Pre-filled syringe containing avacincaptad formulation

Abstract

Avacincaptad pegol, also known under the trademarks Izervay or Zimura, is a molecule comprising an aptamer sequence and a polyethylene glycol polymer (PEG) -moiety. The aptamer sequence binds to complement C5-protein, which C5 protein is known to be involved in many eye diseases. Avacincaptad pegol is approved to treat Age-related Macular Degeneration (AMD) secondary to Geographic Atrophy (GA) and is applied by intravitreal injection into the eye. The pharmaceutical product is currently only offered as a liquid in a vial. This patent application discloses Avacincaptad in a more stable presentation, namely in a pre-filled syringe, which surprisingly results in very significantly improved stability of the product.

Description

[0001] Pre-filled syringe containing Avacincaptad formulation

[0002] Field of the invention

[0003] Avacincaptad pegol, also known under the trademarks Izervay or Zimura, is a molecule comprising an aptamer sequence and a polyethylene glycol polymer (PEG) -moiety. The aptamer sequence binds to complement C5-protein, which 05 protein is known to be involved in many eye diseases. Avacincaptad pegol is approved to treat Age-related Macular Degeneration (AMD) secondary to Geographic Atrophy (GA) and is applied by intravitreal injection into the eye. The pharmaceutical product is currently only offered as a liquid in a vial. This patent application discloses Avacincaptad in a more stable presentation, namely in a pre-filled syringe, which surprisingly results in very significantly improved stability of the product.

[0004] Background of the invention

[0005] Avacincaptad pegol, also known under the trademarks Izervay or Zimura, is a molecule comprising an aptamer sequence (SEQ ID NO 1 of sequence protocol) and a polyethylene glycol polymer (PEG) -moiety. The aptamer sequence represents a 39-mer oligonucleotide which contains many modified nucleotides to increase the half-life and stability of the molecule. The aptamer sequence was developed by screening for aptamer sequences binding to complement C5-protein, which C5 protein is known to be involved in many eye diseases such as wet and dry Age-related Macular Degeneration (AMD) and geographic atrophy (GA). Avacincaptad pegol is approved to treat Age-related Macular Degeneration (AMD) secondary to Geographic Atrophy (GA) and is applied by intravitreal injection into the liquid of the eyeball, the vitreous humor. The pharmaceutical product is currently only offered as a liquid in a vial in the form of Avacincaptad pegol sodium salt (see Figure 9).

[0006] The molecule Avacincaptad pegol, among others has been described in W02006088888, WG2005079363, US2015159158, US2006105980, US2006018871 , US2007048248, US2019185858, US2011060027, and US2021332361. The safety and efficacy of Izervay or Zimura (both trade names of Avacincaptad pegol) were evaluated in studies (GATHER1 , NCT02686658 and GATHER2, NCT04435366, respectively) in patients with Geographic Atrophy (GA) due to Age-related Macular Degeneration (AMD). Summary of the invention

[0007] This patent application discloses Avacincaptad in a more stable presentation, namely in a prefilled syringe, which surprisingly results in very significantly improved stability of the product (see table 1 and table 3).

[0008] Detailed Description of the invention

[0009] Avacincaptad pegol has the following structure: where n is about 485

[0010] Each of the two polyethylenglycol (PEG) chains has a molecular weight of about 20 kDa.

[0011] The aptamer as part of Avacincaptad pegol is disclosed as SEQ ID NO. 1 in the sequence protocol has the following structure:

[0012] 5’- fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUm GfCmG-3T-3' wherein fC and fll = 2' fluoro nucleotides, mG and mA = 2'-0Me nucleotides, all other nucleotides are 2'-OH, and 3T indicates an inverted deoxythymidine. G = Guanine, A = Adenine, C = Cytosine, II = Uracil, and T = Thymine.

[0013] The aptamer sequence without the chemical nucleotide modifications is as follows: CGCCGCGGUCUCAGGCGCUGAGUCUGAGUUUACCUGCGT

[0014] Avacincaptad pegol currently is sold as a liquid in a vial having the following formulation of said liquid (IZERVAY package leaflet, USA):

[0015] - Avacincaptad pegol sodium, 20mg / mL 1 .98 mg / mL Na2HPO4 heptahydrate 0.256 mg / mL NaH2PO4 monohydrate 8.3 mg / mL NaCI in water with pH of 7.3 no anti-microbial preservative

[0016] The product is sold in a kit containing:

[0017] Glass vial having a 4 mL total volume containing about 0.3 mL liquid Avacincaptad pegol formulation

[0018] Sterile 5-micron (= 5 pm) filter needle, 19-gauge x 1.5 inch Empty 1 mL Luer lock syringe with a 0.1 mL dose mark Instruction leaflet Outer package

[0019] The product must be stored at 2-8°C, not be frozen and not be shaken. To prepare the product for use, the provided filter needle is attached to the provided empty syringe and the liquid is withdrawn from the vial via the filter needle. This removes any insoluble material from the to be injected solution. Then the filter needle is replaced by a 30-gauge x 0.1 Inch sterile injection needle suitable for intravitreal (IVT = injection into eyeball) injections, and potential air bubbles in the syringe and any excess volume above 0.1 mL are removed from the syringe. Finally, the remaining 0.1 mL of liquid in the syringe is injected into the eye by intravitreal injection (= injection into the liquid of the eyeball).

[0020] Avacincaptad pegol is currently sold as a liquid in a vial, which prior to injection into the liquid of the eyeball (into the vitreous humor) of a patient needs to be filled into a syringe. This extra step has the following disadvantages: risk of contamination of the pharmaceutical product, resulting in harm to the eye of the treated patient risk of introduction of air-bubbles into the syringe and finally the eye of the patient which can harm the eye of the patient it takes extra worktime and work-cost for the medical personnel to prepare the syringe (filter liquid by use of the filter needle, exchanging the filter-needle for an intravitreal injection needle) the work-step of exchanging the filter-needle for the injection-needle bears the risk of using the wrong (much too big) filter needle instead of the injection needle for the injection of the product into the eye, if this step accidentally is omitted by the user needs a higher amount of liquid of the very costly pharmaceutical formulation to be present in the vial to ensure that a sufficient volume of the medicament can be loaded into the syringe and finally can be injected into the eye of the patient, which extra amount of costly liquid increases the cost of the medicament

[0021] All these disadvantages of the currently offered Avacincaptad pegol formulation, provided as a liquid in a vial, can be avoided by providing the Avacincaptad pegol formulation in a pre-filled syringe.

