Methods for treating eye diseases

Abstract

This invention provides a method for treating patients with neovascular eye disease. [Solution] A method for treating proliferative diabetic retinopathy (PDR) in a patient, a) Administer the patient three individual doses of a VEGF antagonist at 6-week intervals, and b) Administering one or more additional doses of the VEGF antagonist to the patient once every 12 weeks (q12w regimen), wherein the first additional dose is administered 12 weeks after the third individual dose in step a).

Description

[Technical Field]

[0001] Sequence List This application is submitted electronically in ASCII format and is hereby referred to in its entirety. Includes the sequence listing used. The aforementioned ASCII copy was created on July 28, 2020. - The file name is PAT058689_SEQ_LISTING_ST25.txt, The size is 8KB.

[0002] The present invention relates to a method for treating eye diseases with a VEGF antagonist. The present invention provides a treatment regimen for diabetic retina with less frequent dosing than currently approved treatment regimens. This relates to the treatment of neovascular eye diseases such as diabetic retinopathy and proliferative diabetic retinopathy. [Background technology]

[0003] Diabetes mellitus (DM) is the most common endocrine disorder in developed countries, and the estimated prevalence is It affects between 2 and 5% of the world's population. Diabetic retinopathy (DR) and diabetic macular edema. Diabetic mesenteric neuropathy (DME) is a common microvascular complication in patients with diabetes, affecting visual acuity (VA). It can affect and weaken the eyes, potentially leading to blindness.

[0004] Diabetic retinopathy (DR) is the most common cause of vision loss in people with diabetes, especially in those of working age. High blood glucose levels are a major cause of visual impairment and blindness in humans. This occurs when damage is caused to the blood vessels. These blood vessels swell and leak. Or these blood vessels may become blocked, stopping the flow of blood. In some cases, abnormal new blood vessels may grow in the retina. Diabetic retinopathy is a type of non-proliferative diabetes. Diabetic retinopathy (nPDR) and proliferative diabetic retinopathy (PDR), a more advanced form of the disease. This includes both of the above. DME frequently manifests as a symptom of DR (Riordan-Eva, 2004, Eye (Lond). 2004, 18:1161-8), patients with DR It is the main cause of visual impairment in DR. Diabetic macular edema (DME) is a major cause of all DR stools. While it can occur at any stage, diabetic macular edema is more likely to appear after severe nPDR and PDR. many.

[0005] Currently, healthcare providers are actively monitoring mild to moderate nPDRs and severe nPDs. Treatment for R and PDR is being withheld. LUCENTIS (registered trademark) and EYLEA ( (Registered trademark) also recently received approval for DR in the United States. To treat DR, EYLE The recommended dose for A (registered trademark) is 2 mg (0.05 mL) in 5 injections. The treatment involves administering the drug every four weeks, followed by one injection every eight weeks. Therefore, the recommended dosage for LUCENTIS® is once per month. The dosage is 0.3 mg (0.05 mL). Two drugs have been approved to treat DR. However, the current standard treatments are panretinal photocoagulation (PRP) and laser treatment. Despite having treatment options, reducing the frequency of injections and achieving a better anatomical response Therefore, there remains a need for treatments that avoid invasive laser therapy. [Overview of the project] [Means for solving the problem]

[0006] This invention relates to a therapeutic VEGF antagonist for treating proliferative diabetic retinopathy (PDR). Provided is a method for administering varnish. In one aspect, the present invention is a method for treating PDR, comprising administering to a mammal at least two individual doses of a VEGF antagonist at 6-week intervals (q6w) during an induction period, and then additional doses during a maintenance period, wherein the doses administered during the maintenance period are spaced at least 6 weeks apart. A method is provided. In one aspect, the doses during the maintenance period are administered once every 12 weeks (q12w) or more. In one aspect, the dosing frequency is adjusted based on the results of the disease activity assessment, for example, using established visual and anatomical criteria. In one aspect, during the maintenance period, at any time (e.g., after 48 weeks measured from the first treatment dose), the treatment interval may be extended up to 24 weeks, once every 6 weeks, at the discretion of the treating provider based on an assessment of the activity of diabetes. In another aspect, the dosing frequency during the maintenance period can be adjusted by decreasing the dosing interval from once every 12 weeks (q12w) to once every 6 weeks (q6w) if disease activity is detected at any scheduled treatment visit. A method for treating PDR, comprising administering to a mammal at least two individual doses of a VEGF antagonist at 6-week intervals (q6w) during an induction period, and then additional doses during a maintenance period, wherein the doses administered during the maintenance period are spaced at least 6 weeks apart. A method for treating PDR, comprising administering to a mammal at least two individual doses of a VEGF antagonist at 6-week intervals (q6w) during an induction period, and then additional doses during a maintenance period, wherein the doses administered during the maintenance period are spaced at least 6 weeks apart. A method for treating PDR, comprising administering to a mammal at least two individual doses of a VEGF antagonist at 6-week intervals (q6w) during an induction period, and then additional doses during a maintenance period, wherein the doses administered during the maintenance period are spaced at least 6 weeks apart. In one aspect, the doses during the maintenance period are administered once every 12 weeks (q12w) or more. In one aspect, the dosing frequency is adjusted based on the results of the disease activity assessment, for example, using established visual and anatomical criteria. In one aspect, during the maintenance period, at any time (e.g., after 48 weeks measured from the first treatment dose), the treatment interval may be extended up to 24 weeks, once every 6 weeks, at the discretion of the treating provider based on an assessment of the activity of diabetes. In one aspect, during the maintenance period, at any time (e.g., after 48 weeks measured from the first treatment dose), the treatment interval may be extended up to 24 weeks, once every 6 weeks, at the discretion of the treating provider based on an assessment of the activity of diabetes. In one aspect, during the maintenance period, at any time (e.g., after 48 weeks measured from the first treatment dose), the treatment interval may be extended up to 24 weeks, once every 6 weeks, at the discretion of the treating provider based on an assessment of the activity of diabetes. In one aspect, during the maintenance period, at any time (e.g., after 48 weeks measured from the first treatment dose), the treatment interval may be extended up to 24 weeks, once every 6 weeks, at the discretion of the treating provider based on an assessment of the activity of diabetes. In another aspect, the dosing frequency during the maintenance period can be adjusted by decreasing the dosing interval from once every 12 weeks (q12w) to once every 6 weeks (q6w) if disease activity is detected at any scheduled treatment visit. In another aspect, the dosing frequency during the maintenance period can be adjusted by decreasing the dosing interval from once every 12 weeks (q12w) to once every 6 weeks (q6w) if disease activity is detected at any scheduled treatment visit.

[0007] The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). The present invention also provides a VEGF antagonist for use in a method for treating an eye disease, particularly a neovascular eye disease, more particularly diabetic retinopathy (DR) and proliferative diabetic retinopathy (PDR) in a patient, wherein the VEGF antagonist is initially provided during an induction period, during which the patient receives 3 individual doses of the VEGF antagonist at 6-week intervals, and then the VEGF antagonist is provided during a maintenance period, during which the patient receives additional doses of the VEGF antagonist once every 12 weeks (q12w). EGF antagonists are also provided. In one embodiment, the frequency of administration is determined by the expected disease activity. If not detected at the time of treatment visit, one treatment every 24 weeks (q24w) for 6 weeks at a time. The interval can be extended by increasing the medication interval. In another embodiment, The frequency is once every 12 weeks (q1) if disease activity is detected at a scheduled treatment visit. Adjust by reducing the medication interval from 2 weeks to once every 6 weeks (q6w). It is possible.

[0008] The present invention also relates to a method for treating DR, wherein the induction phase is at intervals of 6 weeks (q6w). ) followed by at least two individual doses of a VEGF antagonist, and then additional doses during the maintenance phase. The dose is administered to mammals, and the dose administered during the maintenance phase is at least We also offer a method to separate the doses by 6 weeks. In one embodiment, the maintenance dose is 12 weeks It is administered at least once per (q12w). In one embodiment, the frequency of administration is determined by disease activity assessment. Based on the evaluation results, adjustments are made, for example, using predefined visual and anatomical criteria. In one embodiment, at any time during the maintenance phase (for example, 48 times from the initial therapeutic dose), After the first week, the treatment interval is 6 weeks, up to a maximum of 24 weeks, and the activity of diabetes is assessed. The treatment may be extended at the discretion of the treatment provider based on value. In another embodiment, during the maintenance period The medication frequency is every 12 weeks if disease activity is detected during any scheduled treatment visit. By reducing the medication interval from once a day (q12w) to once every six weeks (q6w), , can be adjusted. In another embodiment, the patient also has macular edema (e.g., diabetic jaundice). They also have variegated edema.

[0009] This invention relates to the progression of non-proliferative diabetic retinopathy (PDR) in patients. A method to prevent progression to NPDR, with a 6-week interval (q6) during the induction phase. w) At least two individual doses of a VEGF antagonist, followed by maintenance doses The additional dose administered to mammals, including the dose administered during the maintenance phase, is small. Further methods are provided to separate them by 6 weeks. In one embodiment, the dose during the maintenance phase is It is administered at least once every 12 weeks (q12w). In one embodiment, the frequency of administration depends on the disease. Based on the results of the activity assessment, for example, using predefined visual and anatomical criteria, It is adjusted. In one embodiment, at any time during the maintenance phase (e.g., measured from the initial therapeutic dose) After 48 weeks, the treatment interval is 6 weeks at a time, up to a maximum of 24 weeks, depending on the activity of diabetes. The treatment period may be extended at the discretion of the treatment provider based on an assessment of mobility. In another embodiment, the maintenance period The frequency of medication in this case is 12 when disease activity is detected at any scheduled treatment visit. Reduce the medication interval from once a week (q12w) to once every six weeks (q6w). It can be adjusted by... In one embodiment, the patient first... In another embodiment, the patient is first treated for DR.

[0010] The present invention also relates to drug containers containing VEGF antagonists and DR, NPDR, or PD. Instructions for using VEGF antagonists to treat patients diagnosed with R The three doses of the VEGF antagonist are administered at 6-week intervals (q6w), and this is the most After the first dose, an additional individual dose of VEGF antagonist is administered at 12-week intervals (q12w). Next, a kit will also be provided. In one aspect, the kit will provide one or more doses of 6 mg of brol. Contains cizumab; each dose delivers a 6 mg dose when administered in a 0.05 mL volume. In a single-use vial containing enough brolucizumab to do so, or 6 mg of brolucizumab Provided in a pre-filled syringe containing cizumab. In another embodiment, If PDR disease activity is observed in the eye being treated, the medication interval should be q12w. Further instructions are given to adjust the medication once every six weeks. In another aspect, the instructions state that the PDR disease activity If no movement is observed in the eye being treated, administer the medication at the q12w interval once every 24 weeks. Further instructions are given to extend to VEGF Antagon. In yet another embodiment, the instructions are given to VEGF Antagon. Nist provides visual and / or / a visual and / or / a visual to determine disease activity before or after any q12w dose. Or the judgment of the treatment provider (e.g., a physician or other qualified medical professional) based on anatomical results. Further instructions are given to administer it discreetly, as needed, i.e., on an ad-hoc basis (PRN).

[0011] In one embodiment, the VEGF antagonist used in the method of the present invention is an anti-VEGF antagonist. It is an F antibody. In certain embodiments, the anti-VEGF antibody is a single-chain antibody (scFv) or Fab antibody. It is one of the two. In particular, the anti-VEGF antibody is brolucizumab.

