the disease, or stopping the progression at a certain time, or combinations thereof in other embodiments.

[0029] “Treating” embraces in another embodiment, the amelioration of an existing condition. The skilled artisan would understand that treatment does not necessarily result in the complete absence or removal of symptoms. Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition. The alleviation of a condition that results in a more serious condition is encompassed by this term.

[0030] In one embodiment, “preventing” may encompass, inter alia, to delaying the onset of symptoms, preventing relapse of a disease, decreasing the number or frequency ofP-634033-PC relapse episodes, increasing latency between symptomatic episodes, or a combination thereof.

[0031] A skilled artisan would appreciate that “amyloid-associated retinal disease” arise when one of an ever-growing list of proteins (the amyloid-forming protein in its native conformation, also referred to as the amyloidogenic precursor) acquires an alternative folding state (the misfolded state), starts to aggregate and to form oligomers, then protofibrils and finally fibrillar structures (termed amyloid fibrils) which eventually deposit within tissues. Antibodies According to the amyloid hypothesis, amyloid-beta (Abeta), a major constituent of extracellular plaques found in Alzheimer’s disease (AD) brains and other neurodegenerative diseases, Abeta exists as various species, including monomers with different length of the amino acid chain, soluble aggregates of varying size (e.g., oligomers and protofibrils), and insoluble fibrils in plaques.

[0032] There are currently three monoclonal antibodies targeting Abeta oligomers and protofibrils approved or in late-phase clinical development, lecanemab, aducanumab, and donanemab. Additional antibodies of this class might follow soon. The specific affinity of this class of antibodies to Abeta oligomers and protofibrils has recently been described. Lecanemab and aducanumab showed no affinity to Abeta monomers in ELISA binding experiments. However, they showed affinity to Abeta oligomers and protofibrils with different pattern. Lecanemab was distinctive with preferred binding to oligomers and particularly to protofibrils. Aducanumab and gantenerumab preferred binding to fibrils. This selectivity for oligomers and protofibrils is the basis for the therapeutic effect in Alzheimer`s disease. The binding to deposited Abeta (e.g. plaques) does not contribute to clinicalP-634033-PC efficacy. The clinical usefulness of these antibodies for Alzheimer's disease declines in the order lecanemab > donanemab > aducanumab >> gantenerumab > other less specific Abeta antibodies. That is reflected by their binding pattern.

[0033] In some embodiments, the high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises lecanemab, aducanumab and donanemab. In one embodiment, the high affinity antibody selective for amyloid beta protein (Abeta) oligomers and protofibrils comprises lecanemab. In another embodiment, the high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises aducanumab. In another embodiment, the high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises donanemab.

[0034] A person skilled in the art would understand Lecanemab is a monoclonal antibody medication used for the treatment of Alzheimer's disease. Lecanemab is an amyloid beta- directed antibody. It is given via intravenous infusion. The most common systemic side effects of lecanemab include headache, infusion-related reactions and amyloid-related imaging abnormalities (ARIA), a side effect known to occur with the class of antibodies targeting Abeta.

[0035] A person skilled in the art would understand aducanumab is a medication designed to treat Alzheimer's disease (AD). It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Abeta) found in the brains of people with Alzheimer's disease to reduce its toxicity. Aducanumab is given via intravenous infusion. A person skilled in the art would understand donanemab is a biological drug that has shown to slow the progression of Alzheimer's disease in a Phase III trial. Donanemab is also known as N3pG-Abeta humanized monoclonal antibody. Donanemab recognizes particularly Abeta(p3-42), a pyroglutamate form of Abeta that is acting as aP-634033-PC seed for the formation of Abeta oligomers and protofibrils, which may be a factor in Alzheimer's disease. Amyloid associated retinal disease

[0036] In some embodiments, the present disclosure relates to a method of preventing or treating an amyloid-associated retinal disease in an individual in need thereof. In some embodiments, the amyloid-associated retinal disease is related to misfolding and aggregation of amyloid beta. In some embodiments, amyloid beta comprises Abeta1-42, Abeta1-40, Abetap3–42,derivates thereof or any combination thereof.

[0037] A skilled artisan would understand “amyloid-associated disease” as a pathology that is characterized by an accumulation and deposition of amyloid proteins in certain tissues of the body accompanied by a functional deficit of the respective organs.