[0022] Pre-filled syringes could also be used for intravitreal injection of sustained-release formulations such as Silica Matrix- based formulations, e.g. formulations offered by DelSiTech, Turku, Finland. Such formulations might be injected in longer than monthly intervals between injections such as by injections every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or every 12 months. According to DelSiTech their Silica Matrix or composite intravitreal formulations are biodegradable, are suitable for injections using 30-gauge needles and can stable release protein and macromolecule drugs, such as RNA, DNA, and complex carbohydrates from several months up to a year with zero order release kinetics and with low burst or even burst-free release. DelSiTech mentions on their webpage a cooperation with IVERIC BIO, the manufacturer of Avacincaptad pegol (trade names: Izervay®, or Zimura®). Alternatively, to DelSiTEch’s sustained-release formulations other sustained-release formulations can be used, for example PLGA- or PLA-polymers (PGLA = Poly-Lactic Acid-co-Glycolic Acid, PLA = Poly- Lactic Acid).

[0023] Syringes:

[0024] In general, any type of syringe, which is suitable for intravitreal injections, can be used for the invention. Syringes can be made from glass such as Type I borosilicate glass, or polymers such as cyclic olefine polymer or copolymer (COP or COC), or other suitable materials. The size of the syringe is typically about 1 mL, and the syringe typically has a clearly visible mark on the barrel of the syringe, showing the correct position of the plunger in or order to inject the correct volume, which volume typically is 0.05 to 0.1 mL. Low volumes require more precise syringes and more precise injection technique of the user and may result in decreased accuracy of the injected volume, as well as decrease the ease at which the medical personnel can perform a visual inspection of the contents of the syringe for discolorations, particles, or air bubbles. The syringe typically has a Luer-lock connector to assemble an injection needle to it. However, other methods to connect the needle with the syringe are also suitable. To be suitable for intravitreal injection, the needle has a very narrow diameter, typically 31 to 29-gauge, preferably 30-gauge injection needle diameter, and about 0.5 Inch injection needle length. Injection needle and syringe are sterilized and individually packed, or the injection needle is assembled (stalked) with the syringe, and both together are sterilized and then packed. If injection needle and syringe are pre-assembled, a Luer-lock is not needed but still might be used. Separate, sterile packaging of the injection needle and the syringe is more typical and according to the invention is preferred. However, if the injection needle and syringe are pre-assembled, the pre-filled volume of the syringe eventually might be smaller, which would allow to save part of the needed overfill, which would save manufacturing costs, as the liquid formulation of Avacincaptad pegol is a quite costly material. Especially glass syringes are normally siliconized to ensure lubrications and functionality and to ensure easier and more precise injection volume. To avoid silicone droplets to be injected into the eye as a side-effect of the use of siliconized syringes, there are also available silicone-free syringes.

[0025] Syringe and injection needle should be sterilized, e.g. by gas sterilization, using for example, vaporized hydrogen peroxide, ethylene oxide, peracetic acid or nitrogen dioxide. The Avacincaptad pegol solution preferably is sterilized prior to being filled into the syringe by use of non-thermal methods such as filtering.

[0026] Pre-filled syringes can be manufactured by using stoppering technique called vacuum placement or vacuum stoppering, resulting in pre-filled syringes which do contain no or very limited amounts of gas inside the barrel of the syringe. Alternatively pre-filled syringes can be manufactured using vent (slip) stoppering (also called vented placement) resulting in pre-filled syringes with some more headspace (as compared to vacuum placement assembled syringes) which headspace is filled with gas.

[0027] If a pre-filled syringes contains any headspace, the gas in the headspace can be regular air, but preferably would be an inert gas not reacting with the liquid formulation, typically nitrogen. The headspace preferably should be as small as technically possible without undue high manufacturing costs and efforts, e.g. the headspace could be equal or below 0.05 mL, 0.1 mL, 0.2 ml, 0.3 mL, 0.4 mL or 0.5 mL. Alternatively, the headspace could be measured relatively to the volume of liquid formulation in the pre-filled syringe and could be about 50%, about 25% or about 10% of the volume of the liquid formulation in the pre-filled syringe, as measured at regular air-pressure at sea level (about 1.0013 millibar). Too large headspace bears the risk of plunger movement when the syringe is exposed to different atmospheric pressure, e.g. low pressure during airplane shipping. This plunger movement could e.g. pull contaminants into the syringe. Most advantages of pre-filled syringes without headspace will also apply to pre-filled syringes with a certain headspace, e.g. the gas-volume relative to the liquid volume will be much smaller as compared to the currently sold 4 mL vials with only about 0.3 mL liquid Avacincaptad pegol. Therefore, any oxidation due to oxygen in the headspace would be very limited. Also, condensation of solvent inside the headspace would be very limited, and finally also the movement of the liquid in the barrel during transportation still would be very much limited as there is only a limited headspace filled with gas, as compared to the situation in a 4 mL vial filled with only about 0.3 mL liquid.

[0028] Filling and stoppering of pre-filled syringes:

[0029] Pre-filled syringes can be filled and stoppered by different techniques. First the barrel of the syringe is filled with the desired volume of liquid Avacincaptad pegol. In a second step the stopper of the plunger is inserted into the syringe barrel. This can be done for example by use of a vent tube placed on top of the syringe barrel through which the stopper is inserted into the barrel of the syringe. During the insertion process through the vent tube the stopper is compressed and once the compressed stopper reaches the barrel of the syringe the stopper de- compresses and thereby exactly fits into the barrel of the syringe. Alternatively, the stopper can also be placed into the barrel of the syringe by vacuum stoppering. For this process a different vent is placed on top of the syringe barrel, a stopper is inserted into the vent and the space below the stopper in the vent and above the liquid in the syringe barrel is subjected to a vacuum. The vacuum results in the stopper being sucked into the barrel of the syringe. In both cases subsequently the plunger of the syringe is connected to the stopper. Vacuum stoppering results in lower, almost no headspace between the liquid in the syringe and the stopper, and therefore is preferred. Preferably the headspace of the prefilled Syringe of the invention is below about 50%, more preferably below 25%, most preferably below about 10% of the volume of the liquid formulation filled into the prefilled syringe. For example, if the syringe contains 0.2 mL liquid the headspace would be below about 0.1 mL, below about 0.05 mL or below 0.02 mL. Optionally prefilled syringes might be prepared in a way, that the headspace, if there is headspace present, is filled with an inert gas such as nitrogen.

