Low concentration VEGF receptor fusion protein containing formulations

Abstract

The present invention provides ophthalmic formulations having low concentrations of vascular endothelial growth factor (VEGF) receptor fusion protein and high stability during storage for extended release from an implantable reservoir under physiological conditions. Methods for treating angiogenic eye disorders using the low concentration formulations are also provided.

Description

LOW CONCENTRATION VEGF RECEPTOR FUSION PROTEIN CONTAINING FORMULATIONS

[0001] This Application claims the benefit of U.S. provisional patent application no. 63 / 631 ,782; filed April 9, 2024, which is herein incorporated by reference in its entirety.REFERENCE TO A SEQUENCE LISTING

[0002] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 11549WO01_Sequence, created on April 9, 2025 and containing 5,449 bytes.TECHNICAL FIELD

[0003] Embodiments herein relate generally to low concentration VEGF receptor fusion protein containing formulations suitable for ocular administration from an implantable device. More particularly, embodiments herein provide liquid pharmaceutical formulations for intravitreal administration, where the formulations include less than 40 mg / ml VEGF receptor fusion protein, and show pharmaceutically acceptable potency and stability under physiological conditions for a period of up to six months or more.BACKGROUND OF THE INVENTION

[0004] The development of a therapeutically useful liquid formulation requires a combination of ingredients, at differing amounts, to provide a functional and stable delivery vehicle for a drug of interest. This is particularly true where the drug is a protein, which may be subject to a variety of degradation pathways, including aggregation and fragmentation. To ensure the desired activity and administration, such formulations typically require a pharmaceutically acceptable potency and protein stability, which may be influenced by the specific formulation excipients and concentrations, as well as the protein concentration.

[0005] Ocular delivery of therapeutic proteins from intraocular implants has gained popularity in recent years, and both nonbiodegradable and biodegradable are available in the market (Shastri et al., Pharmaceutics, 15, 205, pp. 1 -40, 2023). Such devices can deliver therapeutics with a constant rate directly at the ocular site, but without the need to perform repeated injections intravitreally. One such device is a micropump designed to be implanted episclerally in the superotemporal quadrant to deliver multiple microdoses of a drug directly into the vitreous cavity. The micropump is an example of a microelectromechanical systems (MEMS) device consisting of a drug reservoir with a refill port, a battery, electronics, and an electrolysis chamber to deliver the desired dosage volume when the formed gases (H2and O2) generate pressure in the reservoir forcing the drug through the cannula then these gases recombine to form water when the pump isturned off. The reservoir of the micropump can be refilled at desired intervals to extend its useful lifetime (Gutierrez-Hernandez et al., Tran Vis Sci Tech., 3(3):9, pp. 1 -13, 2014; Humayan et al., Trans Vis Sci Tech., 3(6) :5, pp. 1-8, 2014).

[0006] Delivery of therapeutic proteins from implantable devices, while desirable to ease administration burdens on patients and healthcare providers, presents a new set of formulation challenges. Protein stability and potency are more difficult to maintain at higher temperatures (e.g., physiological temperature), especially for extended periods of storage time in the reservoir of an implanted delivery device.

[0007] One such protein in need of formulations for maintenance of stability and potency under physiological conditions for extended periods is the vascular endothelial growth factor (VEGF) receptor fusion protein. VEGF receptor fusion proteins are used to block VEGF function in a number of ophthalmic formulations, for example, EYLEA® (Regeneron Pharmaceuticals, Inc.). VEGF receptor fusion protein containing formulations that are capable of maintaining stability and potency under physiological conditions for extended periods could allow for use of such protein formulations in implantable delivery devices to provide for frequent dosing without the need for repeated intravitreal injections.

[0008] The present invention is directed toward overcoming one or more of the problems discussed above.SUMMARY OF THE INVENTION

[0009] Various embodiments described herein encompass stable low concentration protein containing formulations (e.g., which are suitable for intravitreal administration from a sustained delivery system (SDS), e.g., a ocular implantable device), and in particular, low concentration vascular endothelial growth factor (VEGF) receptor fusion protein containing formulations. Low concentration VEGF receptor fusion protein containing formulations that are stable for a period of up to at least six months under physiological conditions (e.g., 37°C) provide a number of benefits, including reduced ocular administration volumes, and reduction or elimination of the need for intraocular injections.

[0010] The present invention provides an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein (e.g., aflibercept), anti-VEGF antibody or antigen-binding fragment or VEGF binding molecule at a concentration of less than or equal to about 25 mg / ml; a thermal stabilizer; a buffer; and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2. The present invention provides aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein (e.g., aflibercept), at a concentration of less than or equal to about 25 mg / ml; a sugar; a buffer (e.g., a histidine-based buffer); and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2. The present invention provides an aqueous pharmaceutical formulation comprising: a VEGFreceptor fusion protein (e.g., aflibercept), at a concentration of less than or equal to about 25 mg / ml; a sugar (e.g., sucrose); a histidine-based buffer; and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2. The present invention provides an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein (e.g., aflibercept), at a concentration of less than or equal to about 25 mg / ml; a sugar; a histidine- based buffer; and polysorbate; wherein the formulation has a pH of about 5.8 to about 6.2. The present invention provides an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein (e.g., aflibercept), at a concentration of less than or equal to about 25 mg / ml; sucrose; a histidine-based buffer; and polysorbate; wherein the formulation has a pH of about 5.8 to about 6.2. The present invention provides an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein (e.g., aflibercept) at a concentration of less than or equal to about 25 mg / ml; about 10%-25% w / v sucrose; a histidine-based buffer; and about 0.02%-0.04% w / v non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2.

[0011] Preferably, such formulation are suitable for intravitreal administration (e.g., intravitreal administration from a sustained delivery system, e.g., a ocular implantable device).

[0012] The present invention provides an aqueous pharmaceutical formulation including thermal stabilizer (e.g., a sugar such as sucrose) and VEGF receptor fusion protein (e.g., aflibercept) at a molar ratio of thermal stabilizer to VEGF receptor fusion protein of less than about 350, less than about 700, less than about 1400, less than about 2300, or less than about 5700.

[0013] The present invention provides an aqueous pharmaceutical formulation including a thermal stabilizer (e.g., a sugar such as sucrose), VEGF receptor fusion protein (e.g., aflibercept) at a concentration of about 10 mg / ml; a buffer which is a histidine-based buffer; pH of about 5.8; and a molar ratio of thermal stabilizer to VEGF receptor fusion protein (e.g., aflibercept) is less than about 2300.

[0014] In an embodiment of the invention, VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is: (i) a VEGF receptor fusion protein comprising two polypeptides that comprise (1 ) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232- 457 of SEQ ID NO:2; (ii) a VEGF receptor fusion protein comprising two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of a VEGFR2, and a multimerizing component; (iii) a VEGF receptor fusion protein comprising two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2,an Ig domain 4 of VEGFR2 and a multimerizing component; (iv) a VEGF receptor fusion protein comprising two VEGFR1 R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO:1 ; or (v) selected from the group consisting of: bevacizumab, ranibizumab, pegaptanib, brolucizumab, an anti- VEGF DARPin and a bispecific anti- VEGF / ANG2 antibody. Preferably, the VEGF receptor fusion protein (e.g., aflibercept or conbercept) or anti-VEGF antibody or antibody fragment or VEGF binding molecule is a VEGF receptor fusion protein, preferably aflibercept. In an embodiment of the invention, the VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is a VEGF receptor fusion protein at a concentration of from about 10 mg / ml to about 20 mg / ml (e.g., about 10 mg / ml; about 10.5 mg / ml; about 11 mg / ml; about 11 .5 mg / ml; about 12 mg / ml; about 12.5 mg / ml; about 13 mg / ml; about 13.5 mg / ml; about 14 mg / ml; about 14.5 mg / ml; about 15 mg / ml; about 15.5 mg / ml; about 16 mg / ml; about 16.5 mg / ml; about 17 mg / ml; about 17.5 mg / ml; about 18 mg / ml; about 18.5 mg / ml; about 19 mg / ml; about 19.5 mg / ml; or about 20 mg / ml.

[0015] In an embodiment of the invention, the formulation is characterized such that: (i) the osmolality is about 400 to about 850 mmol / Kg; and / or (ii) the viscosity is from about 1 -3 cP at 20°C. In an embodiment of the invention, the formulation is isotonic or near isotonic. In an embodiment of the invention, the formulation pH is about 5.8.

[0016] In an embodiment of the invention, the thermal stabilizer is a sugar, a polyol sugar and / or an amino acid (e.g., sucrose, trehalose, erythritol, mannitol, xylitol, isomalt, lactitol, threitol, maltitol, sorbitol, L-proline, L-arginine, L-arginine monohydrochloride, a substituted acrylamide, propane sulfonic acid, glycerol and / or taurine). For example, in an embodiment of the invention, the concentration of thermal stabilizer is about 10-25% w / v, e.g., 15%-20% w / v sucrose.

[0017] In an embodiment of the invention, the non-ionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 and mixtures thereof, e.g., polysorbate 20. In an embodiment of the invention, the formulation includes 0.03% w / v non-ionic surfactant.

[0018] In an embodiment of the invention, the buffer is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer, and / or a citrate-based buffer, preferably histidine-based buffer, e.g., including histidine hydrochloride, e.g., about 5 mM to 15 mM (e.g., 10 mM) histidine-based buffer.

[0019] In an embodiment of the invention, the percentage of high molecular weight (HMW) species increases after storage (e.g., storage in a container, for example, an implantable ocular device, for example, in or on an eye) at about 37°C for about 6 months by about 1% or less, 2% or less, 3% or less, or 4% or less; and / or the total percentage of high molecularweight species after storage at about 37°C for about 6 months is about 2% or less, 3% or less, 4% or less, or 5% or less; and / or the total percentage of high molecular weight species immediately after manufacture is about 1% or less; and / or the total percentage of high molecular weight species after storage at about 37°C for about 6 months is less than that of a formulation having: 40 mg / ml aflibercept, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20, 5% (w / v) sucrose, pH6.2; or having: 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03 % (w / v) polysorbate 20, 50 mM L-arginine monohydrochloride, pH 5.8; after about 6 months storage at about 37°C.

[0020] The present invention provides a formulation selected from the group consisting of: Formulation A: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation B: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation C: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation D: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation E: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation F: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation G: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation H: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation I: I Q- 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation J: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation K: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation L: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation M: 10-20 mg / ml ± 1 mg / ml VEGFreceptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation N: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation O: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation P: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation Q: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation R: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation S: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation T: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation U: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation V: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation W: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation X: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation Y: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation Z: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation AA: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation BB: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation CC: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation DD: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-basedbuffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation EE: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation FF: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation GG: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation HH: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation II: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation JJ: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation KK: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation LL: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation MM: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation NN: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation OO: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation PP: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation QQ: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation RR: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation SS: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation TT: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation UU: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation VV: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ±0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation WW: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation XX: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation YY: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation ZZ: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation AAA: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation BBB: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation CCC: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation DDD: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation EEE: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation FFF: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation GGG: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation HHH: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation III: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation JJJ: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation KKK: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation LLL: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation MMM: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation NNN: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ±0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation OOO: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation PPP: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation QQQ: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation RRR: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation SSS: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; or Formulation TTT: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8. In an embodiment of the invention, formulation A-TTT is characterized such that it includes a percentage of high molecular weight species increases after storage (e.g., storage in a container, for example, an implantable ocular device, e.g., in or on an eye) at about 37°C for about 6 months by about 1% or less, 2% or less, 3% or less, or 4% or less; and / or a total percentage of high molecular weight species after storage at about 37°C for about 6 months is about 2% or less, 3% or less, 4% or less, or 5% or less; and / or a total percentage of high molecular weight species immediately after manufacture is about 1% or less; and / or a total percentage of high molecular weight species after storage at about 37°C for about 6 months is less than that of a formulation having: 40 mg / ml aflibercept, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20, 5% (w / v) sucrose, pH6.2; or having: 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03 % (w / v) polysorbate 20, 50 mM L-arginine monohydrochloride, pH 5.8; after about 6 months storage at about 37°C.

[0021] In an embodiment of the invention, an aqueous pharmaceutical formulation of the present invention does not contain NaCI; and / or does not contain arginine.

[0022] The present invention provides a container including a formulation as set forth herein, for example, which is a vial, syringe, autoinjector, or pre-filled syringe.

[0023] A formulation of the present invention may be in a sustained delivery system, e.g., a ocular implantable device {e.g., which is refillable), an injectable intravitreal implant, an intrascleral implant, or an episcleral implant. In an embodiment of the invention, the ocular implantable device is a micropump. A micropump is a type of device that delivers a substance actively (as opposed to passively by simple diffusion). In an embodiment of the invention, the ocular implantable device is refillable.

[0024] The present invention also provides a method for preparing a formulation of the present invention including combining the components of said formulation into a single composition. The method may further includes the step of loading a volume of the formulation into a container or sustained delivery system, e.g., a ocular implantable device.

[0025] The present invention also provides a method for administering a formulation of the present invention to a subject (e.g., a subject suffering from an angiogenic eye disorder (e.g., wet AMD, DR, DME and / or ME-RVO)), comprising loading the formulation into a sustained delivery system, e.g., a ocular implantable device, for intravitreal administration into an eye of the subject such that the device proceeds to introduce the formulation into the eye. In an embodiment of the invention, the sustained delivery system, e.g., a ocular implantable device, has been previously implanted into or onto the eye of the subject; or the method further comprises implanting the device into or onto the eye.

[0026] The present invention also provides a method for treating an angiogenic eye disorder (e.g., wet AMD, DR, DME and / or ME-RVO) in a subject in need thereof comprising intraocularly administering about 0.01-0.4 mg / day VEGF receptor fusion protein (e.g., in an aqueous pharmaceutical formulation) to one or more eyes of the subject.

[0027] The present invention also provides a method for treating an angiogenic eye disorder (e.g., wet AMD, DR, DME and / or ME-RVO) in a subject in need thereof comprising intraocularly administering a therapeutically effective dose of formulation of the present invention to one or more eyes of the subject, e.g., wherein the dose is administered from a sustained delivery system, e.g., a ocular implantable device. For example, at a dose of 0.01 -0.4 mg / day delivered continuously. In an embodiment of the invention, about 0.001 ml of the formulation is delivered per day.