[0012] Non-limiting embodiments of this disclosure are described in the following embodiments. 1. A method for treating proliferative diabetic retinopathy (PDR) in a patient, a) Administer the patient three individual doses of a VEGF antagonist at 6-week intervals and b) Add one or more VEGF antagonists every 12 weeks (q12w regimen). This includes administering the dose to the patient, the first additional dose being the third individual dose of step a). A method administered 12 weeks later. 2. For each dose of q12w, assess the patient's PDR disease activity before or after administration. The method of Embodiment 1, further comprising the following: 3. Disease activity is measured by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neoplasia. The method of Embodiment 2, which is evaluated based on the confirmation of vascular status and peripheral vision. 4. If worsening of PDR disease activity is observed after the q12w dose, the patient should receive the q6w dose. The regimen was switched, and the additional dose was administered once every 6 weeks instead of once every 12 weeks. A method according to embodiment 2 or 3 is provided. 5. PDR disease activity worsens when compared to any previous assessment. Retinal neovascularization, reperfusion of retinal neovascularization, increase in ETDRS DRSS score, peripheral vision The method of Embodiment 4, which involves loss of vision and / or the development of complications affecting visual acuity. 6. During the 12-week period, the treatment interval may be adjusted based on disease activity compared to the previous disease activity assessment. If the condition is stable or improving, 18 weeks (q18w) or 24 weeks (q24w) The method of embodiment 2 or 3, which is extended to the extent of. 7. The patient is human, according to one of embodiments 1 to 6. 8. The anti-VEGF antagonist is brolucizumab, any one of embodiments 1 to 7. Two methods. 9. The VEGF antagonist is administered by intravitreous injection, as in Embodiments 1-8. Either way or one way. 10. The dosage of the VEGF antagonist is 3 mg or 6 mg, according to Embodiments 1 to 9. Either one method. 11. For the treatment of diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) The law stipulates that in the induction phase, three individual doses are administered at 6-week intervals, followed by 12 doses in the maintenance phase. Weekly (q12w regimen) additional doses of the anti-VEGF antibody VEGF antagonist This includes administering approximately 3 mg or 6 mg of to the patient, and is optional for DR patients. This method also involves macular edema (such as diabetic macular edema). 12. For each dose of q12w, assess the patient's DR or PDR disease activity before or after administration. The method of Embodiment 11 further includes doing the following. 13. Disease activity is measured by best corrected visual acuity (BCVA), ETDRS DRSS score, and neoretinal neoplasia. The method of Embodiment 12, which is evaluated based on the status of the living blood vessels and the confirmation of the peripheral vision. 14. During the maintenance phase, the medication interval may be adjusted at any time if disease activity is higher than the previous disease activity assessment. If it is improving or stable, the period may be extended up to 24 weeks (q24w), according to the embodiment. 12 or 13 methods. 15. If worsening of PDR disease activity is observed after the q12w dose, the patient should receive q6 The regimen was switched to the W regimen, and the additional dose was changed from once every 12 weeks to once every 6 weeks. The methods of embodiment 11 to 13, which are administered. 16. PDR disease activity worsens when compared to any previous assessment. Presence of retinal neovascularization, reperfusion of retinal neovascularization, increased ETDRS DRSS score, peripheral vision The method of Embodiment 15, which involves field loss and / or the development of complications affecting visual acuity. 17. The patient is human, according to any one of embodiments 11 to 16. 18. The anti-VEGF antagonist is brolucizumab, as in any of embodiments 11-17. One of these methods. 19. The VEGF antagonist is administered by intravitreous injection, Embodiments 11-1 One of the eight methods. 20. In patients, treatment for diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) A VEGF antagonist for use in a method for therapeutic purposes, wherein VEGF The antagonist is a) Three individual doses at 6-week intervals and b) Thereafter, once every 12 weeks (q12w regimen), as an additional dose A VEGF antagonist administered to patients. 21. The method involves, for each dose of q12w, before or after administration, checking the disease activity of DR or PDR. VEGF ant for use according to Embodiment 20, further including evaluating the patient Gonist. 22. Disease activity is measured by best corrected visual acuity (BCVA), ETDRS DRSS score, and neoretinal neoplasia. Use according to Embodiment 21, which is evaluated based on the status of the living blood vessels and confirmation of the peripheral vision. A VEGF antagonist for this purpose. 23. If disease activity worsens after the q12w dose, the patient should be given the q6w regimen. The dosage has been switched to men, and the additional dose is now administered once every 6 weeks instead of once every 12 weeks. A VEGF antagonist for use according to embodiment 21 or 22. 24. Worsening of disease activity is a new or worsening of the disease compared to any previous assessment. Reperfusion of membrane neovascularization, retinal neovascularization, and increase in ETDRS DRSS score (2 steps or less) These include the increase in the above, loss of peripheral vision, and / or the development of complications affecting visual acuity. A VEGF antagonist for use according to Embodiment 23. 25. During the maintenance phase, the medication interval may be adjusted at any time if disease activity is higher than the previous disease activity assessment. If it is improving or stable, the period may be extended up to 24 weeks (q24w), according to the embodiment. A VEGF antagonist for use with any one of the following 20-22. 26. The patient is human, VE for use in any one of embodiments 20-25. GF Antagonist. 27. The anti-VEGF antagonist is brolucizumab, as in any of embodiments 20-26. A VEGF antagonist for use with any one of the following. 28. The VEGF antagonist is administered by intravitreous injection, Embodiments 20-2 A VEGF antagonist for use by any one of the seven. 29. The dose of the VEGF antagonist is approximately 3 mg to approximately 6 mg, Embodiments 20-2 A VEGF antagonist for use by any one of the 8. 30. In patients, treatment for diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) A VEGF antagonist for use in a method for therapeutic purposes, wherein VEGF The agonist is initially provided during the induction phase, during which time the patient receives VE at 6-week intervals. Receive three individual doses of approximately 3 mg or 6 mg of a GF antagonist, followed by VEGF The antagonist is provided during the maintenance phase, during which the patient receives one dose every 12 weeks (q (12-week regimen), receive an additional dose of approximately 3 mg or 6 mg of VEGF antagonist. A VEGF antagonist. 31. The method involves, for each dose of q12w, before or after administration, checking the disease activity of DR or PDR. VEGF ant for use according to Embodiment 30, further including evaluating the patient Gonist. 32. Disease activity is measured by best corrected visual acuity (BCVA), ETDRS DRSS score, and neoretinal neoplasia. The use according to Embodiment 31 is evaluated based on the status of the blood vessels and the confirmation of the peripheral vision. A VEGF antagonist for this purpose. 33. Worsening of disease activity is a new or worsening of the disease compared to any previous assessment. Reperfusion of membrane neovascularization, retinal neovascularization, and increase in ETDRS DRSS score (2 steps or less) These include the increase in the above, loss of peripheral vision, and / or the development of complications affecting visual acuity. A VEGF antagonist for use according to Embodiment 31 or 32. 34. PDR disease activity worsens when compared to any previous assessment. Presence of retinal neovascularization, reperfusion of retinal neovascularization, increased ETDRS DRSS score, peripheral vision Use according to Embodiment 33 results in field loss and / or the development of complications affecting visual acuity. A VEGF antagonist for this purpose. 35. During the maintenance phase, the medication interval may be adjusted at any time if disease activity is higher than the previous disease activity assessment. If it is improving or stable, the period may be extended up to 24 weeks (q24w), according to the embodiment. A VEGF antagonist for use with any one of the following 30-32. 36. The patient is human, VE for use in any one of embodiments 30-35. GF Antagonist. 37. The anti-VEGF antagonist is brolucizumab, as in any of embodiments 30-36. A VEGF antagonist for use with any one of the following. 38. The VEGF antagonist is administered by intravitreous injection, Embodiments 30-3 A VEGF antagonist for use by any one of the seven. 39.a) Drug containers containing VEGF antagonists and b) Use of VEGF antagonists to treat patients diagnosed with DR or PDR. The instructions include a prescription for administering three doses of the VEGF antagonist at 6-week intervals (q6w). Administered, and after this last dose, VEGF antagonists are administered at 12-week intervals (q12w). A kit that continues with additional individual doses. 40.(a) Each dose delivers a dose of 6 mg when administering a volume of 0.05 mL. In a single-use vial containing a sufficient amount of brolucizumab, or 6 mg of brolucizumab A single dose of 6 mg or more is provided in a pre-filled syringe containing cizumab. Brolucizumab or b) Each dose is sufficient to deliver a 3 mg dose when administered in a 0.05 mL volume. In a single-use vial containing brolucizumab or 3 mg of brolucizumab One or more doses of 3 mg of brolucin provided in a pre-filled syringe containing Zumab A kit of embodiment 39, including the kit of embodiment 39. 41. Instructions are given when DR or PDR disease activity is observed in the eye being treated, q Embodiments 39 or 4 further instruct to adjust the 12-week medication interval to once every 6 weeks. Kit 0. 42. If disease activity is not observed in the eye being treated, prescribe medication q12w. The implementation plan further instructs that the interval be extended to 6 weeks at a time, up to once every 24 weeks. Kits for models 39 or 40. 43. The instruction states that VEGF antagonists may be administered before or after any q12w dose of the disease activity Treatment providers (e.g., physicians or) based on visual and / or anatomical results to determine dyskinetics. (PRN) A kit of embodiment 39 or 40, which provides further instructions for administration. 44. In patients, proliferative diabetic retinopathy (PDR) is sometimes followed by non-proliferative diabetic retinopathy (N). A method to prevent progression to PDR, a) Administer the patient three individual doses of a VEGF antagonist at 6-week intervals and b) Then, once every 12 weeks (q12w regimen), an additional VEGF antagonist is administered. A method that includes administering a certain amount to a patient. 45. For each dose of q12w, assess the patient's disease activity before or after administration. The method of Embodiment 44 further includes the method of Embodiment 44. 46. ​​Disease activity is measured by best corrected visual acuity (BCVA), ETDRS DRSS score, and neoretinal neoplasia. The method of Embodiment 45, which is evaluated based on the status of the living blood vessels and the confirmation of the peripheral vision. 47. If disease activity worsens after the q12w dose, the patient should be given the q6w regimen. The dosage has been switched to men, and the additional dose is now administered once every 6 weeks instead of once every 12 weeks. The method according to embodiment 45 or 46. 48. Worsening of disease activity is a new or worsening of the disease compared to any previous assessment. Reperfusion of membrane neovascularization, retinal neovascularization, and increase in ETDRS DRSS score (2 steps or less) These include the increase in the above, loss of peripheral vision, and / or the development of complications affecting visual acuity. The method of Embodiment 47. 49. At 48 weeks after the first dose is administered, the treatment interval for q12w is 6 weeks per dose. The interval may be extended up to a maximum of 24 weeks (q24w), according to one of the embodiments 45 to 46. Law. 50. The patient is human, according to any one of embodiments 44 to 49. 51. Anti-VEGF antagonists include the sequence of SEQ ID NO: 3, as described in Embodiments 44-50. Either way or one way. 52. The VEGF antagonist is administered by intravitreous injection, Embodiments 44-5 One of the following methods. 53. The dose of the VEGF antagonist is approximately 3 mg to approximately 6 mg, Embodiments 44-5 One of the two methods.

[0013] Specific preferred embodiments of the present invention are described below in more detail for a particular preferred embodiment. This will become clear from the description and claims. [Modes for carrying out the invention]

[0014] definition The following definitions and descriptions are as follows unless explicitly and clearly changed in the following examples or Things that are difficult to understand through the application of meaning, or that are inherently difficult to understand. Unless we make it so, it means controlling any future interpretations and intentions. Therefore, depending on the interpretation of the term, it may become difficult to understand or inherently difficult to understand. If that happens, the definition is, Webster's Dictionary, 3 rd Edi tion or Oxford Dictionary of Biochemistry and Molecular Biology(Ed.Anthony Smith,O (e.g., Oxford University Press, Oxford, 2004) It should be selected from dictionaries known to those in the industry.