[0030] Non-syrinqe containers without / with low headspace

[0031] The advantages regarding the improved stability of Avacincaptad pegol stored in pre-filled syringes, can also be obtained by using alternative containers different to syringes, if these containers are filled in a way that they contain no headspace, or contain a headspace which is smaller than the headspace of the currently commercially available 4 mL vials filled with about 0.3 mL Avacincaptad pegol liquid formulation. Examples of such containers are regular vials (i.e. , with minimal volume of 4 ml) or smaller, non-regular vials (i.e. , smaller than 4 mL), which are filled with liquid Avacincaptad pegol volumes higher than 0.3 mL. For example a non-regular vial of 2 mL, filled with 1 mL of liquid Avacincaptad pegol would have a headspace of 1 mL and a liquid volume of 1 mL (= about 1-fold headspace relative to liquid = lower risk of stability problems), whereas the current commercial liquid Avacincaptad pegol is sold in a 4 mL vial containing about 0.3 mL Avacincaptad pegol (= about 12-fold higher head-space relative to liquid in the vial = higher risk of stability problems because of more gas in headspace, more condensation of solvent within the headspace, and more space for the liquid to move during transport and storage).

[0032] Also, ampoules could be used instead of regular vials to reduce the headspace above liquid formulations of Avacincaptad pegol in order to improve the stability of Avacincaptad pegol. Optionally any headspace might be filled with an inert gas such as nitrogen. Use of the pre-filled syringes

[0033] Pre-filled syringes can be used with liquid formulations of Avacincaptad pegol, sustained- release formulations of either Avacincaptad pegol or of only the Aptamer part of Avacincaptad pegol lacking the PEG moiety. Pre-filled syringes with liquid or sustained-release formulations may be used in combination with a second ocular therapeutically active substance such as Faricimab, Aflibercept Bevacizumab or Ranibizumab, wherein the second therapeutic active substance is administered simultaneously together with Avacincaptad with a single intravitreal injection or is administered separately to Avacincaptad.

[0034] Ocular diseases which can be treated with Avacincaptad in prefilled syringes can be Geographic Atrophy (GA), nascent GA (= nGA), GA secondary to Age-related Macular Degeneration (AMD), also abbreviated GA 2ndto AMD, wet AMD, dry AMD, neovascular AMD (= nAMD), iRORA (incomplete RPE and outer retinal atrophy), cRORA (complete RPE and outer retinal atrophy), Stargardt’s disease (a genetic form of central vision loss), high-risk drusen combined with a condition selected from the group consisting of risk factors for the progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate AMD, dry AMD, and wet AMD.

[0035] High-risk drusen refers to drusen associated with a high risk of AMD and / or a high risk of disease progression from an earlier-stage AMD to a later-stage AMD. High-risk drusen may have any of the following characteristics. For example, high-risk drusen may be characterized by the presence of at least one druse with a diameter of at least 250 pm observed on fundus biomicroscopy or color fundus photography and / or a total volume of drusen of at least 0.03 mm3 as measured by SD-OCT within a 3 mm diameter circle centered on the fovea. High-risk drusen may have a diameter of at least 300 pm and exist within a 500 pm diameter circle centered on the fovea. In another embodiment, high-risk drusen is characterized by the presence of at least one druse with a diameter of at least about 150 pm. In addition, high-risk drusen may be characterized by other morphological features. Furthermore, high-risk drusen may be characterized in terms of maximum lesion height and diameter, lesion internal reflectivity, presence and extent of overlying intraretinal hyperreflective foci, and choroidal thickness both sub-foveally and below drusen. In addition, high-risk drusen may exhibit hyperreflective foci overlying the drusen, heterogeneous internal reflectivity of drusen, or choroidal thickness less than 135 pm below the drusen baseline. In addition, high-risk drusen may be soft, large, indistinct, and / or confluent. The to be injected volume of Avacincaptad pegol depends on concentration of Avacincaptad pegol and the desired dose of Avacincaptad pegol. The currently marketed product of Avacincaptad pegol according to the manufacturer has a concentration of 20 mg / mL and is intended to be injected at a dose of 2 mg per eye (2 mg on oligonucleotide / Aptamer basis) resulting in a volume of 0.1 mL / per eye. If lower or higher doses such as doses of 0.3 to 5 mg / eye, e.g. 0.3, 1.0, 3.0, 4.0 or 5.0 mg / eye are intended the concentration and volume of liquid Avacincaptad pegol should be adjusted accordingly.

[0036] During preparation of liquid formulations, such as Avacincaptad pegol formulations, it is routine to determine viscosity of the resulting solution, in order to determine if this viscosity allows the proper handling of the liquid solution during its manufacturing process and during its medical use. In the case of Avacincaptad pegol higher concentrations than 20 mg / mL are not feasible due to high viscosities of concentrations above 20 mg / mL. Lower concentrations then 20 mg / mL are possible but are limited by the volume which safely can be injected into the eyeball, which is commonly regarded as 0.1 mL / eye. This means, if a dose of 2 mg / eye is desired, a volume of 0.1 mL / eye with a concentration of 20 mg / mL is chosen. If too high volumes of liquids are injected into the eyeball the pressure inside the eyeball might increase too much, with the associated risk of damage to the pressure-sensitive retina of the eye.

[0037] Viscosity of Avacincaptad aptamer without covalently bound PEG-moieties is probably lower than Avacincaptad pegol viscosity. However, if Avacincaptad aptamer without covalently bound PEG-moieties are combined with an extended-release polymer, this probably will increase again the viscosity, which routinely would be determined and considered during development of liquid formulations in pre-filled syringes.

