Personalized treatment of ophthalmic diseases

Abstract

The present invention relates to antibodies that bind to VEGF and ANG2 for use in the treatment of ocular vascular diseases, such as neovascular AMD (nAMD) (also referred to as choroidal angiogenesis [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy, in particular diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO).

Description

[0001] This application is a divisional application of the invention patent application with application date of August 6, 2020, application number 202080055774.8, and invention name “Personalized Treatment of Ophthalmic Diseases”. Technical Field

[0002] The present invention relates to antibodies that bind to VEGF and ANG2 for use in the treatment of ocular vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy, in particular diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO). Background Art

[0003] Ocular vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy and especially diabetic macular edema (DME) are serious diseases that often lead to vision loss and blindness.

[0004] Neovascular age-related macular degeneration (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD) is a late stage of AMD that can lead to acute and severe vision loss and remains the leading cause of visual impairment in the elderly (Bourne et al., Lancet Glob Health 2013; 1: e339-49; Wong et al., Lancet Glob Health 2014; 2: e106-16). Several biochemical and biological processes (such as angiogenesis, inflammation, and oxidative stress) are known to play a role in the pathogenesis of nAMD, which is characterized by abnormal proliferation of choriocapillaris that penetrate Bruch's membrane and migrate to or through the retinal pigment epithelium. CNV leaks fluid, lipids, and blood into the outer retina and, if left untreated, can lead to severe, irreversible central vision loss.

[0005] Before the use of anti-vascular endothelial growth factor (anti-VEGF) agents, laser photocoagulation and photodynamic therapy using verteporfin were standard care and were shown to stabilize vision. Although such treatments remain a treatment option for selected patients, the treatment of nAMD has been significantly improved by the introduction of biomolecules that target an important factor in pathological angiogenesis (VEGF-A) (Brown et al., N Engl J Med 2006; 355: 1432-44; Rosenfeld et al., N Engl J Med 2006; 355: 1419-31; Heier et al., Ophthalmology 2012; 119: 2537-48). Since 2006, nAMD has been widely used in the treatment of AMD. Since the initial approval of ranibizumab, the significant benefits of anti-VEGF therapy and its ability to restore vision have been widely recognized (American Academy of Ophthalmology 2015).

[0006] A key challenge of currently available anti-VEGF therapies is the need for frequent and long-term administration to maintain visual acuity gains (Heier et al., Ophthalmology 2012; 119: 2537-48; the Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] Research Group 2016, Ophthalmology 2016; 123: 1751-61). Real-world data suggest that many patients with nAMD are not treated at optimal frequencies, and this undertreatment in clinical practice is associated with lower visual acuity (VA) gains than observed in controlled clinical trials (Cohen et al., Retina 2013; 33: 474-81; Finger et al., Acta Ophthalmol 2013; 91: 540-6; Holz et al., Br J Ophthalmol 2015; 99: 220-6 ；Rao et al., Ophthalmology 2018;125:522-28). The undertreatment of nAMD in clinical practice reflects the burden of frequent treatment on patients, caregivers, and the healthcare system (Gohil et al., PLoS One 2015;10:e0129361; Prenner et al., Am J Ophthalmol 2015;160:725-31; Varano et al., Clin Ophthalmol 2015;9:2243-50; CATT Research Group et al., Ophthalmology 2016;123:1751-61; Vukicevic et al., Eye 2016;30:413-21).

[0007] Diabetic macular edema (DME) is a complication of diabetic retinopathy (DR) that can develop at any stage of the underlying disease of the retinal microvasculature (Fong et al., Diabetes Care 2004; 27: 2540-53). The frequency of DME increases as the underlying DR deteriorates from non-proliferative DR (NPDR) to proliferative DR (PDR) (Henricsson et al., Acta Ophthalmol. Scand. 1999: 77: 218-223; Johnson Am J Ophthalmol 2009; 147: 11-21). DME is the most common cause of moderate and severe visual impairment in patients with DR (Ciulla et al., Diabetes Care 2003;26:2653-64; Davidson et al., Endocrine 2007;32:107-16; Leasher et al., Diabetes Care 2016;39:1643-9), and if left untreated, can lead to a visual acuity (VA) loss of 10 or more letters within 2 years in approximately 50% of patients (Ferris and Patz Surv Ophthamol 1984;28 Suppl:452-61; Diabetes Care 2003;26:2653-64 et al., 2003). DME affects approximately 14% of diabetic patients and can be found in both type 1 and type 2 diabetic patients (Girach and Lund-Andersen Int J Clin Practice 2007;61:88-97). In 2013, the number of people with diabetes worldwide was approximately 382 million, and this number is expected to grow to 592 million by 2035 (International Diabetes Federation 2013).

[0008] With advances in imaging technology, DME is now commonly diagnosed by optical coherence tomography (OCT) rather than the traditional Early Treatment Diabetic Retinopathy Study (ETDRS) based ophthalmoscopy criteria. At the molecular level, DME is the result of vascular endothelial growth factor-A (VEGF-A)-mediated increased vascular permeability and pericyte loss, followed by hypoxia-mediated release of proangiogenic, hyperpermeable and proinflammatory mediators (Antonetti et al., Semin Ophthalmol 1999; 14: 240-8). VEGF also upregulates the homeostatic factor, angiopoietin 2 (Ang-2), which acts as an antagonist of Tie2 receptor tyrosine kinase on endothelial cells, counteracting vascular stability maintained by Ang-1-dependent Tie2 activation. Therefore, Ang-2 acts as a vascular destabilizing factor, making the vascular system more elastic and more susceptible to endothelial barrier destruction and sprouting. Excessive Ang-2 and VEGF in retinal tissue promote vascular instability, vascular leakage and neovascularization. Ang-2 is also involved in inflammatory pathways such as lymphocyte recruitment. In summary, VEGF-A and Ang-2 are both considered to be key factors mediating the pathogenesis of diabetic eye diseases (Aiello et al., N Engl J Med 1994; 331: 1480-7; Davis et al., Cell 1996; 87: 1161-9; Maisonpierre et al., Science 1997; 277: 55-60; Gardner et al., Surv Ophthalmol 2002; 47(Suppl 2): ​​S253-62; Joussen et al., Am J Path 2002; 160: 501-9; Fiedler et al., J Biol Chem 2003; 278: 1721-7).

[0009] Although macular laser was once the standard of care (SOC) for the treatment of DME, the development of anti-VEGF drug therapies over the past decade has significantly improved visual outcomes for patients with DME. Currently, anti-VEGF therapies available for DME include ranibizumab and aflibercept. Other approved options for the treatment of DME include periocular or intravitreal (IVT) steroids and steroid implants.

[0010] Despite the strong efficacy of anti-VEGF therapy in DME, a large proportion of patients do not experience clinically meaningful visual improvement in reality. And in some cases, frequent IVT administration is required over a long period of time to achieve maintenance of the observed early benefits of DME treatment. Currently, SOCs for administering anti-VEGF injections require patients to undergo frequent clinical examinations and IVT injections. This places a heavy burden on patients, caregivers, treating physicians, and the healthcare system.

[0011] Large phase III trials of anti-VEGF agents in DME have shown that the number of injections required to maintain visual gains can be reduced after the first year of treatment (Diabetic Retinopathy Clinical Research Network et al., Ophthalmology 2010:117:1064-77. Epub:28 April 2010; Schmidt-Erfurth et al., Ophthalmology 2014;121:193-201; Elman et al., Ophthalmology 2015;122:375-81). However, in order to achieve optimal results in the absence of validated predictive biomarkers for treatment frequency, the standard anti-VEGF approach in DME still relies on frequent monitoring visits, placing a heavy burden on patients and healthcare providers. In addition, anti-VEGF monotherapy does not fully address other pathways that contribute to the exacerbation of diabetic eye disease, including inflammation and pericyte instability.

[0012] New therapies that target other pathways and reduce the burden of IVT injections are needed to address the high unmet medical need in DME. Summary of the invention

[0013] According to one aspect of the present invention, a method, use, bispecific antibody (applied), medicament or pharmaceutical preparation for treating a patient with an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME) is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval (PTI) regimen, wherein the treatment of a patient with an ocular vascular disease selected from nAMD and DME comprises a dosing regimen that extends the administration interval in the case of stable disease-free conditions, or shortens the interval in the case of disease activity. In this way, the patient is optimally treated to ensure improvement and / or maintenance of the patient's vision while reducing unnecessary treatment burden.

[0014] According to another aspect of the present invention, a method, use, bispecific antibody, drug or pharmaceutical preparation for treating a patient with a specific neovascular AMD (nAMD) (also called wet AMD (wAMD)) is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval (PTI) regimen, wherein the treatment of patients with nAMD includes a dosing regimen that extends the administration interval in the case of stable disease-free conditions, or shortens the interval in the case of disease activity. In this way, the patient is optimally treated to ensure improvement and / or maintenance of the patient's vision while reducing unnecessary treatment burden.

[0015] According to one aspect of the present invention, a method, use, bispecific antibody, medicament or pharmaceutical preparation for treating a patient suffering from the method is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2),

[0016] Treatment of patients with AMD includes dosing regimens with extended dosing intervals after initiation of treatment in patients who are stable and disease-free, or shortened dosing intervals in patients with active disease.

[0017] One embodiment is such a method, use, bispecific antibody, medicament or pharmaceutical formulation for treating a patient with neovascular AMD (nAMD), the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval, wherein

[0018] a) Patients first received 4 doses of the bispecific

[0019] Treatment with VEGF / ANG2 antibodies;

[0020] b) At Weeks 20 and 24, disease activity was assessed, whereby disease activity was determined if one of the following criteria was met:

[0021] i) Increase in central subfield thickness (CST) compared to the average CST value of the first two planned examinations

[0022] >50 μm, with the planned visits at Weeks 12 and 16 used for the Week 20 assessment, and the planned visits at Weeks 16 and 20 used for the Week 24 assessment, or

[0023] ii) CST increased by ≥75 μm compared with the lowest CST value recorded in any of the two previous planned examinations;

[0024] iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the average BCVA of the two previous scheduled visits due to nAMD disease activity,

[0025] iv) a decrease in BCVA of ≥10 letters compared with the highest BCVA value recorded at either of the first two scheduled visits due to nAMD disease activity, or

[0026] v) New macular hemorrhages due to nAMD activity

[0027] c) Then, the patient

[0028] i) Patients who meet disease activity criteria at Week 20 will be treated at an 8-week (Q8W) dosing interval starting at Week 20 (with the first Q8W dose at Week 20);

[0029] ii) Patients who meet disease activity criteria at Week 24 will be treated on a 12-week (Q12W) dosing interval starting at Week 24 (with the first Q12W dose at Week 24); and

[0030] iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated at a every 16-week (Q16W) dosing interval starting at Week 28 (with the first Q16W dose at Week 28).

[0031] In one embodiment, the personalized treatment interval will be extended, shortened, or maintained after week 60, wherein

[0032] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0033] Q16W):

[0034] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0035] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0036] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0037] No decrease in BCVA of ≥10 letters,

[0038] iii) no new macular hemorrhage;

[0039] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0040] or

[0041] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0042] i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits, or CST increase of ≥75 μm compared to the lowest dosing visit measurement,

[0043] ii) a decrease in BCVA of ≥5 letters compared to the average of the two most recent dosing visits; or

[0044] A decrease in BCVA of ≥10 letters compared with the highest dosing exam measurement,

[0045] iii) New macular hemorrhage.

[0046] According to another aspect of the present invention, a method, use, bispecific antibody (application), medicament or pharmaceutical preparation for treating patients with diabetic retinopathy, in particular diabetic macular edema (DME), is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval (PTI) regimen, wherein the treatment of patients with DME includes a dosing regimen that extends the administration interval in the case of stable disease-free conditions, or shortens the interval in the case of disease activity. In this way, the patient is optimally treated, ensuring improvement and / or maintenance of the patient's vision, while reducing unnecessary treatment burden.

[0047] One embodiment is such a method, use, bispecific antibody, medicament or pharmaceutical formulation for treating a patient with diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval, wherein

[0048] a) patients initially received treatment with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval until the central subdomain thickness (CST) reached a predetermined reference CST threshold (CST < 325 μm for Spectralis SD-OCT, or < 315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured at or after Week 12);

[0049] b) Then, increase the dosing interval from 4 weeks to an initial Q8W dosing interval every 8 weeks;

[0050] c) From this point on, the dosing interval is extended, shortened, or maintained based on the assessment performed at the dosing visit, which is based on CST and best corrected visual acuity (BCVA)

[0051] relative changes compared with the corresponding reference CST and BCVA;

[0052] in

[0053] i) The said interval is extended by 4 weeks in the following cases:

[0054] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA

[0055] ≥10 letters;

[0056] ii) The interval will be maintained if:

[0057] - If the CST decreases by >10%, or

[0058] - If the CST value increases or decreases by ≤10% with an associated decrease in BCVA

[0059] ≥10 letters; or

[0060] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0061] iii) The interval is shortened by 4 weeks in the following cases:

[0062] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0063] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0064] iv) if the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks;

[0065] wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and

[0066] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0067] In one embodiment, such dosing intervals can be adjusted by 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0068] According to another aspect of the present invention, there is provided a method, use, bispecific antibody (used), medicament or pharmaceutical preparation for treating a patient with macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval (PTI) regimen, wherein the treatment of patients with macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion comprises a dosing regimen that extends the administration interval in the case of stable disease-free, or shortens the interval in the case of disease activity. In this way, the patient is optimally treated, ensuring improvement and / or maintenance of the patient's vision while reducing unnecessary treatment burden.