[0015] As used herein, all percentages, unless otherwise specified, This is a percentage by weight.

[0016] As used herein and unless otherwise indicated, the term “one (a)” And "an" means "one", "at least one", or "one It is understood to mean "or more." Unless otherwise required by the context, this In the specification, singular terms include plural terms, and plural terms are singular words. This shall include:

[0017] The contents of any patents, patent applications, and references cited throughout this specification are not included. The whole thing is invoked by reference.

[0018] The term "VEGF" is defined in Leung et al., Science 246:1306. (1989) and Houck et al., Mol. Endocrin. 5:1806 As described by (1991), 165 amino acid vascular endothelial growth factor and related The 121, 189, and 206 amino acid vascular endothelial growth factors are used in the following ways: This refers to both naturally occurring allele forms and processed forms.

[0019] The term "VEGF receptor" or "VEGFr" refers to a cell receptor for VEGF, usually, It possesses the ability to bind to cell surface receptors found on vascular endothelial cells and to hVEGF. It refers to that variant. One example of a VEGF receptor is in the tyrosine kinase family. It is a transmembrane receptor, FMS-like tyrosine kinase (FLT). DeVries et al. al.,Science 255:989(1992);Shibuya et al. ., Oncogene 5:519 (1990). The flt receptor has an extracellular domain and is membrane It contains a transcatheter domain and an intracellular domain with tyrosine kinase activity. The nucleotide is involved in VEGF binding, while the intracellular domain is involved in signal transduction. Another example of a VEGF receptor is the flk-1 receptor (also known as KDR). tthews et al.,Proc.Nat.Acad.Sci.88:9026( 1991);Terman et al., Oncogene 6:1677(1991) );Terman et al.,Biochem.Biophys.Res.Comm un.187:1579(1992). VEGF binding to the flt receptor is 205,0 At least two having apparent molecular weights of 00 daltons and 300,000 daltons This leads to the formation of a high molecular weight complex. The 300,000 Dalton complex is a single VEGF molecule. It is thought to be a dimer containing two receptor molecules bonded to a single molecule.

[0020] As used herein, “VEGF antagonist” is an in vivo term. This refers to compounds that can reduce or inhibit VEGF activity. The VEGF protein can bind to the VEGF receptor or the VEGF protein can bind to the VEGF receptor. It can prevent binding. VEGF antagonists can, for example, one or Specifically binds to more than one VEGF protein or one or more VEGF receptors. Small molecules that can be combined, anti-VEGF antibodies or their antigen-binding fragments, fusion proteins (A Flibercept or other such soluble decoy receptors), aptamers, antiseptics This can include nucleic acid molecules, interfering RNA, receptor proteins, and other similar substances. Some VEGF antagonists are mentioned in the international publication pamphlet No. 2006 / 047325. It is described in the let.

[0021] In a preferred embodiment, the VEGF antagonist is an anti-VEGF antibody (brolucis). Bispecific antibodies such as mab, ranibizumab, bevacizumab, or falisimab (etc.) or soluble VEGF receptors (such as aflibercept).

[0022] As used herein, the term "antibody" refers to the entire antibody and any antigen-binding fragment thereof. In other words, "antigen-binding portion," "antigen-binding polypeptide," or "immunobinder." "Antibody" includes an immunoobinder or a single chain thereof. A sugar containing at least two heavy (H) chains and two light (L) chains linked together by a molecule. It contains protein or its antigen-binding portion. Each heavy chain has a heavy chain variable region (V H and this statement It consists of the (abbreviated in the book) and heavy chain steady region. The heavy chain steady region consists of three domains It is composed of n, CH1, CH2, and CH3. Each light chain has a light chain variable region (V L It consists of a (abbreviated herein) and a light chain steady region. The light chain steady region is 1 It consists of domains, CLs. H Region and V L The domain is the framework domain (F A more conserved region called the Complementarity Determination Region (CDR) is scattered throughout the area known as R. The range of variability can be further subdivided. Each V H and V L The following order is A It consists of three CDRs and four FRs located from the mino end to the carboxyl end. :FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Heavy chain and light chain The variable region contains a binding domain that interacts with the antigen. The constant region of the antibody is part of the immune system. It may mediate the binding of immunoglobulins to host tissues or host factors containing various cells (such as effector cells) and the first component (C1q) of the classical complement system.

[0023] The terms "single-chain antibody", "single-chain Fv", or "scFv" refer to molecules containing a heavy-chain variable domain of an antibody (or region; V H ) and a light-chain variable domain of an antibody (or region; V L ) intended to be. Such scFv molecules can have a general structure: NH2-V -linker-V L -COOH or NH2-V H -linker- H V L -COOH.

[0024] The term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (such as VEGF). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included within the scope of the term "antigen-binding portion" of an antibody are (i) a Fab fragment, which is a monovalent fragment consisting of V , V , CL, and CH1 domains; (ii) an F(ab’)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of V L and CH1 domains; (iv) an Fv fragment consisting of V H of a single arm of an antibody and V ; (v) a single domain or dAb fragment consisting of V domain (Ward et al., (1989) Natu H of a single arm of an antibody and V L and V H domains; (v) a single domain or dAb fragment consisting of V H domain or dAb fragment (Ward et al., (1989) Natu​​​ re 341:544-546); and (vi) isolated complementary determination regions (CDRs) (vii) Two or more may be optionally joined by a composite linker. Includes a combination of isolated CDRs. Furthermore, two domains of the Fv fragment, V L and V H These are encoded by separate genes, but they function as a single protein chain. By using a synthetic linker that enables the fabrication of a linker, the joining process can be performed using a recombinant method. And can be done, V L Region and V H The regions pair up to form a monovalent molecule (single chain Fv(sc Known as Fv); e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc.N See atl.Acad.Sci.USA 85:5879-5883. Such single-chain antibodies are also included within the scope of the term "antigen-binding portion" of an antibody. These antibody fragments are intended to be obtained using conventional techniques known to those skilled in the art. The fragments are then screened for practical use, similar to intact antibodies. The recombination portion is obtained by recombinant DNA technology or by enzymatic or intact immunoglobulin. Antibodies can be produced by chemical cleavage. Antibodies come in various isotypes, for example IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtype), IgA 1. It can be an IgA2, IgD, IgE, or IgM antibody.

[0025] As used herein, “mammal” includes humans, domesticated animals, livestock, and companion animals. This includes, but is not limited to, companion animals, and includes any animal classified as a mammal. nothing.

[0026] The "eye diseases" or "neovascular eye diseases" that can be treated using the method of the present invention are: Abnormal vascular formation, choroidal neovascularization (CNV), retinal vascular permeability, retinal edema, diabetic retina Membrane diseases (especially proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR)) new CNVs including diabetic macular edema (DME) and nAMD (neovascular AMD) Exudative age-related macular degeneration (AMD), complications associated with retinal ischemia, central retinal venous effusion This includes vascular vein occlusion (CRVO), retinal branch vein occlusion (BRVO), and posterior segmental neovascularization. However, this includes, but is not limited to, conditions, diseases, or disorders related to ocular neovascularization. Preferred In one embodiment, the disease is PDR. In another preferred embodiment, the disease is N It is PDR.

[0027] As used herein, the terms “subject” or “patient” refer to humans and primates. This includes, but is not limited to, non-human animals such as pigs, horses, dogs, cats, sheep, and cows. This refers to mammals. Preferably, the subject or patient is human.

[0028] Treatment regimen In one embodiment, the present invention relates to diabetic retinopathy (DR), non-proliferative diabetic retinopathy (NP). This was a method for treating patients with DR and proliferative diabetic retinopathy (PDR). Therefore, in a treatment schedule including the induction and maintenance phases as described herein, VE The present invention provides a method comprising administering a GF antagonist to a patient. In one embodiment, The present invention relates to a method for preventing progression from NPDR to PDR, and is described herein. As described, the treatment schedule includes the induction and maintenance phases, and VEGF antagonists The present invention provides a method that includes administering a drug to a patient.

[0029] In one embodiment, the patient is at least 18 years old and has diabetes mellitus (DM) 1 Alternatively, the patient is diagnosed with type 2 and HbA1c ≤ 12%. In other embodiments, the patient is treated The PDR is evaluated by the healthcare provider and BCVA ≥ ETDRS (number of characters: 34) The patient has a Snellen equivalent visual acuity chart (20 / 200). For example, standard or wide-field color fundus photographs (Color Fundus Photog raphs)(CFP), optionally using fluorescein angiography (FA), by the treatment provider PDR is diagnosed by [method]. In other embodiments, the patient undergoes panretinal photocoagulation (PRP) I have never received laser treatment.

[0030] In one embodiment, the induction period is at 6-week intervals (q6w), for example, on day 0, and on week 6. , and at least two individual doses administered in the 12th week. In one embodiment, During the maintenance phase, a VEGF antagonist is administered once every 12 weeks (q12w). The regimen and dosage interval are determined by disease activity assessment performed before the dose is administered. Depending on the value, it is adjusted by plus or minus 6 weeks. In one embodiment, disease activity If symptoms are observed before administering the q12w dose, the patient should continue using the q12w dose as planned. Receive one dose, then the next dose 6 weeks later, and so on, until disease activity is no longer observed. It will be placed in the q6w medication regimen. If disease activity is no longer observed, medication will be discontinued. The regimen will be adjusted and returned to the q12w schedule. In another embodiment... During the maintenance phase, if no disease activity is observed, the treatment interval is 6 weeks, q1 It may be extended up to 8 weeks and then for a further 6 weeks, or up to a 24-week interval (q24w). If disease activity is observed in patients on the q24w medication regimen, the treatment interval will be adjusted. Alternatively, the medication regimen may be reverted to the q18w or q12w regimen.

[0031] In one embodiment, the present invention provides a treatment for neovascular eye diseases, including PDR, in mammals. A method for administering multiple doses to mammals at various intervals over a period of at least two years. This includes administering a VEGF antagonist (e.g., an anti-VEGF antibody or a fragment thereof). The method is provided. In one embodiment, the dose is administered in two or three doses at 6-week intervals, The "introduction phase" is followed by the "maintenance phase," which lasts for 6, 7, 8, 9, 10, 11, and 12 weeks. , 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks Additional doses are administered at 23-week or 24-week intervals. Disease activity is assessed during the maintenance phase. This is done at least at all subsequent scheduled doses. Disease activity is as specified herein. Once confirmed as described, the treatment regimen will change from every 12 weeks to every 6 weeks (i.e., every 12 weeks). This can be changed to (q6w). The present invention is for when a 6-week interval should be used and when a 12-week interval should be continued. A specific method established by the inventors based on disease activity assessment to determine the appropriate timing Criteria are provided. In some cases, patients undergo regimens at 12-week intervals for a period of time. The procedure is performed, then switched to a 6-week interval, and then switched back to a 12-week interval. Therefore, patients do not need to continue a regimen at one interval, as described herein. You may move back and forth depending on the evaluation that follows the established criteria.

[0032] In one embodiment, if disease activity is not detected during multiple consecutive treatment visits, The healthcare provider may extend the treatment for an additional 1 to 24 weeks. For example, if the patient has 12 weeks If treatment is being administered at intervals, the treatment provider is 13, 14, 15, 16, 17, 18, 19 Treatment may be extended up to every 20, 21, 22, 23, or 24 weeks; or the patient If treatment is being administered every 6 weeks, the treatment provider will be responsible for 7, 8, 9, 10, 11, or 12 Treatment may be extended up to once a week. If disease activity is confirmed at any treatment visit, treatment may be discontinued. The treatment schedule may be adjusted and returned to a 12-week or 6-week treatment regimen. As used in the specification, “disease activity” is the determination provided herein. This refers to the worsening of an eye disease based on established criteria.