[0038] The syringe configuration with improved stability offers potential benefits over the less stable vial configuration, which is currently on the market, e.g.:

[0039] Product in the vial needs to be stored refrigerated for long-term storage. If stability is improved (as evidenced by stability tests shown in this application), a long-term stability of the syringe product, stored at room temperature instead of refrigerated condition is possible. This would significantly ease the storage and handling burden of the product in pharmacies, hospitals and in the distribution chain and lower costs for shipping and storage of the product and even would enable to use the product in countries where refrigerated storage of pharmaceutical products is not easily possible.

[0040] With improved stability, expose the product to short-term temperature excursions without negative effects on its quality is possible. The current marketed vial product may only be stored for up to 24 hours at room temperature (20-25°C). It would be possible to have stability at temperatures up to 40°C (relevant in warm climate countries) and for longer than 24 hours.

[0041] Alternative Avacincaptad peqol salts

[0042] Avacincaptad pegol currently is commercially sold as Avacincaptad pegol sodium salt (see Figure 9). All advantages of the invention also apply, if alternative salts or the free acid of Avacincaptad pegol are used instead of the sodium salt. As alternative salts can be used any salts, which are pharmaceutically acceptable salts of Avacincaptad pegol.

[0043] Figure legends:

[0044] Figure 1: Visual inspection of syringes after 6 days stability test at three storage conditions: 2- 8°C, 40°C and 50°C (left to right).

[0045] Figure 2: AEX chromatograms of syringe samples stability samples from conditions 2-8°C, 40°C and 50°C (top to bottom). Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak.

[0046] Figure 3: AEX chromatograms of reference sample 1 stability samples (vials + air) from conditions 2-8°C, 40°C and 50°C (top to bottom). Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak.

[0047] Figure 4: AEX chromatograms of reference sample 2 stability samples (vials + nitrogen) from conditions 2-8°C*, 40°C and 50°C (top to bottom). *Note, the reference condition 2-8°C is taken from reference sample 1. Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak. Figure 5: SEC chromatograms of syringe sample stability samples from conditions 2-8°C, 40°C and 50°C (top to bottom). Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak.

[0048] Figure 6: SEC chromatograms of reference sample 1 stability samples (vials + air) from conditions 2-8°C, 40°C and 50°C (top to bottom). Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak.

[0049] Figure 7: SEC chromatograms of reference sample 2 stability samples (vials + nitrogen) from conditions 2-8°C*, 40°C and 50°C (top to bottom). *Note, the reference condition 2-8°C is taken from reference sample 1. Note: numbers above chromatographic peaks in the chromatograms disclose the area under curve % value of each individual peak.

[0050] Figure 8: Prophetic concentration of Avacincaptad pegol (based on Aptamer content), or the prophetic concentration of the Avacincaptad aptamer with or without PEG part of Avacincaptad pegol. Measurement would be done in the liguid of the human eyeball after a single intravitreal injection at timepoint 0 months of: a sustained release formulation (dashed line) versus Avacincaptad pegol standard formulation in phosphate-buffered saline (solid line).

[0051] Figure 9: Structure of Avacincaptad pegol sodium salt, which was used in all Examples of the invention.

[0052] Figure 10: Avacincaptad pegol peak area% for confirmatory stability samples as measured by the SEC method.

[0053] Figure 11 : Avacincaptad pegol peak area% for confirmatory stability samples as measured by the AEX method.

[0054] Embodiments of the invention:

[0055] 1. In one embodiment the invention deals with a container containing a liguid formulation of Avacincaptad pegol, preferably in its sodium salt form, or in any other pharmaceutically acceptable salt form, wherein said container has a headspace, which is below 50%, preferably below 25%, more preferably below 10% of the volume of the liguid Avacincaptad pegol formulation. In another embodiment the invention deals with a container according to embodiment 1 , wherein said headspace is filled with an inert gas which does not react with the liquid Avacincaptad pegol formulation. In another embodiment of the inventions deals with a container according to embodiment 1 which does not contain a headspace. In another embodiment of the inventions deals with a container according to embodiments 1 to 3, which is a pre-filled syringe suitable for intravitreal injections. In another embodiment of the inventions deals with a container according to embodiments 1 to 4 which contains Avacincaptad pegol sodium. In another embodiment of the inventions deals with a pre-filled syringe suitable for intravitreal injections according to embodiments 1-5 which contains an amount of Avacincaptad pegol sufficient to inject 2 mg of Avacincaptad pegol (2 mg on oligonucleotide basis) into a human eye. In another embodiment of the inventions deals with a pre-filled syringe suitable for intravitreal injections according to embodiments 1-6 which contains Avacincaptad pegol in aqueous phosphate-buffered saline and does not contain an anti-microbial preservative. In another embodiment of the inventions deals with a pre-filled syringe suitable for intravitreal injections according to embodiments 1-7 which contains sufficient volume of Avacincaptad pegol formulation to inject 0.05 to 0.1 mL of the formulation into an eye. In another embodiment of the inventions deals with a kit containing a pre-filled syringe suitable for intravitreal injections according to embodiments 1-8, an instruction leaflet and an outer packaging, and optionally additional material such as gloves, disinfection materials, injection needles, filters attachable to the syringe, waste containers, etc. In another embodiment of the inventions deals with a method to use a pre-filled syringe suitable for intravitreal injections according to embodiments 1-9 for treatment of an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wet AMD, and GA secondary to AMD. In another embodiment of the inventions deals with a method to use the pre-filled syringe suitable for intravitreal injections according to embodiments 1-9 for treatment of an individual having (i) high-risk drusen and

[0056] (ii) an ophthalmological disease, disorder, and / or condition selected from the group consisting of risk factors for the progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate AMD, dry AMD, and wetAMD

[0057] 12. In another embodiment of the inventions deals with a pre-filled syringe suitable for intravitreal injections according to embodiments 1-8 which contains Avacincaptad pegol in a sustained release formulation, e.g. with Silica Matrix bases formulations allowing to extend from monthly injections to longer intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or every 12 months.

[0058] 13. In another embodiment of the inventions deals with a method for preparing a medicament for treating an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wetAMD, and GA secondary to AMD, comprising the step of filling a liquid formulation of Avacincaptad pegol into a syringe suitable for intravitreal injections, preferably at a dose of 2 mg (2 mg on oligonucleotide base) in 0.1 mL injection volume, preferably using vacuum stoppering or vent (slip) stoppering for filling the syringes, more preferably using vacuum stoppering for filling the syringes.