[0038] In some embodiments, the amyloid-associated retinal disease comprises all forms of age-related macular degeneration (AMD), all forms of glaucoma, or combination thereof. In one embodiment, the amyloid-associated retinal disease comprises all forms of age- related macular degeneration (AMD). In another embodiment, the amyloid-associated retinal disease comprises all forms of glaucoma. In another embodiment, the amyloid- associated retinal disease comprises age-related macular degeneration (AMD) and glaucoma.

[0039] A skilled artisan would understand age-related macular degeneration (AMD) is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read,P-634033-PC or perform other activities of daily life. Visual hallucinations may also occur, but these do not represent a mental illness.

[0040] In some embodiments, the age-related macular degeneration (AMD) comprises dry AMD, atrophic AMD, geographic atrophy, early AMD, intermediate AMD, late AMD, wet AMD, and neovascular AMD. In one embodiment, the age-related macular degeneration (AMD) comprises dry AMD. In another embodiment, the age-related macular degeneration (AMD) comprises atrophic AMD. In another embodiment, the age-related macular degeneration (AMD) comprises geographic atrophy. In another embodiment, the age-related macular degeneration (AMD) comprises early AMD. In another embodiment, the age-related macular degeneration (AMD) comprises intermediate AMD. In another embodiment, the age-related macular degeneration (AMD) comprises late AMD. In another embodiment, the age-related macular degeneration (AMD) comprises wet AMD. In another embodiment, the age-related macular degeneration (AMD) comprises neovascular AMD.

[0041] A skilled artisan would understand glaucoma as a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. Risk factors for glaucoma include increasing age, high pressure in the eye, a family history of glaucoma, certain genetic mutations, trauma, and use of steroid medication.

[0042] In some embodiments, the glaucoma comprises primary and secondary angle- closure glaucoma, primary and secondary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, glaucoma from pigmentary dispersion syndrome, glaucoma from pseudoexfoliation syndrome, neovascular glaucoma, normotension glaucoma, glaucoma from uveitis and other non-further specified eye pathologies. In another embodiment, the glaucoma comprises primary and secondary angle-closure glaucoma. In another embodiment, the glaucoma comprises primary and secondary open-angle glaucoma. InP-634033-PC another embodiment, the glaucoma comprises steroid-induced glaucoma. In another embodiment, the glaucoma comprises traumatic glaucoma. In another embodiment, the glaucoma comprises glaucoma from pigmentary dispersion syndrome. In another embodiment, the glaucoma comprises glaucoma from pseudoexfoliation syndrome. In another embodiment, the glaucoma comprises neovascular glaucoma. In another embodiment, the glaucoma comprises normotension glaucoma. In another embodiment, the glaucoma comprises glaucoma from uveitis and other non-further specified eye pathologies. Dosage and administration

[0043] In some embodiments, the administration is ocular administration.

[0044] In some embodiments, the ocular administration is by eye drops, eye creams, eye ointments, eye sprays, intraocular depot formulations, by injection including intraocular injection, intra- or periocular injections, comprising intraocular fluids, intravitreal injections, injections into the supra-arachnoidal or the subretinal space, depot formulations, solid and semisolid intraocular carriers and matrices, or ocular devices, like contact lenses and films.

[0045] In one embodiment, the ocular administration is by eye drops. In another embodiment, the ocular administration is by eye creams. In another embodiment, the ocular administration is by eye ointments. In another embodiment, the ocular administration is by eye sprays. In another embodiment, the ocular administration is by intraocular depot formulations. In another embodiment, the ocular administration is by injection. In another embodiment, the ocular administration is by ocular devices.

[0046] In one embodiment, the ocular device is contact lenses. In another embodiment, the ocular device is a film.

[0047] In one embodiment, the injections include intraocular injection, intra- or periocular injections, comprising intraocular fluids, intravitreal injections, injections into theP-634033-PC supra-arachnoidal or the subretinal space, depot formulations or solid and semisolid intraocular carriers and matrices.

[0048] In some embodiments, the antibody is formulated for administration as an eye drop or an ocular depot formulation. In one embodiment, the antibody is formulated for administration as an eye drop formulation. In another embodiment, the antibody is formulated for administration as an ocular depot formulation.

[0049] In one embodiment, the ocular depot formulation is based on a device.

[0050] In some embodiments, the administration is systemic administration.

[0051] In some embodiments, the systemic administration comprises intravenous administration, oral administration, rectal administration, transmucosal administration, transnasal administration, intramuscular injection, subcutaneous injection, or intraperitoneal administration.