[0033] In one embodiment, the present invention relates to eye diseases, more specifically ocular neovascular diseases, and more specifically PDR. A method for treatment, administered to the mammals in need according to the following schedule. The present invention provides a method including the administration of an EGF antagonist: Injections are administered at 6-week intervals (i.e., "q6" or "q6w") (for example, on day 0, week 6, and week 12). The "introduction phase" of the three doses administered and The "maintenance phase" involves administering additional doses at 12-week intervals (i.e., "q12" or "q12w"). .

[0034] In one embodiment, the "maintenance period" is 6, 7, 8, 9, 10, 11, 12, 13, 14, Additional doses at intervals of 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks. The dosage may be determined based on disease activity assessment as described herein. It can be adjusted as described herein.

[0035] In one embodiment, the "induction phase" is administered at q6w intervals, with doses 2, 3, 4, 5, or It can be administered in 6 doses. In another embodiment, "during the induction period, once every 4 weeks ( The dosage can be 2, 3, 4, 5, or 6 times, administered at q4w intervals.

[0036] In one embodiment, disease activity assessment ("DAA") is performed every scheduled treatment session. It is performed during hospital hours. In one embodiment, the patient's disease activity is determined by the healthcare provider. The presence of sexually transmitted, for example, new or worsened retinal neovascularization compared to any previous assessment. Reperfusion of retinal neovascularization, increase in ETDRS DRSS score (DR disease activity) Complications affecting visual acuity include an increase of two or more steps, loss of peripheral vision, and / or other complications affecting visual acuity. Based on the onset of symptoms, the patient will be reassigned to a q6w or q12w medication regimen.

[0037] During the evaluation week, the patient is currently receiving a regimen, for example, at 6-week, 12-week, or 24-week intervals. Therefore, the evaluation can determine whether the patient should continue the current interval or It can decide whether to switch between different intervals.

[0038] In one embodiment, the VEGF antagonist used in the method of the present invention is Brolucizumab, administered as an intravitreal injection in doses of 1, 2, 3, 4, 5, or 6 mg (e.g., 6 mg) It is administered in a dose of mg / 0.05 mL.

[0039] The evaluations described herein preferably relate to visual function, retinal structure, and leakage. To evaluate the activity of the opposing VEGF antagonist (e.g., brolucizumab), one or more This includes the following tests listed above. • Best corrected visual acuity according to charts such as ETDRS at 4 meters • ETDRS DRSS score based on 7-field stereo color fundus photography (CFP) Optical coherence tomography (OCT), standard or wide-field fluorescein angiography (FA), OC Anatomical retinal determination by T-angiography and / or wide-field CFP / FA. • Peripheral field of view evaluated by visual field measurement • Contrast sensitivity

[0040] Visual acuity is determined by a fully corrected refractive error (protocol refraction). It can be evaluated using the positive value (best correction) (BCVA). BCVA measurements are taken in a seated position using, for example, a visual acuity chart such as ETDRS. It can be measured.

[0041] Optical coherence tomography (OCT), color fundus photography, and fluorescein angiography are known to those skilled in the art. It can be evaluated according to the established method.

[0042] Further criteria for assessing disease activity include changes in central retinal thickness (CST). This includes, but is not limited to, the retinal pigment epithelium (RPE) to the internal limiting membrane (ILM). The average thickness of a 1 mm circular area centered on the fovea, including both up to the fovea. CST, for example, uses spectral domain optical coherence tomography (SD-OCT). It can be measured using this method.

[0043] The means for performing the above inspections are well understood by those skilled in the art and are generally It is being used.

[0044] Disease activity is characterized by clinically significant improvement in BCVA, a decrease in central retinal thickness (CST), and body Decreased fluid retention (e.g., retinal fluid), and / or diabetes. The reduction in the severity of retinopathy is evaluated. If disease activity is worsening (for example, BCVA compared to the patient's baseline records or any previous assessment. A decrease in the number of letters measured, an increase in CST, an increase in fluid retention, and / or the severity of diabetic retinopathy. As the severity of the condition increases, more frequent medication intervals are prescribed thereafter. Improvement in disease activity is observed. If there is no worsening or improvement in disease activity, a less frequent medication interval will be prescribed. (i.e., if the patient's condition is stable), the medication interval is maintained or extended. (Not very frequently). The fluid measured in the eye is intraretinal exudate. It can be al fluid and / or subretinal fluid.

[0045] The status of disease activity can be assessed, for example, by ophthalmoscopic examination, standard or wide-field color vision spectroscopy. - Fundus photography and / or standard or wide-field fluorescein angiography (FA) and / or occlusion ETD based on T-angiography, BCVA, and 7-field stereocolor fundus photography (CFP). RS DRSS score, anatomical retinal assessment by optical coherence tomography (OCT), and visual field measurement. Based on the peripheral vision and / or contrast sensitivity evaluated therein, diabetic retinopathy Rapid changes in the severity (e.g., retinal neovascularization) (e.g., baseline assessment) This can be based on the decrease in the measured value compared to the previous evaluation. For example, this could be based on a decline in BCVA due to disease activity compared to the previous assessment. This is possible. The treating clinician may include clinical factors other than the standard visual acuity criteria. It should be understood that decisions can be made based on the view. Disease activity assessment includes visual acuity and It may include both anatomical criteria. In one embodiment, disease activity is The following is evaluated when the following is observed: a new or new evaluation compared to any previous evaluation. This includes worsening retinal neovascularization, reperfusion of retinal neovascularization, and an increase in ETDRS / DRSS scores. In addition (such as an increase of two or more steps in DR disease activity), peripheral vision loss, and / or The onset of complications affecting vision.

[0046] In one embodiment, the assessment of disease activity to establish the patient's disease status is performed by This is performed at the start of treatment (week 0; first treatment). It assesses disease activity between treatment regimens. (DAA) is the judgment of the person making the assessment (e.g., the treatment provider), and the patient's baseline Visual, anatomical, morphological, and clinical assessments based on the disease status at the time of (week 0). Based on changes in parameters.

[0047] In another embodiment, during the maintenance phase, VEGF antagonists determine disease activity. Treatment providers (e.g., physicians or other medical professionals) should determine the appropriate treatment based on visual and / or anatomical results. (PRN) is administered as needed, i.e., on an ad-hoc basis, at the discretion of a qualified medical professional. ru.

[0048] Anti-VEGF antagonist In one embodiment, the VEGF antagonist used in the method of the present invention is an anti-V EGF antibodies, for details, refer to International Publication No. 200, which is incorporated by reference. This is an anti-VEGF antibody described in the 9 / 155724 pamphlet.

[0049] In one embodiment, the anti-VEGF antibody used in the method of the present invention is SEQ ID NO: 1 Variable heavy chain having the sequence described below and a variable heavy chain having the sequence described in Sequence ID No. 2 Includes variable light chains. VH: Sequence ID 1 EVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQ APGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAGGDHNSGWGLDIWGQGTLVTVSS VL: Sequence ID 2 EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKP GKAPKLLIYLASTLASGVPSRFSGSGSGAEFLTISSLQP DDFATYYCQNVYLASTNGANFGQGTKLTVLG

[0050] In another embodiment, the anti-VEGF antibody used in the method of the present invention is SEQ ID NO: 3 Includes the sequence described in [location]. [ka]

[0051] In a preferred embodiment, the method of the present invention (for example, to treat DR or PDR) Anti-VE used in methods for preventing progression from or from nPDR to PDR The GF antibody is brolucizumab (containing the sequence of SEQ ID NO: 3). Brolucizumab sequence This is described in Sequence ID No. 4. Methionine derived from the start codon in the expression vector. If not cleaved after translation, it is present in the final protein, as follows: [ka]

[0052] In another embodiment, the anti-VEGF antibody used in the method of the present invention is as follows: Furthermore, it consists of three light chain CDRs (CDRL1, CDRL2, and CDRL3) and three heavy chain C Includes DR (CDRH1, CDRH2, CDRH3). [ka]

[0053] Brolucizumab is a humanized single-chain VEGF with a molecular weight of approximately 26 kDa, Fv(sc) Fv) It is an antibody fragment inhibitor. RTH258 is a VEGF-A inhibitor, and VEGF - It acts by binding to the receptor binding site of the A molecule, thereby affecting the surface of endothelial cells. It prevents the interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface. Increased levels of signaling through the VEGF pathway are associated with pathological ocular vascularization and retinal effusion. It is related to tumors. Inhibition of the VEGF pathway is associated with neovascular lesions in patients with nAMD. It was shown to inhibit proliferation and reduce retinal edema.

[0054] Pharmaceutical preparations In one embodiment, the method of the present invention includes the use of a pharmaceutical formulation containing an anti-VEGF antibody. "Drug formulations" make it possible to clearly demonstrate the effectiveness of the biological activity of antibodies or antibody derivatives. It has a form that is toxic to the subject to which the preparation is administered, and further components are toxic to the subject to which the preparation is administered. This refers to preparations that do not contain [specific ingredient]. "Pharmacologically acceptable" excipients (vehicles, additives) are [specific excipients]. to appropriately administer the active ingredient used to the target mammal in order to provide an effective dose. It is an excipient that can achieve this.

[0055] A "stable" formulation is a therapeutic agent, such as an anti-VEGF antibody or its antibody derivative, that can be stored. In doing so, its physical stability and / or chemical stability and / or biological activity are essentially preserved. This is a formulation that measures protein stability. Various analytical techniques for measuring protein stability are available in this field. It is available for use in, for example, Peptide and Protein Drug De livery,247-301,Vincent Lee Ed.,Marcel De kker, Inc., New York, NY, Pubs. (1991) and Jon es,A.Adv.Drug Delivery Rev.10:29-90(1993 This is outlined in [reference]. Stability can be measured at a selected time and temperature. Preferably, the preparation should be kept at room temperature (approximately 30°C) or 40°C for at least one week. It is stable and / or stable at approximately 2-8°C for at least 3 months to 2 years. Furthermore, The formulation is preferably stable after freezing (e.g., down to -70°C) and thawing.

[0056] Antibodies or antibody derivatives may be subjected to visual inspection for color and / or clarity, or UV light. By light scattering (UV light scattering) or size exclusion chromatography It is measured by a roughie or other suitable method recognized in the art. Thus, if the product meets the specified shipping standards for aggregation, decomposition, precipitation, and / or modification, "Maintains its physical stability" within the pharmaceutical formulation.

[0057] An antibody or antibody derivative has a chemical stability over a specified period of time that is defined as the biological stability of the antibody. If the protein is still considered to retain its activity, then in the pharmaceutical formulation "It maintains its chemical stability." Chemical stability refers to the chemical changes in the protein. It can be evaluated by detecting and quantifying the morphology. Chemical changes are, for example, Iz exclusion chromatography, SDS-PAGE, and / or matrix-assisted laser chromatography. Determination is performed using desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). It includes the ability to change the size (e.g., clipping). This is also acceptable. Other types of chemical changes can be determined, for example, by ion exchange chromatography. This includes possible changes in charge (e.g., resulting from deamide).

[0058] Antibodies or antibody derivatives are tested for their biological activity over a predetermined period of time, for example, in antigen-binding assays. As determined in the above, approximately 10% of the biological activity exhibited when the pharmaceutical formulation was prepared is If it is within the range (within the assay error range), the pharmaceutical formulation will "maintain its biological activity." "Possesses." Other "biological activity" assays for antibodies are described below in this specification. This will be explained in more detail.