[0069] One embodiment is such a method, use, bispecific antibody, medicament or pharmaceutical formulation for treating a patient with macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval, wherein

[0070] a) Patients were first treated with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval from day 1 to week 20

[0071] b) starting from week 24, the patient receives the bispecific VEGF / ANG2 antibody at a frequency of Q4W until the central subdomain thickness (CST) reaches a predetermined reference CST threshold;

[0072] c) extending, shortening, or maintaining the dosing interval from this time point onwards based on the assessment performed at the dosing visit, which is based on the relative change in CST and best-corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0073] in

[0074] i) The interval is extended by 4 weeks in the following cases

[0075] If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters; or

[0076] ii) The interval is maintained if any of the following criteria is met:

[0077] If the CST value decreases by >10%; or

[0078] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0079] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0080] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0081] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0082] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or

[0083] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0084] iv) In the following cases, the interval is shortened to Q4W

[0085] If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters,

[0086] where the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met and if the CST is reduced by >10% from the previous reference CST for two consecutive dosing visits and the value obtained is within 30

[0087] μm, the reference CST is adjusted so that the CST value obtained in the next examination will be used as the new reference CST; and

[0088] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0089] In one embodiment, such dosing intervals can be adjusted by 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. In one embodiment of the present invention, the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein

[0090] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0091] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0092] And among them

[0093] iii) The bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index).

[0094] In one embodiment of the invention, the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy (eg, monotherapy) (treatment naive).

[0095] In one embodiment of the invention, the patient suffering from an ocular vascular disease has been previously treated with an anti-VEGF therapy (eg, monotherapy).

[0096] In one embodiment of the present invention, the disclosed bispecific antibodies are administered as determined by a software tool. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 : Figure 1 An overview of the nAMD study design

[0098] aPatients will undergo disease activity assessments at Weeks 20 and 24. Patients with anatomical or functional signs of disease activity at these time points will receive Q8W or Q12W dosing, respectively, rather than Q16W dosing.

[0099] bThe primary endpoint was change from baseline in BCVA based on the mean at Weeks 40, 44, and 48 (as assessed on an ETDRS chart with a starting distance of 4 meters).

[0100] cBeginning at week 60 (when all patients in group A are scheduled to receive fariximab), patients in group A will be treated according to the PTI dosing schedule (between Q8W and Q16W).

[0101] BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; IVT = intravitreal; PTI = individualized treatment interval; Q8W = every 8 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; W = week.

[0102] Figure 2 : Figure 2 An overview of the study design for DME

[0103] Patients randomized to Group A will receive 6 mg IVT RO6867461 (Fariximab) injections (Q4W) until Week 20, followed by 6 mg IVT RO6867461 (Fariximab) injections (Q8W) until Week 96, followed by a final study visit at Week 100.

[0104] Patients randomized to Arm B (Personalized Treatment Interval PTI) will receive 6 mg IVT RO6867461 (fariximab) injections (Q4W) until at least Week 12, followed by PTI dosing (see PTI dosing criteria below), 6 mg IVT RO6867461 (fariximab) injections until Week 96, followed by a final study visit at Week 100.

[0105] Patients randomized to Group C will receive 2 mg IVT aflibercept injection (Q4W) until Week 16, followed by 2 mg IVT aflibercept injection (Q8W) until Week 96, followed by a final study visit at Week 100.

[0106] Patients in all three treatment groups will complete scheduled study visits Q4W throughout the duration of the study (100 weeks). Patients in all three treatment groups will undergo sham procedures at applicable visits to maintain masking between treatment groups.

[0107] IVT = intravitreal; Q8W = every 8 weeks; PTI = individualized treatment interval (see section 3.1.2 for further details); W = week.

[0108] aThe 1-year definition for the primary efficacy endpoint—defined as the change from baseline in BCVA as measured on the ETDRS chart at a starting distance of 4 meters at 1 year—was the average of the Week 48, 52, and 56 visits.

[0109] Figure 3 :DME personalized treatment interval diagram - Figure 3 An algorithm for interval decision making based on relative changes in CST and BCVA compared with reference CST and reference BCVA is outlined.

[0110] Figure 3 The meaning of * and ** in Chinese:

[0111] *Reference Central Subfield Thickness (CST): The CST value at which the initial CST threshold criteria are met. If the CST at two consecutive study drug administration visits decreases by >10% from the previous reference CST and the values ​​obtained are within 30 μm, the reference CST is adjusted. Immediately starting from that visit, the CST value obtained at the latter visit will be used as the new reference CST.

[0112] ** Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[0113] Figure 4 : Based on published results (comparison of drug (Ranibizumab), Schematic comparison of durability (time to re-treatment) and efficacy (DME) of other treatment options for DME and nAMD, including aflibercept, brolucizumab, and VA2 (RO6867461 / fariximab).

[0114] Figure 5 : Comparison of the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) (12 and 16 weeks interval) and ranibizumab (4-week intervals), BCVA increased relative to baseline in patients with neovascular age-related macular degeneration (nAMD).

[0115] Figure 6: Time to necessary retreatment for diabetic macular edema (DME) based on disease activity assessed by two assessments: BCVA decrease of ≥5 letters, CST increase of ≥50 μm after cessation of dosing (after 20 weeks or 6 months dosing = time after last intravitreal (IVT) administration). Bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) versus ranibizumab In comparison, longer time to retreatment has been shown to be required.

[0116] Figure 7 : Figure 1 An overview of the study design for the treatment of macular edema secondary to retinal vein occlusion (RVO)

[0117] IVT = intravitreal; PTI = individualized treatment interval; Q4W = every 4 weeks; W = week

[0118] Figure 8 : Schematic diagram of personalized treatment intervals for the treatment of macular edema secondary to retinal vein occlusion (RVO) - Figure 8 An algorithm for interval decision making based on relative changes in CST and BCVA compared with reference CST and reference BCVA is outlined.

[0119] BCVA = best corrected visual acuity; CST = central subfield thickness; Q4W = every 4 weeks.

[0120] aInitial reference CST = CST value at which the initial CST threshold criteria are met, but no earlier than Week 20. If the CST decreases by >10% from the previous reference CST at two consecutive fariximab dosing visits and the values ​​obtained are within 30 μm, the reference CST is adjusted. Immediately starting from that visit, the CST value obtained at the subsequent visit will be used as the new reference CST.

[0121] b Reference BCVA = the average of the three best BCVA scores obtained at any prior dosing visit. DETAILED DESCRIPTION

[0122] Methods, uses, bispecific antibodies, drugs or pharmaceutical preparations for treating ocular vascular diseases selected from nAMD and DME include sequential administration of initial doses ("treatment start"). In some embodiments, the initial dose can vary, for example, 3 to 7 administrations per month; in one embodiment, treatment start includes 3 to 4 months of administration, in one embodiment, treatment start includes 4 to 5 months of administration; in one embodiment, treatment start includes 4 to 6 months of administration; in one embodiment, treatment start includes at least 4 months of administration; in one embodiment, treatment start includes 5 to 7 months of administration, in one embodiment, treatment start includes 6 months of administration.

[0123] In one embodiment of the invention, the bispecific antibody, medicament or pharmaceutical formulation is administered at a dose of about 5 to 7 mg (at each treatment). In one embodiment, the bispecific antibody is administered at a dose of 6 mg + / - 10% (at each treatment). In one embodiment, the bispecific antibody is administered at a dose of about 6 mg (at each treatment) (in one embodiment at a dose of 6 mg (at each treatment)).

[0124] In one embodiment of the invention, the bispecific antibody, medicament or pharmaceutical formulation is administered at a concentration of about 120 mg / ml (+ / - 12 mg / ml) of the bispecific antibody.

[0125] Macular degeneration is a medical disease, primarily seen in older people, in which the center of the inner layer of the eye (an area called the macula of the retina) thins, shrinks, and in some cases bleeds. The disease can lead to a loss of central vision, resulting in an inability to see fine detail, read, or recognize faces. According to the American Academy of Ophthalmology, the disease is currently the leading cause of central vision loss (blindness) in people over the age of 50 in the United States. Although certain macular dystrophies that affect younger people are sometimes referred to as macular degeneration, the term usually refers to age-related macular degeneration (AMD or ARMD).

[0126] As used herein, "age-related macular degeneration (AMD)" refers to a serious eye disease when the small central part of the retina (called the macula) degenerates. AMD includes wet AMD and neovascular AMD. The wet form of AMD (wet AMD (wAMD) is also called neovascular AMD (nAMD)) is characterized by the growth of abnormal blood vessels in the choroid below the macula. This is called choroidal neovascularization. These blood vessels cause blood and fluid to leak into the retina (below and), resulting in (retinal elevation and) visual distortion, making straight lines look wavy, as well as blind spots and central vision loss. These abnormal blood vessels eventually form scars, resulting in permanent central vision loss. The symptoms of AMD include dark, blurred areas in the center of vision; and color vision is weakened or changed. AMD can be detected in a routine ophthalmological examination. One of the most common early symptoms of macular degeneration is the appearance of drusen, which is a tiny yellow deposit and pigment agglomeration under the retina.

[0127] There are two forms of advanced AMD that lead to severe vision loss: dry and wet. Central geographic atrophy is the dry form of advanced AMD, caused by atrophy of the retinal pigment epithelium beneath the retina, leading to vision loss through the loss of photoreceptors (rods and cones) in the central part of the eye. While there is no treatment for this condition, the National Eye Institute and others have shown that vitamin supplements containing high doses of the antioxidants lutein and zeaxanthin can slow the progression of dry macular degeneration and improve vision in some patients.

[0128] As used herein, "diabetic macular edema" (DME) refers to a serious eye disease that affects diabetic patients (type 1 or type 2). When blood vessels in the retina leak into the macula and fluid and protein deposits accumulate above or below the macula of the eye and cause thickening and swelling (edema), macular edema occurs. Since the macula is located near the center of the retina at the back of the eyeball, swelling may distort the central vision of the person. The main symptoms of DME include, but are not limited to, blurred vision, floating, contrast loss, diplopia, and eventual vision loss. The pathological characteristics of DME are the destruction of the blood-retinal barrier (which normally prevents the movement of fluid in the retina), so that fluid accumulates in the retinal tissue, and retinal thickening occurs. DME is currently diagnosed in an eye examination, which consists of a visual acuity test (determining the smallest letter a person can read on a standard chart), a dilated eye examination (for checking the symptoms of the disease), an imaging examination (such as optical coherence tomography (OCT) or fluorescein angiography (FA)) and a tonometer (an instrument for measuring intraocular pressure). The following studies are also performed to determine treatment methods: optical coherence tomography (OCT), fluorescein angiography, and color stereo fundus photography. DME can be roughly divided into two main categories: focal DME and diffuse DME. Focal DME is characterized by the presence of specific areas of separation and obvious leakage in the macular area, where the macular blood flow is sufficient. Diffuse DME is caused by leakage of the entire capillary bed surrounding the macula, and this leakage is caused by the breakdown of the blood-retinal barrier inside the eye. In addition to focal DME and diffuse DME, DME is also divided into clinically significant macular edema (CSME), non-CSME, and centrally involved CSME (CSME-CI, which involves the fovea) based on clinical examination results. The present invention includes methods for treating the above-mentioned categories of DME.

[0129] Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases and is associated with varying degrees of vision loss (Hayreh and Zimmerman 1994). It is reported that RVO is the second leading cause of blindness in patients with retinal vascular diseases after diabetic retinopathy (DR) (Cugati S, Wang JJ, Rochtchina E et al., Arch Ophthalmol 2006; 124: 726-732; Klein R, Knudtson MD, Lee KE et al., Ophthalmology 2008; 115: 1859-1868; Rogers S, McIntosh RL, Cheung N et al., Ophthalmology 2010 Feb; 117: 313-9.e1; Yasuda M, Kiyohara Y, Arakawa S et al., Invest Ophtahlmol Vis Sci 2010; 51: 3205-3209).

[0130] The main types of RVO include branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). The most common complaint of RVO is an acute, painless loss of central vision due to macular edema.

[0131] The main types of macular edema secondary to RVO include macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), and macular edema secondary to central retinal vein occlusion (CRVO).