[0052] In one embodiment, the systemic administration comprises intravenous administration. In another embodiment, the systemic administration comprises oral administration. In another embodiment, the systemic administration comprises rectal administration. In another embodiment, the systemic administration comprises transmucosal administration. In another embodiment, the systemic administration comprises transnasal administration. In another embodiment, the systemic administration comprises intramuscular injection. In another embodiment, the systemic administration comprises subcutaneous injection. In another embodiment, the systemic administration comprises intraperitoneal administration.

[0053] In some embodiments, the antibody is administered once a day, two times a week, three times a week, every other day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every fourP-634033-PC months, once every five months, once every six months, once every nine months or once a year.

[0054] In one embodiment, the antibody is administered once a day. In another embodiment, the antibody is administered two times a week. In another embodiment, the antibody is administered three times a week. In another embodiment, the antibody is administered every other day. In another embodiment, the antibody is administered once a week. In another embodiment, the antibody is administered once every two weeks. In another embodiment, the antibody is administered once every three weeks. In another embodiment, the antibody is administered once a month. In another embodiment, the antibody is administered once every two months. In another embodiment, the antibody is administered once every three months. In another embodiment, the antibody is administered once every four months. In another embodiment, the antibody is administered once every five months. In another embodiment, the antibody is administered once every six months. In another embodiment, the antibody is administered once every seven months. In another embodiment, the antibody is administered once every eight months. In another embodiment, the antibody is administered once every nine months. In another embodiment, the antibody is administered once every ten months. In another embodiment, the antibody is administered once every eleven months. In another embodiment, the antibody is administered once a year.

[0055] In some embodiments, the lecanemab is administered IV at a 1-20 mg / kg dose. In one embodiment, the lecanemab is administered IV at a 5-15 mg / kg dose. In another the lecanemab is administered IV at a 1 mg / kg dose. In another the lecanemab is administered IV at a 5 mg / kg dose. In another the lecanemab is administered IV at a 10 mg / kg dose. In another the lecanemab is administered IV at a 15 mg / kg doseP-634033-PC

[0056] In some embodiments, the lecanemab is administered by intraocular injection at a 0.01-5 mg per eye per application dose. In one embodiment, the lecanemab is administered by intraocular injection at a 0.01 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 0.05 my per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 0.1 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 0.5 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 1 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 2 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 3 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 4 mg per eye per application dose. In another embodiment, the lecanemab is administered by intraocular injection at a 5 mg per eye per application dose.

[0057] In some embodiments, the method further comprises administering an additional compound for preventing or treating an amyloid-associated retinal disease.

[0058] In some embodiments, the additional compound comprises a complement inhibitor, an anti-vascular endothelial growth factor (VEGF) drug or a combination thereof.

[0059] In one embodiment, the additional compound comprises a complement inhibitor. In another embodiment, the additional compound comprises a VEGF drug. In another embodiment, the additional compound comprises a combination of a complement inhibitor and aVEGF drug.

[0060] In some embodiments, the complement inhibitor comprises pegcetacoplan or avacincaptad pegol. In one embodiment, the complement inhibitor comprisesP-634033-PC pegcetacoplan. In another embodiment, the complement inhibitor comprises avacincaptad pegol.

[0061] In some embodiments, the VEGF drug comprises flibercept, ranibizumab or bevacizumab. In one embodiment, the VEGF drug comprises flibercept. In another embodiment, the VEGF drug comprises ranibizumab. In another embodiment, the VEGF drug comprises bevacizumab.

[0062] In some embodiments, the additional compound comprises β-adrenergic antagonists, carbonic anhydrase inhibitors, cholinergics, α-adrenergic agonists, prostaglandins or combination thereof. In one embodiment, the additional compound comprises β-adrenergic antagonists. In another embodiment, the additional compound comprises carbonic anhydrase inhibitors. In another embodiment, the additional compound comprises cholinergics. In another embodiment, the additional compound comprises α- adrenergic agonists. In another embodiment, the additional compound comprises prostaglandins. In another embodiment, the additional compound comprises prostamides.

[0063] In some embodiments, the β-adrenergic antagonist comprises timolol or betaxolol. In one embodiment, the β-adrenergic antagonist comprises timolol. In another embodiment, the β-adrenergic antagonist comprises betaxolol.

[0064] In some embodiments, the carbonic anhydrase inhibitor comprises dorzolamide or brinzolamide. In one embodiment, the carbonic anhydrase inhibitor comprises dorzolamide. In another embodiment, the carbonic anhydrase inhibitor comprises brinzolamide.