[0059] "Isotonicity" means that the preparation of interest essentially has the same osmotic pressure as human blood. It has a taste. Isotonic preparations generally have an osmotic pressure of approximately 250-350 mOsm. Tonicity is measured, for example, by vapor pressure or ice-freezing type osmometer. It can be measured using this method.

[0060] A "polyol" is a substance that has multiple hydroxyl groups, and is a sugar (reducing sugar and non-reducing sugar). It includes sugars, sugar alcohols, and sugar acids. Preferred polyols in this specification are about 6 Having a molecular weight of less than 00kD (for example, in the range of approximately 120 to 400kD). "Reducing sugars" It can reduce metal ions or interact with lysine and other amino groups in proteins. A reducing sugar containing a hemiacetal group that can undergo bonded reactions, and a "non-reducing sugar" is Non-reducing sugars do not possess these properties of reducing sugars. Examples of reducing sugars include fructose. Mannose, maltose, lactose, arabinose, xylose, ribose, rhamno These are sucrose, galactose, and glucose. Non-reducing sugars include sucrose, trehalose, and sucrose. Contains rubos, melegitose, and raffinose. Mannitol, xylitol, erythritol Trititol, threitol, sorbitol, and glycerol are examples of sugar alcohols. Regarding sugar acids, these include L-gluconates and their metal salts. The formulation is cryostatically stable. If it is desired that the polyol be non-toxic, the polyol preferably destabilizes the antibody in the formulation. This is a polyol that does not crystallize at freezing temperatures (e.g., -20°C). Non-reducing sugars such as rose and trehalose are preferred polyols in this specification. Therefore, due to its superior solution stability, trehalose is better than sucrose. preferable.

[0061] As used herein, "buffer" refers to the action of its acid-base conjugated components. This refers to a buffer that resists changes in pH depending on the application. The buffer of this invention is approximately 4.5 to approximately 8 The pH is 0, preferably in the range of about 5.5 to about 7. Examples of buffers to use include acetic acid (e.g., sodium acetate) and succinic acid (sodium succinate). Contains (such as um), gluconic acid, histidine, citric acid, and other organic acid buffers. If a stable formulation is desired, the buffer is preferably not phosphoric acid.

[0062] In a pharmacological sense, the present invention relates to therapeutic agents, such as anti-VEGF antibodies or antibody inducers. The body's "therapeutic effective dose" is the amount of an antibody or antibody derivative that is effective in preventing or treating a disorder. This refers to the effective amount. This is the pathological amount that makes mammals susceptible to the disorder in question. This includes chronic and acute disorders or diseases, including conditions such as [specific condition].

[0063] "Preservatives" can be included in a formulation to essentially reduce the bacterial activity within it. It is a compound that, therefore, facilitates the production of, for example, multipurpose formulations. Examples of available preservatives include octadecyldimethylbenzylammonium chloride and hexamyl chloride. Tonium, benzalkonium chloride (alkylbenzyl chloride, where the alkyl group is a long-chain compound) A mixture of dimethylammonium and benzethonium chloride. Other types of preservatives These include aromatic alcohols such as phenol, butyl, and benzyl alcohol, and methyl alcohol. Alkylparabens such as propylparaben, catechol, resorcinol, Contains cyclohexanol, 3-pentanol, and m-cresol. This specification contains odor The most preferred preservative is benzyl alcohol.

[0064] The pharmaceutical composition used in the present invention is a VEGF antagonist, preferably an anti-VEGF antagonist. GF antibodies (for example, brolucizumab, etc., with variable light chain sequence and sequence number of SEQ ID NO: 1) An anti-VEGF antibody containing variable heavy chain sequence (of type 2) can be administered to at least one physiologically acceptable agent. It is included together with a carrier or excipient. The pharmaceutical composition may contain, for example, water, a buffer (for example, a neutral one). Buffered saline or phosphate-buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide Sides, carbohydrates (e.g., glucose, mannose, sucrose, or dextran) , such as mannitol, protein, adjuvant, polypeptide or glycine Amino acids, antioxidants, chelating agents such as EDTA or glutathione, and / or may contain one or more of the preservatives. As stated above, Other active ingredients may be included in the pharmaceutical compositions provided herein (but, (It does not need to be included.)

[0065] Carriers are often used to control the stability or bioavailability of compounds. Such substances may be associated with antibodies or antibody derivatives before administration to patients. Carriers for use within pharmaceutical formulations are generally biocompatible and biodegradable. Good. Carriers include, for example, serum albumin (e.g., human or bovine), egg albumin, and pe. Butyrate, polylysine, and aminodextran, etc. Monovalent or Contains polyvalent molecules. Carriers also include, for example, polylactic acid, polyglycolic acid, poly(lactide- Co-glycolide, polyacrylic acid, latex, starch, cellulose, or dextrin This also includes solid support materials such as beads and microparticles containing orchids. The carriers are covalently bonded. In various ways, including (directly or via linker groups), non-covalent interactions, or mixing, It may transport compounds.

[0066] Pharmaceutical compositions include, for example, administration via topical, intraocular, oral, nasal, rectal, or parenteral administration. It may be formulated for any suitable method. In one embodiment, such as intravitreal injection. A composition in a form suitable for intraocular injection is preferred. Other forms include, for example, pills, tablets, Lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions This includes hard or soft capsules, or syrups or elixirs. In other embodiments, the compositions provided herein are formulated as lyophilized products. The term parenteral, as used herein, refers to subcutaneous, intradermal, intravascular (e.g., parenteral). (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, and intraperitoneal injections, and any similar injections. Including injection or injection techniques.

[0067] The pharmaceutical composition contains an active agent (i.e., a VEGF antagonist) in the vehicle and A sterile aqueous or oily suspension for injection that is suspended or dissolved in a vehicle depending on its concentration. It may also be prepared as an agent. Such compositions may be suitable as those mentioned above. It may be formulated according to known techniques using a dispersant, wetting agent, and / or suspending agent. i. Among the permissible vehicles and solvents that may be used are water, 1,3-butanediol. Ringer's solution, isotonic saline, and sterile non-volatile oil are available as solvents or suspensions. It may be used as a medium. For this purpose, any synthetic mono or diglycerides may be used. Non-volatile oils that are not irritating may be used. In addition, fats such as oleic acid may be used. Acids may be used in the preparation of injectable compositions as local anesthetics, preservatives, and / or Adjuvants, such as buffering agents, can be dissolved in the vehicle.

[0068] dosage The dosage used in the method of the present invention is based on the specific disease or condition being treated. The term "therapeutic effective dose" refers to the amount needed to achieve, or at least partially achieve, the desired effect. Defined as a sufficient amount (e.g., partial or complete regression of retinal neovascularization, >1) A change of 2, 3, 4, or 5 letters in BCVA, or a DRSS score of <61). The therapeutically effective dose may even bring about a gradual change in the symptoms or condition associated with the disease. If possible, that is sufficient. The therapeutically effective dose does not need to completely cure the disease, nor completely eliminate the symptoms. There is no need to do so. Preferably, the therapeutically effective dose is given to patients who already have the disease. It can at least partially prevent the disease and / or its complications. Effective for this use. The dosage will depend on the severity of the disorder being treated and the overall state of the patient's own immune system. .

[0069] The dosage is determined by a physician with the usual skill in treating the disease or condition. This can be easily determined using adjustment techniques. VE used in the method of the present invention The therapeutically effective dose of a GF antagonist should take into consideration, for example, the desired drug dose and mode of administration. This is determined by the amount. Typically, therapeutically effective compositions are 0.00 per dose. It is administered in doses ranging from 1 mg / ml to approximately 200 mg / ml. Preferably, The dosage used in the method of the invention is approximately 60 mg / ml to approximately 120 mg / ml. (For example, the dosage could be 60, 70, 80, 90, 100, 110, or 120 mg / ml) (This is the case.) In a preferred embodiment, the method of the present invention (for example, treating DR or PDR) Anti-VE used in methods for treating or preventing the progression of nPDR to PDR The dosage of GF antibodies is 60 mg / ml or 120 mg / ml.

[0070] In one embodiment, the dose is administered directly to the patient's eye. In one embodiment, the dose is administered directly to the eye. The appropriate dose is at least about 0.5 mg to about 6 mg. The preferred dose per eye is Approximately 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1. 2mg, 1.4mg, 1.6mg, 1.8mg, 2.0mg, 2.5mg, 3.0mg, Contains 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6.0 mg. In one embodiment, the dose per eye is at least about 3 mg to about 6 mg or less, particularly The dosage is approximately 3 mg or approximately 6 mg. For example, 3 mg / 50 μl or 6 mg / 50 μl. It is administered in various volumes suitable for ophthalmic administration, such as 50 μl or 100 μl. It is possible to include 20 μl or less, for example, about 20 μl, about 10 μl, or about 8.0 μl. Smaller volumes can also be used. In one embodiment, 2.4 mg / 20 μg. Use in doses of 1.2 mg / 10 μl, or 1 mg / 8.0 μl (e.g., 1 mg / 8.3 μl). The amount used to treat or induce remission of one or more of the diseases and disorders listed above. It is then delivered to the patient's eye. Delivery can be, for example, by intravitreal injection. ru.

[0071] As used herein, the term "about" includes and describes the value or parameter itself. For example, "about x" includes and describes "x" itself. As used herein, the term "about" when used in relation to a measured value or when used to modify a value, unit, constant, or series of values, refers to a variation of ±1 to 10% in addition to including the value or parameter itself. In some embodiments, the term "about" when used in relation to a measured value or when used to modify a value, unit, constant, or series of values, refers to a variation of ±1, ±2, ±3, ±4, ±5, ±6, ±7, ±8, ±9, or ±10%. み、且つ説明するものである。例えば、「約x」は、「x」それ自体を含み、且つ説明す るものである。本明細書において使用されるように、用語「約」は、測定値に関連して使 用される場合又は値、単位、定数、若しくは一連の値を修飾するために使用される場合、 値又はパラメーターそれ自体を含むことに加えて±1~10%の変動を指す。いくつかの 実施形態では、用語「約」は、測定値に関連して使用される場合又は値、単位、定数、若 しくは一連の値を修飾するために使用される場合、±1、±2、±3、±4、±5、±6 、±7、±8、±9、又は±10%の変動を指す。

[0072] The aqueous formulation of the anti-VEGF antibody used in the method of the present invention is prepared in a pH buffer. Preferably, the buffer of such an aqueous formulation has a pH in the range of about 4.5 to about 8.0, preferably about 5.5 to about 7.0, and most preferably about 6.75. In one embodiment, the pH of the aqueous pharmaceutical composition of the present invention is about 7.0 to 7.5 or about 7.0 to 7.4, about 7.0 to 7.3, about 7.0 to 7.2, about 7.1 to 7.6, about 7.2 to 7.6, about 7.3 to 7.6, or about 7.4 to 7.6. In one embodiment, the aqueous pharmaceutical composition of the present invention has a pH of about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of ≧7.0. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.2. In another preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.4. In another preferred embodiment, the water 製される。好ましくは、そのような水性製剤のバッファーは、約4.5~約8.0、好ま しくは約5.5~約7.0の範囲にある、最も好ましくは約6.75のpHを有する。一 実施形態では、本発明の水性医薬組成物のpHは、約7.0~7.5若しくは約7.0~ 7.4、約7.0~7.3、約7.0~7.2、約7.1~7.6、約7.2~7.6、 約7.3~7.6、又は約7.4~7.6である。一実施形態では、本発明の水性医薬組 成物は、約7.0、約7.1、約7.2、約7.3、約7.4、約7.5のpHを有する。好ましい実施形態では、水性医薬組成物は、≧7.0のpHを有する。 のpHを有する。好ましい実施形態では、水性医薬組成物は、約7.2のpHを有する。別の好ましい実施 好ましい実施形態では、水性医薬組成物は、約が、約7.4のpHを有する。別の好ましい実施形態では、水 形態では、水性医薬組成物は、約7.4のpHを有する。別の好ましい実施形態では、水 The pharmaceutical composition has a pH of approximately 7.6. A buff controls the pH within this range. Examples of acetic acid include acetic acid (e.g., sodium acetate), succinic acid (e.g., sodium succinate), and glycerin. It contains luconic acid, histidine, citrate, and other organic acid buffers. The buffer concentration is For example, depending on the desired isotonicity of the buffer and formulation, preferably about 1 mM to about 50 mM. The saturation can be set to approximately 5 mM to approximately 30 mM.