[0028] The present invention also provides a method for treating an angiogenic eye disorder (e.g., wet AMD, DR, DME and / or ME-RVO) in a subject in need thereof, comprising loading a volume of the formulation of the present invention into a sustained delivery system, e.g., a ocular implantable device, which delivers a dose of the formulation into an eye of the subject at a given rate over (e.g., continuously) a dosing period (e.g., 3-6 months, 6-12 months, 6 months, more than 6 months, or less than 6 months). In an embodiment of the invention, the method further includes implanting the sustained delivery system, e.g., a ocular implantable device, into or onto the eye of the subject; or the sustained delivery system, e.g., a ocular implantable device, has been previously implanted into or onto the eye of the subject.

[0029] In an embodiment of the invention, the angiogenic eye disorder is age-related macular degeneration (wet), macular edema, macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO) branch retinalvein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and / or proliferative diabetic retinopathy.

[0030] The present invention also provides a kit comprising a container containing a formulation of the present invention, and instructions for loading a volume of the formulation into a sustained delivery system, e.g., a ocular implantable device. In an embodiment of the invention, the ocular implantable devices is a micropump, is refillable, an injectable intravitreal implant, an intrascleral implant, an episcleral implant. In an embodiment of the invention, the kit includes instructions for loading comprise instructions for initially filing a reservoir of the ocular implantable device with the formulation, and instructions for refilling the reservoir of the ocular implantable device with the formulation.

[0031] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges and all values falling within such ranges are encompassed within the scope of the present disclosure. Each of the values discussed above or herein may be expressed with a variation of 1%, 5%, 10% or 20%. Other embodiments will become apparent from a review of the ensuing detailed description.DETAILED DESCRIPTION

[0032] The present invention provides formulations having low concentrations of VEGF receptor fusion proteins e.g., aflibercept), showing excellent functional and storage properties under physiological conditions to facilitate use of these formulations in implantable devices for administration of the therapeutic VEGF receptor fusion protein to treat eye diseases or disorders, or cancer. Sustained delivery systems, such as ocular implantable devices, are known in the art. Some ocular implantable devices, such as the port delivery system and the micropump are generally refillable (e.g., about every six months) following a dosing period during which time the drug product contained within the ocular implantable device is subjected to physiological temperatures as it is administered continuously or at predetermined intervals over the course of the dosing period that corresponds to the size of the reservoir in the ocular implantable device and the dosing schedule / amount. In an embodiment of the invention, the reservoir is about 200 microliters.

[0033] Reference will now be made in detail to representative embodiments. It should be understood that the following descriptions are not intended to limit the embodiments to one preferred embodiment. To the contrary, they are intended to cover alternatives, modifications, and equivalents as can be included within the spirit and scope of the described embodiments as defined in the appended claims.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. So for example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1%, 99.2%, 99.3%, 99.4%, etc.).

[0035] Note that for purposes herein, "intravitreal injection" refers to injection into the vitreous of the eye (near the retina at the back of the eye) either from a syringe or by some other means, e.g., from a sustained delivery system, e.g., a ocular implantable device, including a reservoir containing a formulation discussed herein. The expressions "suitable for intravitreal administration,” “suitable for intravitreal injection,” and the like mean that the formulation in question can be safely injected into the vitreous of a subject's eye without causing any adverse reactions beyond those known to be associated with intravitreal injection of EYLEA.

[0036] The term "pharmaceutical formulation” herein refers to formulations including pharmaceutically acceptable carriers, e.g., used to administer VEGF receptor fusion proteins (e.g., aflibercept or conbercept) to a subject for a therapeutic / medicinal use.

[0037] The term "pharmaceutically acceptable" refers to a formulation that within the scope of sound medical judgement is suitable for administration with the eye.

[0038] The term "subject" herein refers to any mammalian (e.g., rabbit, mouse, rat or monkey) subject, particularly a human, e.g., for whom diagnosis, prognosis or therapy is desired with the formulations as described herein.

[0039] The term “aqueous” formulation refers to a formulation which includes water.

[0040] The term "treat" or "treatment" refers to a therapeutic measure that reverses, stabilizes or eliminates an undesired disease or disorder (e.g., an angiogenic eye disorder or cancer), for example, by causing the regression, stabilization or elimination of one or more symptoms or indicia of such disease or disorder by any clinically measurable degree, e.g., with regard to an angiogenic eye disorder, by causing a reduction in or maintenance of diabetic retinopathy severity score (DRSS), by improving or maintaining vision (e.g, in best corrected visual acuity e.g., as measured by an increase in ETDRS letters), increasing or maintaining visual field and / or reducing or maintaining central retinal thickness and, withrespect to cancer, stopping or reversing the growth, survival and / or metastasis of cancer cells in the subject. Typically, the therapeutic measure is administration of one or more doses of a therapeutically effective amount of VEGF receptor fusion protein to the subject with the disease or disorder.

[0041] “Prevent” or “prevention” refer to a prophylactic measure to cease the development of an undesired disease or disorder {e.g., an angiogenic eye disorder).

[0042] SE-UPLC can be used in the present invention to quantitate the presence of high molecular weight species or low molecular weight species in a formulation. SE refers to size exclusion chromatography. UPLC refers to ultra-performance liquid chromatography. Suitable SE columns, which may be used in a UPLC system, to characterize such HMW species or LMW species of VEGF receptor fusion proteins {e.g., aflibercept or conbercept) in a formulation, are capable of resolving molecules in the molecular weight range of about 10,000-450,000 Daltons. See for example, the ACQUITY UPLC Protein BEH SEC 200A Column. In an embodiment of the invention, two of such columns are connected in tandem when quantitating HMW species or LMW species in a formulation. UPLC brings improvements over HPLC (high performance liquid chromatography) in sensitivity and resolution. UPLC uses instrumentation that operates at high pressures and uses finer particles (typically less than about 2.5pm) than that used in HPLC. Moreover, the UPLC mobile phases operate at high linear velocities than HPLC. CE-SDS (capillary electrophoresis sodium dodecyl sulfate) is another technique used to quantitate the presence of low molecular weight species in a formulation. Both techniques are well-known in the art and would be familiar to the skilled artisan.

[0043] Embodiments herein include formulations that comprise a low concentration {e.g., about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, or about 25 mg / ml) of VEGF receptor fusion protein {e.g., aflibercept or conbercept). Suitable formulations included herein comprise a low concentration of VEGF receptor fusion protein, a buffer, a thermal stabilizer and a surfactant. In some aspects, a suitable formulation further includes a viscosity reducing agent. In other aspects, the suitable formulation substantially excludes all viscosity reducing agents. Typical formulations have a pH of from about 5.6 to about 6.2 {e.g., 5.8).

[0044] The present invention includes formulations that include a VEGF receptor fusion protein {e.g., aflibercept or conbercept) in association with one or more further therapeutic agents {e.g., an Ang-2 inhibitor {e.g., an anti-ANG2 antibody or antigen-binding fragment thereof or nesvacumab), a Tie-2 receptor activator, an anti-PDGF, PDGF receptor or PDGF receptor beta antibody or antigen-binding fragment thereof and / or an additional VEGF antagonist such as bevacizumab, ranibizumab, pegaptanib or a soluble form of human vascular endothelial growth factor receptor-3 (VEGFR-3) comprising extracellular domains 1 -3, expressed as an Fc-fusion protein) as well as methods of prevention or treatment comprising administering such formulations as discussed herein. In an embodiment of the invention, a formulation of the present invention includes a VEGF receptor fusion protein, such as aflibercept, but excludes any further therapeutic agent (e.g., which is an antibody or antigen-binding fragment thereof).

[0045] The term "in association with" indicates that a formulation and a further therapeutic agent can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit). The further therapeutic agent may, itself, be formulated in its own pharmaceutical formulation. Each can be administered to a subject at the same time as the other or at a different time than when the other is administered; for example, each administration may be given non-simultaneously (e.g., separately or sequentially) at intervals over a given period of time. Moreover, the formulation and the further therapeutic agent may be administered to a subject by the same or by a different route.VEGF inhibitors

[0046] The present invention includes formulations including VEGF inhibitors as well as methods of use thereof.

[0047] For purposes herein, a “VEGF receptor fusion protein” refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as a "VEGF-Trap" or “VEGF Trap”. VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include, chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also known as Flt1) and / or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain). Preferably, the VEGF receptor fusion protein is aflibercept.

[0048] An exemplary VEGF receptor fusion protein is a molecule referred to as VEGF1 R2- FcAC1 (a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79- 1374 or 79-1371 thereof.

[0049] VEGF1 R2-FcAC1 (a) comprises three components:(1 ) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2;(2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and(3) a multimerization component ("FcAC1 (a)") comprising amino acids 232 to 457 of SEQ ID NO:2 (the C-terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U.S. Patent No. 7,396,664 or 7,354,579,incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence.

[0050] In an embodiment of the invention, the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 of SEQ ID NO: 2.MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVT LKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTISDVVLSP SHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTID GVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK (SEQ ID NO: 2)

[0051] In an embodiment of the invention, the VEGF receptor fusion protein comprises(1 ) an immunoglobin-like (Ig) domain 2 of a first VEGF receptor (e.g., VEGFR1 ), and(2) an Ig domain 3 of a second VEGF receptor (e.g., VEGFR2),(3) and, optionally, further including an Ig domain 4 of the second VEGF receptor (e.g., VEGFR2) and(4) a multimerizing component (e.g., Fc domain of IgG).For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains:• [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC] (e.g., a homodimer thereof) or• [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC] (e.g., a homodimer thereof).

[0052] In an embodiment of the invention, the VEGF receptor fusion protein is a VEGF mini-trap which is a VEGF trap molecule with a truncated multimerizing component (e.g., Fc), e.g., wherein the mini-trap still includes an Fc hinge region. See e.g., WQ2005 / 00895 or U.S. Patent No. 7,396,664.

[0053] Note that the present disclosure also includes, within its scope, low concentration formulations including, instead of a VEGF receptor fusion proteins, VEGF binding molecules and anti-VEGF antibodies and antigen-binding fragments thereof,• bevacizumab• ranibizumab• an anti-VEGF aptamer such as pegaptanib (e.g., pegaptanib sodium),• a single chain (e.g., VL-VH) anti-VEGF antibody such as brolucizumab,• an anti-VEGF DARPin such as the Abicipar Pegol DARPin, or• a bispecific anti-VEGF antibody, e.g., which also binds to ANG2, such as RG7716.In order to minimize the repetitiveness of the embodiments discussed herein, it is contemplated that the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein.Preferably, the VEGF inhibitor is aflibercept.

[0054] DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a -turn and two anti-parallel a-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition.

[0055] An “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0056] Illustrative VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.). See International patent application publication no.W02005 / 121176 or W02007 / 112675. The terms “aflibercept” and “conbercept” include biosimilar versions thereof. A biosimilar version of a reference product (e.g., aflibercept) generally refers to a product comprising the identical amino acid sequence, but includes products which are biosimilar under the U.S. Biologies Price Competition and Innovation Act.

[0057] Pharmaceutical formulations of the present invention are “low concentration”. Low concentration pharmaceutical formulations of the present invention include VEGF receptor fusion protein at a concentration of less than 40 mg / ml, less than 35 mg / ml, less than 30 mg / ml, less than 25 mg / ml, less than 20 mg / ml, less than 15 mg / ml, or less than 10 mg / ml. At the lower end of any such “low concentration” range, the concentration of the pharmaceutical formulations may comprise from about 1 mg / ml to about 10 mg / ml, such that ranges of from about 1 mg / ml to about 10 mg / ml, 5 mg / ml to about 15 mg / ml, 8 mg / ml to 12 mg / ml, 15 mg / ml to about 25 mg / ml, 18 mg / ml to 22 mg / ml, and the like are encompassed within the scope of the present disclosure. In some aspects, the VEGF receptor fusion protein concentration in the formulation is about any of the following concentrations: 1 mg / ml; 1 .5 mg / ml; 2 mg / ml; 2.5 mg / ml; 3 mg / ml; 3.5 mg / ml; 4 mg / ml; 4.5 mg / ml; 5 mg / ml; 5.5 mg / ml; 6 mg / ml; 6.5 mg / ml; 7 mg / ml; 7.5 mg / ml; 8 mg / ml; 8.5 mg / ml; 9 mg / ml; 9.5 mg / ml; 10 mg / ml; 10.5 mg / ml; 11 mg / ml; 11 .5 mg / ml; 12 mg / ml; 12.5 mg / ml; 13 mg / ml; 13.5 mg / ml; 14 mg / ml; 14.5 mg / ml; 15 mg / ml; 15.5 mg / ml; 16 mg / ml; 16.5 mg / ml; 17 mg / ml; 17.5 mg / ml; 18 mg / ml; 18.5 mg / ml; 19 mg / ml; 19.5 mg / ml; 20 mg / ml; 20.5 mg / ml; 21 mg / ml; 21 .5 mg / ml; 22mg / ml; 22.5 mg / ml; 23 mg / ml; 23.5 mg / ml; 24 mg / ml; 24.5 mg / ml; or 25 mg / ml-preferably I Q- 20 mg / ml. Ranges defined by any pair of these amounts are also encompassed within the scope of the present disclosure. Other VEGF receptor fusion protein concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein.

[0058] The present invention includes any of the formulations set forth under “Illustrative Formulations" herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section (“VEGF Receptor Fusion Proteins and Other VEGF inhibitors”).Buffers

[0059] Buffers for use herein refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.6 to about 6.4, and more typically, from about 5.8 to about 6.2, and most typically, at about 5.8. In some cases, the pH of the formulation of the present invention is about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1 , about 6.2, about 6.3, or about 6.4. Example buffers for inclusion in formulations herein include histidine-based buffers, for example, including histidine and histidine hydrochloride or histidine acetate. Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example, sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above described pH ranges. In some cases, the buffer concentration is from about 5 mM to about 25 mM, typically, about 5 mM to about 15 mM, or more typically from about 8 mM to about 12 mM. Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM-preferably 10 mM.

[0060] In a preferred embodiment of the invention, the buffer is a histidine-based buffer, e.g., which includes histidine and histidine monohydrochloride.Surfactants

[0061] Surfactant for use herein refers to ingredients that protect the VEGF receptor fusion protein from various surface and interfacial induced stresses. As such, surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation, and promote protein solubility. Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety. Illustrative surfactants in this categoryinclude: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof-preferably polysorbate 20 (PS-20). Surfactants in the formulations can be present at from about 0.01% to about 0.1% weight per volume (w / v), and more typically, about 0.02% to about 0.04% (w / v). In some cases, the surfactant is about 0.01% (w / v), about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.07% (w / v), about 0.08% (w / v), about 0.09% (w / v), or about 0.1% (w / v)- preferably 0.03%.Thermal Stabilizers

[0062] Thermal stabilizers for use herein refers to ingredients that provide thermal stability against thermal denaturation of the VEGF receptor fusion protein, as well as protect against loss of VEGF receptor fusion protein potency or activity. Suitable thermal stabilizers include sugars or polyols, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine {e.g., L-arginine monohydrochloride), or taurine- preferably sucrose. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid.