[0132] Rarely, patients may have a history of transient vision loss that lasts from a few seconds to a few minutes before full recovery of vision. These symptoms may recur over days to weeks, followed by permanent loss of vision. Metamorphopsia and visual field loss have also been described (Achiron A, Lagstein O, Glick M, et al., Acta Ophthalmologica 2015;93:e649-53; Manabe K, Osaka R, Nakano Y, et al., PLoS One 2017;12:e0186737).

[0133] The pathogenesis of macular edema in these patients begins with an increase in intraluminal pressure caused by vascular occlusion, which leads to decreased perfusion and ischemia in the area. Ischemia leads to upregulation and secretion of vascular endothelial growth factor (VEGF) (Boyd SR, Zachary I, Chakravarthy U et al., Arch Ophthalmol 2002; 12: 1644-1650; Noma H, Minamoto A, Funatsu H et al., Graefes Arch Clin Exp Ophthalmol 2006; 244: 309-315) and angiopoietin-2 (Ang-2), both of which are well-known pro-angiogenic and vascular hyperpermeability cytokines and Ang-2 contributes additional pro-inflammatory and vascular destabilizing properties (Maisonpierre PC, Suri C, Jones PF et al., Science 1997; 277: 55-60; Hackett SF, Ozaki H, Strauss RW et al., J Cell Physiol 2000; 184: 275-284; Fiedler U, Reiss Y, Scharpfenecker M et al., Nat Med 2006; 234: 235-236). 2006;12:235-239, Epub:2006 Feb 5). It has been found that RVO patients have the highest vitreous levels of Ang-2 and VEGF of all retinal vascular diseases (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994;331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288). Elevated levels of Ang-2 and VEGF in retinal tissue lead to pathological changes in the retina and, in many patients, macular edema with decreased vision. A hallmark of RVO is a characteristic pattern of retinal hemorrhages, tortuosity and dilation of retinal veins in the affected area of ​​the retina (one quadrant in BRVO, two quadrants in HRVO, and the entire retina in CRVO). In more severe cases, patients develop retinal ischemia, followed by retinal neovascularization, hemorrhage, anterior segment neovascularization leading to erythema or neovascular glaucoma, and some patients may develop optic disc edema.

[0134] Although macular edema due to RVO and diabetic macular edema (DME) have different origins, they share a common pathophysiology. Both are characterized by macular thickening due to fluid accumulation caused by disruption of the blood-retinal barrier and pathological increase in retinal vascular permeability, which may lead to irreversible vision loss in both diseases.

[0135] Anti-VEGF drug therapy is currently the mainstay of treatment for macular edema due to RVO and has demonstrated efficacy in several pivotal randomized clinical studies, although in some cases, macular laser and intravitreal (IVT) steroids - particularly steroid implants - are also used. Although anti-VEGF is the most effective therapy for the treatment of macular edema due to RVO, data from anti-VEGF clinical trials indicate that many patients do not achieve optimal best corrected visual acuity (BCVA) and anatomic outcomes, and that many patients require frequent, long-term injections to maintain gains achieved during initial intensive treatment. Furthermore, real-world data analyses suggest that many RVO patients fail to achieve the gains seen in clinical trials due to suboptimal injection frequency (Vaz-Pereira, S, Marques IP, Matias J et al., Eur J Ophthalmol 2017;27:756-761; Wecker T, Ehlken C, Buhler A et al., Br J Ophthalmol 2017;101:353-359; Jumper JM, Dugel PU, Chen S et al., Clin Ophthalmol 2018;12:621-629). Data suggest that many patients with macular edema due to BRVO and most patients with macular edema due to CRVO require closer monitoring and treatment for a longer period of time as well as a more durable and effective treatment regimen (Bhisitkul RB, Campochiaro PA, Shapiro H, et al., Ophthalmology 2013;120:1057-1063; Scott IU, Neal NL, Van Veldhuisen, et al., JAMA Ophthalmol 2019;E1-E10).

[0136] Nonclinical studies have shown that in vitro, Ang-2 and VEGF act synergistically to modulate the vasculature and increase retinal endothelial cell permeability. In a laser-induced CNV model in non-human primates, simultaneous inhibition of Ang-2 and VEGF using the bispecific monoclonal antibody faricimab resulted in greater reductions in leakage and severity of choroidal neovascularization (CNV) lesions compared with molar equivalents of anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a spontaneous CNV mouse model showed that dual inhibition of Ang-2 and VEGF consistently outperformed monotherapy inhibition of either target alone in terms of reductions in vessel growth, leakage, edema, leukocyte infiltration, and photoreceptor loss (Regula JT, Lundh vonLeithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288).

[0137] In addition, aqueous and vitreous concentrations of Ang-2 and VEGF are upregulated in patients with neovascular age-related macular degeneration (nAMD), DR, and RVO (Tong JP, Chan WM, Liu DT, et al., Am J Ophthalmol 2006; 141:456-462; Penn JS, Madan A, Caldwell RB, et al., Prog Retin Eye Res 2008; 27:331-371.; Kinnunen K ...141:456-462. T, M et al., Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S, Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh vonLeithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288; Ng DS, Yip YW, Bakthavatsalam M et al., Sci Rep 2017;7:45081). Therefore, simultaneous neutralization of both targets, Ang-2 and VEGF, may further normalize pathological ocular vasculature compared to anti-VEGF therapy alone. Data from completed Phase II studies in DME and nAMD (see below) also support the hypothesis that targeting Ang-2 has the potential to extend the durability of the effect beyond anti-VEGF therapy alone in diseases affecting the retinal vasculature.

[0138] Faricimab has been studied for the treatment of nAMD and DME in two Phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME). Four global Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) in DME and GR40306 (TENAYA) and GR40844 (LUCERNE) in nAMD.

[0139] Based on the mechanism of action of faricimab, nonclinical and clinical trial data, and the pathophysiology of macular edema caused by RVO, we hypothesized that faricimab may cause stabilization of the pathological ocular vasculature and improve visual and anatomical outcomes in RVO compared with anti-VEGF monotherapy.

[0140] Macular edema secondary to / due to RVO is the most common retinal vascular disease (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994; 331: 1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016; 8: 1265-1288). The effects of Ang-2 and VEGF inhibition in nonclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288) and from phase I and phase II studies of faricimab in patients with nAMD and DME provide evidence of efficacy against common pathological pathways in all three retinal vascular diseases: nAMD, DME / DR, and macular edema due to RVO (phase I study BP28936 in nAMD; phase II studies AVENUE in nAMD, STAIRWAY in nAMD, and BOULEVARD in DME).

[0141] Because of the pathophysiological similarities between DME and macular edema due to RVO, data from the phase II BOULEVARD study are reported here. Although the triggers of macular edema in patients with diabetes and RVO are different, the downstream pathophysiology of hypoxia-induced macular edema and subsequent vision loss is similar and driven by the same proangiogenic, proinflammatory, vascular instability, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6). The BOULEVARD study provides preliminary evidence of a positive benefit-risk profile for the use of 6 mg IVT injections of faricimab in patients with DME and supports further evaluation of faricimab in a phase III DME study. The study met its primary efficacy endpoint, demonstrating a statistically significant improvement in mean change from baseline in BCVA at week 24 in patients not receiving anti-VEGF therapy who received 6 mg of faricimab compared with 0.3 mg of ranibizumab. Best corrected visual acuity (BCVA) is determined using a method adapted from the 4-meter Early Treatment Diabetic Retinopathy Study [ETDRS] protocol (using the Early Treatment Diabetic Retinopathy Study (ETDRS), as shown in the chart) and deriving a corresponding letter score. In one embodiment, the BCVA determination in such method, use, bispecific antibody (applied), medicament or pharmaceutical formulation is based on an eye chart adapted from the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and is assessed at a starting distance of 4 meters.

[0142] Disease activity is determined, for example, by a decrease in BCVA / ETDR letter scores and / or macular thickening, for example, by spectral domain optical coherence tomography (SD-OCT), involving the center of the macula, such as central subfield thickness (CST) (also known as subfoveal thickness). In a preferred embodiment, central subfield thickness (CST) is determined using spectral domain optical coherence tomography (SD-OCT): In a preferred embodiment, CST is measured by Spectralis TM The CST is measured by spectral domain optical coherence tomography (SD-OCT) of the device; in a preferred embodiment, CST is measured by Cirrus TM The CST is measured by spectral domain optical coherence tomography (SD-OCT) of the device; in one embodiment, the CST is measured by Topcon TM The CST is measured by spectral domain optical coherence tomography (SD-OCT) of the device; in one embodiment, the CST is measured by Optovue TMThe spectral domain optical coherence tomography (SD-OCT) of the device is measured. As used herein, the term "patient suffering from..." refers to a person who exhibits one or more symptoms or indications and / or has been diagnosed with an ocular vascular disease as described herein. The term "patient suffering from..." may also include, for example, a person who exhibits (or has exhibited) one or more indications of vascular eye disease before treatment, such as, for example, retinal angiogenesis, neovascularization, vascular leakage, retinal thickening in the center of the fovea, retinal thickening in the center of the fovea with adjacent retinal thickening and retinal thickening in at least 1 optic disc area (any part of which is within 1 optic disc diameter of the center of the fovea), hard yellow exudate in the center of the fovea, blurred vision, floaters, loss of contrast, diplopia, and final vision loss.

[0143] As used herein, the term "patient suffering from" an ocular vascular disease (e.g., nAMD or DME) may include a subset of the population that is more sensitive to nAMD or DME or may show elevated levels of nAMD-related or DME-related biomarkers. For example, a "patient suffering from DME" may include a subject who has had diabetes for more than 10 years, frequently experiences high blood glucose levels or high fasting blood glucose levels. In certain embodiments, the term "patient suffering from DME" includes a subject who suffers from or is diagnosed with diabetes prior to or at the time of administration of a bispecific anti-VEGF / ANG2 antibody. In certain embodiments, the term "patient suffering from nAMD" includes a subject who is over 50 years old prior to or at the time of administration of an anti-VEGF / ANG2 antibody. In some embodiments, the term "patient suffering from..." includes a smoker or a subject suffering from high blood pressure or high cholesterol.

[0144] As used herein, the term "patients suffering from" an ocular vascular disease, e.g., macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemi-retinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO) may include a subset of the population that is more susceptible to developing macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemi-retinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO) or may show elevated levels of RVO-related biomarkers. For example, "patients suffering from RVO or macular edema secondary to RVO" may include subjects with elevated levels of VEGF, ANG2, or IL-6. In some embodiments, the term "patients suffering from..." includes smokers or subjects suffering from high blood pressure or high cholesterol. The present invention includes a method or (use of) a bispecific antibody, a medicament or a pharmaceutical formulation for treating, preventing or reducing the severity of an ocular vascular disease, comprising administering a therapeutically effective amount of a bispecific anti-VEGF / ANG2 antibody (or a medicament or a pharmaceutical formulation comprising a bispecific anti-VEGF / ANG2 antibody) to a subject in need thereof, wherein the bispecific antibody, medicament or pharmaceutical formulation comprising such bispecific anti-VEGF / ANG2 antibody is administered to the subject (intravitreally) in multiple doses, e.g., as part of a specific treatment dosing regimen.

[0145] One embodiment of the invention is a method of treatment, a use, a bispecific antibody, a medicament or a pharmaceutical formulation as described herein, wherein the patient suffering from an ocular vascular disease has not been previously treated (is treatment naive) with an anti-VEGF therapy (e.g., monotherapy).

[0146] One embodiment of the invention is a method of treatment, a use, a bispecific antibody, a medicament or a pharmaceutical formulation as described herein, wherein the patient suffering from an ocular vascular disease has previously been treated with an anti-VEGF therapy (e.g., as a monotherapy, e.g., with Ranibizumab, Aflibercept or Brolocizumab).

[0147] One embodiment of the present invention is a method, use, bispecific antibody, medicament or pharmaceutical formulation for treating a patient with neovascular AMD (nAMD), the method comprising administering to the patient an effective amount of a bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval, wherein

[0148] a) Patients first received 4 doses of the bispecific

[0149] Treatment with VEGF / ANG2 antibodies;

[0150] b) At Weeks 20 and 24, disease activity was assessed, whereby disease activity was determined if one of the following criteria was met:

[0151] i) Increase in central subfield thickness (CST) compared to the average CST value of the first two planned examinations

[0152] >50 μm, where the scheduled visits at weeks 12 and 16 are used for the week 20 assessment, and the scheduled visits at weeks 16 and 20 are used for the week 24 assessment, or ii) CST increases by ≥75 μm compared with the lowest CST value recorded at any of the first two scheduled visits;

[0153] iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the average BCVA of the two previous scheduled visits due to nAMD disease activity,

[0154] iv) a decrease in BCVA of ≥10 letters compared with the highest BCVA value recorded at either of the first two scheduled visits due to nAMD disease activity, or

[0155] v) New macular hemorrhages due to nAMD activity

[0156] c) Then, the patient

[0157] i) Patients who meet disease activity criteria at week 20 will be followed by

[0158] (Q8W) dosing interval (first Q8W dose at week 20);

[0159] ii) Patients who meet disease activity criteria at week 24 will be treated with

[0160] Treatment was given at a 12-week (Q12W) dosing interval (with the first Q12W dose at Week 24); and

[0161] iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval starting from Week 28 (with the first Q16W dose at Week 28).