[0073] Polyols acting as isotonic agents (tonicizers) can affect antibodies in aqueous formulations. It may be used for stabilization. In a preferred embodiment, the polyol is sucrose Alternatively, it may be a non-reducing sugar such as trehalose. If desired, the polyol may be used in the formulation. It is added to the formulation in an amount that may vary based on the desired isotonicity. Preferably, an aqueous formulation. It is isotonic, and in this case, the appropriate concentration of polyol in the formulation is, for example, about 1%~ It is in the range of approximately 15% w / v, preferably in the range of approximately 2% to approximately 10% w / v. However, Hypertonic or hypotonic formulations may also be suitable. The amount of polyol added may also be... The molecular weight of riol may be used as a reference. For example, disaccharides (such as trehalose) In comparison, a smaller amount of monosaccharide (e.g., mannitol) may be added.

[0074] Surfactants are also added to aqueous antibody formulations. An example surfactant is polysorbate. (e.g., polysorbate 20, 80, etc.) or poloxamer (e.g., poloxamer 18) 8) Contains nonionic surfactants such as the above. The amount of added surfactant is the formulation To reduce the aggregation of antibodies / antibody derivatives and / or minimize particle formation in formulations. and / or an amount that reduces adsorption. For example, the surfactant is about 0.001%~ Approximately 0.5%, preferably about 0.005% to about 0.2%, most preferably about 0.01% to about It may be present in the formulation at a concentration of 0.1%.

[0075] In one embodiment, the aqueous antibody preparation used in the method of the present invention is benzyl alcohol. A, phenol, m-cresol, chlorobutanol, and benzethonium Cl, etc. Essentially, there are no preservatives, one or more. In another embodiment, the preservative is particularly in the formulation. If it is a high-dose formulation, it may be included in the formulation. The concentration of the preservative is approximately 0.1%. It may be in the range of approximately 2%, most preferably approximately 0.5% to approximately 1%. Remington 's Pharmaceutical Sciences 21st edition, One or more, such as those described in Osol, A. Ed. (2006) If any of the above-mentioned other pharmaceutically acceptable carriers, excipients, or stabilizers are present in the preparation, This is also acceptable, provided that they do not adversely affect the desired characteristics of the formulation. Acceptable carriers, excipients, or stabilizers may be used in the recipient's dosage and concentration. It is non-toxic to the target group and contains buffers, cosolvents, ascorbic acid, and methionine as antioxidants. Chelating agents such as EDTA, metal complexes (e.g., Zn-protein complexes), Biodegradable polymers such as polyesters, and / or salts such as sodium. It also contains the counterions that make up the pair.

[0076] The preparations used for in vivo administration must be sterile. This can be easily achieved by filtration through a sterile filter membrane before or after the preparation of the formulation.

[0077] In one embodiment, the VEGF antagonist is administered to the eye of a mammal requiring treatment according to known methods for ocular delivery. Preferably, the mammal is a human, the VEGF antagonist is an anti-VEGF antibody (preferably, ranibizumab), and the antibody is administered directly to the eye. Administration to the patient can be accomplished, for example, by intravitreal injection. Preferably, the mammal is a human, the VEGF antagonist is an anti-VEGF antibody (preferably, ranibizumab), and the antibody is administered directly to the eye. Administration to the patient can be accomplished, for example, by intravitreal injection. In one embodiment, the VEGF antagonist is administered to the eye of a mammal requiring treatment according to known methods for ocular delivery. Preferably, the mammal is a human, the VEGF antagonist is an anti-VEGF antibody (preferably, ranibizumab), and the antibody is administered directly to the eye. Administration to the patient can be accomplished, for example, by intravitreal injection. 、眼に直接投与される。患者への投与は、例えば硝子体内注射によって達成することができる。 Administration to the patient can be accomplished, for example, by intravitreal injection.

[0078] The VEGF antagonist in the method of the present invention can be administered as a single treatment or in combination with other agents or therapies useful for treating the condition in question. The VEGF antagonist in the method of the present invention can be administered as a single treatment or in combination with other agents or therapies useful for treating the condition in question.

[0079] A preferred formulation for intravitreal injection of ranibizumab comprises about 4.5% - 11% (w / v) sucrose, 5 - 20 mM sodium citrate, and 0.001% - 0.05% (w / v) polysorbate 80, and the pH of the formulation is about 7.0 - about 7.4. A preferred formulation for intravitreal injection of ranibizumab comprises about 4.5% - 11% (w / v) sucrose, 5 - 20 mM sodium citrate, and 0.001% - 0.05% (w / v) polysorbate 80, and the pH of the formulation is about 7.0 - about 7.4. A preferred formulation for intravitreal injection of ranibizumab comprises about 4.5% - 11% (w / v) sucrose, 5 - 20 mM sodium citrate, and 0.001% - 0.05% (w / v) polysorbate 80, and the pH of the formulation is about 7.0 - about 7.4. One such formulation comprises 5.9% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 6 mg of ranibizumab. One such formulation comprises 5.9% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 6 mg of ranibizumab. Another such formulation comprises 6.4% (w / v) or 5.8% sucrose, 12 mM or 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 3 mg of ranibizumab. Preferred concentrations of ranibizumab are about 120 mg / ml and about 60 mg / ml. The dose can be delivered, for example, at concentrations of 6 mg / 50 μL and 3 mg / 50 μL. Another such formulation comprises 6.4% (w / v) or 5.8% sucrose, 12 mM or 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 3 mg of ranibizumab. Preferred concentrations of ranibizumab are about 120 mg / ml and about 60 mg / ml. The dose can be delivered, for example, at concentrations of 6 mg / CO μL and 3 mg / 50 μL. Another such formulation comprises 6.4% (w / v) or 5.8% sucrose, 12 mM or 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 3 mg of ranibizumab. Preferred concentrations of ranibizumab are about 120 mg / ml and about 60 mg / ml. The dose can be delivered, for example, at concentrations of 6 mg / JO μL and 3 mg / 50 μL. Preferred concentrations of ranibizumab are about 120 mg / ml and about 60 mg / ml. The dose can be delivered, for example, at concentrations of 6 mg / 50 μL and 3 mg / 50 μL. Preferred concentrations of ranibizumab are about 1CO mg / ml and about 60 mg / ml. The dose can be delivered, for example, at concentrations of 6 mg / 50 μL and 3 mg / 50 μL.

[0080] Kit The present invention also relates to a drug container containing a VEGF antagonist drug (e.g., brolucizumab). For example, vials or pre-filled syringes) and for treating patients diagnosed with PDR The kit also includes instructions for using the drug. In one embodiment, the instructions are The medication should be administered to the patient's eyes as needed, as follows: at 6-week intervals. Three doses of approximately 6 mg of VEGF antagonist are administered, followed by additional doses every 12 weeks. An additional dose of approximately 6 mg of VEGF antagonist. In one embodiment, the instructions are initially The three doses are administered during the "induction phase," and additional doses are administered during the "maintenance phase." I instruct them to cooperate.

[0081] In one embodiment, the kit comprises one or more doses of brolucizumab at a dose of 6 mg each The dosage is such that when administering a volume of 0.05 mL, a sufficient amount of broth is needed to deliver a dose of 6 mg. In a single-use vial containing lucizumab or containing 6 mg of brolucizumab It is provided in a pre-filled syringe.

[0082] In one embodiment, the instruction sheet is issued to the treatment provider (e.g., a physician or other qualified medical professional). If disease activity is observed in the treated eye during the maintenance phase, the medication interval may be adjusted. Further instructions will be given to allow for adjustment from once every 12 weeks to once every 6 weeks.

[0083] In another embodiment, the instruction sheet is issued to the treatment provider (e.g., a physician or other qualified medical professional). If disease activity is not observed in the treated eye, the medication interval will be extended to the maintenance period. In between, each treatment can last 6 weeks, and can be extended from once every 12 weeks to once every 24 weeks. Further instructions will be given to do so.

[0084] In yet another embodiment, the instructions state that the VEGF antagonist, during the maintenance phase, causes disease Treatment providers (e.g., medical professionals) based on visual and / or anatomical results to determine disease activity. At the discretion of a qualified medical professional (PR), as needed, i.e., on an ad-hoc basis. N) Further instructions will be given to administer the drug.

[0085] The following examples are included to demonstrate preferred embodiments of the present invention. The technologies disclosed herein are deemed by the inventors to be fully functional in the implementation of the present invention. The techniques shown are presented and therefore constitute a preferred mode for their implementation. Those skilled in the art should fully understand that this is possible. However, In consideration of this disclosure, the manufacturers may make many changes without departing from the spirit and scope of the invention. However, this is done in the specific embodiments disclosed and does not result in the same or similar outcome. They should fully understand what is possible. [Examples]

[0086] The clinical trial focused particularly on panretinal photodynamics in patients with proliferative diabetic retinopathy (PDR). To determine the efficacy and safety of brolucizumab compared to platelet-rich plasma (PRP) treatment. It was designed for this purpose.

[0087] The trial involved a 96-week two-group trial in patients with proliferative diabetic retinopathy (PDR). This will be a single-blind, multi-center, real-controlled, non-inferiority trial of dam construction.

[0088] Patients who consent will have their eligibility determined based on certain selection and exclusion criteria. They undergo a screening evaluation. They meet all selection criteria and all exclusion criteria. Randomize the elements that are not included in a 1:1 ratio: Brolucizumab 6mg: Initiated 3 times a day for 6 weeks, then maintained for 12 weeks a day until week 90, optional. You can choose to extend the treatment interval by 6 weeks at a time, up to a maximum of 24 weeks, starting from week 48. . • PRP: Initial treatment 1-3 times up to week 12, then additional treatments as needed up to week 90. PRP treatment.

[0089] Regardless of whether treatment is being administered, patients will visit the clinic every six weeks from the beginning to the end of the trial.

[0090] Brolucizumab group: During the induction phase, brolucizumab treatment is administered every 6 weeks, with three consecutive injections. Day 0 (baseline), week 6, and week 12).

[0091] The treatment intervals during the maintenance phase are as follows: • Patients in the first year of treatment, during the maintenance phase, i.e., at weeks 24, 36, and 48. I received the Q12W injection. During the maintenance phase, additional visits (e.g., at week 30) are for disease monitoring, not for therapeutic administration. It is planned for the ring. However, the condition has worsened compared to the previous visit. For example, if there are new or spreading neovascularizations in the retina, additional injections are administered as part of the treatment. These medications may be administered at the discretion of the doctor during these visits. If retinal neovascularization is stable, injection may be administered. It should not be administered. • From week 48 onwards ○The treatment interval will be determined based on the provider's assessment of disease activity, starting from the previous injection visit. Whether the disease is stable or regressing, for example, whether retinal neovascularization has regressed. Whether the condition is stable or not, at the discretion of the treatment provider, each treatment period may last 6 weeks, up to a maximum of 24 weeks. It may be extended until [a certain date]. Therefore, at week 48, the treatment provider extends the treatment interval from 12 weeks to 18 weeks. You may choose to do so if the disease has not worsened between weeks 36 and 48, and you receive the injection at week 42. If not, the tested eye may be treated at week 66. At week 66, the treatment provider, You may choose to further extend the treatment interval from 18 weeks to 24 weeks, and the disease may persist until 48 weeks. If the condition has not worsened between weeks 54 and 60, and injections were not given at weeks 54 and 60, 9 The eye in question may be treated in week 0. • Based on the treatment provider's assessment of disease activity, if the patient requires more frequent treatment. The treatment provider may decide to revert to the q12w injection.