[0063] In some cases, the formulations herein include both a sugar {e.g., a polyol sugar, for example, erythritol, mannitol, xylitol, isomalt, lactitol, glycerol, threitol, sorbitol or maltitol) and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid. In addition, formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L- proline, taurine and propane sulfonic acid.

[0064] Embodiments herein typically have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 5% (w / v) to about 30% (w / v), or about 10% (w / v) to about 25% (w / v), or about 15% (w / v) to about 20% (w / v). Thermal stabilizers in the formulation can be at a concentration of about 10% (w / v), about 11% (w / v), about 12% (w / v), about 13% (w / v), about 14% (w / v), about 15% (w / v), about 16% (w / v), about 17% (w / v), about 18% (w / v), about 19% (w / v), about 20% (w / v), about 21% (w / v), about 22% (w / v), about 23% (w / v), about 24% (w / v), or about 25% (w / v) -preferably 20%.Viscosity Reducing Agents

[0065] Viscosity reducing agents typically are used to reduce viscosity and may reduce protein aggregation. Viscosity reducing agents may not be present in the formulations discussed herein, but if included, may be selected from: sodium chloride, magnesium chloride, D- or L-arginine {e.g., L-arginine monohydrochloride), lysine, or mixtures thereof.When present herein, viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM.Formulation Viscosity

[0066] Formulations in accordance with embodiments herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection, or for intravitreal administration from a sustained delivery system, e.g., a ocular implantable device. Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example). Typical viscosities of formulations in accordance with embodiments herein are from about 1.0 cP (centipoise) to about 10 cP, from about 1 .0 cP to about 5.0 cP, or from about 1 .0 cP to about 3.0 cP. As such, formulation viscosity herein can be about 1 cP, about 1.5, about 2 cP, about 2.5 cP, about 3 cP, about 3.5 cP, about 4 cP, about 4.5 cP, about 5 cP, about 5.5 cP, about 6 cP, about 6.5 cP, about 7 cP, about 7.5 cP, about 8 cP, about 8.5 cP, about 9 cP, about 9.5 cP, or about 10 cP (e.g., when measured at 20°C).

[0067] Various embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities. As such, embodiments herein include formulations that have had substantially no, or no added, sodium chloride (NaCI), magnesium chloride (MgCh), D- or L-arginine hydrochloride, lysine or other viscosity reducing agent.Formulation Osmolality

[0068] It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. In an embodiment of the invention, the osmolality of a formulation of the present invention is from about 250 to about 850 mmol / Kg., e.g., about 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825 or 850 mmol / Kg.Purity and Stability of Formulations

[0069] Low concentration VEGF receptor fusion protein containing formulations described herein are stable during manufacture and storage (e.g., under physiological temperaturesduring storage in a sustained delivery system, such as a reservoir of an ocular implantable device, as discussed herein). The term "stable" herein refers to formulations that include VEGF receptor proteins that retain both chemical and physical stability over the period of formulation manufacturing and storage, e.g., that maintains integrity and has minimal degradation, denaturation, or unfolding. VEGF receptor protein stability can be determined using analytical techniques available in the art at different temperatures and over different periods of time. In particular, VEGF receptor chemical stability (potency) can be determined using various bioassays (for example, a BAF / 3 VEGFR1 / EPOR cell line used to determine VEGF165 binding by the VEGF receptor fusion proteins herein), and physical stability, by size exclusion (SE) chromatographic analysis, UPLC (ultra-performance liquid chromatography) size exclusion (SE) chromatography, visual appearance, OD, pH, charge variant formation, and rate of high molecular weight (HMW) species or low molecular weight (LMW) species formation. A stable VEGF receptor fusion protein is one that shows limited or manageable change in its OD, pH, formation of charge variants, formation of HMW species, and formation of LMW species.

[0070] A “high molecular weight” (HMW) species as used herein, with reference to VEGF Trap (e.g., aflibercept) refers to a species including VEGF traps that have a higher molecular weight than a native VEGF trap, e.g., that elutes from a size exclusion column (e.g., SE- UPLC) ahead of (e.g., with a higher molecular weight than) native VEGF Trap. In an embodiment of the invention, a HMW species of aflibercept, under conditions that do not break apart or reduce disulfide bonds between aflibercept polypeptides, includes dimer of aflibercept (dimer of the aflibercept dimer) or multimer thereof. The percentage of HMW species refers to the percentage of such species relative to the overall quantity of polypeptides in the formulation, e.g., by SE-UPLC analysis. The present invention includes formulations including detectable quantities of HMW species of aflibercept, e.g., as discussed herein.

[0071] A “low molecular weight” (LMW) species as used herein, with reference to VEGF Trap (e.g., aflibercept) refers to a species including VEGF traps or fragments thereof that have a lower molecular weight than a native VEGF trap, e.g., that elutes from a size exclusion column (e.g., SE-UPLC) after (e.g., with a lower molecular weight than) native VEGF Trap. In an embodiment of the invention, a LMW species of aflibercept, includes dimer of aflibercept wherein one or both of the polypeptides in the dimer are truncated. In an embodiment of the invention, a LMW species of half-aflibercept (a single, non-dimerized polypeptide molecule), for example when analyzed by CE-SDS (capillary electrophoresis sodium dodecyl sulfate). The percentage of LMW species refers to the percentage of such species relative to the overall quantity of polypeptides in the formulation, e.g., by SE-UPLCanalysis. NR1 LMW species of aflibercept include T90 to G221 ; S1 to G221 ; N91 to G221 ; S1 to G221 ; L93 to G221 ; S1 to G221 ; H95 to G221 ; S1 to G221 ; (pyro-Q)97 to G221 ; S1 to G221 ; T100 to G221 ; and S1 to G221 (of mature aflibercept molecule). A low molecular weight species of aflibercept may have a deletion in one or both of the VEGFR2 domains wherein there is a cleavage site between residues K148 and K149 and between R153 and D154 (of mature aflibercept molecule) (NVGIDFNWZ YP S SKHQHK1 8 / K149LVNR153 / D154LKTQSG), wherein I denotes cleavage site. LMW fragments of aflibercept due to Cathepsin-D digestion include L93 to G221 and S1 to G221 (of mature aflibercept molecule). LMW fragments of aflibercept due to hydrolysis include T100 to G221 and S1 to G221 (of mature aflibercept molecule). The present invention includes formulations including detectable quantities of LMW species of aflibercept, e.g., as discussed herein.

[0072] A “native” species as used herein, with reference to VEGF Trap (e.g., aflibercept) refers to a species including a full, non-truncated molecule having two homodimerized polypeptides thereof. The percentage of native species refers to the percentage of such species relative to the overall quantity of polypeptides in the formulation, e.g., by SE-UPLC analysis.

[0073] In an embodiment of the invention, after a period of storage of a formulation of the present invention at about 37°C, e.g., about 1 , 3, 6, 9 or 12 months, the potency of the VEGF receptor fusion protein is between 50 and 150% of that of the protein before storage. In an embodiment of the invention ,the potency is as measured by a functional blocking ELISA wherein an ELISA plate is coated with human VEGF receptor peptides (e.g., human VEGFR1 and VEGFR2) and contacted with VEGF receptor fusion protein that was preincubated with human VEGF165; and free VEGF165 able to bind the immobilized human VEGF receptor is determined; such that more binding between VEGF165 and immobilized receptor indicates less binding of VEGF165 to the VEGF receptor fusion protein.

[0074] In an embodiment of the invention, as discussed more fully in the Examples below, stable formulations show significant VEGF receptor fusion protein potency and physical stability for a period of up to 6 months, up to 9 months, and / or up to 12 months when at about 37°C; or at the temperature to which a sustained delivery system, e.g., a ocular implantable device, having a volume of the formulation reaches when situated in or on the eye.

[0075] In an embodiment of the invention, a formulation of the present invention is one that:• Includes aflibercept having one or more oxidized methionine residues, e.g., at Met10, Met 192 and / or Met 237;• Includes aflibercept having one or more glycation sites at a lysine residue, e.g., Lys311 and / or Lys62;• No significant change in charge variants after up to 6 months at 5°C;• Contains one or more LMW species of aflibercept, e.g., NR1 and / or having a deletion in one or both of the VEGFR2 domains wherein there is a cleavage site between residues K148 and K149 and between R153 and D154 (of mature aflibercept molecule);• At 37°C storage, when at a pH of about 6.4, there is a lower extent R1 clipping that what is observed at pH of about 5.8, but the overall fragmentation was not significantly different between formulations;• There is no significant difference in NR1 clipping when stored at about 5°C at pH of about 6.4 and about 5.8;• Includes 1 , 2, 3, 4 or 5 N-glycans on each arm;• After about 6 months at about 37°C has about a 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6. 5, 7, 7.5, 8, or 8.5%; or 1 .5-5%; increase in high molecular weight species (e.g., as measured by SE-UPLC or SEC);• After about 6 months at about 37°C has about a <5% total high molecular weight species, e.g., including <1% multimer species (e.g., as measured by SE-UPLC or SEC);• After about 6 months at about 37°C has less than or equal to about 8.5, 8, 7.5, 7, 6.5, 6.0, 5.5, 5, 4.5 or 4% high molecular weight species (e.g., as measured by SE-UPLC or SEC);• After about 6 months at about 37°C has about a 8, 9, 10, 11 , 12, 13, 14, 15, 16 or17% (or 8-17%) increase in low molecular weight species (e.g., as measured by CE- SDS);• After about 6 months at about 37°C has at least about 90, 90.5, 91 , 91 .5, 92, or 92.5% native conformation (main species) (e.g., as measured by SE-UPLC or SEC);• After about 6 months at about 37°C has a potency, relative to potency at t=0, of 50%- 150% or >70% (e.g., about 68-97%) as measured by bioassay such as, for example, determining binding of VEGF165 to a BAF / 3 VEGFR1 / EPOR cell line (which is known in the art) and / or as measured by blocking ELISA assay;• at t=0, has about 0 % LMW species; after about 0.5 months storage when stored at about 5°C, has about 0 % LMW species; after about 1 month storage has about 0 % LMW species; after about 3 months storage has about 0 % LMW species; after about 6 months storage has about 0 % LMW species; e.g., wherein the formulation has apH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 99.2 % native species; after about 0.5 months storage when stored at about 5°C, has about 99.2 % native species; after about 1 month storage, has about 99.3 % native species; after about 3 months storage, has about 99.3 % native species; after about 6 months storage, has about 99.3 % native species; e.g., wherein the formulation has a pH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.8 % HMW species; after about 0.5 months storage when stored at about 5°C, has about 0.8 % HMW species; after about 1 month storage, has about 0.7 % HMW species; after about 3 months storage, has about 0.8 % HMW species; after about 6 months storage, has about 0.8 % HMW species; e.g., wherein the formulation has a pH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0 % LMW species; after about 0.5 months storage when stored at about 37°C, has about 0.3 % LMW species; after about 1 month storage has about 0.3 % LMW species; after about 2 months storage has about 1 .1 % LMW species; after about 3 months storage has about 1 .4 % LMW species; after about 4 months storage has about 1 .7 % LMW species; after about 5 months storage has about 2 % LMW species; after about 6 months storage has about 2.1 % LMW species; e.g., wherein the formulation has a pH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 99.2 % native species; after about 0.5 months storage when stored at about 37°C, has about 98.8 % native species; after about 1 month storage, has about 98.7 % native species; after about 2 months storage, has about 97.5 % native species; after about 3 months storage, has about 96.8 % native species; after about 4 months storage, has about 96 % native species; after about 5 months storage, has about 94.7 % native species; after about 6 months storage, has about 93.7 % native species; e.g., wherein the formulation has a pH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.8 % HMW species; after about 0.5 months storage when stored at about 37°C, has about 0.8 % HMW species; after about 1 month storage, hasabout 1 % HMW species; after about 2 months storage, has about 1 .4 % HMW species; after about 3 months storage, has about 1 .8 % HMW species; after about 4 months storage, has about 2.3 % HMW species; after about 5 months storage, has about 3.3 % HMW species; after about 6 months storage, has about 4.1 % HMW species; e.g., wherein the formulation has a pH of about 5.8 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.6 % LMW species; after about 0.5 months storage when stored at about 5°C, has about 0 % LMW species; after about 1 month storage has about 0 % LMW species; after about 3 months storage has about 0.2 % LMW species; after about 6 months storage has about 0 % LMW species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 98.5 % native species; after about 0.5 months storage when stored at about 5°C, has about 99.1 % native species; after about 1 month storage, has about 99.2 % native species; after about 3 months storage, has about 98.9 % native species; after about 6 months storage, has about 99 % native species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.9 % HMW species; after about 0.5 months storage when stored at about 5°C, has about 0.9 % HMW species; after about 1 month storage, has about 0.8 % HMW species; after about 3 months storage, has about 0.9 % HMW species; after about 6 months storage, has about 1 % HMW species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.6 % LMW species; after about 0.5 months storage when stored at about 37°C, has about 0.3 % LMW species; after about 1 month storage has about 0.3 % LMW species; after about 2 months storage has about 0.9 % LMW species; after about 3 months storage has about 0.9 % LMW species; after about 4 months storage has about 1 .4 % LMW species; after about 5 months storage has about 1 .6 % LMW species; after about 6 months storage has about 1 .7 % LMW species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 98.5 % native species; after about 0.5 months storage when stored at about 37°C, has about 98.5 % native species; after about 1 month storage, has about 98.3 % native species; after about 2 months storage, has about 97 % native species; after about 3 months storage, has about 96.5 % native species; after about 4 months storage, has about 95.4 % native species; after about 5 months storage, has about 94 % native species; after about 6 months storage, has about 93 % native species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.9 % HMW species; after about 0.5 months storage when stored at about 37°C, has about 1.1 % HMW species; after about 1 month storage, has about 1 .4 % HMW species; after about 2 months storage, has about 2.1 % HMW species; after about 3 months storage, has about 2.7 % HMW species; after about 4 months storage, has about 3.3 % HMW species; after about 5 months storage, has about 4.4 % HMW species; after about 6 months storage, has about 5.3 % HMW species; e.g., wherein the formulation has a pH of about 6.2 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0 % LMW species; after about 0.5 months storage when stored at about 5°C, has about 0.1 % LMW species; after about 1 month storage has about 0 % LMW species; after about 3 months storage has about 0.3 % LMW species; after about 6 months storage has about 0 % LMW species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 99.2 % native species; after about 0.5 months storage when stored at about 5°C, has about 99 % native species; after about 1 month storage, has about 99.2 % native species; after about 3 months storage, has about 98.9 % native species; after about 6 months storage, has about 99.2 % native species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.8 % HMW species; after about 0.5 months storage when stored at about 5°C, has about 0.8 % HMW species; after about 1 month storage, has about 0.8 % HMW species; after about 3 months storage, has about 0.9 % HMW species; after about 6 months storage, has about 0.8 % HMW species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for exampleincluding about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0 % LMW species; after about 0.5 months storage when stored at about 37°C, has about 0.3 % LMW species; after about 1 month storage has about 0.6 % LMW species; after about 2 months storage has about 0.7 % LMW species; after about 3 months storage has about 0.9 % LMW species; after about 4 months storage has about 1 .4 % LMW species; after about 5 months storage has about 1 .6 % LMW species; after about 6 months storage has about 1 .8 % LMW species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 99.2 % native species; after about 0.5 months storage when stored at about 37°C, has about 98.6 % native species; after about 1 month storage, has about 98.2 % native species; after about 2 months storage, has about 97.5 % native species; after about 3 months storage, has about 96.9 % native species; after about 4 months storage, has about 95.8 % native species; after about 5 months storage, has about 94.5 % native species; after about 6 months storage, has about 93.5 % native species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.8 % HMW species; after about 0.5 months storage when stored at about 37°C, has about 0 % HMW species; after about 1 month storage, has about 1 .3 % HMW species; after about 2 months storage, has about 1 .8 % HMW species; after about 3 months storage, has about 2.3 % HMW species; after about 4 months storage, has about 2.8 % HMW species; after about 5 months storage, has about 3.9 % HMW species; after about 6 months storage, has about 4.7 % HMW species; e.g., wherein the formulation has a pH of about 6.0 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.6 % LMW species; after about 0.5 months storage when stored at about 5°C, has about 0 % LMW species; after about 1 month storage has about 0 % LMW species; after about 3 months storage has about 0.2 % LMW species; after about 6 months storage has about 0 % LMW species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 98.2 % native species; after about 0.5 months storage when stored at about 5°C, has about 98.9 % native species; after about 1 month storage, has about 98.9 % native species; after about 3 months storage, has about 98.7 % native species; after about 6 months storage, has about 98.8 % native species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 1 .2 % HMW species; after about 0.5 months storage when stored at about 5°C, has about 1.1 % HMW species; after about 1 month storage, has about 1 .1 % HMW species; after about 3 months storage, has about 1 .2 % HMW species; after about 6 months storage, has about 1 .2 % HMW species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 0.6 % LMW species; after about 0.5 months storage when stored at about 37°C, has about 0.3 % LMW species; after about 1 month storage has about 0.3 % LMW species; after about 2 months storage has about 0.9 % LMW species; after about 3 months storage has about 1 .1 % LMW species; after about 4 months storage has about 1 .2 % LMW species; after about 5 months storage has about 1 .4 % LMW species; after about 6 months storage has about 1 .6 % LMW species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 98.2 % native species; after about 0.5 months storage when stored at about 37°C, has about 98.3 % native species; after about 1 month storage, has about 98 % native species; after about 2 months storage, has about 96.6 % native species; after about 3 months storage, has about 95.7 % native species; after about 4 months storage, has about 94.7 % native species; after about 5 months storage, has about 93.3 % native species; after about 6 months storage, has about 92.2 % native species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20);• at t=0, has about 1 .2 % HMW species; after about 0.5 months storage when stored at about 37°C, has about 1 .4 % HMW species; after about 1 month storage, has about 1 .7 % HMW species; after about 2 months storage, has about 2.6 % HMW species; after about 3 months storage, has about 3.3 % HMW species; after about 4months storage, has about 4.1 % HMW species; after about 5 months storage, has about 5.3 % HMW species; after about 6 months storage, has about 6.2 % HMW species; e.g., wherein the formulation has a pH of about 6.4 and about 20 mg / ml aflibercept, for example including about 20 mg / ml aflibercept, 10 mM histidine, 20% sucrose and 0.03% PS20); and / or• When administered intravitreally to a mammal, such as a human or rabbit or mouse (e.g., with an angiogenic eye disorder such as wet AMD), does not cause any adverse events that are clinically different from those observed for EYLEA (e.g., when EYLEA is dosed intravitreally at 0.5 or 2.0 mg); or does not cause clinically significant inflammation in the eye, prolonged intraocular pressure (IOP) increases, prolonged increases in blood pressure or decreases and / or retinal detachment.