[0162] In one embodiment, the personalized treatment interval will be extended, shortened, or maintained after week 60, wherein

[0163] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0164] Q16W):

[0165] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0166] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0167] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0168] No decrease in BCVA of ≥10 letters,

[0169] iii) no new macular hemorrhage;

[0170] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0171] or

[0172] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0173] i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits, or CST increase of ≥75 μm compared to the lowest dosing visit measurement,

[0174] ii) a decrease in BCVA of ≥5 letters compared to the average of the two most recent dosing visits; or

[0175] A decrease in BCVA of ≥10 letters compared with the highest dosing exam measurement,

[0176] iii) New macular hemorrhage.

[0177] In one embodiment, disease activity assessments prior to the personalized treatment interval will be at weeks 16 and 20, or at weeks 24 and 28.

[0178] In one embodiment, the personalized treatment interval that is further extended, shortened or maintained will be started at different time points depending on disease activity, for example, between weeks 50 and 70, for example, after week 52 or after week 65. Another embodiment of the present invention is a method, use, bispecific antibody, medicament or pharmaceutical formulation for treating a patient with diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), using a personalized treatment interval, wherein

[0179] a) patients initially received treatment with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval until the central subdomain thickness (CST) reached a predetermined reference CST threshold (CST < 325 μm for Spectralis SD-OCT, or < 315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured at or after Week 12);

[0180] b) Then, increase the dosing interval by 4 weeks to an initial Q8W dosing interval;

[0181] c) From this point on, the dosing interval is extended, shortened, or maintained based on the assessment performed at the dosing visit, which is based on CST and best corrected visual acuity (BCVA)

[0182] relative changes compared with the corresponding reference CST and BCVA;

[0183] in

[0184] i) The said interval is extended by 4 weeks in the following cases:

[0185] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA

[0186] ≥10 letters;

[0187] ii) The interval will be maintained if:

[0188] - If the CST decreases by >10%, or

[0189] - If the CST value increases or decreases by ≤10% with an associated decrease in BCVA

[0190] ≥10 letters; or

[0191] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0192] iii) The interval is shortened by 4 weeks in the following cases:

[0193] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0194] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0195] iv) if the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks;

[0196] wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and

[0197] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0198] In one embodiment, such dosing intervals can be adjusted by 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0199] Another embodiment of the present invention is a method, a use, a bispecific antibody (for use), a medicament or a pharmaceutical formulation for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, or treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI), wherein

[0200] a) Patients were first treated with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval from day 1 to week 20

[0201] b) Starting from Week 24, patients received the bispecific VEGF / ANG2 antibody Q4W until the central subdomain thickness (CST) reached the pre-defined reference CST threshold (CST <325 μm for Spectralis SD-OCT, or <315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured on or after Week 24);

[0202] c) extending, shortening, or maintaining the dosing interval from this time point onwards based on the assessment performed at the dosing visit, which is based on the relative change in CST and best-corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0203] in

[0204] i) The interval is extended by 4 weeks in the following cases

[0205] If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters; or

[0206] ii) The interval is maintained if any of the following criteria is met:

[0207] If the CST value decreases by >10%; or

[0208] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0209] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0210] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0211] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0212] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or

[0213] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0214] iv) In the following cases, the interval is shortened to Q4W

[0215] If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters,

[0216] wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and

[0217] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0218] In one embodiment, such dosing intervals can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W by 4-week increments. As used herein, "antibody" refers to a binding protein comprising an antigen binding site. As used herein, the term "binding site" or "antigen binding site" refers to one or more regions of an antibody molecule to which a ligand actually binds. The term "antigen binding site" comprises an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) (VH / VL pairs).

[0219] Antibodies specifically refer to the selective recognition of a specific epitope of an antigen by an antibody. For example, natural antibodies are monospecific.

[0220] According to the present invention, a "bispecific antibody" is an antibody with two different antigen binding specificities. The antibody of the present invention has specificity for two different antigens, wherein VEGF is the first antigen and ANG-2 is the second antigen.

[0221] As used herein, the term "monospecific" antibody refers to an antibody that has one or more binding sites that each bind to the same epitope of the same antigen.

[0222] The term "valency" as used in this application indicates the presence of a specified number of binding sites in an antibody molecule. Thus, the terms "bivalent", "tetravalent" and "hexavalent" indicate the presence of two binding sites, four binding sites and six binding sites in an antibody molecule, respectively. The bispecific antibody according to the present invention is preferably "bivalent".

[0223] As used herein, the terms "bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), "bispecific anti-VEGF / ANG2 antibody" and "bispecific <vegf ang2>"Antibody" are used interchangeably and refer to an antibody that has at least two different antigen binding sites, a first antigen binding site that binds to VEGF and a second antigen binding site that binds to ANG2.

[0224] Bispecific anti-VEGF / ANG2 antibodies are described in, for example, WO2010040508, WO2011 / 117329, WO2012 / 131078, WO2015 / 083978, WO2017 / 197199 and WO2014 / 009465. WO2014 / 009465 describes bispecific anti-VEGF / ANG2 antibodies specifically designed for the treatment of ocular vascular diseases. The bispecific anti-VEGF / ANG2 antibodies of WO2014 / 009465 (which is incorporated herein by reference in its entirety) are particularly suitable for the treatment of ocular vascular diseases as described herein and treatment regimens thereof.

[0225] In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein

[0226] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0227] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0228] And among them

[0229] iii) The bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index).

[0230] In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are bivalent.

[0231] In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are characterized by:

[0232] i) the first antigen binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain VL, and

[0233] ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain VL.

[0234] In one aspect of the invention, such bispecific bivalent antibody according to the invention is characterized in that it comprises:

[0235] a) a heavy chain and a light chain of a first full-length antibody that specifically binds to VEGF;

[0236] b) A modified heavy chain and a modified light chain of a second full length antibody specifically binding to ANG-2, wherein the constant domains CL and CH1 are replaced with each other.

[0237] This bispecific, bivalent antibody format of a bispecific antibody specifically binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is described in WO 2009 / 080253 (comprising a CH3 domain modified with a knob-in-hole structure). Antibodies based on this bispecific, bivalent antibody format are called CrossMAbs.

[0238] In one embodiment, such bispecific, bivalent anti-VEGF / ANG2 antibody is characterized in comprising:

[0239] a) a heavy chain of a first full-length antibody having the amino acid sequence of SEQ ID NO: 17, and a light chain of a first full-length antibody having the amino acid sequence of SEQ ID NO: 18; and

[0240] b) a modified heavy chain of a second full length antibody having the amino acid sequence of SEQ ID NO: 19, and a modified light chain of a second full length antibody having the amino acid sequence of SEQ ID NO: 20.

[0241] In one embodiment, such bispecific, bivalent anti-VEGF / ANG2 antibody is characterized by comprising the amino acid sequence of SEQ ID NO: 17, the amino acid sequence of SEQ ID NO: 18, the amino acid sequence of SEQ ID NO: 19, and the amino acid sequence of SEQ ID NO: 20. In a preferred embodiment, such bispecific, bivalent anti-VEGF / ANG2 antibody is fariximab.

[0242] Therefore, one embodiment of the present invention is a bispecific bivalent antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, the bispecific bivalent antibody being characterized by comprising the amino acid sequence of SEQ ID NO: 17, the amino acid sequence of SEQ ID NO: 18, the amino acid sequence of SEQ ID NO: 19, and the amino acid sequence of SEQ ID NO: 20. In a preferred embodiment, such bispecific bivalent anti-VEGF / ANG2 antibody is fariximab.

[0243] In one embodiment, the CH3 domain of the bispecific bivalent antibody according to the present invention is altered by the "knob-into-holes" technology, which is described in detail with several examples in, for example, WO 96 / 027011, Ridgway, JB et al., Protein Eng 9 (1996) 617-621 and Merchant, AM et al., Nat Biotechnol. 16 (1998) 677-681. In this method, the interaction surfaces of the two CH3 domains are altered to increase the heterodimerization of the two heavy chains comprising the two CH3 domains. One of the two CH3 domains (of the two heavy chains) can be a "knob" and the other a "hole". The introduction of disulfide bridges stabilizes the heterodimers (Merchant, AM et al., Nature Biotech 16 (1998) 677-681; Atwell, S. et al., J. Mol. Biol. 270 (1997) 26-35) and improves the yield.

[0244] In a preferred aspect of the present invention, the bispecific anti-VEGF / ANG2 antibody according to the present invention is characterized in that

[0245] The CH3 domain of one heavy chain meets the CH3 domain of the other heavy chain each at an interface that comprises the initial interface between antibody CH3 domains;

[0246] wherein the interface is altered to facilitate formation of a bispecific antibody, wherein the alteration is characterized by:

[0247] a) the CH3 domain of one heavy chain is altered,

[0248] so that within the initial interface where the CH3 domain of one heavy chain meets the initial interface of the CH3 domain of the other heavy chain within the bispecific antibody,

[0249] The amino acid residue is substituted with an amino acid residue having a larger side chain volume, thereby generating a protrusion within the interface of the CH3 domain of one heavy chain, which protrusion can be positioned in a cavity within the interface of the CH3 domain of the other heavy chain;

[0250] and

[0251] b) the CH3 domain of the other heavy chain is altered,

[0252] so that within the initial interface of the second CH3 domain that meets the initial interface of the first CH3 domain within the bispecific antibody,

[0253] The amino acid residues are substituted with amino acid residues having smaller side chain volumes, thereby generating a cavity within the interface of the second CH3 domain, which cavity can be positioned in the protrusion within the interface of the first CH3 domain.

[0254] Therefore, the bispecific anti-VEGF / ANG2 antibodies as described herein are preferably characterized in that

[0255] the CH3 domains of the heavy chain of the full length antibody of a) and the CH3 domains of the heavy chain of the full length antibody of b) each meet at an altered interface comprising the original interface between the antibody CH3 domains;

[0256] wherein i) in the CH3 domain of a heavy chain

[0257] The amino acid residue is substituted with an amino acid residue having a larger side chain volume, thereby generating a protrusion within the interface of the CH3 domain of one heavy chain, which protrusion can be positioned in a cavity within the interface of the CH3 domain of the other heavy chain;

[0258] And among them

[0259] ii) in the CH3 domain of another heavy chain

[0260] The amino acid residues are substituted with amino acid residues having smaller side chain volumes, thereby generating a cavity within the interface of the second CH3 domain, which cavity can be positioned in the protrusion within the interface of the first CH3 domain.

[0261] Preferably, the amino acid residue with a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y) and tryptophan (W).

[0262] Preferably, the amino acid residue with a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T) and valine (V).

[0263] In one aspect of the present invention, the two CH3 domains are further altered by introducing cysteine ​​(C) as an amino acid at the corresponding position of each CH3 domain, so that a disulfide bond can be formed between the two CH3 domains.

[0264] In one embodiment, the bispecific antibody comprises a T366W mutation in the CH3 domain of the "knob chain" and a T366S, L368A, Y407V mutation in the CH3 domain of the "hole chain". Additional interchain disulfide bridges between CH3 domains may also be used (Merchant, AM et al., Nature Biotech 16 (1998) 677-681), for example, by introducing an S354C mutation into one CH3 domain and a Y349C mutation into another CH3 domain.

[0265] In another preferred embodiment, the bispecific antibody comprises S354C and T366W mutations in one of the two CH3 domains and Y349C, T366S, L368A, Y407V mutations in the other of the two CH3 domains. In another preferred embodiment, the bispecific antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains (the additional Y349C or S354C mutation in one CH3 domain and the additional S354C or Y349C mutation in the other CH3 domain form an interchain disulfide bond), wherein the mutations are numbered according to the Kabat EU index (Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

[0266] Other CH3 modification techniques for implementing heterodimerization are contemplated as alternatives to the present invention and are described, for example, in WO 96 / 27011, WO 98 / 050431, EP 1870459, WO 2007 / 110205, WO 2007 / 147901, WO 2009 / 089004, WO 2010 / 129304, WO 2011 / 90754, WO 2011 / 143545, WO 2012 / 058768, WO 2013 / 157954 and WO 2013 / 096291.

[0267] In one embodiment, the heterodimerization method described in EP 1 870 459A1 is used alternatively. The method is based on the substitution / mutation of charged amino acids with opposite charges introduced at specific amino acid positions at the CH3 / CH3 domain interface between the two heavy chains. A preferred embodiment of the multispecific antibody is the amino acid R409D and K370E mutations in the CH3 domain of one heavy chain of the multispecific antibody and the amino acid D399K and E357K mutations in the CH3 domain of another heavy chain (numbered according to the Kabat EU index).