[0092] When administering a 0.05 mL volume of brolucizumab, a dose of 6 mg is delivered. In a single-use sterile glass vial containing a sufficient amount of brolucizumab, or in a pre-filled vial. It is provided in a syringe (PFS).

[0093] Brolucizumab is administered to the diseased eye on day 0 (baseline). Evaluation and If treatment is to be administered on the same day, the treatment will be performed after the effectiveness evaluation described below has been completed. It must be done.

[0094] PRP group: Patients in the PRP group will receive their initial treatment at baseline. Treatment will be carried out in the local clinical setting. Therefore, it may be divided into 2-3 sessions up to week 12. If the disease worsens, additional P RP may be performed on the subject's eye at the discretion of the principal investigator, in accordance with local procedures. .

[0095] Selection Criteria Candidates eligible for selection in this examination must meet all of the following criteria: stomach: 1. The consent form must be signed before participating in this examination. 2. The patient is 18 years of age or older at the time of screening. 3. Participants provided sufficient cooperation regarding appropriate fundus photographs and retinal images. 4. Patients have type 1 or 2 diabetes mellitus (DM) and HbA1c ≤ 12% at the time of screening. He has been diagnosed with this condition. 5. If drug therapy is being given for diabetes mellitus, drug therapy for the management of diabetes may be necessary. It must be stable for three months prior to dam construction, and medically acceptable conditions must be met throughout the testing period. It is expected to remain stable to a similar degree. test eye 6. PDR is assessed by the principal investigator using standard or wide-field CFP, FA. Furthermore, there is no evidence that PRP was performed previously, and in the opinion of the principal investigator, anti-VEGF or PRP Treatment with RP is required. 7. BCVA ≥ ETDRS (number of characters: 34) (Snellen's visual acuity chart: 20 / 200).

[0096] Exclusion criteria Subjects that meet any of the following criteria are not eligible for selection in this examination. Eye condition 1. In the opinion of the principal investigator, the following conditions apply to the subject's eye at screening or baseline. Associated conditions or eye disorders: a. It may interfere with the functional or structural response to treatment with the investigational drug or b. May confuse the interpretation of test results or c. May impair eyesight or d. The patient requires a planned medical or surgical intervention during the initial 54-week trial period. 2. The subject's eye at screening or baseline, as evaluated by the principal investigator. The presence of center-involved diabetic macular edema. 3. Any active intraocular or in the eye of the subject at screening or baseline Periorocular infection or active intraocular inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, infectious eye) Blepharitis (inflammation of the eyelids, uveitis). 4. Intraocular pressure (IOP) > 25 mmH at screening or baseline, or during drug therapy. Uncontrolled glaucoma in the test eye, as defined by g or according to the opinion of the principal investigator. . 5. Clear visualization of the macula and / or optic disc in the test eye at baseline. Moderate or dense preretinal or vitreous hemorrhage that interferes with or interferes with PRP treatment. 6. Fibrous vascular proliferation or tractional retinal detachment in the posterior pole of the eye being examined. 7. Neovascularization of the iris or anterior chamber angle, or neovascular glaucoma, in the tested eye. 8. Amblyopia, amaurosis, or other conditions in the same eye with BCVA < 20 / 200 at the time of screening. This refers to the presence of an eye disorder (a condition in which VA may be improved by surgery, for example, a condition caused by cataracts). (Excluding combined shipments). Ocular treatment in the test eye 9. PRP at any point in time prior to the baseline. 10. Intravitreal anti-VEGF treatment within 6 months prior to baseline. 11. Vitreoretinal surgery at any point prior to baseline or within the next 12 months. The need for vitreoretinal surgery is anticipated. 12. Laser treatment of the macula within 3 months prior to baseline. 13. Intravitreal implantation of fluocinolone acetonide at any point prior to baseline. Treatment with tablets (e.g., ILUVIEN® or RETISERT®) Other intraocular corticosteroid treatments within the 6 months prior to baseline. 14. Aphakia due to the absence of the posterior capsule. 15. Intraocular surgery within 3 months prior to baseline or expected white eye surgery within the next 12 months. The need for internal organ removal surgery. General condition and treatment 16. Stroke or myocardial infarction during the 6-month period prior to baseline. 17. End-stage renal disease requiring dialysis or kidney transplantation. 18. Systolic value ≥ 180 mmHg or diastolic value at screening or baseline Poorly controlled blood pressure is defined as ≥100 mmHg. (When there is an increase in blood pressure readings) The test should be repeated after 20 minutes. If the repeated measurement is elevated, the patient should not be tested. (Not eligible to register). 19. Systemic anti-VEGF therapy at any point in time. 20. Lenses, retina, or optic nerves used during the 6-month period prior to baseline. Systemic drugs known to be toxic (e.g., deferoxamine, chloroquine) (Hydroxychloroquine, tamoxifen, phenothiazine, and ethambutol). 21. To any of the investigational drugs or their excipients as evaluated by the principal investigator. Hypersensitivity to or similar classes of drugs or clinically significant reactions to fluorescein dye A history of severe hypersensitivity. 22. Treatment within the past five years, regardless of whether there is evidence of local recurrence or metastasis. A history of any malignant disease of any organ system, whether treated or untreated (e.g., localized basal cell carcinoma of the skin or (Except for cervical intraepithelial neoplasia). 23. In the opinion of the principal investigator, scheduled trial visits, completion of the trial, or safe administration of the investigational drug. A medical history of a condition that may interfere (e.g., metabolic disorders other than type 1 or 2 diabetes mellitus) (Physical examination findings, or clinical laboratory findings). 24. Within 5 half-lives of baseline or within 30 days / Expected pharmacological effect Whichever is longer until returning to the baseline; or according to local regulations if necessary. Longer-term systemic use of investigational drugs (requiring the use of commercially available vitamins, supplements, or food) Observational clinical trials are not excluded. others 25. Pregnant or breastfeeding women, where pregnancy is defined as a positive human chorionic gonadotropin test. A woman who has conceived and is pregnant from the time of conception until the end of her pregnancy, as confirmed by a tropin (hCG) pregnancy test. This is defined as the state of [this condition]. 26. Highly effective contraception during administration of the investigational drug and during the 22 days after discontinuing the investigational drug. Unless otherwise specified, this is defined as all women who are physiologically capable of becoming pregnant. A woman of childbearing potential.

[0097] Effectiveness (Assessment of disease activity) The following assessments assess visual function, diabetic retinopathy status, and the structure of the retina and blood vessels. This procedure is performed to determine the effectiveness of lorcizumab. • Best corrected visual acuity according to charts such as ETDRS at 4 meters • ETDRS DRSS score based on 7-field stereo color fundus photography (CFP) • Anatomical retinal assessment using SD-OCT, FA, OCT angiography, and wide-field CFP / FA. • Peripheral field of view evaluated by visual field measurement

[0098] All efficacy evaluations are performed before every dose of treatment.

[0099] eyesight Visual acuity (VA) was measured in the test eye at each trial visit, as well as during screening and at 54 weeks. Refraction testing (protocol ref) was performed on the eye and the same eye at the 96-week / EOS visit. The best correction value (BC) is determined from the ratio. BCVA is evaluated using VA. BCVA measurements are taken first at a test distance of 4 meters, ET Visual acuity is measured while seated using a visual acuity chart such as DRS. Refractive correction techniques and VA testing are also used. Details of the evaluation and training materials are provided in the relevant manual. Evaluation Procedure Furthermore, the certification of the evaluators is carried out before any judgment is made on the subject of the test.

[0100] Color fundus photography and fluorescein angiography. Seven-field stereocolor fundus imaging (CFP) was performed at baseline, 54 weeks, and 9 weeks. The procedure is performed in both eyes at week 6 and in the eye being treated at weeks 18 and 72.

[0101] Sites with applicable equipment may use optional wide-field (at least 100 degrees) color eye vision. Whole-frontal cell imaging (WFCFP) was performed in both eyes at baseline, week 54, and week 96, and This should be performed on eyes being treated at 18 weeks and 72 weeks. WFCFP images If images were not taken at baseline, they should not be used at subsequent visits. FCFP images are not a substitute for 7-field CFP images.

[0102] Standard or wide-field fluorescein angiography (FA) was performed at baseline, 54 weeks, and 96 weeks. This procedure is performed on the eye being treated at the week-week visit, as well as on the same eye at the baseline visit. FA may be performed at another visit at the discretion of the treatment provider. The type of FA camera should not be changed during the treatment period.

[0103] For screening purposes, as long as FA is performed within 3 days of the baseline visit FA images taken during previous periodic assessments may be used.

[0104] The treatment provider will evaluate the images according to standard clinical practice and make decisions regarding treatment. To inform, use any of the CFP, WFCFP, and FA imaging findings. good.

[0105] Optical coherence tomography Spectral domain optical coherence tomography (SD-OCT) images were obtained, and baseline, 5 Treatment was provided in both eyes at the 4th and 96th week visits, and at all other visits. To evaluate with a discerning eye.

[0106] These assessments are performed on-site by trained technicians or healthcare providers, and BCV It should be performed after an A evaluation and before any treatment. The treatment provider should consider macular edema. SD-OCT images are interpreted to evaluate the status.

[0107] Only SD-OCT devices can be used (i.e., even with time-domain OCT, wave (Not a long-sweep OCT). The SD-OCT model used for each individual patient varied depending on the treatment period. It should not be changed.

[0108] Central retinal thickness (CSFT) is measured using SD-OCT. The determined CSFT is: This is the average retinal thickness of the circular area within a 1 mm diameter range around the fovea.

[0109] In addition to standard SD-OCT evaluation, wide-field or standard OCT angiography is performed where possible. However, this may be performed at each visit in the eye being treated. OCT angiography is the baseline. If it is not evaluated at some point, it should not be used at a later visit. OCT angiography is Used by treatment providers to supplement the assessment of retinal neovascularization as part of disease activity assessment. It may also be used.

[0110] The treatment provider interprets the OCT images according to their clinical practice.

[0111] Peripheral vision Visual field testing in the treated eye was performed using automated perimetry at baseline and 18 weeks. The eye examination will be performed at weeks 54, 72, and 96. Visual field testing will be performed when treatment is completed during the visit. If so, it should be performed before treatment. The accepted testing methods are full threshold and S wedish Interactive Thresholding Algorithm Humphrey 24-2, 30-2, and 60-4 according to the m(SITA) standard method do.

[0112] The present invention and embodiments thereof have been described in detail. However, the scope of the present invention is limited to the present invention. Any process, manufacture, synthesis, compound, means, method, and / Or, it is not intended to be limited to any particular embodiment of the step. The spirit and / Or, without deviating from the essential characteristics, various modifications, substitutions, and changes may be made to the disclosed structure. This can be done with respect to the constituent elements. Therefore, those skilled in the art will understand the method described herein. Subsequent modifications that substantially perform the same function as the embodiment or substantially achieve the same results, Substitutions and / or modifications may be utilized in accordance with such related embodiments of the present invention. It will be readily apparent from this disclosure that there are good points. Therefore, the following claims are as specified herein. Processes, manufactures, compounds, means, methods, and / or steps disclosed herein The claims are intended to include modifications, substitutions, and changes to within their scope. Unless otherwise specified, the order or elements listed are limited to those listed. It should not be possible to deviate from the scope of the attached claims. Various changes in form and detail should not deviate from the scope of the attached claims. It should be understood that this can be done without resorting to escapism.