[0076] In an embodiment of the invention, a formulation of the present invention has less than about 0.2, 0.4 or 0.5 EU (endotoxin units) / ml of endotoxin.

[0077] In an embodiment of the invention, a formulation of the present invention is essentially free of particulate matter or particulate matter of about 1 , 2, 5, 10, 25 or 50 micrometers (or more) in size.

[0078] Storage of a formulation of the present invention at about 37°C may refer to storage in a vial or ocular delivery device or other container whether in or on the eye of a subject (e.g., wherein the temperature may be slightly below 37°C) or otherwise such as separate from an eye.Illustrative Formulations

[0079] Illustrative low concentration VEGF receptor fusion protein containing formulations include the following:

[0080] Formulation A: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0081] Formulation B: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0082] Formulation C: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0083] Formulation D: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0084] Formulation E: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0085] Formulation F: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0086] Formulation G: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0087] Formulation H: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0088] Formulation I: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0089] Formulation J: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0090] Formulation K: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0091] Formulation L: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0092] Formulation M: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0093] Formulation N: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0094] Formulation O: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0095] Formulation P: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0096] Formulation Q: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0097] Formulation R: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0098] Formulation S: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0099] Formulation T: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0100] Formulation U: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0101] Formulation V: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0102] Formulation W: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0103] Formulation X: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0104] Formulation Y: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0105] Formulation Z: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0106] Formulation AA: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0107] Formulation BB: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0108] Formulation CC: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0109] Formulation DD: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0110] Formulation EE: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0111] Formulation FF: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0112] Formulation GG: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0113] Formulation HH: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0114] Formulation II: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0115] Formulation JJ: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0116] Formulation KK: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0117] Formulation LL: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0118] Formulation MM: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0119] Formulation NN: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0120] Formulation 00: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0121] Formulation PP: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0122] Formulation QQ: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0123] Formulation HR: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0124] Formulation SS: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0125] Formulation TT: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0126] Formulation UU: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0127] Formulation VV: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0128] Formulation WW: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0129] Formulation XX: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0130] Formulation YY: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0131] Formulation ZZ: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of5.8 to 6.2;

[0132] Formulation AAA: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0133] Formulation BBB: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0134] Formulation CCC: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0135] Formulation DDD: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0136] Formulation EEE: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0137] Formulation FFF: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0138] Formulation GGG: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0139] Formulation HHH: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;

[0140] Formulation III: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0141] Formulation JJJ: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0142] Formulation KKK: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0143] Formulation LLL: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0144] Formulation MMM: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0145] Formulation NNN: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0146] Formulation OOO: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0147] Formulation PPP: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0148] Formulation QQQ: 10-20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0149] Formulation RRR: 10 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0150] Formulation SSS: 15 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;

[0151] Formulation TTT: 20 mg / ml ± 1 mg / ml conbercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation UUU: 20 ± 2 mg / ml mg / mL Aflibercept, 10mM Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;

[0152] Formulation VVV: 10 mg / mL ± 1 mg / ml Aflibercept, 10mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;

[0153] Formulation WWW: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 8% ± 0.8% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;

[0154] Formulation XXX: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;

[0155] Formulation YYY: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 8%w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 5.8;

[0156] Formulation ZZZZ: 40 mg / mL ± 4 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0157] Formulation AAAA: 40 mg / mL ± 4 mg / ml Aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8

[0158] Formulation BBBB: 40 mg / mL ± 4 mg / ml Aflibercept, 20 mM ± 2 mM histidine- based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0159] Formulation CCCC: 40 mg / mL ± 4 mg / ml Aflibercept, 20 mM ± 2 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0160] Formulation DDDD: 40 mg / mL ± 4 mg / ml Aflibercept, 15 mM ± 1 .5 mM histidine- based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0161] Formulation EEEE: 25 mg / ml_ ± 2.5 mg / ml Aflibercept, 10 mM ± 1 mM histidine- based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0162] Formulation FFFF: 2 5mg / mL ± 2.5 mg / ml Aflibercept, 15 mM ± 1 .5 mM histidine- based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0163] Formulation GGGG: 25 mg / mL ± 2.5 mg / ml Aflibercept, 15 mM ± 1 .5 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0164] Formulation HHHH: 25 mg / mL ± 2.5 mg / ml Aflibercept, 20 mM ± 2 mM histidine- based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0165] Formulation Illi: 10 mg / ml_± 1 mg / ml Aflibercept, 1 OmM histidine-based buffer, 5% ± 0.5%w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0166] Formulation JJJJ: 10 mg / mL± 1 mg / ml Aflibercept, 10mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0167] Formulation KKKK: 10 mg / mL± 1 mg / ml Aflibercept, 20mM ± 2 mM histidine-based buffer, 5%± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0168] Formulation LLLL: 10 mg / mL ± 1 mg / ml Aflibercept, 20mM ± 2 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0169] Formulation MMMM: 10 mg / ml_± 1 mg / ml Aflibercept, 15mM ± 1.5 mM histidine- based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0170] Formulation NNNN: 20 mg / ml_ ± 2 mg / ml Aflibercept, 10mM ± 1 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;

[0171] Formulation OOOO: 20 mg / mL ± 2 mg / ml Aflibercept, 10mM ± 1 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 6.2;

[0172] Formulation PPPP: 20 mg / ml_ ± 2 mg / ml Aflibercept, 10mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 6.0;

[0173] Formulation QQQQ: 20 mg / mL ± 2 mg / ml Aflibercept, 10mM ± 1 mM histidine- based buffer, 20% ± 2% w / v Sucrose, 0.03% w / v PS20, pH 6.4;

[0174] Formulation RRRR: VEGF Receptor Fusion Protein / Aflibercept / Conbercept or Aflibercept: 10-20 mg / ml ± 1 mg / ml, Histidine-Based Buffer or sodium phosphate-based buffer: 10 mM ± 1 mM, sugar or polyol or sucrose: 15-20% ± 1% (w / v), non-ionic surfactant or polysorbate 20: 0.03% ± 0.01% (w / v), pH Range: 5.8 to 6.2;

[0175] Formulation SSSS: 10-40 mg / ml ± 4 mg / ml Conbercept or Aflibercept:, 10-20 mM ± 2 mM Histidine-based buffer or Sodium Phosphate-based buffer, 5-20% ± 2% (w / v) sugar,polyol or sucrose, 0.03% ± 0.01% (w / v) non-ionic surfactant or polysorbate 20, pH 5.8 to 6.4; and

[0176] Formulation TTTT: 10-40 mg / ml ± 4 mg / ml Aflibercept, 10-20 mM ± 2 mM Histidine- based buffer or Sodium Phosphate-based buffer, 5-20% ± 2% (w / v) sucrose, 0.03% ± 0.01% (w / v) polysorbate 20, pH 5.8 to 6.4; or any formulation which is set forth herein; preferably, 10-20 mg / ml aflibercept, 10 mM histidine-based buffer, 20% sucrose, 0.03% polysorbate 20 (PS-20), pH 5.8.

[0177] In an embodiment of the invention, the concentration of any formulation constituent {e.g., all constituents) listed above {e.g., any one of formulations A- TTTT) or which is discussed herein is ± about 3%, ± about 5% or ± about 10% of the concentration specifically mentioned.Methods of Manufacture

[0178] Embodiments herein include methods of manufacturing a pharmaceutical formulation of the present invention including a VEGF receptor fusion protein {e.g., any of formulations A-TTT or other formulations as set forth herein) comprising combining the components of the formulation into a single composition, and, optionally, introducing the formulation into, for example, a vessel, device, vial, delivery device, pre-filled syringe, sustained delivery system or ocular implantable device. The formulations, vials, systems and devices that are the product of such methods are part of the present invention.

[0179] In an embodiment of the invention, the method of manufacturing a VEGF receptor fusion protein containing pharmaceutical formulation of the present invention {e.g., any of formulations A-TTT or other formulations as set forth herein) comprises the steps of culturing a host cell {e.g., Chinese hamster ovary cell) comprising one or more polynucleotides encoding a VEGF receptor fusion protein {e.g., aflibercept) in a culture medium and under conditions whereby the protein is expressed; and, purifying the protein from the host cell and / or culture medium and combining a portion of the protein with excipients of a pharmaceutical formulation as set forth herein, and, optionally, loading a volume of the formulation into a container, pre-filled syringe or sustained delivery device, e.g., an ocular implantable device. Again, such compositions are part of the present invention.

[0180] In an embodiment of the invention, a determination is made as to the amount and type of VEGF receptor fusion protein needed in the formulation to make it a low concentration and for its end-use. The same determination is made regarding the amount and type of buffer, the amount and type of surfactant, the amount and type of thermal stabilizer, and the inclusion, or specific exclusion, of a viscosity reducing agent. These components are combined and mixed, making sure that the formulation pH is at the desired value, e.g., between about 5.8 and about 6.2 {e.g., 5.8), and / or that the viscosity is at adesired value, e.g., about 1 -3 cP at 20°C. In an embodiment of the invention, low concentration VEGF receptor fusion protein containing formulations can be sterilized and stored in a stable condition, e.g., for up to 24 or 36 months at 2°C to 8°C (e.g., 5°C) before use (e.g., loading into a sustained delivery device, e.g., an ocular implantable device).