[0268] In another embodiment, the multispecific antibody comprises an amino acid T366W mutation in the CH3 domain of the "knob chain" and amino acid T366S, L368A and Y407V mutations in the CH3 domain of the "hole chain"; and further comprises amino acid R409D and K370E mutations in the CH3 domain of the "knob chain" and amino acid D399K and E357K mutations in the CH3 domain of the "hole chain".

[0269] In one embodiment, the heterodimerization method described in WO2013 / 157953 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366K mutation, and the CH3 domain of another heavy chain comprises an amino acid L351D mutation. In another embodiment, the CH3 domain of one heavy chain further comprises an amino acid L351K mutation. In another embodiment, the CH3 domain of another heavy chain further comprises an amino acid mutation selected from Y349E, Y349D and L368E (in one embodiment, L368E).

[0270] In one embodiment, the heterodimerization method described in WO2012 / 058768 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises amino acid L351Y and Y407A mutations, and the CH3 domain of another heavy chain comprises amino acid T366A and K409F mutations. In another embodiment, the CH3 domain of another heavy chain further comprises amino acid mutations at positions T411, D399, S400, F405, N390 or K392. In one embodiment, the amino acid mutation is selected from the group consisting of:

[0271] a) T411N, T411R, T411Q, T411K, T411D, T411E and T411W,

[0272] b)D399R, D399W, D399Y and D399K,

[0273] c) S400E, S400D, S400R and S400K,

[0274] d)F405I, F405M, F405T, F405S, F405V and F405W,

[0275] e) N390R, N390K and N390D,

[0276] f) K392V, K392M, K392R, K392L, K392F and K392E.

[0277] In another embodiment, the CH3 domain of one heavy chain comprises amino acid L351Y and Y407A mutations, and the CH3 domain of the other heavy chain comprises amino acid T366V and K409F mutations. In another embodiment, the CH3 domain of one heavy chain comprises amino acid Y407A mutation, and the CH3 domain of the other heavy chain comprises amino acid T366A and K409F mutations. In another embodiment, the CH3 domain of the other heavy chain further comprises amino acid K392E, T411E, D399R and S400R mutations.

[0278] In one embodiment, the heterodimerization method described in WO2011 / 143545 is used instead.In one embodiment, the amino acid modification according to WO2011 / 143545 is introduced into the following position in the CH3 domain of the heavy chain, the position being selected from the group consisting of 368 and 409.

[0279] In one embodiment, the heterodimerization method described in WO2011 / 090762 is used alternatively, which also uses the above-mentioned knob-in-hole structure technology. In one embodiment, the CH3 domain of one heavy chain comprises the amino acid T366W mutation, and the CH3 domain of the other heavy chain comprises the amino acid Y407A mutation. In one embodiment, the CH3 domain of one heavy chain comprises the amino acid T366Y mutation, and the CH3 domain of the other heavy chain comprises the amino acid Y407T mutation.

[0280] In one embodiment, the multispecific antibody is of IgG2 isotype and alternatively the heterodimerization method described in WO2010 / 129304 is used.

[0281] In one embodiment, the heterodimerization method described in WO2009 / 089004 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid replacement of a negatively charged amino acid pair K392 or N392 (in one embodiment, comprising a glutamic acid (E) or aspartic acid (D) replacement; in another embodiment, comprising a K392D or N392D mutation), and the CH3 domain of the other heavy chain comprises an amino acid replacement of a positively charged amino acid pair D399, E356, D356 or E357 (in one embodiment, comprising a lysine (K) or arginine (R) replacement; in another embodiment, comprising a D399K, E356K, D356K or E357K replacement; and in another embodiment, comprising a D399K or E356K mutation). In another embodiment, the CH3 domain of a heavy chain further comprises an amino acid replacement of a negatively charged amino acid pair K409 or R409 (in one embodiment, comprising a glutamic acid (E) or aspartic acid (D) replacement; in another embodiment, comprising a K409D or R409D mutation). In another embodiment, the CH3 domain of a heavy chain further or alternatively comprises an amino acid replacement of a negatively charged amino acid pair K439 and / or K370 (in one embodiment, a glutamic acid (E) or aspartic acid (D) replacement).

[0282] In one embodiment, the heterodimerization method described in WO2007 / 147901 is used instead.In one embodiment, the CH3 domain of one heavy chain comprises amino acid K253E, D282K and K322D mutations, and the CH3 domain of the other heavy chain comprises amino acid D239K, E240K and K292D mutations.

[0283] In one embodiment, the heterodimerization method described in WO2007 / 110205 is used instead.

[0284] In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein

[0285] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0286] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0287] And among them

[0288] iii) the bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index); and wherein

[0289] iv) in the heavy chain constant region, the T366W mutation is contained in one CH3 domain, and

[0290] The T366S, L368A, Y407V mutations are contained in another CH3 domain (numbering according to the Kabat EU index).

[0291] In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein

[0292] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0293] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0294] And among them

[0295] iii) the bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index); and wherein

[0296] iv) in the heavy chain constant region, S354C and T366W mutations are contained in one CH3 domain, and Y349C, T366S, L368A and Y407V mutations are contained in the other CH3 domain (numbering according to the Kabat EU index).

[0297] In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are bivalent.

[0298] In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are characterized by:

[0299] i) the first antigen binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain VL, and

[0300] ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain VL.

[0301] In one aspect of the invention, such bispecific bivalent antibody according to the invention is characterized in that it comprises:

[0302] a) a heavy chain and a light chain of a first full-length antibody that specifically binds to VEGF;

[0303] b) A modified heavy chain and a modified light chain of a second full length antibody specifically binding to ANG-2, wherein the constant domains CL and CH1 are replaced with each other.

[0304] As used herein, the term "VEGF" refers to human vascular endothelial growth factor (VEGF / VEGF-A) 165-amino acid human vascular endothelial cell growth factor (amino acids 27-191 of the precursor sequence of human VEGF165: SEQ ID NO: 24; amino acids 1-26 represent the signal peptide) and the related 121, 189 and 206 vascular endothelial cell growth factor isoforms, as described in the following documents: Leung, DW et al., Science 246 (1989) 1306-9; Houck et al., Mol. Endocrin. 5 (1991) 1806-1814; Keck, PJ et al., Science 246 (1989) 1309-12; and Connolly, DT et al., J. Biol. Chem. 264 (1989) 20017-24; as well as naturally occurring allelic forms and processed forms of these growth factors. VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors and intraocular diseases (Ferrara, N. et al., Endocr. Rev. 18 (1997) 4-25; Berkman, RA et al., J. Clin. Invest. 91 (1993) 153-159; Brown, LF et al., Human Pathol. 26 (1995) 86-91; Brown, LF et al., Cancer Res. 53 (1993) 4727-4735; Mattern, J. et al., Brit. J. Cancer. 73 (1996) 931-934; and Dvorak, HF et al., Am. J. Pathol. 146 (1995) 1029-1039). VEGF is a homodimeric glycoprotein that has been isolated from a variety of sources and includes a variety of isoforms. VEGF has a highly specific mitogenic activity for endothelial cells. VEGF antagonists / inhibitors inhibit the binding of VEGF to its receptor VEGFR. Known VEGF antagonists / inhibitors include bispecific anti-VEGF / ANG2 antibodies as described in WO2014 / 009465.

[0305] As used herein, the term "ANG-2" refers to human angiopoietin-2 (ANG-2) (alternatively abbreviated as ANGPT2 or ANG2) (SEQ ID NO: 25), which is described in, for example, Maisonpierre, PC et al., Science 277 (1997) 55-60; and Cheung, AH et al., Genomics 48 (1998) 389-91. Angiopoietin-1 (SEQ ID NO: 26) and angiopoietin-2 were found to be ligands for Ties, a family of tyrosine kinases selectively expressed in vascular endothelium (Yancopoulos, GD et al., Nature 407 (2000) 242-48). The angiopoietin family now includes four defined members. Angiopoietin-3 and angiopoietin-4 (Ang-3 and Ang-4) may represent widely different counterparts of the same locus in mice and humans (Kim, I. et al., FEBS Let, 443 (1999) 353-56; Kim, I. et al., J Biol Chem 274 (1999) 26523-28). ANG-1 and ANG-2 were originally identified as agonists and antagonists, respectively, in tissue culture experiments (for ANG-1, see: Davis, S. et al., Cell 87 (1996) 1161-69; for ANG-2, see: Maisonpierre, PC et al., Science 277 (1997) 55-60). All known angiopoietins bind primarily to their receptor TIE2 (SEQ ID NO: 27), and both Ang-1 and Ang-2 bind to TIE2 with an affinity of 3 nM (Kd) (Maisonpierre, PC et al., Science 277 (1997) 55-60). ANG2 antagonists / inhibitors inhibit the binding of ANG2 to its receptor TIE2. Known ANG2 antagonists / inhibitors include bispecific anti-VEGF / ANG2 antibodies as described in WO2014 / 009465.

[0306] The antigen binding site of the bispecific antibodies of the present invention comprises six complementary determining regions (CDRs), which contribute to the affinity of the antigen binding site to varying degrees. There are three heavy chain variable domain CDRs (CDRH1, CDRH2, and CDRH3) and three light chain variable domain CDRs (CDRL1, CDRL2, and CDRL3). The extent of the CDRs and framework regions (FRs) are determined by comparison with a compiled database of amino acid sequences, in which those regions have been defined based on the variability between sequences.

[0307] The antibodies of the invention comprise immunoglobulin constant regions derived from one or more immunoglobulin classes of human origin, wherein such immunoglobulin classes include IgG, IgM, IgA, IgD and IgE classes, and in the case of IgG and IgA, including their subclasses, particularly IgG1 and IgG4.

[0308] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to a preparation of multiple antibody molecules that are identical in their amino acid composition.

[0309] The term "chimeric antibody" refers to an antibody comprising a variable region (i.e., binding region) from one source or species and at least a portion of a constant region derived from a different source or species, which is usually prepared by recombinant DNA technology. Chimeric antibodies comprising a mouse variable region and a human constant region are preferred. Other preferred forms of "chimeric antibodies" encompassed by the present invention are antibodies in which the constant region has been modified or altered relative to the original antibody to produce the properties described in accordance with the present invention, especially with respect to C1q binding and / or Fc receptor (FcR) binding. Such chimeric antibodies are also referred to as "class-switched antibodies". Chimeric antibodies are the product of expressed immunoglobulin genes, which comprise a DNA fragment encoding an immunoglobulin variable region and a DNA fragment encoding an immunoglobulin constant region. Methods for producing chimeric antibodies involve conventional recombinant DNA, and gene transfection techniques are well known in the art. See, for example: Morrison, SL et al., Proc. Natl. Acad. Sci. USA 81 (1984) 6851-6855; US Pat. No. 5,202,238 and US Pat. No. 5,204,244.

[0310] The term "humanized antibody" refers to an antibody in which the framework or "complementarity determining region" (CDR) has been modified to contain CDRs of an immunoglobulin with different specificity compared to the parent immunoglobulin. In a preferred embodiment, the murine CDRs are grafted into the framework region of a human antibody to prepare a "humanized antibody". See, for example: Riechmann, L. et al., Nature 332 (1988) 323-327; and Neuberger, MS et al., Nature 314 (1985) 268-270. Particularly preferred CDRs correspond to those sequences representing the antigens that recognize the above-mentioned chimeric antibodies. Other forms of "humanized antibodies" encompassed by the present invention are those antibodies whose constant regions have been additionally modified or altered relative to the original antibodies to produce the properties according to the present invention, especially with respect to C1q binding and / or Fc receptor (FcR) binding.

[0311] The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies are well known in the art (van Dijk, MA and van de Winkel, JG, Curr. Opin. Chem. Biol. 5 (2001) 368-374). Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable of producing a complete library or specific portions of human antibodies after immunization without producing endogenous immunoglobulins. Transfection of the human germline immunoglobulin gene array in such germline mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits, A. et al., Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A. et al., Nature 362 (1993) 255-258; Bruggemann, M. et al., Year Immunol. 7 (1993) 33-40). Human antibodies can also be produced in phage display libraries (Hoogenboom, HR and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, JD et al., J. Mol. Biol. 222 (1991) 581-597). Human monoclonal antibodies can also be prepared using the techniques of Cole et al. and Boerner et al. (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); and Boerner, P. et al., J. Immunol. 147 (1991) 86-95). As already mentioned for chimeric antibodies and humanized antibodies according to the invention, the term "human antibody" as used herein also includes such antibodies which have been modified in the constant region to produce the properties according to the invention, in particular with respect to C1q binding and / or FcR binding, for example, by "class switching", for example, changes or mutations in the Fc part (e.g., from IgG1 to IgG4 and / or IgG1 / IgG4 mutations).