[0065] In some embodiments, the cholinergics comprises pilocarpine.

[0066] In some embodiments, the α-adrenergic agonist comprises brimonidine.P-634033-PC

[0067] In some embodiments, the prostaglandin comprises latanoprost or travoprost. In one embodiment, the prostaglandin comprises latanoprost. In another embodiment, the prostaglandin comprises travoprost.

[0068] In some embodiments, the prostamide comprises bimatoprost.

[0069] In some embodiments, the method of prevention or treatment of the current disclosure, further comprises surgical procedures. Pharmaceutical compositions

[0070] The herein-described compositions can be incorporated into pharmaceutical compositions suitable for administration. In one embodiment, a "pharmaceutical composition" or a “pharmaceutical formulation” refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a "pharmaceutical composition" or a “pharmaceutical formulation” is to facilitate administration of a compound to a subject. In certain embodiments, a “pharmaceutical composition” or a “pharmaceutical formulation” provides the pharmaceutical dosage form of a drug.

[0071] In some embodiments, "active ingredient" refers to the molecule which is accountable for the biological effect. In some embodiments, the active ingredient comprises high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils.

[0072] In some embodiments, the pharmaceutical composition comprises an excipient. A skilled artisan would appreciate that, in some embodiments, excipients are selected according to the delivery mode of the pharmaceutical composition.

[0073] In one embodiment, the antibody with high affinity and specificity for amyloid beta (Abeta) oligomers and protofibrils is an active ingredient of a pharmaceutical composition which also includes a physiologically acceptable carrier.P-634033-PC

[0074] Pharmaceutical compositions typically comprise a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference.

[0075] Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are carbohydrates, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc, solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol (PEG); alginic acid; emulsifiers, such as the Tween™ brand emulsifiers; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the compound is basically determined by the way the compound is to be administered. If the subject compound is to be injected, in one embodiment, the pharmaceutically-acceptable carrier is sterile, physiological saline, with a blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

[0076] In some embodiments, the pharmaceutical compositions further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch,P-634033-PC potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI., acetate, phosphate, histidine) of various pH, osmolarity, and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates), adjuvants, or any combination thereof.

[0077] In one embodiment, the formulations provided herein also comprise preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcysteine, sodium metabisulfite and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueous compositions as needed. The compositions also comprise local anesthetics or other actives. The compositions can be used as sprays, mists, drops, and the like.P-634033-PC EXAMPLES Example 1 – AMD model.

[0078] AMD model selection: Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. The animal model selected for the following study was based on the model described by Fisichella et al.2016 (attached herein as reference). The advantage of this model is that it uses Abeta oligomers to induce the retina pathology and is therefore considered most relevant to the rationale of this scientific approach.

[0079] Abeta oligomers: Human Abeta1-42(order number H-1368; Bachem, Bubendorf, Switzerland) was suspended in 100% hexafluoroisopropanol (HFIP, Sigma Aldrich) to approximately 1 mg / 400 µL HFIP and shaken at 37°C for 1.5 hours. The HFIP was removed by evaporation using a Speedvac for approximately 30 minutes, and when completely dry, aliquots of 100 µg Abeta1-42were stored at -20°C. The Abeta1-42was dissolved in DMSO (Sigma Aldrich) to a concentration of 100 µM with the aid of an ultrasonic water bath. This solution was further diluted using Ringer solution at the final concentration of 10 mM Abeta.

[0080] Lecanemab: LEQEMBITM(lecanemab-irmb) for intravenous infusion has been FDA approved in 2023 for the treatment of early Alzheimer’s disease. LEQEMBI has been purchased in a public pharmacy. Each vial contains lecanemab at a concentration of 100 mg / mL. The recommended dosage for humans is 10 mg / kg once every two weeks administered IV.

[0081] Animal treatment: Adult male Sprague Dawley rats (250–300 g) were purchased from Harlan (Netherlands). The animals were fed on standard laboratory food andP-634033-PC were allowed free access to water in an air-conditioned room with a 12-h light / 12-h dark cycle.

[0082] Of the Abeta oligomers solution, 1 µL was intravitreally (IVT) injected once. Before any IVT injection, animals were anesthetized by intravenous injection of 5 mg / kg Zoletil (tiletamine and zolazepam, Virbac, Bridgeton, MO, US) and 1 eye drop of the local anesthetic Novesina (Oxybuprocaine, Novartis, Switzerland).