[0181] See, e.g., Hardman, et al. (2001 ) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, etal. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, etal. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.Angiogenic Eye Disorders and Cancer

[0182] The pharmaceutical formulations of the present invention comprising VEGF receptor fusion proteins (e.g., any of pharmaceutical formulations A-TTT or other formulations discussed herein) can be used in the treatment or prevention of any angiogenic eye disorder by administration of a therapeutically effective amount of VEGF receptor fusion protein in a formulation of the present invention to a subject in need thereof, e.g., by intravitreal injection, for example via administration from a sustained delivery device, e.g., an ocular implantable device. Angiogenic eye disorders herein refer to any disease of the eye that is caused by or associated with the growth or proliferation of blood vessels and / or by blood vessel leakage. Non-limiting examples of angiogenic eye disorders that are treatable or preventable using the formulations and methods herein, include:• age-related macular degeneration (wet),• macular edema,• macular edema following retinal vein occlusion,• retinal vein occlusion (RVO),• central retinal vein occlusion (CRVO),• branch retinal vein occlusion (BRVO),• diabetic macular edema (DME),• choroidal neovascularization (CNV),• iris neovascularization,• neovascular glaucoma,• post-surgical fibrosis in glaucoma,• proliferative vitreoretinopathy (PVR),• optic disc neovascularization,• corneal neovascularization,• retinal neovascularization,• vitreal neovascularization,• pannus,• pterygium,• vascular retinopathy,• diabetic retinopathies (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of about 47 or 53) or proliferative diabetic retinopathy; e.g., in an subject that does not suffer from DME) and• Diabetic retinopathy in a patient who has diabetic macular edema (DME).

[0183] The pharmaceutical formulations of the present invention comprising VEGF receptor fusion proteins (e.g., any of pharmaceutical formulations A-TTT or other formulations discussed herein) can be used in the treatment or prevention of any cancer by administration of a therapeutically effective amount of VEGF receptor fusion protein in a formulation of the present invention to a subject in need thereof, e.g., by intramuscular, intratumoral, subcutaneous or intravenous injection. Cancers include those whose growth, proliferation, survival and / or metastasis is dependent, to a degree, on angiogenesis. In an embodiment of the invention, the cancer is colorectal cancer, lung cancer, skin cancer, breast cancer, brain cancer, stomach cancer, renal cancer, prostate cancer, liver cancer or pancreatic cancer.

[0184] Thus, the present invention provides methods for treating or preventing an angiogenic eye disorder in a subject in need thereof comprising administering a therapeutically effective amount of VEGF receptor fusion protein (e.g., aflibercept), e.g., in a pharmaceutical formulation according to the present invention, intraocularly, e.g., into the vitreous, of an eye of the subject. In an embodiment of the invention, both eyes are administered the VEGF receptor fusion protein. In an embodiment of the invention, therapeutically effective doses of the VEGF receptor fusion protein are administered continuously via a sustained delivery device, e.g., an ocular implantable device, in the eye for a period of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks 18 weeks, 19 weeks, 20 weeks, 21 , weeks, 22 weeks, 23 weeks or 24 weeks. In an embodiment of the invention, such methods of treatment or prevention are done in the absence of significant increases in blood pressure (systolic and / or diastolic)and / or the development of hypertension (e.g., Grade 1 , Grade 2 or Grade 3) and / or abnormally high intraocular pressure in the subject. In an embodiment of the invention, the method includes the step of, following said administration, monitoring the subject for significant increases in blood pressure (systolic and / or diastolic) and / or the development of hypertension (e.g., Grade 1 , Grade 2 or Grade 3) and / or abnormally high intraocular pressure.Modes of Administration

[0185] The pharmaceutical formulations of the present invention which include a VEGF inhibitor, e.g., a VEGF receptor fusion protein, may be administered in accordance with known medically approved delivery systems, e.g., sustained delivery systems. In embodiments herein, these delivery systems may include administering the formulations to the patient by ocular, intraocular, intrachoroidal, intravitreal or subconjunctival injection. Pharmaceutical formulations of the present invention can be administered to the patient from a sustained delivery device, e.g., an ocular implantable device, e.g., intravitreally. Other possible routes of delivery for the formulations herein include topical (e.g., via eye drops, eye gels, eye ointments, and the like), intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral.

[0186] In an embodiment of the invention, intravitreal injection of a pharmaceutical formulation of the present invention includes the step of piercing the eye with a syringe and needle (e.g., 30-gauge injection needle) containing the formulation and injecting the formulation (e.g., less than or equal to about 100 microliters; about 40, 50, 55, 56, 57, 57.1 , 58, 60, 70 or 75 microliters) into the vitreous of the eye (e.g., with a sufficient volume as to deliver a therapeutically effective amount of VEGF receptor fusion protein. Optionally, the method includes the steps of administering a local anesthetic (e.g., proparacaine, lidocaine or tetracaine), an antibiotic (e.g., a fluoroquinolone), antiseptic (e.g., povidone-iodine) and / or a pupil dilating agent to the eye being injected. In an embodiment of the invention, a sterile field around the eye to be injected is established before the injection. In an embodiment of the invention, following intravitreal injection, the subject is monitored for elevations in intraocular pressure and / or blood pressure. In an embodiment of the invention, the other eye is also injected by the same procedure.

[0187] In an embodiment of the invention, administration of a pharmaceutical formulation of the present invention includes loading the formulation into an ocular implantable device designed to deliver one or more doses of the VEGF inhibitor, e.g., VEGF receptor fusion protein, to the eye following implantation. A variety of ocular implantable devices are known in the art.Amounts of VEGF Receptor Fusion Protein to be Administered

[0188] Each dose of VEGF receptor fusion protein delivered to a subject over the course of a treatment may contain the same or substantially the same amount of fusion protein.

[0189] An effective or therapeutically effective amount of VEGF receptor fusion protein for treating or preventing cancer (e.g., which is mediated, at least in part, by angiogenesis) or an angiogenic eye disorder refers to the amount of the VEGF receptor fusion protein sufficient to cause the regression, stabilization or elimination of the cancer or angiogenic eye disorder, e.g., by regressing, stabilizing or eliminating one or more symptoms or indicia of the cancer or angiogenic eye disorder by any clinically measurable degree, e.g., with regard to an angiogenic eye disorder, by causing a reduction in or maintenance of diabetic retinopathy severity score (DRSS), by improving or maintaining vision (e.g., in best corrected visual acuity e.g., as measured by an increase in ETDRS letters), increasing or maintaining visual field and / or reducing or maintaining central retinal thickness and, with respect to cancer, stopping or reversing the growth, survival and / or metastasis of cancer cells in the subject. In an embodiment of the invention, an effective or therapeutically effective amount of VEGF receptor fusion protein for treating or preventing an angiogenic eye disorder is about 1-100 micrograms per dose. For example, in an embodiment of the invention, a sustained delivery device, e.g., an ocular implantable device, delivers the formulation to the eye continuously over time at a rate of about 0.01-0.4 mg per day. In an embodiment of the invention, an effective or therapeutically effective amount of VEGF receptor fusion protein for treating or preventing cancer is about 4 mg / kg (e.g., intravenously). This dose may be administered, for example, every 2 weeks.

[0190] In an embodiment of the invention, a VEGF receptor fusion protein is administered in a volume sufficient to deliver the desired dose of VEGF receptor fusion protein, e.g., as discussed above. In an embodiment of the invention, the volume is delivered continuously over time at a rate of about 0.5-20 microliters per day.

[0191] The present invention also includes an ocular implantable device including or consisting or consisting essentially of a “single device volume” of a pharmaceutical formulation of the present invention (e.g., any of formulations A-TTT), i.e., the total volume that the ocular implantable device can hold, e.g., in a reservoir of the device. In an embodiment of the invention, the volume is 100, 200, 300 or 400 microliters.Containers and Injection Devices

[0192] Low concentration VEGF receptor fusion protein formulations in accordance with embodiments herein (e.g., any of formulations A-TTT or other formulations discussed herein) can be pre-packaged or pre-loaded in various useful containers, injection devices, or sustained delivery devices such as ocular implantable devices. Thus, the present inventionincludes containers, injection devices and sustained delivery devices containing such formulations. In one embodiment herein, the container is a vial which may be sterile. In another embodiment herein, the container is a test tube which may be sterile. In an embodiment of the invention, an injection device (which may be sterile) is a syringe (e.g., a pre-filled syringe or autoinjector). In an embodiment of the invention, the sustained delivery device is an ocular implantable device (e.g., an intravitreal implant or a refillable intravitreal implant).

[0193] A “pre-filled” syringe is a syringe which is filled with a formulation of the present invention prior to sale or use by the physician or patient.

[0194] A “sustained delivery system” allows delivery of a substance (e.g., a formulation of the present invention), not in a single instance, but continuously at a given rate for a period of time. A “sustained delivery system” (SDS) may be a device ( / .e., a sustained delivery device) or substance, e.g., a particle. A sustained delivery system may be a composition loaded or impregnated with a formulation of the present invention, e.g., which releases the formulation over time. For example, SDS may be a microfilm, microparticle (e.g., collagen microparticle), biodegradable sheet or set of multiple such sheets or layered hydrogel loaded or impregnated with a formulation of the present invention. Release of the formulation from the SDS may occur over time, for example, due to diffusion from the components of the SDS or degradation of the components.

[0195] A sustained delivery system may be an ocular implantable device. An “ocular implantable device” is a device that can be implanted onto or into the eye and contain a substance that can be delivered to the eye of a subject. Ocular implantable devices are known in the art and include, for example, scleral implants (including scleral implant plugs), intrascleral implants, intravitreal implants, and episcleral implants. Ocular implantable devices may be biodegradable or non-biodegradable. See e.g., Shastri et al., Ocular Delivery of Therapeutic Proteins: A Review. Pharmaceutics. 2023 Jan 6;15(1 ):205. The formulations of the present invention, are compatible with use in conjunction with such technologies. Thus, such devices including a formulation of the present invention are part of the present invention. Methods of using such a device form part of the present invention, for example, methods for delivering a therapeutically effective amount of VEGF inhibitor (e.g., aflibercept) in a formulation of the present invention (e.g., any of the formulations set forth herein, e.g., any of A-TTT)) to the eye comprising implanting the device into or onto the eye such that the VEGF inhibitor is delivered from the device to the eye (e.g., to the eye vitreous) over time and / or introducing the formulation to the device (e.g., into a reservoir in the device) that is already in or on the eye such that the VEGF inhibitor is delivered from the device to the eye over time. In an embodiment of the invention, the formulation is delivered to the eye,from the sustained delivery device (e.g., ocular implantable device), in such a manner as to reach the retina of the eye. In an embodiment of the invention, the rate of delivery to the eye is about 0.5-20 microliters per day which may be delivered continuously.

[0196] Continuous administration refers to an essentially unbroken course of administration over time.

[0197] In an embodiment of the invention, the ocular implantable device delivers the therapeutic product by way of a cannula or some other conveyance through the tissues of the eye and into the vitreous of the eye.

[0198] A micropump may include a propellant chamber and drug reservoir wherein the propellant chamber, filled with and pressurized by a propellant (e.g., a fluorocarbon), conveys pressure to the drug reservoir. The pressurized drug reservoir can then expel formulation in the drug reservoir from the micropump and, e.g., into the eye on or in which it is implanted.

[0199] The present invention also encompasses filling and re-filling operations whereby formulation is introduced into an ocular implantable device either before or after implantation into or onto the eye. Such a method may include the steps of introducing the formulation into the device, for example, by way of a septum or port on the device, such that a reservoir in the device receives a volume of the formulation. In an embodiment of the invention, the device was previously implanted and has become partly or fully depleted of the formulation before additional formulation is introduced.

[0200] The therapeutic product in the formulation (e.g., aflibercept) can be delivered to the eye, e.g., the vitreous cavity, actively by means of an ocular implantable device which is a micropump. In an embodiment of the invention, the therapeutic product (e.g., aflibercept) in the formulation is delivered to the eye actively by means of a propellant (e.g., a fluorocarbon) in a chamber that pressurizes a reservoir containing the formulation in the micropump which expels the formulation from the micropump and, e.g., into the eye.

[0201] In an embodiment of the invention, the therapeutic product (e.g., aflibercept) in the formulation is delivered to the eye, e.g., the vitreous cavity, by way of passive diffusion from the device to the eye. See e.g., SUSVIMO™ ocular delivery device.

[0202] Ocular implantable devices can be implanted into or onto the surface of the eye. For example, the device can be implanted into the subconjunctival space and, e.g., secured using scleral sutures. In an embodiment of the invention, the device is implanted in the eye through an incision in the sclera and pars plana.In an embodiment of the invention, the ocular implantable device is microelectromechanical systems (MEMS) device such as the Replenish micropump (Replenish Inc., Pasadena, CA). See Gutierrez-Hernandez et al., One-Year Feasibility Study of Replenish MicroPump forIntravitreal Drug Delivery: A Pilot Study, Tran. Vis. Sci. Tech 3(3): 9 (2014)

[0203] "Sterile" herein refers to aseptic or free from substantially all, or all, living microorganisms and their spores.

[0204] Syringes as used herein include barrels made, for example, of glass or polymer, for example, cycloolefin as described in U.S. Patent Publication No. 2017 / 0232199, incorporated herein for all purposes, a plunger and a needle.

[0205] Containers and injection devices may be coated with silicone (e.g., silicone oil or baked-silicone).

[0206] In an embodiment of the invention, a container or injection device is substantially metal-free or substantially tungsten-free or low-tungsten.

[0207] In an embodiment of the invention, the syringe contains one or more dose line graduations and / or is a dose metering system.

[0208] Containers in accordance with embodiments herein can hold the low concentration VEGF receptor fusion protein formulations. In some aspects, the container can include a label stating indications of use. In some instances, the container can include package inserts with instructions for use as described throughout this specification. In some cases, the container (e.g., a vial or prefilled syringe) can include instructions for loading a VEGF receptor fusion protein formulation into an ocular implantable device (either as an initial fill, or for refilling (e.g., under aseptic conditions) the reservoir of the device).

[0209] While the invention has been particularly shown and described with reference to a number of embodiments, it would be understood by those skilled in the art that changes in the form and details may be made to the various embodiments disclosed herein without departing from the spirit and scope of the invention and that the various embodiments disclosed herein are not intended to act as limitations on the scope of the claims.EXAMPLES

[0210] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. Efforts have been made to ensure accuracy with respect to numbers used, but some experimental errors and deviations should be accounted for. Any formulations set forth in these examples are part of the present invention including embodiments wherein any one or more excipient concentrations and / or pHs are ±10% the stated value.