[0312] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies isolated from host cells (such as NS0 or CHO cells) or from animals (e.g., mice) that have transferred human immunoglobulin genes, or antibodies expressed by transfection into host cells using recombinant expression vectors. Such recombinant antibodies have variable and constant regions in rearranged form. The recombinant antibodies according to the present invention have been subjected to in vivo somatic hypermutation. Therefore, the amino acid sequences of the VH and VL regions of the recombinant antibodies are the following sequences, which, although derived from and related to human germline VH and VL sequences, may not be present in the human antibody germline repertoire in vivo under natural conditions.

[0313] As used herein, "variable domain" (variable domain of light chain (VL), variable domain of heavy chain (VH)) refers to each of a pair of light chain domains and heavy chain domains that are directly involved in the binding of an antibody to an antigen. Human light chain variable domains and heavy chain variable domains have the same general structure, and each domain comprises four framework (FR) regions, whose sequences are widely conserved and connected by three "hypervariable regions" (or complementary determining regions, CDRs). The framework regions adopt a β-sheet conformation, and the CDRs can form loops connecting the β-sheet structures. The CDRs in each chain maintain their three-dimensional structure through the framework regions, and together with the CDRs in the other chain form an antigen binding site. The heavy and light chain CDR3 regions of antibodies play a particularly important role in the binding specificity / affinity of the antibodies according to the present invention, and therefore provide further objects of the present invention.

[0314] As used herein, the terms "hypervariable region" or "antigen-binding portion of an antibody" refer to the amino acid residues in an antibody that are responsible for antigen binding. The hypervariable region comprises amino acid residues from the "complementarity determining regions" or "CDRs". The "framework" or "FR" regions are those variable domain regions other than the hypervariable region residues as defined herein. Thus, the light chain variable domain and the heavy chain variable domain of an antibody comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from N-terminus to C-terminus. The CDRs on each chain are separated by such framework amino acids. In particular, CDR3 of the heavy chain is the region that is most conducive to antigen binding. CDR and FR regions are determined according to the standard definitions of Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

[0315] The term "full-length antibody" refers to an antibody consisting of two "full-length antibody heavy chains" and two "full-length antibody light chains". A "full-length antibody heavy chain" is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant heavy chain domain 1 (CH1), an antibody hinge region (HR), an antibody heavy chain constant domain 2 (CH2), and an antibody heavy chain constant domain 3 (CH3) in the N-terminal to C-terminal direction, abbreviated as VH-CH1-HR-CH2-CH3; if it is an antibody of the IgE subtype, it is optionally composed of an antibody heavy chain constant domain 4 (CH4). Preferably, a "full-length antibody heavy chain" is a polypeptide consisting of VH, CH1, HR, CH2, and CH3 in the N-terminal to C-terminal direction. A "full-length antibody light chain" is a polypeptide consisting of an antibody light chain variable domain (VL) and an antibody light chain constant domain (CL) in the N-terminal to C-terminal direction, abbreviated as VL-CL. The antibody light chain constant domain (CL) may be κ (kappa) or λ (lambda). The two full-length antibody chains are linked together by inter-polypeptide disulfide bonds between the CL domain and the CH1 domain and between the hinge regions of the full-length antibody heavy chains. Examples of typical full-length antibodies are natural antibodies, such as IgG (e.g., IgG1 and IgG2), IgM, IgA, IgD, and IgE. The full-length antibodies according to the present invention can be from a single species, such as humans, or they can be chimeric antibodies or humanized antibodies. The full-length antibodies according to the present invention generally comprise two antigen binding sites, each of which is formed by a pair of VH and VL, both of which specifically bind to the same antigen. The C-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the C-terminus of the heavy or light chain. The N-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the N-terminus of the heavy or light chain.

[0316] The term "constant region" used in this application represents the sum of the antibody domains except the variable region. The constant region does not directly participate in the combination of the antibody and the antigen, but exhibits a variety of effector functions. According to the different amino acid sequences of the constant region of its heavy chain, antibodies are divided into the following categories: IgA, IgD, IgE, IgG and IgM and some of them can be further divided into subclasses, such as IgG1, IgG2, IgG3 and IgG4 and IgA1 and IgA2. The heavy chain constant domains corresponding to different classes of antibodies are respectively referred to as α, δ, ε, γ and μ. The light chain constant regions that can be found in all five antibody classes are referred to as κ (kappa) and λ (lambda).

[0317] As used in the present application, the term "human-derived constant region" or "human constant region" refers to the constant heavy chain region and / or constant light chain kappa or lambda region of a human antibody of subclass IgG1, IgG2, IgG3 or IgG4. Such constant regions are well known in the art and are described, for example, by Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, e.g., Johnson, G., and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA, et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). The European Union numbering system (EU Index) for position and mutation numbering in this application is according to Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Using Public Health Service, National Institutes of Health, Bethesda, MD (1991) and is referred to as "numbering is according to the Kabat EU Index."

[0318] In one embodiment, the bispecific antibody according to the present invention has a constant region of human IgG1 subclass (derived from human IgG1 subclass). However, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and the C-terminal lysine (Lys447) of the Fc region may or may not be present.

[0319] In one embodiment, the bispecific antibody as described herein is of IgG1 isotype / subclass and comprises the constant heavy chain domain of SEQ ID NO: 23 or the heavy chain amino acid sequence of SEQ ID NO: 17 and the constant portion of the heavy chain amino acid sequence of SEQ ID NO: 18. In one embodiment, the C-terminal glycine (Gly446) is additionally present. In one embodiment, the C-terminal glycine (Gly446) and the C-terminal lysine (Lys447) are additionally present.

[0320] Unless otherwise specified herein, the numbering of amino acid residues in the constant region is according to the EU numbering system, also known as the EU index of Kabat, as described in Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0321] In one embodiment, the bispecific antibody according to the present invention is a human IgG1 subclass with mutations L234A (Leu235Ala), L235A (Leu234Ala) and P329G (Pro329Gly). Such antibodies have reduced FcR binding (in particular, they show no longer binding to FcRgammaI, FcRgammaII and FcRgammaIII). It is particularly suitable for reducing potential side effects, such as thrombosis (Meyer, T. et al., J. Thromb. Haemost. 7 (2009) 171-81).

[0322] While the described Pro329Ala mutation removes only two thirds of the FcgammaRIIIa sandwich interaction, Pro329Gly in the antibodies according to the invention fully confers binding of the Fc part to FcgammaRIII. This is particularly useful since binding to FcgammaRIII involves ADCC (antibody-dependent cellular cytotoxicity) which leads to cell death, a process that may be helpful in the treatment of cancer diseases but which may lead to severe side effects in antibody-based treatments of other vascular or immune diseases. Thus, antibodies according to the invention of the IgG1 subclass with the mutations L234A, L235A and P329G and of the IgG4 subclass with the mutations S228P, L235E and P329G are particularly useful since they all show no longer binding to FcRgammaI, FcRgammaII and FcRgammaIII.

[0323] An "effective amount" of an agent (eg, a pharmaceutical formulation or a bispecific anti-VEGF / ANG2 antibody) refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0324] In one embodiment of the invention, the bispecific antibody, medicament or pharmaceutical formulation as described herein is administered by intravitreal application, e.g., by intravitreal injection ("intravitreal" administration). This can be performed according to standard procedures known in the art. See, e.g., Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5.

[0325] In some embodiments, the therapeutic kit of the invention may comprise one or more doses of a bispecific antibody present in a drug or drug formulation, a suitable device for intravitreal injection of the drug or drug formulation, and instructions detailing subjects suitable for injection and protocols for injection. In these embodiments, the drug or drug formulation is typically administered to a subject in need of treatment by intravitreal injection. This can be performed according to standard procedures known in the art. See, for example, Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5.

[0326] Regardless of the route of administration chosen, the bispecific antibodies described herein are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

[0327] One embodiment is a method of treatment or a bispecific antibody (drug or pharmaceutical preparation) for treating an ocular vascular disease according to any of the preceding claims, wherein the antibody is administered according to the determination made by a software tool.

[0328] Another embodiment is a method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising:

[0329] receiving, at a computing system, patient data including the patient's CST and best corrected visual acuity (BCVA), and optionally information regarding an assessment of new macular hemorrhage;

[0330] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0331] Based on the results of this study on different ocular vascular diseases (such as nAMD, DME or jaundice secondary to RVO),

[0332] PTI was generated from dosing intervals based on criteria described for plaque edema (P<0.05).

[0333] Another embodiment is a computer device / computing system using / for implementing such a method.

[0334] Description of amino acid sequence

[0335]

[0336]

[0337] List embodiments of the present invention below:

[0338] 1. A bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2) (or a medicament or medicament formulation comprising the bispecific antibody, or a bispecific antibody for preparing a medicament) for treating an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), or treating a patient suffering from an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), wherein the treatment comprises a personalized treatment interval (PTI).

[0339] 2. The bispecific antibody (drug or pharmaceutical preparation) according to (use) of Example 1 for use in treating neovascular age-related macular degeneration (nAMD) or treating a patient suffering from nAMD.

[0340] 3. The bispecific antibody (drug or pharmaceutical preparation) according to embodiment 2, wherein the treatment comprises a personalized treatment interval, wherein

[0341] a) Patients first received 4 doses of the bispecific

[0342] Treatment with VEGF / ANG2 antibodies;

[0343] b) At Weeks 20 and 24, disease activity was assessed, whereby disease activity was determined if one of the following criteria was met:

[0344] i) Increase in central subfield thickness (CST) compared to the average CST value of the first two planned examinations

[0345] >50 μm, with the planned visits at Weeks 12 and 16 used for the Week 20 assessment, and the planned visits at Weeks 16 and 20 used for the Week 24 assessment, or

[0346] ii) CST increased by ≥75 μm compared with the lowest CST value recorded in any of the first two planned examinations;

[0347] iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the average BCVA of the two previous scheduled visits due to nAMD disease activity,

[0348] iv) a decrease in BCVA of ≥10 letters compared with the highest BCVA value recorded at either of the first two scheduled visits due to nAMD disease activity, or

[0349] v) New macular hemorrhages due to nAMD activity

[0350] c) Then, the patient

[0351] i) Patients who meet disease activity criteria at week 20 will be followed by

[0352] (Q8W) dosing interval (first Q8W dose at week 20);

[0353] ii) Patients who meet disease activity criteria at week 24 will be treated with

[0354] Treatment was given at a 12-week (Q12W) dosing interval (with the first Q12W dose at Week 24); and

[0355] iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval starting from Week 28 (with the first Q16W dose at Week 28).

[0356] 4. The bispecific antibody (drug or drug formulation) according to Example 3, wherein the personalized treatment interval will be extended, shortened or maintained after week 60, wherein

[0357] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0358] Q16W):

[0359] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0360] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0361] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0362] No decrease in BCVA of ≥10 letters,

[0363] iii) no new macular hemorrhage;

[0364] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0365] or

[0366] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0367] i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits, or CST increase of ≥75 μm compared to the lowest dosing visit measurement,

[0368] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0369] or a decrease in BCVA of ≥10 letters compared with the highest dosing exam measurement,

[0370] iii) New macular hemorrhage.

[0371] 5. The bispecific antibody (drug or pharmaceutical preparation) according to (use) of Example 1, for use in treating diabetic macular edema (DME) or treating a patient suffering from DME.

[0372] 6. The bispecific antibody (drug or pharmaceutical preparation) according to (for use) of embodiment 5, wherein the treatment comprises a personalized treatment interval (PTI), wherein

[0373] a) Patients first received bispecific VEGF / ANG2 antibody treatment every 4 weeks (Q4W) dosing interval until central subdomain thickness (CST) reached a pre-defined reference CST threshold (CST <325 μm for Spectralis SD-OCT, or <315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured at or after Week 12);

[0374] b) Then, the dosing interval is increased by 4 weeks to an initial Q8W dosing interval;

[0375] c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment made at the dosing visit, the assessment being based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0376] in

[0377] i) The said interval is extended by 4 weeks in the following cases:

[0378] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0379] 10 letters;

[0380] ii) The interval will be maintained if:

[0381] - If the CST decreases by >10%, or

[0382] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0383] 10 letters; or

[0384] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0385] iii) The interval is shortened by 4 weeks in the following cases:

[0386] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0387] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0388] iv) if the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks;

[0389] wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and

[0390] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0391] 7. The bispecific antibody (drug or pharmaceutical preparation) according to (use) of Example 6, wherein the dosing interval can be adjusted by increments of 4 weeks to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0392] 8. A bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2) for use in treating an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, or in treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI), wherein

[0393] a) Patients were first treated with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval from day 1 to week 20

[0394] b) Starting from Week 24, patients received the bispecific VEGF / ANG2 antibody Q4W until the central subdomain thickness (CST) reached the pre-defined reference CST threshold (CST <325 μm for Spectralis SD-OCT, or <315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured on or after Week 24);

[0395] c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment made at the dosing visit, the assessment being based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0396] in

[0397] i) The interval is extended by 4 weeks in the following cases

[0398] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0399] 10 letters; or

[0400] ii) The interval is maintained if any of the following criteria is met:

[0401] If the CST value decreases by >10%; or

[0402] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0403] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0404] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0405] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0406] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or

[0407] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0408] iv) In the following cases, the interval is shortened to Q4W

[0409] If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters,

[0410] where the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met and if the CST is reduced by >10% from the previous reference CST for two consecutive dosing visits and the value obtained is within 30

[0411] μm, the reference CST is adjusted so that the CST value obtained in the next examination will be used as the new reference CST; and

[0412] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0413] 9. The bispecific antibody (drug or pharmaceutical preparation) according to (use) of Example 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0414] 10. The bispecific antibody (drug or pharmaceutical preparation) according to (use of) Examples 1-9, wherein the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody, which comprises a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein

[0415] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0416] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0417] And among them

[0418] iii) The bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index).