[0059] 14. In another embodiment of the inventions deals with a method for preparing a medicament for treating an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wetAMD, and GA secondary to AMD, wherein a liquid formulation of Avacincaptad pegol is filled into a syringe suitable for intravitreal injections, and wherein said medicament is in the form of a sustained-release formulation.

[0060] Experimental methods and results

[0061] Example 1 : Preparation of samples

[0062] Preparation of Avacincaptad pegol liquid formulation:

[0063] Buffer components were 19.8 mg disodium hydrogen phosphate heptahydrate, 2.89 mg monobasic sodium phosphate dihydrate and 83.0 mg sodium chloride were weighted in a glass beaker. 5 mL of purified water was added and mixed until all buffer components were dissolved. Next, 922.5 mg Avacincaptad pegol was added and mixed until it was completely dissolved. The solution was transferred to 10 mL volumetric flask and the beaker was rinsed two times with purified water for complete transfer of the primary solution. Volumetric flask was filled to the 10 mL mark.

[0064] The contents of the volumetric flask were filtered with the help of a plastic syringe through Pall Acrodisc 13 mm mini-spike, pore size 0.2 pm filter (Merck) directly into 4 mL vials.

[0065] Avacincaptad pegol was manufactured as described in Patent US 7,538,211 B2, the process is shortly described below.

[0066] The oligonucleotide chain was synthesized by solid-phase synthesis (phosphonamidite chemistry; the whole synthesis consists of about 160 reactions) to yield the 39-mer with a 5'- terminal amino linker. A two-step cleavage & deprotection process was employed to cleave the oligonucleotide from the solid support and remove the base-labile protecting groups in the first step, whereas the silyl protecting groups were removed in the second step.

[0067] The Avacincaptad oligonucleotide chain was desalted, purified by AEX, and subsequently desalted again to prepare it for the conjugation step. The activated PEG was then conjugated to the oligonucleotide moiety in a standard reactor (solution chemistry). The desired product, Avacincaptad pegol, was finally purified (AEX), desalted, and lyophilized.

[0068] Reference sample 1 (vial with air):

[0069] 0.3 mL Avacincaptad pegol liquid formulation was filled in glass vials (VIALA13-C4 (2R), manufactured by NUOVA OMPI) having a volume of 4 mL. Vials were closed with rubber stoppers (STOPPER SERUM, 13 MM, FM 140 / 0, FLNC1 , V9024, manufactured by

[0070] DATWYLER). The headspace within the vials contained regular air with natural oxygen content.

[0071] Reference sample 2 (vial with nitrogen):

[0072] Two sample vials, prepared with the method described in the previous paragraph above, were taken and the gas in the headspace was exchanged to nitrogen with the following procedure: sample vials were transferred into a chamber with nitrogen atmosphere and their rubber stoppers removed. Vials were left to stand for approximately 30 minutes to allow for headspace atmosphere to exchange to nitrogen. Sample vials were then capped with rubber stoppers without opening the chamber, as to afford samples with nitrogen headspace.

[0073] Syringe sample:

[0074] Neopak XSI 1ML LONG, 29G syringe, Becton Dickinson, was stoppered with plunger stopper HYPAK TSCF1 M LL 4023 / 50 FL and a plunger rod. The cap of the needle on the syringe was removed and content of vials from Reference sample 1 were drawn into syringe by use of a syringe needle. The cap of the needle was placed back to seal the syringe. The content of the solution in the syringe was about 0.3 mL. Syringes prepared as in example 1 correspond to syringes prepared by vacuum stoppering, as both methods result in the same type of pre-filled syringes, namely pre-filled syringes which have no headspace, or almost no headspace.

[0075] Example 2: Stability tests

[0076] So called “accelerated stability tests” are commonly performed by subjecting pharmaceutical preparations to elevated temperatures, which are above the normal storage temperature of the to be tested pharmaceutical formulation. According to IVERIC bio Inc., the manufacturer of Avacincaptad pegol in liquid form in vials, this product normally has to be stored at temperatures from 2 to 8 °C. Increasing the storage temperature to 40°C or 50°C for a time of for example 6 days was performed to simulate long-term storage of the product at 2-8°C and to determine storage stability of the product. Such stability data is also useful in determining detrimental effects of inadvertent temperature excursions, such as may occur during transport or handling. Each, reference sample 1 (vial with air), reference sample 2 (vial with nitrogen) and syringe sample (no gas headspace) were stored refrigerated at 2-8 °C, in a temperature chamber at 40°C, and in a temperature chamber at 50°C for 6 days. Immediately after storage all samples were tested according to the method of Example 3.

[0077] After stability storage, samples were analyzed to determine their stability under these conditions and after these time-intervals. Analysis was done with anion-exchange liquid chromatography (AEX) to determine extent of degradation (amount of impurities), with size-exclusion chromatography (SEC) to determine, e.g. aggregation (instability of monomeric Avacincaptad pegol), and with UV spectroscopy to determine oligonucleotide concentration.

[0078] After 6 days of stability storage, appearance of syringes was examined. There were not observed any visual changes such as color-changes, precipitates, etc. of the liquid sample within the syringes. Also, no apparent leaking or other mechanical dysfunctionality of the syringes were noticed. After removal of the protective cap, it was easily possible to expel the syringe content by pressing the plunger without any stoppage or difficulties. The liquid content was transparent with no observable precipitation, discoloration, or other visual changes. The syringe samples after the stability test are shown in Figure 1.

[0079] The mass of entire filled syringes was taken before and after stability test. The change in mass was determined by subtracting the initial mass from the final mass. The change in mass was less than 3 milligrams for each of the three syringes stored at 2-8°C, 40°C, and 50°C, corresponding to less than 1% loss of the syringe content. This shows that there was no product loss / leakage or evaporation throughout the stability test period. In conclusions a syringe is an appropriate container for Avacincaptad pegol solution.

[0080] The concentration of Avacincaptad pegol in the syringe-stored samples was equal to that of the vial sample. There was no reduction of Avacincaptad pegol concentration due to, e.g. adsorption to the syringe interior / barrel, the stopper of the plunger, or the needle.