[0211] In these examples, when an experiment is conducted at 37°C, the temperature is targeted to 37°C with a tolerance of +3°C variation.EXAMPLE 1 : Stable VEGF Receptor Fusion Protein Formulations for Sustained Release - Feasibility Screening

[0212] This feasibility screening study evaluated various formulations at 37SC for sustained release. The purpose of the feasibility screening experiments was to investigate the possibility of a 372C stable formulation that would enable 6-month sustained delivery and allow for extended dosing frequency. The evaluated formulations included aflibercept concentrations of from 10 mg / mL to 40 mg / mL with varying concentrations of excipients, including sodium phosphate, sodium chloride, sucrose, polysorbate 20 (PS20), and histidine. A stability study was initiated in glass-vials to assess formulation stability at 372C for 6 months. Results identified an improvement in stability at lower aflibercept concentrations (10mg / ml_) and higher thermal stabilizer concentrations (20% w / v). Furthermore, the formulation in histidine buffer (pH 5.8) showed even better stability than the same formulation in sodium phosphate buffer (pH 6.2) with sodium chloride.

[0213] More specifically, the overall goal of this project was to develop a formulation for Aflibercept which is stable at 372C for 6 months. This was a screening study which focused on understanding the boundaries of our formulation design space and understanding the impact of excipients and their levels at 37SC. An initial set of formulations focused on understanding the role of Aflibercept concentration, sucrose concentration, sodium phosphate / histidine buffer, and pH. The purpose of this study was to determine if dilution of the Commercial Eylea® formulation to a lower Aflibercept concentration would be feasible as a potential formulation for use in an ocular implantable device. However, in addition to using the same excipient compositions as the commercial formulation, additional formulation conditions such as the use of histidine buffer, lower pH 5.8, and higher sucrose concentration were investigated. Aflibercept concentration range for this evaluation was between 10mg / mL-40mg / ml with varying concentrations of sucrose and in presence of histidine or sodium phosphate buffer.

[0214] The formulations evaluated in this study are shown in Table 1-1 , below.Table 1-1. Formulations for Example 1.

[0215] Following compounding, each formulation was sterile filtered prior to aliquoting into 2R RTU glass vials with a fill volume of 0.7 mL / vial. At each time point, vials were pooled (2 vials pooled into 1 ) to have sufficient volume for analyses. All vials were incubated at 372C for evaluation at different time points.

[0216] The stability study assessed the impact of reducing protein concentration (F1 A- F3A), increasing thermal stabilizer concentration (F3A-F5A), and changing the buffer and pH (F4A, F6A) had on aflibercept’s stability at 37°C (physiological body temperature). All formulations were investigated in glass vials incubated at 37SC. The temperature condition and time points evaluated for each formulation are shown in the tables below.

[0217] Results of the screening studies at 37°C are shown in Tables 1-2 to 1 -7, below. Aggregation rates (over 12 months @ 37°C) and calculated molar ratios of protein to sucrose are shown in Table 1 -8. Fragmentation and post-translational modification (PTM) data, as a function of storage at 37°C, are shown in Tables 1 -9 to 1 -11.Table 1-2. Summary of Analyses for F1 A.Table 1-3. Summary of Analyses for F2A.Table 1-4. Summary of Analyses for F3A.Table 1-5. Summary of Analyses for F4A.Table 1-6. Summary of Analyses for F5A.Table 1-7. Summary of Analyses for F6A.Table 1-8. Calculated Molar Ratios of Stabilizer: Protein and Aggregation Rates for all Formulations Over 12 Months Incubation at 379CTable 1-9. Summary of Non-Reduced CE-SDS Data for F1, F4, and F6 Over 6m Incubation at 37°C.Table 1-10. Summary of Reduced CE-SDS Data for F1, F4, and F6 over 6m incubation at 37°C.Table 1-11. Post-Translational Modifications (PTM) Analysis Summary.

[0218] Based on results from SEC-UPLC, the following order represents formulations from most stable (low %HMW) to least stable (high %HMW species): F6A (10mg / mL aflibercept, 10mM Histidine, 8% w / v Sucrose, 0.03% w / v PS20, pH 5.8) > F5A (20mg / ml_ aflibercept, 10mM Sodium Phosphate, 40mM NaCI, 5% w / v Sucrose, 0.03% w / v PS20, pH 6.2) > F4A (1 Omg / mL aflibercept, 10mM Sodium Phosphate, 40mM NaCI, 8% w / v Sucrose, 0.03% w / v PS20, pH 6.2) > F3A (1 Omg / mL aflibercept, 10mM Sodium Phosphate, 40mM NaCI, 5% w / v Sucrose, 0.03% w / v PS20, pH 6.2) > F2A (20mg / mL aflibercept, 10mM Sodium Phosphate, 40mM NaCI, 5% w / v Sucrose, 0.03% w / v PS20, pH 6.2) > F1A (40mg / mL aflibercept, 10mM Sodium Phosphate, 40mM NaCI, 5% w / v Sucrose, 0.03% w / v PS20, pH 6.2).

[0219] Molar Ratio of Stabilizer to aflibercept has an inverse relationship with aggregation rate; i.e., the higher the molar ratio of stabilizer to aflibercept, the lower is the aggregation rate.

[0220] F4A (1 Omg / mL aflibercept; 8% Sucrose) and F6A (1 Omg / mL aflibercept in Histidine; 8% Sucrose) have the same molar ratio, but the aggregation rate is slower for F6A, indicating that Histidine buffer (pH 5.8) plays a role in reducing the extent of aflibercept aggregation at 372C.

[0221] F5A (1 Omg / mL aflibercept; 8% Sucrose) was observed to have a higher aggregation rate than F6A (1 Omg / mL sflibercept in Histidine; 8% Sucrose) indicating buffer and pH may have a stronger impact on aggregation rate than thermal stabilizer (Sucrose).

[0222] No change in protein recovery of aflibercept was observed after 12m incubation at 37aC for all formulations.

[0223] Low sub-visible particle counts were observed in all formulations, however, formulations containing 10mg / ml aflibercept (F3A-F6A) were observed to have the lowest sub-visible particle counts (data not shown).

[0224] All formulations show an increase in charge variants in %Region 1 , and a decrease in %Region 2 and %Region 3. F6A (10mg / mL aflibercept, 10mM Histidine, 8% w / v Sucrose, 0.03% w / v PS20, pH 5.8) had the least %change in charge variant species at 37°C after 6 months.

[0225] Fragmentation (%LMW) was observed to increase with incubation time at 37°C for all formulations tested (F1 A, F4A, F6A) up to 6m with no differences between formulations seen in the Non-Reduced assay. In the Reduced assay, fragmentation appears to be slightly lower for the Histidine formulation, F6A. There was no correlation between aflibercept concentration and fragmentation observed by CE-SDS.

[0226] All formulations passed acceptance criteria for potency by ELISA, however, a decreasing trend in potency is observed for all formulations.

[0227] Asn deamidation and Met oxidation levels are detected in the formulations tested (F1 A, F4A, and F6A). Asn deamidation and Met oxidation levels were lower in the histidine formulation (F6A).

[0228] F6A (10mg / mL aflibercept, 10mM Histidine, 8% w / v Sucrose, 0.03% w / v PS20, pH 5.8) was observed to be the most stable amongst all formulations tested.EXAMPLE 2: Stable VEGF Receptor Fusion Protein Formulation for Sustained Release - Evaluation of Excipients

[0229] The purpose of this Design-of-Experiment (DOE) study was to evaluate a range of formulations spanning 10-40mg / mL aflibercept, 10-20 mM Histidine, and 5-20% w / v Sucrose, containing 0.03% w / v PS20 at pH 5.8 to identify aflibercept formulation(s) that would enable 6-month sustained delivery and allow for extended dosing frequency. The design of this experiment (DOE) design leveraged data collected in Example 1 , as well as historical data.

[0230] The study was initiated using 14 different aflibercept formulations evaluated in glass-vials to assess formulation stability at 37aC for 6 months. Results identified two formulations, one at 10mg / mL and one at 20mg / mL aflibercept, that show good protein purity and recovery, with some limitations regarding fragmentation and potency.

[0231] The formulations evaluated in this study are shown in Table 2-1 , below.Table 2-1. Formulations.

[0232] Following the initial screening study of Example 1 , it was evident that aflibercept concentration, thermal stabilizer concentration and pH had an impact on formulation stability at 37SC when stressed up to 6 months. The following observations were made from the initial screening study:• No change in %Recovery of Aflibercept after 12 months incubation at 37SC for all formulations;• No major differences in particle counts by MFI (micro-flow imaging) were observed between all formulations; no meaningful trends were detected in particle concentration up to 6 months incubation at 37°C;• Molar Ratio Stabilizer: Protein had an inverse relationship with aggregation rate;• Formulation 10 mg / mL Aflibercept, 10 mM Sodium Phosphate, 40 mM NaCI, 8 %w / v Sucrose, 0.03%w / v PS20-SR (super-refined grade), pH 6.2 and Formulation 10mg / ml_ Aflibercept, 10mM Histidine, 8 %w / v Sucrose, 0.03% w / v PS20, pH 5.8 have the same molar ratio, but aggregation rate is slower for 10 mg / mL Aflibercept, 10mM Histidine, 8% w / v Sucrose, 0.03 %w / v PS20-SR, pH 5.8 suggesting Histidine buffer (pH 5.8) plays a role in stability;• Fragmentation and potency were determined to be comparable across all formulations up to 6 months incubation at 37°C;• Formulation 10 mg / mL Aflibercept, 10mM Sodium Phosphate, 40 mM NaCI, 20% w / v Sucrose, 0.03 %w / v PS20-SR, pH 6.2 and Formulation 10mg / mL Aflibercept, 10mM Histidine, 8% w / v Sucrose, 0.03%w / v PS20-SR, pH 5.8 show the best stability out of allsix formulations tested at 37°C after 12 months;• The order of formulations from most to least stable based on protein purity was as follows:• F6 (1 Omg / mL VGT in Histidine; 8% Sucrose) > F5 (1 Omg / mL VGT ; 20% Sucrose) > F4 (1 Omg / mL VGT; 8% Sucrose) > F3 (1 Omg / mL VGT; 5% Sucrose) > F2 (20mg / mL VGT; 5% Sucrose) > F1 (40mg / mL VGT; 5% Sucrose).

[0233] Therefore, the purpose of this study was to expand on the study of Example 1 by performing a systematic DOE study designed to capture a set of potential formulation compositions between a range of aflibercept, histidine and sucrose concentrations at pH 5.8 and generate a design space where it is possible to predict a potential formulation that may be used for any ocular device containing aflibercept for sustained or controlled release in the eye.

[0234] The range of aflibercept and excipient concentrations in the DOE study were 10-40 mg / ml for aflibercept, 5-20 % for sucrose and 10-20 mM for histidine. Polysorbate was kept constant at 0.03% w / v and pH 5.8.

[0235] One of the factors that was considered while designing the present study was the molar ratio of thermal stabilizer to aflibercept. The idea was to have a D-optimal design with formulations that have a meaningful formulation composition based an understanding of the impact of thermal stabilizer on protein stability. Therefore, keeping in mind the correlation between molar ratio of thermal stabilizer to protein and its impact on the aggregation rate, a design which had a molar ratio of thermal stabilizer to protein from 355 to 5673 was selected. The range selected was quite wide as there was no prior data on formulations which varied the excipient and aflibercept concentrations at 37°C.

[0236] Ranges for aflibercept concentration, histidine concentration, and sucrose concentration were chosen based on historical data and consideration for clinical efficacy.Using JMP Software, a D-Optimal design was chosen to focus on precise estimates of the effects, which in this case was aggregation rate. A matrix showing all the possible combinations of high and low levels for each factor (aflibercept concentration, histidine concentration, and sucrose concentration), allowed predictions to be made anywhere in that space. Based on this matrix, 14 formulations were determined to capture the design space of interest and identify a formulation stable at 37°C for up to 6 months.

[0237] Following compounding, each formulation was sterile filtered prior to aliquoting into 2R RTU glass vials with a fill volume of 1 ,2mL / vial. All vials were incubated at 37SC for evaluation at different time points, as shown in the tables below.

[0238] Results of the analyses for the various formulations at 37°C are shown in Tables 2- 2 to 2-15, below. Aggregation and aggregation rates (over 6 months @ 37°C) are shown in Table 2-16. Summaries of fragmentation and potency are shown in Tables 2-17 and 2-18, and a summary of PTM analysis is shown in Table 2-19.Table 2-2. Summary of Analyses for F1 B.Table 2-3. Summary of Analyses for F2B.Table 2-4. Summary of Analyses for F3B.NR: Not RunFR: Failed RunTable 2-5. Summary of Analyses for F4B.Table 2-6. Summary of Analyses for F5B.Table 2-7. Summary of Analyses for F6B.Table 2-8. Summary of Analyses for F7B.Table 2-9. Summary of Analyses for F8B.Table 2-10. Summary of Analyses for F9B.Table 2-11. Summary of Analyses for F10B.Table 2-12. Summary of Analyses for F11B.Table 2-13. Summary of Analyses for F12B.Table 2-14. Summary of Analyses for F13B.NR: Not RunFR: Failed RunTable 2-15. Summary of Analyses for F14B.NR: Not RunFR: Failed RunTable 2-16. Summary of %Total HMW and change in %HMW (delta) for up to 6 Months Incubation at 37°C in Order of Decreasing %Total HMW.Table 2-17. Summary of Reduced CE-SDS Data for Selected Formulations Over 6 Months at 37°C.Table 2-18. Summary of Fragmentation and Potency for Select Formulations after 6 Months Incubation at 37°C.Table 2-19. PTM Analysis Summary

[0239] From these data, the following conclusions were drawn:• Aggregation Rate for each formulation was shown to model the main effects and interactions with an R20.99 and an RMSE of 0.081 % HMW / mo, which correlates to having a prediction model capable of predicting aggregation of Aflibercept between the concentrations of 10-40 mg / ml;• Based on Prediction model up to 6 months, the most stable formulations were identified at 10 and 20mg / mL aflibercept. Interaction of [Aflibercept]*[Sucrose] and [Sucrose]*[Sucrose] was significant (p < 0.05);• Predicted HMW exposure levels are lower than clinical experience with Eylea DP and HD Eylea.;• No meaningful change in %PS20 recovery, or sub-visible particle concentration up to 6m for all formulations.;• Change in charge variants over 6m at 37aC was comparable across formulations;• Decreasing trend in Potency by ELISA is observed for all formulations for up to 6m however, all formulations passed acceptance criteria of 50-150%;• LMW formation was detected by CE-SDS (Reduced) and shown to increase from tO to 6m at 37SC;• No meaningful difference observed on %LMW formation for [Histidine], [Sucrose] and [Aflibercept] between 10 and 25mg / mL which indicated the formation of LMW species is independent of aflibercept concentration, and may be related to a hydrolytic reaction at a constant rate; and• Colour change observed in formulations containing higher concentrations of Histidine at higher concentrations of Aflibercept.