[0083] Of the lecanemab solution, 100 µL (10 mg lecanemab) were injected intraperitoneally (IP), starting 1 weeks before the Abeta oligomer IVT injection. For intraocular treatment, 1 µL (0.1 mg lecanemab) was injected intravitreally (IVT) starting a week before the first Abeta oligomer IVT injection. On the day both Abeta and lecanemab are administered, lecanamab injection (intravitreally (IVT) or intraperitoneally (IP)) preceded the Abeta oligomer administration by 3 hours. Animals were sacrificed 48 hours after the Abeta oligomer IVT injection.

[0084] The animals were randomly divided in four experimental groups of 6 animals each: 1) Control with saline IP and IVT 2) Control with lecanemab IP and IVT 3) Abeta oligomers IVT once and saline IP twice 4) Abeta oligomers IVT once and lecanemab IP twice 5) Abeta oligomers IVT once and lecanemab IVT twice

[0085] Read out: Abeta oligomers injected IVT are known to induce apoptosis in the retina (Fisichella et al. 2026). That is the basis to use Abeta oligomer injection as a model for the neurodegenerative damage in AMD. Induction of apoptosis goes hand in hand with changes in the expression of the cytoplasmatic proteins Bacl-2 and Bax, which regulate theP-634033-PC programmed cells death. Bcl-2 proteins prevent apoptotic cell death while Bax plays a pro- apoptotic role. In this study, both of these proteins were measured with a Westerm Blot method.

[0086] Results - One single injection of Abeta oligomers into the vitreous body of the rat eye (IVT) is sufficient to induce a significant apoptotic reaction in the cells of the retina within 48 hours (Group 1) which is due to the highly neurotoxic activity of the Abeta oligomers. This is interpreted as an acute animal model of retinal neurodegeneration, as typically seen in dry AMD (degeneration of photoreceptors). Apoptosis is biochemically characterized by the increase of the pro-apoptotic marker Bax (Fig.1) and a decrease of the apoptosis-preventive maker Bcl-2 (Fig.2).

[0087] Administration of lecanemab alone, either IP and / or IVT does not change apoptosis in the retina (Group 2).

[0088] However, if lecanemab is co-administered with Abeta oligomers, it can block the neurotoxic effect of Abeta oligomers. That has been shown with systemic administration and with intraocular injection. The fact that lecanemab works with systemic administration (IP) suggests that the marketed drug Leqembi can directly be used as infusion treatment of AMD. In addition, lecanemab can also be injected IVT, an application route widely used in dry AMD and wet AMD. The advantage of this application route is that systemic side effects of the drug will occur less.

[0089] In addition, much less drug is required for local IVT treatment of AMD than for systemic treatment of Alzheimer's disease. It is expected the for local ocular AMD treatment less than 1% of the amount for Alzheimer is required. A clear commercial advantage for a costly to manufacture antibody drug.P-634033-PC

[0090] Furthermore, the effective duration of one single injection into the eye will last much longer, since there are far fewer degrading enzymes in the eye than in the systemic circulation of the body. It is expected that the residence time of the antibody within the eye will be several months (up to 6-12 months) since the macromolecular antibody is trapped in the eye and neither diffusion into bloodstream nor metabolism is possible easily. Example 2 – Microbead induced glaucoma model in mice

[0091] Based on the hypothesis that Ab toxicity and neurodegeneration play a key role in the pathology of glaucoma, the current example aims to investigate the effect of Lecanemab in a glaucoma mouse model. A model was chosen in which Intraocular Pressure (IOP) is raised through the induction of microbeads. Ultimately, the elevated IOP leads to the formation of Ab oligomers which could be targeted by Lecanemab.

[0092] The current experiment used normal C57BL / 6 mice, which were not genetically modified, meaning that they express murine Ab. This murine Ab has 3 different amino acids compared to human Ab. To ensure perfect target affinity the murine version of Lecanemab, mAb158, was used.

[0093] Animal treatment – after measuring an IOP baseline for 7 days, two groups of 17 mice each received a unilateral magnetic microbead injection on day zero. One day prior to that microbead injection the control group received 1 ml saline as a vehicle, whereas the treatment group received 1 ml mAb158, both as an intravitreal injection to reduce the risk of systemic side effects. On day 13 both groups received a second vehicle / treatment injection and IOP was measured at regular intervals to ensure that IOP remained stable throughout the whole experiment. On day 28 the animals were sacrificed and retinal wholemounts were collected to perform an immunostaining of retinal ganglion cells afterwards.P-634033-PC

[0094] Results - a significant difference between the vehicle and the treatment group was observed. In presence of mAb158 significantly more retinal ganglion cells survived, indicating a neuroprotective effect of mAb158 / Lecanemab.