[0081] Example 3: Analytical methods to determine Avacincaptad pegol stability

[0082] The result of stability testing highly depends on the type of stability test done, and the type of molecule tested, because different stability tests measure different aspects of stability, e.g. the results of the AEX-method (mainly measures degradation) and the SEC-method (mainly measures aggregation) are different. This explains, why the stability values of e.g. the AEX- and the SEC-method in Table 1 show different values depending on the type of stability test used.

[0083] Also, if different molecules are tested using the same stability test, each type of stability test likely will measure different stabilities, depending on type of molecule measured. For example, measuring the stability of Avacincaptad pegol with a certain stability test, will result in different values as compared to measuring the Avacincaptad aptamer (without covalently linked PEG- moiety) using the same stability test. For example, AEX measures Avacincaptad pegol degradation products based on ion-ion interaction, meaning molecules with charges, such as oligonucleotides or aptamer sequences can be measured well, whereas PEG-molecules which are not covalently connected to an aptamer do not bind very well AEX chromatography columns. On the other hand, SEC-stability tests are efficient in determining large molecules, e.g. large PEG-molecules or PEG-aggregates, but are not so well suited for measuring small degradation products of Avacincaptad pegol.

[0084] Accordingly, we measured the stability of Avacincaptad pegol using AEX- as well as SEC- stability tests, as Avacincaptad pegol contains different molecular properties (heavily charged aptamer sequence and large PEG-polymers), and each stability tests covers specific stability aspects of the Avacincaptad pegol molecule.

[0085] It is generally understood that the stability, as determined with the used stability tests, reflects the purity of the pharmaceutically active molecule Avacincaptad pegol. This purity is of importance for the suitability of the Avacincaptad pegol for use as a medicament to treat human eye diseases. Aggregates of Avacincaptad pegol, if injected into the liquid within the eyeball (= the vitreous humor), could result in particles floating around in the vitreous humor within the eyeball which could negatively affect vision of the patient. On the other hand, small degradation products, e.g. fragments of the aptamer sequence likely will have a different three-dimensional structure and therefore probably will not bind, or will only bind with lower affinity to the Avacincaptad pegol target molecule, Complement C5, and therefore would be inactive, or less active as a pharmaceutical substance. This would at least change the effective concentration of the Avacincaptad pegol medicament applied to the eye. In the worst-case, aptamer fragments originating from instable or degraded Avacincaptad pegol, would bind to other, non-C5- complement proteins and have completely different unpredictable effects on biochemical functions within the human eye. This could lead to serious, negative side-effects for the patients. Therefore, stability and purity of Avacincaptad pegol is very important for its save and effective use to treat eye diseases. AEX, Anion Exchange chromatography

[0086] Mobile phase A was 20 millimolar sodium phosphate buffer, pH=7 with 5% of acetonitrile. Mobile phase B was 1 molar sodium bromide solution. Column type used was DNAPac PA200 RS 4 pm 150x4.6 mm anion exchange columns designed for nucleic acids (Thermo Scientific), heated to 30 °C. The UV detector was set to wavelength 260 nm. Mobile phase flow was 0.6 mL / min with a gradient from 80% to 65% mobile phase A from minute 0 to minute 26, followed by 65% to 40% mobile phase A from minute 26 to minute 34, returning to 80% mobile phase A at minute 34.1 , eguilibrating the column up to minute 40. Samples were diluted to concentration of about 0.2 mg / mL (calculated based on oligonucleotide content), using phosphate buffered saline as the diluent. Injection volume was 5 microliters. Area under the curve values for peaks of the chromatogram were determined using Empower software version 3 (Waters). Using this method, the peak representing Avacincaptad pegol eluted at approximately 23 minutes. Peaks representing Avacincaptad pegol impurities eluted either partially resolved from or close to the main peak (early eluting impurities), or as wide peaks at retention times above 26 minutes (late eluting impurities).

[0087] Phosphate buffered saline was prepared from commercially available product from Sigma (product number P4417): One tablet of P4417 dissolved in 200 mL of deionized water yields 0.01 M phosphate buffer, 0.0027 M potassium chloride and 0.137 M sodium chloride, pH 7.4, at 25 °C.

[0088] Determination of Avacincaptad pegol concentration by UV method: oligonucleotide concentration was determined by measuring absorbance at wavelength 260 nm and calculating oligonucleotide content using the molar extinction coefficient method.

[0089] AEX is primarily determining the stability of the Avacincaptad pegol molecule regarding degradation into fragments, which show different strength of ion-ion interaction with the AEX chromatographic residues and therefore can be separated from each other by use of AEX.

[0090] Size Exclusion chromatography

[0091] Mobile phase was phosphate buffered saline with 5% of 2-propanol, filtered through a 0.2 pm filter. Column type was XBridge Premier Protein SEC Column, 250A, 2.5 pm, 4.6 mm x 300mm (Waters Corporation), held at room temperature. UV detector was set to wavelength 260 nm and recorded for 20 minutes. Mobile phase flow was 0.3 mL / min. Samples were diluted to concentration of about 0.2 mg / mL (calculated based on oligonucleotide content), using phosphate buffered saline as the diluent. Injection volume was 5 microliters. Using this method, the main peak representing Avacincaptad pegol eluted after approximately 6 - 7 minutes. Area under the curve values for peaks of the chromatogram were determined using Empower software version 3 (Waters). Peaks representing Avacincaptad pegol eluted at timepoint of about 7.5 minutes of the SEC chromatography. Impurities eluted either earlier than the Avacincaptad pegol peak (aggregation impurities) or after the Avacincaptad pegol peak (low molecular wight impurities). SEC primarily separates molecules based on their physical size and molecular weight and therefore is especially suited to separate larger molecules such as proteins, nucleic acids, polymers and other macromolecules, such as Avacincaptad pegol, a macromolecule consisting of a large 39-mer of an Aptamer (nucleic acid) chemically coupled to an even larger polyethylene glycol (polymer). If such an already large molecule forms dimers, multimers or even bigger aggregates, these can be separated from non-aggregated Avacincaptad pegol molecules. In general, the larger a molecule is, the earlier it elutes from an SEC column.

[0092] Table 1 : Analytical results of concentration, thus results are not reported (NR). AEX = anion exchange chromatography, SEC = size exclusion chromatography, %-values in Table 1 represent the area under the curve of the data in Figures 2-7 of the peak corresponding to intact, non-degraded, monomeric Avacincaptad pegol.