Claims

1. A method for treating proliferative diabetic retinopathy (PDR) in patients, a) Administering three individual doses of a VEGF antagonist to the patient at 6-week intervals, and b) Once every 12 weeks (q12w regimen), one or more doses of the VEGF antagonist. This includes administering an additional dose to the patient, the first additional dose being the third dose of step a). A method in which the individual dose is administered 12 weeks later.

2. For each dose of q12w, the patient shall be evaluated for PDR disease activity before or after administration. The method according to claim 1, further comprising:

3. Disease activity is assessed by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neovascularization. The method according to claim 2, which is evaluated based on the status of the tube and the peripheral field of view.

4. If worsening of PDR disease activity is observed after the q12w dose, the patient should receive q6 The regimen was switched to the W regimen, and the aforementioned additional dose was changed from once every 12 weeks to every 6 weeks. The method according to claim 2 or 3, administered as a single dose.

5. The aforementioned worsening of PDR disease activity is a new or worsening compared to any previous assessment. Retinal neovascularization, reperfusion of retinal neovascularization, increased ETDRS DRSS score, peripheral vision The method according to claim 4, wherein the loss of field of vision and / or the development of complications affecting visual acuity.

6. During the aforementioned q12w, the treatment interval may be adjusted as the disease activity compares to the previous disease activity assessment. If all are stable or improving, 18 weeks (q18w) or 24 weeks (q24w) The method according to claim 2 or 3, which is extended to ).

7. The method according to any one of claims 1 to 6, wherein the patient is a human.

8. The anti-VEGF antagonist is brolucizumab, any one of claims 1 to 7. The method described in section [section number].

9. The VEGF antagonist is administered by intravitreous injection, according to claims 1 to 8. The method described in either of the above terms.

10. The dosage of the VEGF antagonist is 3 mg or 6 mg, according to claims 1 to 9. The method described in either of the above terms.

11. Methods for treating diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) In the initial phase, three individual doses are administered at 6-week intervals, followed by a 12-week maintenance phase. Each time (q12w regimen), an additional dose of the anti-VEGF antibody, a VEGF antagonist, is administered. This includes administering approximately 3 mg or approximately 6 mg to the patient, and is optional for DR patients. Furthermore, it can also present with macular edema (such as diabetic macular edema).

12. For each dose of q12w, the patient's DR or PDR disease activity is evaluated before or after administration. The method according to claim 11, further comprising doing the following.

13. Disease activity is assessed by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neovascularization. The method according to claim 12, which is evaluated based on the status of the tube and the peripheral field of view.

14. During the aforementioned maintenance period, the medication interval may be adjusted at any time if disease activity is higher than the previous disease activity assessment. If the condition is improving or stable, it may be extended up to 24 weeks (q24w), claim 1 The method described in 2 or 13.

15. If worsening of PDR disease activity is observed after the q12w dose, the patient should receive q6 The regimen was switched to the W regimen, and the aforementioned additional dose was changed from once every 12 weeks to every 6 weeks. The method according to any one of claims 11 to 13, administered as a single dose.

16. The aforementioned worsening of PDR disease activity is a new or worsening compared to any previous assessment. Retinal neovascularization, reperfusion of retinal neovascularization, increased ETDRS DRSS score, peripheral vision The method according to claim 15, wherein the loss of field of vision and / or the development of complications affecting visual acuity. 。

17. The method according to any one of claims 11 to 16, wherein the patient is human.

18. The anti-VEGF antagonist is brolucizumab, as per any of claims 11 to 17. The method described in item 1.

19. Claims 11-18, the VEGF antagonist is administered by intravitreous injection. The method described in any one of the items.

20. In patients, the treatment of diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) A VEGF antagonist for use in a method for the purpose of, wherein the VEGF The antagonist is a) Three individual doses at 6-week intervals and b) Thereafter, once every 12 weeks (q12w regimen), as an additional dose A VEGF antagonist administered to the aforementioned patient.

21. The above method involves, for each dose of q12w, checking the DR or PDR disease activity before or after administration. The VEGF for use according to claim 20 further comprises evaluating the patient. An antagonist.

22. Disease activity is assessed by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neovascularization. The use according to claim 21 is evaluated based on the tube status and confirmation of peripheral vision. A VEGF antagonist.

23. If disease activity worsens after the q12w dose, the patient should be given the q6w dose. The dosage is switched to men, and the additional dose is administered once every 6 weeks instead of once every 12 weeks. A VEGF antagonist for use according to claim 21 or 22, provided.

24. The aforementioned worsening of disease activity is a new or worsening of the disease compared to any previous assessment. Reperfusion of membrane neovascularization, retinal neovascularization, and increase in ETDRS DRSS score (2 steps or less) These include the above-mentioned increase, loss of peripheral vision, and / or the development of complications affecting visual acuity. A VEGF antagonist for use according to claim 23.

25. During the maintenance phase, the medication interval may be adjusted at any time if disease activity has improved compared to the previous disease activity assessment. If the condition is improving or stable, it may be extended up to 24 weeks (q24w), claim 20- A VEGF antagonist for use as described in any one of paragraphs 22.

26. The patient is human, VE for use according to any one of claims 20 to 25 GF antagonist.

27. The anti-VEGF antagonist is brolucizumab, as per any of claims 20 to 26. A VEGF antagonist for use as described in item 1.

28. The VEGF antagonist is administered by intravitreal injection, claims 20-27. A VEGF antagonist for use as described in any one of the items.

29. The dose of the VEGF antagonist is approximately 3 mg to approximately 6 mg, claims 20 to 28. A VEGF antagonist for use as described in any one of the items.

30. In patients, the treatment of diabetic retinopathy (DR) or proliferative diabetic retinopathy (PDR) A VEGF antagonist for use in a method for the purpose of, wherein the VEGF The antagonist is initially provided during the induction phase, during which the patient receives treatment at 6-week intervals. After receiving three individual doses of approximately 3 mg or approximately 6 mg of the aforementioned VEGF antagonist, The VEGF antagonist is provided during the maintenance phase, during which the patient receives 12 Once every week (q12w regimen), an additional 3 mg or so of the VEGF antagonist. A VEGF antagonist administered at a dose of approximately 6 mg.

31. The above method involves, for each dose of q12w, checking the DR or PDR disease activity before or after administration. The VEGF for use according to claim 30 further comprises evaluating the patient. An antagonist.

32. Disease activity is assessed by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neovascularization. The use described in claim 31 is evaluated based on the tube status and confirmation of peripheral vision. A VEGF antagonist.

33. Worsening disease activity is defined as new or worsened retinal neoplasia compared to any previous assessment. Reperfusion of living blood vessels and retinal neovascularization, increase in ETDRS DRSS score (2 steps or more) Claims include: increased vision, loss of peripheral vision, and / or the development of complications affecting visual acuity. A VEGF antagonist for use as described in item 31 or 32.

34. The aforementioned worsening of PDR disease activity is a new or worsening compared to any previous assessment. Retinal neovascularization, reperfusion of retinal neovascularization, increased ETDRS DRSS score, peripheral vision The use according to claim 33, which is a loss of field of vision and / or the development of complications affecting visual acuity. A VEGF antagonist for this purpose.

35. During the aforementioned maintenance period, the medication interval may be adjusted at any time if disease activity is higher than the previous disease activity assessment. If the condition is improving or stable, it may be extended up to 24 weeks (q24w), claim 3 A VEGF antagonist for use as described in any one of items 0 to 32.

36. The patient is human, VE for use according to any one of claims 30 to 35 GF antagonist.

37. The anti-VEGF antagonist is brolucizumab, as per any of claims 30 to 36. A VEGF antagonist for use as described in item 1.

38. The VEGF antagonist is administered by intravitreal injection, claims 30-37. A VEGF antagonist for use as described in any one of the items.

39. a) Drug containers containing VEGF antagonists and b) Using the VEGF antagonist to treat patients diagnosed with DR or PDR. The instructions for use include the three doses of the VEGF antagonist, administered at 6-week intervals (q It is administered at 6 weeks, and after this last dose, the aforementioned VEGF agent is administered at 12-week intervals (q12w). The kit continues with additional individual doses of the tagonist.

40. (a) Each dose is used to deliver a dose of 6 mg when administering a volume of 0.05 mL. In a single-use vial containing sufficient brolucizumab or 6 mg of brolucizumab One or more doses of 6 mg of bromide provided in a pre-filled syringe containing mab Lucizumab or b) Each dose is sufficient to deliver a 3 mg dose when administered in a 0.05 mL volume. In a single-use vial containing brolucizumab or 3 mg of brolucizumab One or more doses of 3 mg of brolucin provided in a pre-filled syringe containing Zumab The kit according to claim 39, including the following:

41. The aforementioned instruction is given when DR or PDR disease activity is observed in the eye being treated, q Claim 39 or 40 further instructs to adjust the 12-week dosing interval to once every six weeks. The kit described above.

42. The aforementioned prescription is for the administration of q12w if no disease activity is observed in the eye being treated. The claim further instructs that the interval be extended up to once every 24 weeks, with each extension being 6 weeks. The kit described in 39 or 40.

43. The aforementioned instructions state that the VEGF antagonist may be administered before or after any q12w dose. Treatment providers (e.g., medical professionals) based on visual and / or anatomical results to determine disease activity. At the discretion of a qualified medical professional (PR), as needed, i.e., on an ad-hoc basis. N) The kit according to claim 39 or 40, further instructing to be administered.

44. In patients, proliferative diabetic retinopathy (PDR) progresses to non-proliferative diabetic retinopathy (NPD). A method to prevent progression to R), a) Administering three individual doses of a VEGF antagonist to the patient at 6-week intervals, and b) Subsequently, once every 12 weeks (q12w regimen), the VEGF antagonist is administered again. A method comprising administering an additional dose to the patient.

45. For each dose of q12w, the patient shall be evaluated for disease activity before or after administration. The method according to claim 44, further comprising:

46. Disease activity is assessed by best corrected visual acuity (BCVA), ETDRS DRSS score, and retinal neovascularization. The method according to claim 45, which is evaluated based on the status of the tube and the peripheral field of view.

47. If disease activity worsens after the q12w dose, the patient should be given the q6w dose. The dosage is switched to men, and the additional dose is administered once every 6 weeks instead of once every 12 weeks. The method according to claim 45 or 46.

48. The aforementioned worsening of disease activity is a new or worsening of the disease compared to any previous assessment. Reperfusion of membrane neovascularization, retinal neovascularization, and increase in ETDRS DRSS score (2 steps or less) These include the above-mentioned increase, loss of peripheral vision, and / or the development of complications affecting visual acuity. The method according to claim 47.

49. At 48 weeks after the initial dose was administered, the treatment interval at q12w was 6 weeks per dose. The method according to claim 45 or 46, which is extended up to a maximum of 24 weeks (q24w).

50. The method according to any one of claims 44 to 49, wherein the patient is human.

51. The anti-VEGF antagonist comprises the sequence of Sequence ID No. 3, according to any of claims 44 to 50. The method described in any one of the items.

52. Claims 44-51, the VEGF antagonist is administered by intravitreous injection. The method described in any one of the items.

53. The dose of the VEGF antagonist is approximately 3 mg to approximately 6 mg, claims 44 to 52. The method described in any one of the items.

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