[0240] Regarding predicting optimal formulations at 10 and 20mg / mL aflibercept: Aggregation Rate for each formulation was shown to model the main effects and interactions with an R2 0.99 and an RMSE of 0.081 %HMW / mo; The model can accurately reflect the actual response observed in the data set and is therefore, reliable for predictions of aggregation rates for 10-40mg / mL VEGF Trap formulations with varying levels of Histidine and Sucrose; A prediction profiler was used to predict most stable formulations based on aggregation rate at 10mg / mL Aflibercept and 20mg / mL Aflibercept.Based on the observed data, and using prediction profiling while maximizing desirability to minimize aggregation, the best stability at 10 mg / mL is attained with: 10 mg / mL aflibercept, 15% Sucrose, 10 mM Histidine, 0.03% PS20 at pH 5.8; and the best stability at 20 mg / mL is attained with: 20 mg / mL aflibercept, 20% Sucrose, 10 mM Histidine, 0.03% PS20 at pH 5.8.

[0241] Using prediction profiler and maximizing desirability to minimize aggregation best stability at 10 mg / mL Formulation is attained with: 10 mg / mL Aflibercept, 15% Sucrose, 10mM Histidine, 0.03% PS20 at pH 5.8. Using prediction profiler and maximizing desirability to minimize aggregation: best stability at 20 mg / mL Formulation is attained with: 20 mg / mL Aflibercept, 20% Sucrose, 10 mM Histidine, 0.03% PS20 at pH 5.8.EXAMPLE 3: Stable VEGF Receptor Fusion Protein Formulation for Sustained Release - Fragmentation Study

[0242] This study is an investigation into fragmentation observed in the evaluation of a 37°C stable formulation for sustained release. The purpose of this experiment was todetermine whether fragmentation could be mitigated to potentially improve potency. Based on results from Example 2, two formulations were identified to have greatest stability at 37°C for 6 months based on aggregation rate, however fragmentation was observed and appeared to correlate with a decrease in overall potency. Of the two formulations, the one at the higher concentration (20 mg / mL Aflibercept, 10 mM Histidine, 20% w / v Sucrose, 0.03% w / v PS20, pH 5.8) was selected for evaluation at varying pH. Fragmentation mitigation was investigated by increasing the pH from pH 5.8 to pH 6.4 (to control enzymatic and hydrolytic impact). A stability study was initiated in glass-vials to assess formulation stability at 37°C for 6 months and extended 12 months. Results identified reduced R1 clipping at higher pH, but potency was not significantly impacted. Furthermore, protein purity and charge variants were severely affected at higher pH. The formulations identified in the previously discussed DOE study of Example 2 at pH 5.8 were decided to be the most optimal.

[0243] The formulations evaluated in this study are shown in Table 3-1 , below.Table 3-1. Formulations.

[0244] A DOE study (Example 2) was performed to identify an optimal formulation in Histidine buffer (based on Example 1 screening study) that would be stable at 37°C for 6 months, for use in an implantable Micropump, and maximize the therapeutic dose.Previously discussed experiments were successful at mitigating %HMW formation, however fragmentation was observed in lead formulations which correlates with reduced potency. Cathepsin-D, a host cell enzyme that gets purified with Aflibercept, has historically been implicated in fragmentation of the receptor region and can be the potential cause of fragmentation observed in lead formulations.

[0245] The rationale for this study was to evaluate a range of pH between 5.8 and 6.4 for Aflibercept Formulations identified in Example 2. Increasing the pH of current formulations is of interest because pH is known to mitigate Cathepsin-D activity and ultimately can reduce the fragmentation currently observed at pH 5.8.

[0246] The formulations tested in the present study have the same composition, but vary in pH, as shown in Table 3-1 , above. The range of pH investigated was pH 5.8, pH 6.0, pH 6.2, and pH 6.4, and was selected based on the role pH plays in both enzymatic cleavage and hydrolysis.

[0247] Based on the DOE study, the maximum recommended concentration of Aflibercept for optimal stability is 20mg / mL with 10mg / mL Aflibercept being optimal. Formulations in the current study targeted the maximum concentration of Aflibercept and Sucrose at varying pH levels to identify whether an increase in pH leads to improved (less) fragmentation by CE- SDS. A comprehensive testing panel at 37°C and 2-8°C for 6 months was evaluated in this investigation.

[0248] The pH range investigated was chosen based on previous understanding of Cathepsin-D, a host cell enzyme that gets purified with aflibercept, which has historically been implicated in fragmentation of the receptor region and can be the potential cause of fragmentation observed in the formulations of Example 2. Increasing pH was observed to slow the rate of enzyme activity, however, increasing pH has also historically indicated destabilization of aflibercept. This facilitated the selection of a narrow yet impactful pH range between pH 5.8 and pH 6.4.

[0249] Four formulations were determined to capture the pH range for mitigating fragmentation occurring at 37°C after 6 months incubation. Aflibercept FCP (185.6mg / mL Aflibercept, 10.6mM Histidine) was used to generate each of the 4 formulations in combination with a distinct concentrated excipient buffer to target the specified pH.

[0250] Following compounding, each formulation was sterile filtered prior to aliquoting into 2R RTU glass vials with a fill volume of 1 .2 mL / vial. All vials were incubated at 5°C or 37SC for evaluation at different time points, as shown in the tables below.

[0251] The results of the analyses of the formulations of the present study are shown in Tables 3-2 to 3-9, below. Aggregation and aggregation rates (over 6 months @ 37°C) are shown in Table 3-10. Summaries of fragmentation and are shown in Tables 3-11 and 3-12 for the formulations incubated at 37°C and 5°C, respectively.Table 3-2. Summary of Analyses at 5°C for F1C.NR = Not RunFR = Failed RunTable 3-3. Summary of Analyses at 37°C for F1C.NR = Not RunNR*=not run-unable to integrate*t0 was run in duplicate, t=1m, 3m were run as n=1 , and t=4m, 6m was run as n=3Table 3-4. Summary of Analyses at 5°C for F2C.NR = Not RunTable 3-5. Summary of Analyses at 37°C for F2C.NR = Not RunNR* = Not Run - unable to integrate*t0 was run in duplicate, t=1m, 3m were run as n=1 , and t=4m, 6m was run as n=3Table 3-6. Summary of Analyses at 5°C for F3C.NR = Not RunTable 3-7. Summary of Analyses at 37°C for F3C.NR = Not RunNR* = Not Run - unable to integrate*t0 was run in duplicate, t=1m, 3m were run as n=1 , and t=4m, 6m was run as n=3Table 3-8. Summary of Analyses at 5°C for F4C.NR = Not RunNR* = Not Run because no TBD samples left for a 12m time point.Table 3-9. Summary of Analyses at 37°C for F4C.NR = Not RunNR‘ = Not Run - unable to integrate*t0 was run in duplicate, t=1m, 3m were run as n=1 , and t=4m, 6m was run as n=3Table 3-10. Summary of Total and Delta %HMW Over 6 Months Incubation at 5°C and 37°C.‘Formulation contains 20mg / mL Aflibercept, 10mM Histidine, 20% Sucrose, 0.03% PS20 NR = Not Run; no TBD samples left for a 12m time pointTable 3-10A. Summary of Total and delta %HMW over 6 months incubation at 37°C.‘Formulation contains 20mg / mL Aflibercept, 10mM Histidine, 20% Sucrose, 0.03% PS20Table 3-11. Summary of Reduced CE-SDS Data for F1C-F4C over 6m incubation at 37°CTable 3-12. Summary of Reduced CE-SDS Data for F1C-F4C Over 6m Incubation at 5°CNR = Not Run

[0252] Aflibercept aggregation (%Total HMW Species) profile over 6 months at 37°C datashowed formulation stability in the following order: F1 (pH 5.8) > F3 (pH 6.0) > F2 (pH 6.2) > F4 (pH 6.4). Increasing pH resulted in higher overall %HMW at tO and increases aggregation (total %HWM species) over time at 37°C. Aggregates were the majority Dimers with <0.3% Multimer species detected at 37°C for up to 6 months in all formulations.

[0253] This study was intended to understand the impact of pH on aflibercept formulations at 2 temperatures: 5SC and 37aC. Only one formulation was investigated across pH 5.8-6.4 at 20mg / ml aflibercept, 10mM Histidine, 20% w / v Sucrose, 0.03% w / v PS20. The conclusions drawn from the data are set forth below.• No change in % total HMW species was observed at 5aC compared to tO at 6 months, for all formulations between pH 5.8-6.4. However, at 37aC a clear trend in the extent of degradation was observed across varying pHs; o pH 6.4 was observed to have a higher rate of aggregation compared to pH 5.8. Following 6 months incubation at 37°C, pH 5.8 was the most stable formulation condition with only 3.3 %HMW increase from tO. All aggregates were majority dimers with <0.1% multimer species detected at 5°C and <4% multimer species detected at 37°C for up to 12 months in all formulations. No reduction in protein recovery was observed in any of the formulations;• No reduction in polysorbate recovery was observed at 12 months for any of the formulations at 5°C or 37°C;• No trends in sub-visible particles were observed for any of the formulations after 12 months incubation at 5°C or 37°C;• No meaningful trends were observed in charge variants up to 12 months at 5°C. At 37aC, charge variant profile by iCIEF was observed to have a significant increase in %Region 1 and reduction in %Region 2 and %Region 3. A pH dependent effect was observed, with a significant impact on charge variants at pH 6.4 compared to pH 5.8. Mechanisms such as deamidation and oxidation may be in involved in changing the charge species of aflibercept; 12m data could not be integrated as it was heavily degraded; peak resolution was completely lost.• At higher pH of 6.4, a lower extent of R1 clipping was observed when compared to pH 5.8, but the overall fragmentation was not significantly different between formulations. There was no impact on fragmentation at 5°C; o Fragmentation was determined to be primarily driven by hydrolysis and not enzymatic cleavage by Intact Mass analysis;• ELISA and Bioassay were performed on all samples, which indicated no significant difference between formulations up to 6 months at 37aC, which indicates that any improvements in fragmentation observed with pH did not translate to improvedpotency; overall decreasing trend remains apparent. No trends were observed by ELISA or Bioassay at 5aC;• Aflibercept and sucrose concentration are the main factors driving aggregation o By reducing aflibercept concentration and increasing sucrose, formulations targeting a total %HMW <%5 with <1% multimer species can be produced to reach a therapeutic dose;• Increasing pH of the formulation to pH 6.4 increased aggregation and had no significant improvement on fragmentation or potency relative to lower pH 5.8;• Formulations containing aflibercept at a concentration of 10-20 mg / mL, sucrose at a concentration of 15-20% w / v, 10 mM histidine buffer, 0.03% w / v polysorbate 20, at a pH of 5.8-+6.2 are stable, potent, and suitable for extended / sustained release for 6 months at 372C.

[0254] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequences or GenelD entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants to relate to each and every individual publication, database entry (e.g., Genbank sequences or GenelD entries), patent application, or patent, each of which is clearly identified in even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0255] The present invention encompasses formulations having excipients as set forth herein at specific concentrations as well as such formulations having one or more of these excipients at concentrations which are about ±10% (e.g., about ± 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%) of the concentration specifically mentioned. Similarly, the invention includes formulations having pH values specifically mentioned herein as well as pH values that are about ±10%.

Claims

What is claimed is:1 . An aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein, anti-VEGF antibody or antigen-binding fragment or VEGF binding molecule at a concentration of less than or equal to about 25 mg / ml; a thermal stabilizer; a buffer; and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2.

2. The aqueous pharmaceutical formulation of claim 1 comprising: a VEGF receptor fusion protein, at a concentration of less than or equal to about 25 mg / ml; a sugar; a buffer; and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2.

3. The aqueous pharmaceutical formulation of any one of claims 1 -2 comprising: a VEGF receptor fusion protein, at a concentration of less than or equal to about 25 mg / ml; a sugar; a histidine-based buffer; and a non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2.

4. The aqueous pharmaceutical formulation of any one of claims 1 -3 comprising: a VEGF receptor fusion protein, at a concentration of less than or equal to about 25 mg / ml; a sugar; a histidine-based buffer; and polysorbate; wherein the formulation has a pH of about 5.8 to about 6.2.

5. The aqueous pharmaceutical formulation of any one of claims 1 -4 comprising: a VEGF receptor fusion protein, at a concentration of less than or equal to about 25 mg / ml;sucrose; a histidine-based buffer; and polysorbate; wherein the formulation has a pH of about 5.8 to about 6.2.

6. The aqueous pharmaceutical formulation of any one of claims 1 -5 comprising: a VEGF receptor fusion protein at a concentration of less than or equal to about 25 mg / ml; about 10%-25% w / v sucrose; a histidine-based buffer; and about 0.02%-0.04% w / v non-ionic surfactant; wherein the formulation has a pH of about 5.8 to about 6.2.

7. The aqueous pharmaceutical formulation of any one of claims 1 -5 comprising: about 10-20 mg / ml aflibercept; about 10 mM histidine-based buffer about 15-20% sucrose about 0.03% polysorbate 20 pH about 5.8-6.2; or, about 10-20 mg / ml aflibercept; about 10 mM histidine-based buffer about 20% sucrose about 0.03% polysorbate 20 pH about 5.8.

8. The formulation of any one of claims 1-7, which is suitable for intravitreal administration.

9. The formulation of any one of claims 1-8, which is suitable for intravitreal administration from an ocular implantable device.

10. The formulation of any one of claims 1 -9 wherein the molar ratio of thermal stabilizer to VEGF receptor fusion protein is less than about 350, less than about 700, less than about 1400, less than about 2300, or less than about 5700.11 . The formulation of any one of claims 1-10 wherein: the VEGF receptor fusion protein is aflibercept at a concentration of about 10 mg / ml;the buffer is histidine-based buffer; the pH is about 5.8; and the molar ratio of thermal stabilizer to VEGF receptor fusion protein is less than about 2300.

12. The formulation of any one or claims 1-11 , wherein the VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is:(i) a VEGF receptor fusion protein comprising two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2;(ii) a VEGF receptor fusion protein comprising two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of a VEGFR2, and a multimerizing component;(iii) a VEGF receptor fusion protein comprising two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1 , an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component;(iv) a VEGF receptor fusion protein comprising two VEGFR1 R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO:1 ; or(v) selected from the group consisting of: bevacizumab, ranibizumab, pegaptanib, brolucizumab, an anti-VEGF DARPin and a bispecific anti-VEGF / ANG2 antibody.

13. The formulation of claim 1 , wherein the VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is a VEGF receptor fusion protein.