[0095] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

P-634033-PC CLAIMS What is claimed is:

1. A method of preventing or treating an amyloid-associated retinal disease in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of an antibody with high affinity and specificity for amyloid beta (Abeta) oligomers, Abeta protofibrils or combination thereof.

2. The method according to claim 1, wherein said high affinity antibody selective for amyloid beta (Aβ) oligomers and protofibrils comprises lecanemab, aducanumab, and donanemab.

3. The method according to claims 1 and 2, wherein said high affinity antibody selective for amyloid beta (Abeta) oligomers and protofibrils comprises lecanemab.

4. The method according to claim 1, wherein said amyloid-associated retinal disease comprises all forms of age-related macular degeneration (AMD), all forms of glaucoma, or combinations thereof.

5. The method according to claim 4, wherein said age-related macular degeneration (AMD) comprises dry AMD, atrophic AMD, geographic atrophy, early AMD, intermediate AMD, late AMD, wet AMD, and neovascular AMD.

6. The method according to claim 4, wherein said glaucoma comprises primary and secondary angle-closure glaucoma, primary and secondary open-angle glaucoma, steroid- induced glaucoma, traumatic glaucoma, glaucoma from pigmentary dispersion syndrome, glaucoma from pseudoexfoliation syndrome, neovascular glaucoma, normotension glaucoma, glaucoma from uveitis and other non-further specified eye pathologies.

7. The method according to claims 1-6, wherein said administration comprises ocular administration.P-634033-PC 8. The method according to claim 7, wherein said ocular administration is by eye drops, eye creams, eye ointments, eye sprays, intraocular depot formulations, by injection including intraocular injection, intra- or periocular injections, comprising intraocular fluids, intravitreal injections, injections into the supra-arachnoidal or the subretinal space, depot formulations, solid and semisolid intraocular carriers and matrices, or ocular devices.

9. The method according to claim 8, wherein said antibody is formulated for administration as an eye drop or an ocular depot formulation.

10. The method according to claim 9, wherein said ocular depot formulation is based on a device.

11. The method according to claims 1-6, wherein said administration is systemic administration.

12. The method according to claim 11, wherein said systemic administration comprises intravenous administration, oral administration, rectal administration, transmucosal administration, transnasal administration, intramuscular injection, subcutaneous injection, or intraperitoneal administration.

13. The method according to any of the previous claims, wherein said antibody is administered once a day, two times a week, three times a week, every other day, once a week, once every two weeks, once every three weeks, once a months, once every two months, once every three months, once every four months, once every five months, once every six months, once every nine months or once a year.

14. The method according to claim 3, wherein said lecanemab is administered IV at a 10 mg / kg dose.

15. The method according to claim 3, wherein said lecanemab is administered by intraocular injection at a 0.01-5 mg per eye per application dose.P-634033-PC 16. The method according to any of the proceeding claims, further comprising administering an additional compound for preventing or treating an amyloid-associated retinal disease.

17. The method according to claim 16, wherein said additional compound comprises a complement inhibitor or a VEGF drug.

18. The method according to claim 17, wherein said complement inhibitor comprises pegcetacoplan or avacincaptad pegol.

19. The method according to claim 17, wherein said VEGF drug comprises flibercept, ranibizumab or bevacizumab.

20. The method according to claim 16, wherein said additional compound comprises β- adrenergic antagonists, carbonic anhydrase inhibitors, cholinergics, α-adrenergic agonists, prostaglandins, prostamides or combination thereof.

21. The method according to claim 20, wherein said β-adrenergic antagonists comprises timolol or betaxolol.

22. The method according to claim 20, wherein said carbonic anhydrase inhibitors comprises dorzolamide or brinzolamide.

23. The method according to claim 20, wherein said cholinergics comprises pilocarpine.

24. The method according to claim 20, wherein said α-adrenergic agonists comprises brimonidine.

25. The method according to claim 20, wherein said prostaglandins comprises latanoprost of travoprost. The method according to claim 20, wherein said prostamide comprises bimatoprost.

26. The method according to any one of the proceeding claims, further comprises surgical procedures.

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