[0419] 11. The bispecific antibody (drug or pharmaceutical preparation) according to (use of) embodiment 10, wherein

[0420] i) the first antigen binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain VL, and

[0421] ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain VL.

[0422] 12. The (use of) bispecific antibody (drug or pharmaceutical preparation) according to Examples 1-9, wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises the amino acid sequence of SEQ ID NO: 17, the amino acid sequence of SEQ ID NO: 18, the amino acid sequence of SEQ ID NO: 19 and the amino acid sequence of SEQ ID NO: 20.

[0423] 13. The bispecific antibody (drug or pharmaceutical preparation) according to (use) of Examples 1-9, wherein the bispecific antibody is fariximab.

[0424] 14. The bispecific antibody (medicament or pharmaceutical preparation) according to (for use) of embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 5 to 7 mg (per treatment).

[0425] 15. The bispecific antibody (medicament or pharmaceutical preparation) according to (for use) of Examples 8-13, wherein the bispecific antibody is administered at a dose of about 6 mg (at each treatment).

[0426] 16. The bispecific antibody (medicament or pharmaceutical preparation) according to (for use) of embodiments 14-15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml.

[0427] 17. The bispecific antibody (medicament or pharmaceutical formulation) according to any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy.

[0428] 18. The bispecific antibody (medicament or pharmaceutical formulation) according to any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has been previously treated with an anti-VEGF therapy.

[0429] 19. The bispecific antibody (drug or pharmaceutical preparation) according to any one of the preceding embodiments, wherein the antibody is administered as determined by a software tool.

[0430] 20. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising:

[0431] Receiving, at a computing system, patient data including the patient's CST and best corrected visual acuity (BCVA), and optionally information regarding an assessment of new macular hemorrhage; and

[0432] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0433] A PTI is generated from the dosing interval, wherein

[0434] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0435] Q16W):

[0436] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0437] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0438] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0439] No decrease in BCVA of ≥10 letters,

[0440] iii) No new macular hemorrhage

[0441] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0442] or

[0443] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0444] i) CST increased by ≥50 μm compared to the average of the two most recent dosing examinations, or CST increased by ≥75 μm compared to the lowest dosing examination measurement;

[0445] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0446] or a decrease in BCVA of ≥10 letters compared with the highest dosing examination measurement;

[0447] iii) New macular hemorrhage.

[0448] 21. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient suffering from DME, the method comprising:

[0449] receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; and

[0450] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0451] A PTI is generated from the dosing interval, wherein

[0452] i) The said interval is extended by 4 weeks in the following cases:

[0453] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0454] 10 letters;

[0455] ii) The interval will be maintained if:

[0456] - If the CST decreases by >10%, or

[0457] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0458] 10 letters; or

[0459] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0460] iii) The interval is shortened by 4 weeks in the following cases:

[0461] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0462] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0463] iv) If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks.

[0464] 22. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient with an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, the method comprising:

[0465] receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; and

[0466] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0467] A PTI is generated from the dosing interval, wherein

[0468] i) The interval is extended by 4 weeks in the following cases

[0469] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0470] 10 letters; or

[0471] ii) The interval is maintained if any of the following criteria is met:

[0472] If the CST value decreases by >10%; or

[0473] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0474] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0475] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0476] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0477] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters, or

[0478] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0479] iv) In the following cases, the interval is shortened to Q4W

[0480] If the CST value increased by >10%, the associated BCVA decreased by ≥10 letters.

[0481] 23. The method of any one of embodiments 20, 21 or 22, further comprising:

[0482] receiving updated patient data at the computing system;

[0483] Using a computing system to continuously update or maintain dosing intervals based on updated patient data; and

[0484] Generate a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0485] 24. Use of a personalized dosing regimen according to a personalized treatment interval (PTI) for treating nAMD, wherein a computing system generates the PTI by:

[0486] Receiving, at a computing system, patient data including the patient's CST and best corrected visual acuity (BCVA), and optionally information regarding an assessment of new macular hemorrhage; and

[0487] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0488] in

[0489] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0490] Q16W):

[0491] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0492] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0493] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0494] No decrease in BCVA of ≥10 letters,

[0495] iii) No new macular hemorrhage

[0496] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0497] or

[0498] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0499] i) CST increased by ≥50 μm compared to the average of the two most recent dosing examinations, or CST increased by ≥75 μm compared to the lowest dosing examination measurement;

[0500] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0501] or a decrease in BCVA of ≥10 letters compared with the highest dosing examination measurement;

[0502] iii) New macular hemorrhage.

[0503] 25. Use of a personalized dosing regimen according to a personalized therapeutic interval (PTI) for treating DME, wherein a computing system generates the PTI by:

[0504] receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and

[0505] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0506] in

[0507] i) The said interval is extended by 4 weeks in the following cases:

[0508] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0509] 10 letters;

[0510] ii) The interval will be maintained if:

[0511] - If the CST decreases by >10%, or

[0512] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0513] 10 letters; or

[0514] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0515] iii) The interval is shortened by 4 weeks in the following cases:

[0516] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0517] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0518] iv) If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks.

[0519] 26. Use of a personalized dosing regimen according to a personalized treatment interval (PTI) for treating macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, wherein a computing system generates the PTI by:

[0520] receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and

[0521] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0522] in

[0523] i) The interval is extended by 4 weeks in the following cases

[0524] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0525] 10 letters; or

[0526] ii) The interval is maintained if any of the following criteria is met:

[0527] If the CST value decreases by >10%; or

[0528] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0529] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0530] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0531] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0532] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters, or

[0533] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0534] iv) In the following cases, the interval is shortened to Q4W

[0535] If the CST value increased by >10%, the associated BCVA decreased by ≥10 letters.

[0536] List embodiments of the present invention below:

[0537] 1. A method of treating a patient having an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2), wherein the treatment comprises a personalized treatment interval (PTI).

[0538] 2. The method of embodiment 1, wherein the ocular vascular disease is neovascular age-related macular degeneration (nAMD).

[0539] 3. The method of embodiment 2, wherein the treatment comprises personalized treatment intervals, wherein

[0540] a) Patients first received 4 doses of the bispecific

[0541] Treatment with VEGF / ANG2 antibodies;

[0542] b) At Weeks 20 and 24, disease activity was assessed, whereby disease activity was determined if one of the following criteria was met:

[0543] i) Increase in central subfield thickness (CST) compared to the average CST value of the first two planned examinations

[0544] >50 μm, with the planned visits at Weeks 12 and 16 used for the Week 20 assessment, and the planned visits at Weeks 16 and 20 used for the Week 24 assessment, or

[0545] ii) CST increased by ≥75 μm compared with the lowest CST value recorded in any of the two previous planned examinations;

[0546] iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the average BCVA of the two previous scheduled visits due to nAMD disease activity,

[0547] iv) a decrease in BCVA of ≥10 letters compared with the highest BCVA value recorded at either of the first two scheduled visits due to nAMD disease activity, or

[0548] v) New macular hemorrhages due to nAMD activity

[0549] c) Then, the patient

[0550] i) Patients who meet disease activity criteria at week 20 will be treated with

[0551] (Q8W) dosing interval (first Q8W dose at week 20);

[0552] ii) Patients who meet disease activity criteria at week 24 will be treated with

[0553] Treatment was given at a 12-week (Q12W) dosing interval (with the first Q12W dose at Week 24); and

[0554] iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval starting from Week 28 (with the first Q16W dose at Week 28).

[0555] 4. The method according to embodiment 3, wherein the personalized treatment interval is extended, shortened or maintained after week 60, wherein

[0556] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0557] Q16W):

[0558] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0559] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0560] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0561] No decrease in BCVA of ≥10 letters,

[0562] iii) no new macular hemorrhage;

[0563] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0564] or

[0565] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0566] i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits, or CST increase of ≥75 μm compared to the lowest dosing visit measurement,

[0567] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0568] or a decrease in BCVA of ≥10 letters compared with the highest dosing exam measurement,

[0569] iii) New macular hemorrhage.

[0570] 5. The method of embodiment 1 for treating diabetic macular edema (DME) or treating a patient suffering from DME.

[0571] 6. The method of embodiment 5, wherein the treatment comprises a personalized treatment interval (PTI), wherein

[0572] a) Patients first received bispecific VEGF / ANG2 antibody treatment every 4 weeks (Q4W) dosing interval until central subdomain thickness (CST) reached a pre-defined reference CST threshold (CST <325 μm for Spectralis SD-OCT, or <315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured at or after Week 12);

[0573] b) Then, the dosing interval is increased by 4 weeks to an initial Q8W dosing interval;

[0574] c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment performed at the dosing visit, which is based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0575] in

[0576] i) The said interval is extended by 4 weeks in the following cases:

[0577] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0578] 10 letters;

[0579] ii) The interval will be maintained if:

[0580] - If the CST decreases by >10%, or

[0581] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0582] 10 letters; or

[0583] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0584] iii) The interval is shortened by 4 weeks in the following cases:

[0585] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0586] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0587] iv) if the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks;

[0588] wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and

[0589] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0590] 7. The method according to embodiment 6, wherein the dosing interval can be adjusted by 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0591] 8. A method of treating a patient having an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2), wherein the treatment comprises a personalized treatment interval (PTI), wherein

[0592] a) Patients were first treated with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval from day 1 to week 20

[0593] b) Starting from Week 24, patients received the bispecific VEGF / ANG2 antibody Q4W until the central subdomain thickness (CST) reached the pre-defined reference CST threshold (CST <325 μm for Spectralis SD-OCT, or <315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured on or after Week 24);

[0594] c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment made at the dosing visit, the assessment being based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA;

[0595] in

[0596] i) The interval is extended by 4 weeks in the following cases

[0597] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0598] 10 letters; or

[0599] ii) The interval is maintained if any of the following criteria is met:

[0600] If the CST value decreases by >10%; or

[0601] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0602] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0603] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0604] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0605] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or

[0606] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0607] iv) In the following cases, the interval is shortened to Q4W

[0608] If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters,

[0609] where the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met and if the CST is reduced by >10% from the previous reference CST for two consecutive dosing visits and the value obtained is within 30

[0610] μm, the reference CST is adjusted so that the CST value obtained in the next examination will be used as the new reference CST; and

[0611] The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

[0612] 9. The method according to embodiment 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0613] 10. The method of any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG-2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein

[0614] i) the first antigen-binding site that specifically binds to VEGF comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6 in the light chain variable domain; and

[0615] ii) said second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,

[0616] And among them

[0617] iii) The bispecific antibody comprises a heavy chain constant region of human IgG1 subclass comprising the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbering according to the Kabat EU index).

[0618] 11. The method of embodiment 10, wherein

[0619] i) the first antigen binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain VL, and

[0620] ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain VL.

[0621] 12. The method of any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises the amino acid sequence of SEQ ID NO: 17, the amino acid sequence of SEQ ID NO: 18, the amino acid sequence of SEQ ID NO: 19, and the amino acid sequence of SEQ ID NO: 20.

[0622] 13. The method according to any one of embodiments 1 to 9, wherein the bispecific antibody is fariximab.

[0623] 14. The method according to embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 5 to 7 mg (at each treatment).

[0624] 15. The method according to embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 6 mg (at each treatment).

[0625] 16. The method of any one of embodiments 14 to 15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml.

[0626] 17. The method of any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy.

[0627] 18. The method of any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has been previously treated with an anti-VEGF therapy.

[0628] 19. The method of any preceding embodiment, wherein the antibody is administered as determined by a software tool.

[0629] 20. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising:

[0630] Receiving, at a computing system, patient data including the patient's CST and best corrected visual acuity (BCVA), and optionally information regarding an assessment of new macular hemorrhage; and

[0631] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0632] A PTI is generated from the dosing interval, wherein

[0633] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0634] Q16W):

[0635] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0636] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0637] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0638] No decrease in BCVA of ≥10 letters,

[0639] iii) No new macular hemorrhage

[0640] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0641] or

[0642] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0643] i) CST increased by ≥50 μm compared to the average of the two most recent dosing examinations, or CST increased by ≥75 μm compared to the lowest dosing examination measurement;

[0644] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0645] or a decrease in BCVA of ≥10 letters compared with the highest dosing examination measurement;

[0646] iii) New macular hemorrhage.