14. The formulation of any one of claims 1 -13, wherein the VEGF receptor fusion protein is selected from the group consisting of: aflibercept and conbercept.

15. The formulation of any one of claims 1 -13, wherein the VEGF receptor fusion protein is aflibercept.

16. The formulation of any one of claims 1 -15, wherein the VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is a VEGF receptor fusion protein at a concentration of from about 10 mg / ml to about 25 mg / ml; or from about 10 mg / ml to about 20 mg / ml.

17. The formulation of any one of claims 1 -16, wherein the VEGF receptor fusion protein or anti-VEGF antibody or antibody fragment or VEGF binding molecule is a VEGF receptor fusion protein at a concentration of:• about 10 mg / ml;• about 10.5 mg / ml;• about 11 mg / ml;• about 11.5 mg / ml;• about 12 mg / ml;• about 12.5 mg / ml;• about 13 mg / ml;• about 13.5 mg / ml;• about 14 mg / ml;• about 14.5 mg / ml;• about 15 mg / ml;• about 15.5 mg / ml;• about 16 mg / ml;• about 16.5 mg / ml;• about 17 mg / ml;• about 17.5 mg / ml;• about 18 mg / ml;• about 18.5 mg / ml;• about 19 mg / ml;• about 19.5 mg / ml; or• about 20 mg / ml.

18. The formulation of any one of claims 1 -17, wherein:(i) the osmolality is about 400 to about 850 mmol / Kg; and / or(ii) the viscosity is from about 1-3 cP at 20°C.

19. The formulation of any one of claims 1-18, wherein the pH is about 5.8.

20. The formulation of claim 1 -19 wherein the thermal stabilizer is a sugar, a polyol sugar and / or an amino acid.21 . The formulation of claim 1 -20 wherein the thermal stabilizer is sucrose, trehalose, sucrose and trehalose, erythritol, mannitol, xylitol, isomalt, lactitol, threitol, maltitol, sorbitol, L-proline, L-arginine, L-arginine monohydrochloride, a substituted acrylamide, propane sulfonic acid, glycerol and / or taurine.

22. The formulation of any one of claims 1-21 wherein the concentration of thermal stabilizer is about 10-25% w / v.

23. The formulation of any one of claims 1-22, which comprises 15%-20% w / v sucrose.

24. The formulation of any one of claims 1-23 comprising, wherein the non-ionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 and mixtures thereof.

25. The formulation of claim 24, wherein the non-ionic surfactant is polysorbate 20.

26. The formulation of any one of claims 1-25, which comprises 0.03% w / v non-ionic surfactant.

27. The formulation of any one of claims 1-26 wherein the buffer is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer, and / or a citrate-based buffer.

28. The formulation of any one of claims 1-27, comprising a buffer which is a histidine- based buffer that comprises histidine hydrochloride.

29. The formulation of claim 28, comprising about 5 mM to 15 mM histidine-based buffer.

30. The formulation of claim 19, comprising a histidine-based buffer that comprises about 10 mM histidine hydrochloride.31 . The formulation of any one of claims 1-30 wherein the rate of increase in high molecular weight (HMW) species (total), during storage at about 37°C for about 12 months, is less than about 1% / month; about 1% / month; about 2% / month (or less); about 3% / month (or less); or about 4% / month (or less).

32. The formulation of any one of claims 1-31 wherein the total percentage of high molecular weight (HMW) species after storage at about 37°C for about 6 months is about 2% or less, 3% or less, 4% or less, or 5% or less; and / or the total percentage of low molecular weight (LMW) species after storage at about 37°C for about 6 months is about 1% or less, 2% or less, or 3% or less.

33. The formulation of any one of claims 1-32 wherein the total percentage of high molecular weight species immediately after manufacture is about 1% or less.

34. The formulation of any one of claims 1-33 wherein the total percentage of high molecular weight species after storage at about 37°C for about 6 months is less than that of a formulation having:40 mg / ml aflibercept,10 mM sodium phosphate,40 mM NaCI,0.03% polysorbate 20,5% (w / v) sucrose, pH 6.2; or having:114.3 mg / ml aflibercept,10 mM histidine-based buffer,5% (w / v) sucrose,0.03 % (w / v) polysorbate 20,50 mM L-arginine monohydrochloride, pH 5.8; after about 6 months storage at about 37°C.

35. A formulation comprising the components in a formulation selected from the group consisting of:Formulation A: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation B: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation C: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation D: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation E: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation F: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation G: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation H: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation I: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation J: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation K: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation L: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation M: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation N: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation O: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation P: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation Q: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation R: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation S: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation T: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation U: 10-20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation V: 10 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation W: 15 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation X: 20 mg / ml ± 1 mg / ml VEGF receptor fusion protein, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation Y: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation Z: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation AA: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation BB: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation CO: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation DD: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation EE: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation FF: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation GG: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2; Formulation HH: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation II: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation JJ: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation KK: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation LL: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation MM: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation NN: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15- 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation GO: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation PP: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation QQ: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation RR: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation SS: 10-20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation TT: 10 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation UU: 15 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; Formulation VV: 20 mg / ml ± 1 mg / ml aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation WW: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine-based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation XX: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation YY: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation ZZ: 20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation AAA: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation BBB: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation CCC: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation DDD: 20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation EEE: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation FFF: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation GGG: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation HHH: 20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8 to 6.2;Formulation III: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation J J J: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation KKK: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation LLL: 20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15-20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation MMM: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine-based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation NNN: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation OOO: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation PPP: 20 mg / ml ± 2 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 15% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation QQQ: 10-20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation RRR: 10 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8;Formulation SSS: 15 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8; orFormulation TTT: 20 mg / ml ± 1 mg / ml conbercept or aflibercept, 10 mM ± 1 mM histidine- based buffer, 20% ± 1% (w / v) sucrose, and 0.03% ± 0.01% (w / v) polysorbate 20, with a pH of 5.8Formulation UUU: 20 ± 2 mg / ml mg / mL Aflibercept, 10 mM Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;Formulation VW: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;Formulation WWW: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 8% ± 0.8% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;Formulation XXX: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM Sodium Phosphate Sodium Phosphate-based buffer, 40mM ± 4 mM Sodium Chloride, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 6.2;Formulation YYY: 10 mg / mL ± 1 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 8%w / v Sucrose, 0.03%± 0.01% w / v PS-20, pH 5.8;Formulation ZZZZ: 40 mg / mL ± 4 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation AAAA: 40 mg / mL ± 4 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8Formulation BBBB: 40 mg / mL ± 4 mg / ml Aflibercept, 20 mM ± 2 mM histidine-based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation CCCC: 40 mg / mL ± 4 mg / ml Aflibercept, 20 mM ± 2 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation DDDD: 40 mg / mL ± 4 mg / ml Aflibercept, 15 mM ± 1 .5 mM histidine-based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation EEEE: 25 mg / mL ± 2.5 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation FFFF: 2 5mg / ml_ ± 2.5 mg / ml Aflibercept, 15 mM ± 1.5 mM histidine-based buffer, 5% ± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation GGGG: 25 mg / mL ± 2.5 mg / ml Aflibercept, 15 mM ± 1.5 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation HHHH: 25 mg / mL ± 2.5 mg / ml Aflibercept, 20 mM ± 2 mM histidine-based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation Illi: 10 mg / ml_± 1 mg / ml Aflibercept, 10 mM histidine-based buffer, 5% ± 0.5%w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation JJJJ: 10 mg / mL± 1 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation KKKK: 10 mg / ml_± 1 mg / ml Aflibercept, 20 mM ± 2 mM histidine-based buffer, 5%± 0.5% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation LLLL: 10 mg / mL ± 1 mg / ml Aflibercept, 20 mM ± 2 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation MMMM: 10 mg / ml_± 1 mg / ml Aflibercept, 15 mM ± 1.5 mM histidine-based buffer, 12.5% ± 1 .25% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation NNNN: 20 mg / mL ± 2 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 5.8;Formulation OOOO: 20 mg / mL ± 2 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 6.2;Formulation PPPP: 20 mg / mL ± 2 mg / ml Aflibercept, 10 mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03%± 0.01% w / v PS20, pH 6.0;Formulation QQQQ: 20 mg / mL ± 2 mg / ml Aflibercept, 10mM ± 1 mM histidine-based buffer, 20% ± 2% w / v Sucrose, 0.03% w / v PS20, pH 6.4;Formulation RRRR: VEGF Receptor Fusion Protein I Aflibercept I Conbercept or Aflibercept: 10-20 mg / ml ± 1 mg / ml, Histidine-Based Buffer or sodium phosphate-based buffer: 10 mM ± 1 mM, sugar or polyol or sucrose: 15-20% ± 1% (w / v), non-ionic surfactant or polysorbate 20: 0.03% ± 0.01% (w / v), pH Range: 5.8 to 6.2;Formulation SSSS: 10-40 mg / ml ± 4 mg / ml Conbercept or Aflibercept:, 10-20 mM ± 2 mM Histidine-based buffer or Sodium Phosphate-based buffer, 5-20% ± 2% (w / v) sugar, polyol or sucrose, 0.03% ± 0.01% (w / v) non-ionic surfactant or polysorbate 20, pH 5.8 to 6.4; and Formulation TTTT: 10-40 mg / ml ± 4 mg / ml Aflibercept, 10-20 mM ± 2 mM Histidine-based buffer or Sodium Phosphate-based buffer, 5-20% ± 2% (w / v) sucrose, 0.03% ± 0.01% (w / v) polysorbate 20, pH 5.8 to 6.4.

36. The formulation of claim 35 wherein the rate of increase in high molecular weight (HMW) species (total), during storage at about 37°C for about 12 months, is less than about 1% / month; about 1% / month; about 2% / month (or less); about 3% / month (or less); or about 4% / month (or less).

37. The formulation of any one of claims 35-36 wherein the total percentage of high molecular weight (HMW) species after storage at about 37°C for about 6 months is about 2% or less, 3% or less, 4% or less, or 5% or less; and / or the total percentage of low molecular weight (LMW) species after storage at about 37°C for about 6 months is about 1 % or less, 2% or less, or 3% or less.

38. The formulation of any one of claims 35-37 wherein the total percentage of high molecular weight species immediately after manufacture is about 1% or less.

39. The formulation of any one of claims 35-38 wherein the total percentage of high molecular weight species after storage at about 37°C for about 6 months is less than that of a formulation having:40 mg / ml aflibercept,10 mM sodium phosphate,40 mM NaCI,0.03% polysorbate 20,5% (w / v) sucrose, pH 6.2; or having:114.3 mg / ml aflibercept,10 mM histidine-based buffer,5% (w / v) sucrose,0.03 % (w / v) polysorbate 20,50 mM L-arginine monohydrochloride, pH 5.8; after about 6 months storage at about 37°C.

40. The formulation of any one of claims 1-39 that does not contain NaCI.41 . The formulation of any one of claims 1-40 that does not contain arginine.

42. A sustained delivery system comprising the formulation of any one of claims 1 -41 .

43. A container comprising the formulation of any one of claims 1-41 .

44. The container of claim 43, which is a vial, syringe, autoinjector or pre-filled syringe.

45. An ocular implantable device comprising the formulation of any one of claims 1-41 .

46. The ocular implantable device of claim 45, which is an injectable intravitreal implant, an intrascleral implant, an episcleral implant.

47. The ocular implantable device of any one of claims 45-46, which comprises a micropump.

48. The ocular implantable device of any one of claims 45-46, which is refillable.

49. A method for preparing the formulation of any one of claims 1-41 , comprising combining the components of said formulation into a single composition.

50. The method of claim 49, further comprising loading a volume of the formulation into a vial, container, sustained delivery system or ocular implantable device.51 . A method for administering a formulation of any one of claims 1-41 to a subject, comprising loading the formulation into an ocular implantable device for intravitreal administration into an eye of the subject.

52. The method of claim 51 , wherein the ocular implantable device has been previously implanted into or onto the eye of the subject.

53. The method of any one of claims 51 -52 wherein the method further comprises implanting the device into or onto the eye.

54. A method for treating an angiogenic eye disorder in a subject in need thereof comprising intraocularly administering about 0.01 -0.4 mg / day VEGF receptor fusion protein to one or more eyes of the subject.

55. A method for treating an angiogenic eye disorder in a subject in need thereof comprising intraocularly administering a therapeutically effective dose of formulation of any one of claims 1-41 to one or more eyes of the subject.

56. A method for treating an angiogenic eye disorder in a subject in need thereof, comprising loading a volume of the formulation of any one of claims 1 -41 into an ocular implantable device, wherein the ocular implantable device delivers a dose of the formulation into an eye of the subject at a given rate over a dosing period.

57. The method of claim 56, further comprising implanting the ocular implantable device into or onto the eye of the subject.

58. The method of claim 56, wherein the ocular implantable device has been previously implanted into or onto the eye of the subject.

59. The method of any one of claims 51 -58, wherein the dosing period is six months in duration.

60. The method of any one of claims 51 -58, wherein the dosing period is up to six months in duration.61 . The method of any one of claims 51 -58, wherein the dosing period is greater than six months in duration.

62. The method of any one of claims 51 -58, wherein the dosing period is from three to six months in duration, or from six to twelve months in duration.

63. The method of any one of claims 51 -62 wherein said administering occurs continuously over time.

64. The method of any one of claims 51 -63, wherein the angiogenic eye disorder is age- related macular degeneration (wet), macular edema, macular edema following retinal vein occlusion, retinal vein occlusion (RVO), central retinal vein occlusion (CRVO) branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and / or proliferative diabetic retinopathy.

65. A kit comprising a container containing the formulation of any one of claims 1 -41 , and instructions for loading a volume of the formulation into an ocular implantable device.

66. The kit of claim 65, wherein the ocular implantable devices is an injectable intravitreal implant, an intrascleral implant, an episcleral implant.

67. The kit of any one of claims 65-66, wherein the episcleral implant is a micropump device.

68. The kit of any one of claims 65-67, wherein the ocular implantable device is refillable.

69. The kit of any one of claims 65-68, wherein the instructions for loading comprise instructions for initially filing a reservoir of the ocular implantable device with the formulation, and instructions for refilling the reservoir of the ocular implantable device with the formulation.

70. An ocular implantable device comprising a reservoir containing a formulation of any one of claims 1-41 .71 . The ocular implantable device of claim 70 which is a Replenish micropump or a port delivery system.

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