[0093] With stability is meant the amount of Avacincaptad pegol molecules (given in % in Table 1), which after storage, e.g. after storage for 6 days at 2-8°C, 40°C or 50°C still are chemically intact, non-aggregated monomers of Avacincaptad pegol molecules. This means, the Avacincaptad pegol molecules are not degraded into fragments or chemically modified molecules and are not aggregated to dimers or to aggregates of more than two Avacincaptad pegol molecules which aggregates are also regarded as degradation in this patent application. Such aggregates can also comprise one or more Avacincaptad pegol molecules aggregated with fragments or chemically modified Avacincaptad pegol molecules, which might explain the shoulder to the right of the main peak in panel 3 of Figure 6.

[0094] The stability of Avacincaptad pegol after stability testing decreased only slightly in the syringe samples. The AEX-measured stability decreased by 2.8% at 40°C and by 10.6 % at 50°C. SEC- measured (SEC = Size Exclusion Chromatography) stability decreased by 0.0% at 40°C and by 0.3% at 50°C. On the other hand, the decrease in AEX-measured stability of the reference sample 1 stored in vials with air was significant with the sample almost completely decomposed at 50°C and only 26.1% stability remaining at 40°C.

[0095] Decrease in stability of samples stored in vials, as measured by SEC, was also very significant. This is depicted by two peaks after storage at 40 °C in vials with air or in vials with nitrogen (Figures 6 and 7, middle panel), whereas the Avacincaptad pegol of all samples stored in syringes, if measured by SEC, even if stored at 40°C or at 50°C, had only one Avacincaptad pegol peak (Figure 5, all three panels), meaning syringe-stored samples were stable under these accelerated stability test conditions. AEX and SEC stability after 6 days storage at 40 °C or 50 °C of reference sample 2 stored under nitrogen (= protective gas) was more than 2-fold more stable than reference sample 1 stored under air (= containing oxygen). This clearly shows a protective effect of nitrogen gas compared to storage under air (see data in Table 1). However, and surprisingly, storage in syringes was still much more effective in stabilizing Avacincaptad pegol, then storage under nitrogen gas in a vial (Reference sample 2).

[0096] It is hypothesized, that the mechanism of protective action by the syringe example is due to exclusion of oxygen contact with Avacincaptad pegol solution. Such an effect could be achieved by exchanging the headspace in the vial with an inert gas, such as nitrogen. This was done in reference sample 2, where the oxygen was excluded from contacting Avacincaptad pegol solution. It was surprisingly found that the level of Avacincaptad pegol degradation was still quite high in the stability test (see data in Table 1). Although some improvement in stability was observed with nitrogen use as an inert, protective gas, there is a very clear, further improvement in stability of the syringe sample (no headspace = no gas) over the reference sample 2 (nitrogen gas in headspace). Thus, exclusion of oxygen from contacting Avacincaptad pegol solution is not the only protective mechanism in the syringe samples.

[0097] One mechanism of Avacincaptad pegol solution degradation in vials may be related to evaporation of water from the solution, causing an increase in Avacincaptad pegol concentration, which leads to aggregation and decreased stability. One could try to improve stability, e.g. by decreasing the headspace over Avacincaptad pegol solution resulting in decreased water evaporation. Or alternatively, one might decrease Avacincaptad pegol concentration in the solution. Another option may be to increase the amount of Avacincaptad pegol solution inside the vial, resulting in a reduced evaporation effect. The success of such approaches can be tested using the methods described in stability and analytical methods sections (Example 3). However, all these potential vial-improvements have disadvantages over syringes: decreasing the headspace in vials requires the use of smaller vials which are more difficult to fill with such small volumes of about 0.3 mL Avacincaptad pegol solution, and such smaller vials are also more difficult to handle by the medical personnel during preparation of the syringes decreasing the Avacincaptad pegol concentration in the liquid formulation would require increasing the injection volume into the eye, with is not desired, because higher injecting volumes result in higher transient increase of the pressure in the liquid within the eyeball, which increases the risk of damage to the retina of the eye

[0098] Increasing the amount (volume) of Avacincaptad pegol solution filled into each vial without changing its concentration would very significantly increase the cost of the product, as Avacincaptad pegol is a very costly substance.

[0099] Also, there is increased mechanical movement of the liquid pharmaceutical formulation within the vial container, whereas within the syringe-barrel, with no or very small headspace, the liquid is subjected only to very limited mechanical movement. This increased mechanical movement within the vial might physically stress the large molecule Avacincaptad pegol during storage and transportation, potentially resulting in decreases stability due to degradation and / or aggregation.

[0100] Example 4 (prophetic example): Sustained-release formulations of Avacincaptad pegol

[0101] Avacincaptad pegol is prepared in a sustained- or extended-release formulation using a Silica Matrix, such as those extended-release Silica Matrix materials developed by DelSiTech, Turko, Finland. There are further suitable polymers which might be used for extended-release formulations such as PLGA or PLA polymers (PGLA = Poly-Lactic Acid-co-Glycolic Acid, PLA = Poly- Lactic Acid). The corresponding extended-release formulation is injected into the eye of a human effected with Geographic Atrophy secondary to Age-related Macular Degeneration (GA 2ndto AMD). Sustained release enables to treat GA 2ndto AMD to be treated by intravitreal injections of Avacincaptad pegol in longer intervals than 1 months, such as intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or every 12 months. The intravitreal release profile could look like shown in prophetic Figure 5. This would have the advantage of less frequent injections with less risks of injection related side effects, higher patient compliance to get the intravitreal injections in the correct time schedule, lower medical costs as less frequent medical doctor consultations are needed, and a more constant concentration of Avacincaptad pegol in the eyeball resulting in a more stable, continuous treatment of GA 2ndto AMD without initial high peaks of Avacincaptad pegol immediately after the intravitreal injection.

[0102] The total amount of Avacincaptad pegol within said extended-release formulation could be different to a dose of 2 mg (based on oligonucleotide / Aptamer content, of the currently marketed liquid in a vial formulation), depending on the duration of the extended release desired for the extended-release product. Also, the active pharmaceutical component within such an extended release product optionally could lack the PEG-part of the Avacincaptad pegol, as the PEG is functioning to protect the oligonucleotide from degradation (which is also accomplished by e.g. a Silica Matrix as offered by DelSiTech), and the PEG-part of Avacincaptad pegol to some limited extend also might result in an extended release of the active pharmaceutical agent, which extended-release functionality could be taken over by the Silica or other polymer matrix. Therefore, the active pharmaceutical agent present in such a Silica or other polymer matrixbased extended-release formulation optionally could comprise only the Aptamer part of Avacincaptad pegol. This would enable to have higher loads of Aptamer within the extended- release formulation, which eventually would be needed to have enough Aptamer substance to support extended-release over prolonged periods of time.

[0103] Example 5: confirmatory samples

[0104] This example was performed, in order to confirm and repeat example 2, and in order to check if syringes in general are suitable for increasing the stability of liquid Avacincaptad pegol formulations. Six samples of Avacincaptad pegol solution, packed into syringes and three samples of Avacincaptad pegol solution, packed into vials were produced and tested for stability. Some of the vials and the syringes in the confirmatory samples of table 2 were the same types of vials and syringes used in example 2. The other syringes, samples 1-5 and 9, represent further types of syringes in order to confirm, that syringes in general as suitable to improve stability of Avacincaptad pegol formulations. One vial and one syringe of each sample no. was placed at 40°C for 6 days and another was placed at 50°C for 6 days. After storage, samples were tested using SEC and AEX analytical methods, as described in example 3.

[0105] Sample details are given in table 2 and results are given in table 3 and figures 10 and 11.

[0106] Table 2: Sample details for confirmatory samples.

[0107] Table 3: Results for confirmatory samples. Avacincaptad pegol stability, given as area % of the main chromatographic peak.

[0108] Table 3 above contains the stability results of Example 2, combined with the stability results of Example 5. Samples tested in Example 2 and 5 which are directly comparable to each other are: • Samples from Line no. G and H (same type of syringe tested)

[0109] • Samples from Line no. J, K and L (same type of vial with air in headspace tested)

[0110] • Samples from Line no. N and O (same type of vial with nitrogen in headspace tested) The results show consistently better stability of Avacincaptad pegol solution, stored in syringes, compared to solutions stored in vials. After 6 days at 40°C and 50°C, the SEC peak of Avacincaptad pegol is above 90 area % for syringes and below 70 area % for vials. The AEX peak of Avacincaptad pegol is above about 80 area % for syringes and below 40 area % for vials (except for one vial sample where it was 65 area %). The variance of the stability in vials is much bigger, as compared to the variance of the stability in syringes, even if different types of syringes are compared. This is another advantage of Avacincaptad pegol solution storage in syringes as compared to storage in vials.

[0111] The short-term stability test was performed for 6 days at elevated temperature (40°C and 50°C). For liquid products, a common storage temperature is refrigerated to 2-8°C. If, however, an improved stability is found, a storage temperature at room temperature may be proposed, if supported by long-term stability data at 25°C. Such a test would follow regulatory guidelines (ICH harmonized tripartite guideline: Stability testing of new drug substances and products) and involve storage at 25°C and testing after 3, 6, 9, 12, 18 and 24 months and yearly afterwards.

Claims

Claims:

1. Container containing a liquid formulation of Avacincaptad pegol, preferably in its sodium salt form, or in any other pharmaceutically acceptable salt form, wherein said container has a headspace, which is below 50%, preferably below 25%, more preferably below 10% of the volume of the liquid Avacincaptad pegol formulation.

2. Container according to claim 1 , wherein said headspace is filled with an inert gas which does not react with the liquid Avacincaptad pegol formulation.

3. Container according to claim 1 , which does not contain a headspace.

4. Container according to claims 1 to 3, which is a pre-filled syringe suitable for intravitreal injections.

5. Container according to claims 1 to 4, which contains Avacincaptad pegol sodium.

6. Pre-filled syringe suitable for intravitreal injections according to claim 1-5 which contains an amount of Avacincaptad pegol sufficient to inject 2 mg of Avacincaptad pegol (2 mg on oligonucleotide basis) into a human eye.

7. Pre-filled syringe suitable for intravitreal injections according to claim 1-6 which contains Avacincaptad pegol in aqueous phosphate-buffered saline and does not contain an antimicrobial preservative.

8. Pre-filled syringe suitable for intravitreal injections according to claim 1-7 which contains sufficient volume of Avacincaptad pegol formulation to inject 0.05 to 0.1 mL of the formulation into an eye.

9. Kit containing a pre-filled syringe suitable for intravitreal injections according to claims 1- 8, an instruction leaflet and an outer packaging, and optionally additional material such as gloves, disinfection materials, injection needles, filters attachable to the syringe, waste containers, etc.

10. Use of a pre-filled syringe suitable for intravitreal injections according to claims 1-9 for treatment of an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wet AMD, and GA secondary to AMD.

11. Use of the pre-filled syringe suitable for intravitreal injections according to claim 1-9 for treatment of an individual having(i) high-risk drusen and(ii) an ophthalmological disease, disorder, and / or condition selected from the group consisting of risk factors for the progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate AMD, dry AMD, and wetAMD12. Pre-filled syringe suitable for intravitreal injections according to claim 1-8 which contains Avacincaptad pegol in a sustained release formulation, e.g. with Silica Matrix bases formulations allowing to extend from monthly injections to longer intervals of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or every 12 months.

13. Method for preparing a medicament for treating an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wetAMD, and GA secondary to AMD, comprising the step of filling a liquid formulation of Avacincaptad pegol into a syringe suitable for intravitreal injections, preferably at a dose of 2 mg (2 mg on oligonucleotide base) in 0.1 mL injection volume, preferably using vacuum stoppering or vent (slip) stoppering for filling the syringes, more preferably using vacuum stoppering for filling the syringes.

14. Method for preparing a medicament for treating an ophthalmological disease selected from incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), nascent Geographic Atrophy (nGA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), Geographic Atrophy (GA), Age-related Macular Degeneration (AMD), intermediate AMD, dry AMD, wetAMD, and GA secondary to AMD, wherein a liquid formulation of Avacincaptad pegol is filled into a syringe suitable for intravitreal injections, and wherein said medicament is in the form of a sustained-release formulation.

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