[0647] 21. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient suffering from DME, the method comprising:

[0648] receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; and

[0649] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0650] A PTI is generated from the dosing interval, wherein

[0651] i) The said interval is extended by 4 weeks in the following cases:

[0652] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0653] 10 letters;

[0654] ii) The interval will be maintained if:

[0655] - If the CST decreases by >10%, or

[0656] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0657] 10 letters; or

[0658] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0659] iii) The interval is shortened by 4 weeks in the following cases:

[0660] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0661] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0662] iv) If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks.

[0663] 22. A method of providing a personalized dosing regimen according to a personalized treatment interval (PTI) for treating a patient with an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, the method comprising:

[0664] receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; and

[0665] Using the computing system, extending, shortening, or maintaining the dosing interval based on comparison of the received patient data with corresponding reference CST and BCVA; and

[0666] A PTI is generated from the dosing interval, wherein

[0667] i) The interval is extended by 4 weeks in the following cases

[0668] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0669] 10 letters; or

[0670] ii) The interval is maintained if any of the following criteria is met:

[0671] If the CST value decreases by >10%; or

[0672] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0673] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0674] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0675] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0676] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters, or

[0677] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0678] iv) In the following cases, the interval is shortened to Q4W

[0679] If the CST value increased by >10%, the associated BCVA decreased by ≥10 letters.

[0680] 23. The method of any one of embodiments 20, 21 or 22, further comprising:

[0681] receiving updated patient data at the computing system;

[0682] Using a computing system to continuously update or maintain dosing intervals based on updated patient data; and

[0683] Generate a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0684] 24. Use of a personalized dosing regimen according to a personalized treatment interval (PTI) for treating nAMD, wherein a computing system generates the PTI by:

[0685] Receiving, at a computing system, patient data including the patient's CST and best corrected visual acuity (BCVA), and optionally information regarding an assessment of new macular hemorrhage; and

[0686] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0687] in

[0688] a) If all of the following criteria are met, the interval is extended by 4 weeks (up to a maximum of

[0689] Q16W):

[0690] i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement,

[0691] ii) No decrease in BCVA compared to the average of the two most recent study drug dosing visits

[0692] ≥5 letters and compared with the highest study drug administration diagnostic measure,

[0693] No decrease in BCVA of ≥10 letters,

[0694] iii) No new macular hemorrhage

[0695] b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W),

[0696] or

[0697] The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage:

[0698] i) CST increased by ≥50 μm compared to the average of the two most recent dosing examinations, or CST increased by ≥75 μm compared to the lowest dosing examination measurement;

[0699] ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits;

[0700] or a decrease in BCVA of ≥10 letters compared with the highest dosing examination measurement;

[0701] iii) New macular hemorrhage.

[0702] 25. Use of a personalized dosing regimen according to a personalized therapeutic interval (PTI) for treating DME, wherein a computing system generates the PTI by:

[0703] receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and

[0704] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0705] in

[0706] i) The said interval is extended by 4 weeks in the following cases:

[0707] - If the CST value increases or decreases by ≤10% without an associated decrease in BCVA ≥

[0708] 10 letters;

[0709] ii) The interval will be maintained if:

[0710] - If the CST decreases by >10%, or

[0711] - If the CST value increases or decreases ≤ 10% and the associated BCVA decreases ≥

[0712] 10 letters; or

[0713] - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0714] iii) The interval is shortened by 4 weeks in the following cases:

[0715] - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0716] - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters;

[0717] iv) If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks.

[0718] 26. Use of a personalized dosing regimen according to a personalized treatment interval (PTI) for treating macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, wherein a computing system generates the PTI by:

[0719] receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and

[0720] Extend, shorten or maintain dosing intervals based on comparison of received patient data with corresponding reference CST and BCVA;

[0721] in

[0722] i) The interval is extended by 4 weeks in the following cases

[0723] If the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA ≥

[0724] 10 letters; or

[0725] ii) The interval is maintained if any of the following criteria is met:

[0726] If the CST value decreases by >10%; or

[0727] If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or

[0728] If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters;

[0729] iii) If any of the following criteria is met, the interval is shortened by 4 weeks:

[0730] If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or

[0731] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or

[0732] If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters;

[0733] iv) In the following cases, the interval is shortened to Q4W

[0734] If the CST value increased by >10%, the associated BCVA decreased by ≥10 letters.

[0735] Examples

[0736] Treatment of patients with vascular eye diseases using bispecific antibodies that bind to human VEGF and to human ANG2

[0737] Example 1:

[0738] Efficacy and durability of treatment in patients with neovascular age-related macular degeneration (nAMD) using personalized treatment intervals

[0739] In an earlier 52-week Phase II investigational study, it was seen, among other things, that RO6867461 (fariximab) had a longer durability of efficacy (longer time to retreatment) when administered at 12- and 16-week intervals in treatment-naive nAMD patients, across all patients involved. Three groups were studied - Group A (Q12W): 6 mg RO6867461 intravitreal (IVT) every 4 weeks to week 12 (4 injections), then 6 mg RO6867461 IVT every 12 weeks to week 48 (injections at weeks 24, 36, and 48; 3 injections) ......................................................................... - Group B (Q16W): 6 mg RO6867461 IVT every 4 weeks to week 12 (4 injections), then 6 mg RO6867461 IVT every 16 weeks to week 48 (injections at weeks 28 and 44; 2 injections) ......................................................................................... - Group C (comparative group): 0.5 mg ranibizumab IVT every 4 weeks to week 48 (13 injections), only one eye was selected as the study eye.

[0740] Figure 5 Results regarding BCVA are shown. Figure 5 Comparison of the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) (12 and 16 weeks interval) and ranibizumab is shown. (0.3 mg dose administered intravitreally) (4-week intervals), BCVA increased relative to baseline in patients with neovascular age-related macular degeneration (nAMD).

[0741] A follow-on Phase III study was initiated that will now evaluate the efficacy, safety, durability, and pharmacokinetics of 6 mg doses of fariximab administered at intervals of up to 16 weeks (with a specific personalized treatment interval (PTI) schedule) compared to Q8W aflibercept monotherapy in patients with CNV secondary to AMD (also known as nAMD). Fariximab will be administered at a concentration of approximately 120 mg / ml.

[0742] The specific objectives and corresponding endpoints of the study are outlined below.

[0743] Table 1. Table 1 Objectives and corresponding endpoints

[0744]

[0745] Table 1 Objectives and corresponding endpoints (continued)

[0746]

[0747] Table 1 Objectives and corresponding endpoints (continued)

[0748]

[0749] Patients with neovascular age-related macular degeneration (nAMD), also known as wet age-related macular degeneration (wet AMD), are treated with a bispecific antibody that binds to human VEGF and human ANG2, the antibody comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (the antibody VEGFang2-0016 and its production are also described in detail in WO2014 / 009465, which is incorporated by reference). The name of this bispecific anti-VEGF / ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016, or faricimab. As an active comparator in treatment, for example, aflibercept will be used. Patients include anti-VEGF treatment naive patients (who have not previously received anti-VEGF treatment using, for example, aflibercept and / or ranibizumab and / or other anti-VEGF treatments). Vials of sterile, colorless to light brown, preservative-free RO6867461 (Fariximab) solution are available for intravitreal (IVT) administration at a dose of 6 mg.

[0750] Study Design

[0751] This is a multicenter, randomized, active comparator, double-blind, parallel-group, 112-week study designed to investigate the efficacy, safety, duration, and pharmacokinetics of fariximab administered at intervals of up to 16 weeks to treatment-naive patients with nAMD.

[0752] Approximately 640 patients will be enrolled globally and randomized 1:1 to one of two treatment groups:

[0753] Arm A (Fariximab up to Q16W) (n=320): Patients randomized to Arm A will receive 6 mg of IVT fariximab Q4W until Week 12 (4 injections). At Week 20, a protocol-defined assessment of disease activity requires patients in Arm A with active disease (see below for criteria) to be treated at that visit and continue to receive fariximab Q8W. At Week 24, a second protocol-defined assessment of disease activity requires patients in Arm A with active disease (excluding patients with active disease at Week 20 who therefore receive fariximab Q8W) to be treated at that visit and continue to receive fariximab Q12W. Patients receiving fariximab who do not have active disease at Weeks 20 and 24 will be treated with fariximab Q16W, according to protocol-defined criteria. Patients will continue to receive faricimab on a fixed schedule every 8, 12, or 16 weeks, depending on disease activity assessments made at weeks 20 and 24, until week 60. Starting at week 60 (when all patients in group A are scheduled to receive faricimab), all patients in group A will be treated according to a personalized treatment interval (PTI) dosing schedule (see Table 2 for PTI dosing criteria) until week 108.

[0754] Group B (Comparison Group) (Q8W): Patients randomized to Group B will receive 2 mg of IVT aflibercept Q4W (3 injections) until Week 8, and then 2 mg of IVT aflibercept Q8W until Week 108.

[0755] Patients in both treatment groups will complete the planned study visits Q4W throughout the study duration (112 weeks). Patients in both treatment groups will undergo sham surgery at the study visits without study treatment to maintain masking between treatment groups.

[0756] Figure 1 Present an overview of the research design

[0757] aPatients will undergo disease activity assessments at Weeks 20 and 24. Patients with anatomical or functional signs of disease activity at these time points will receive Q8W or Q12W dosing, respectively, rather than Q16W dosing.

[0758] bThe primary endpoint was change from baseline in BCVA based on the mean at Weeks 40, 44, and 48 (as assessed on an ETDRS chart with a starting distance of 4 meters).

[0759] cBeginning at week 60 (when all patients in group A are scheduled to receive fariximab), patients in group A will be treated according to the PTI dosing schedule (between Q8W and Q16W).

[0760] BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study;

[0761] IVT = intravitreal; PTI = individualized treatment interval; Q8W = every 8 weeks; Q12W

[0762] = every 12 weeks; Q16W = every 16 weeks; W = week.

[0763] Only one eye will be designated as the study eye. If both eyes are eligible (according to the inclusion and exclusion criteria), the eye with the worse BCVA assessed at screening will be selected as the study eye (unless the investigator determines, for medical reasons, that the other eye is more suitable for the treatment under study).

[0764] At least two investigators will be assigned to each site to meet the study masking requirements. At least one investigator will be designated as the assessing physician who is blinded to each patient's treatment assignment and will perform the ocular assessment. At least one other investigator will be aware of and perform the study treatment.

[0765] The study will include a screening period of up to 28 days (Days -28 to -1) and an approximately 108-week treatment period, followed by a final study visit at Week 112 (at least 28 days after the last study treatment administration).

[0766] Disease activity criteria at weeks 20 and 24

[0767] Active disease was defined at weeks 20 and 24 if any of the following criteria were met:

[0768] CST increase of >50 μm compared to the mean CST value at the two previous scheduled visits (week 12 and week 16 visits for the week 20 assessment, and week 16 and week 20 visits for the week 24 assessment); or

[0769] An increase in CST of ≥75 μm compared with the lowest CST value recorded at either of the two previous scheduled examinations; or

[0770] A decrease in BCVA of ≥5 letters compared with the mean BCVA values ​​at the two previous scheduled visits due to nAMD disease activity (determined by the investigator); or

[0771] A decrease in BCVA of ≥10 letters from the highest BCVA value recorded at either of the first two scheduled visits due to nAMD disease activity (as determined by the investigator); or

[0772] New macular hemorrhages due to nAMD activity (as determined by the investigator)

[0773] Additional considerations at Week 24: If there is significant nAMD disease activity at Week 24 that does not meet the above criteria, but the investigator determines that the disease activity warrants treatment, patients randomized to Arm A will receive 6 mg of fariximab at Week 24 and will continue to receive repeated treatment every 12 weeks. Patients randomized to Arm A who meet disease activity criteria at Week 20 will remain on their Q8W dosing schedule and will not be treated at Week 24. Patients randomized to Arm B will remain on their Q8W dosing schedule and will receive aflibercept at Week 24.

[0774] Personalized Treatment Interval (PTI) Disease Activity Criteria

[0775] Starting at Week 60, when all patients in Group A are scheduled to receive faricimab, the study drug dosing interval for patients in Group A will be extended based on the assessment at the study drug dosing visit. Table 2 describes the study drug dosing interval decisions (and the corresponding algorithm) during the PTI protocol phase of Group A. This decision will be made based on the patient's visit data while they are receiving the drug. When patients are not receiving treatment with faricimab, they will receive a sham procedure at the study visit.

[0776] Table 2 Personalized treatment interval algorithm

[0777]

[0778] BCVA = best corrected visual acuity; CST = central subfield thickness; IRF = intraretinal fluid; nAMD = new

[0779] Vascular age-related macular degeneration; Q8W = every 8 weeks; Q16W = every 16 weeks;

[0780] SRF = subretinal fluid.

[0781] a Stability is defined as a change in CST less than 30 μm

[0782] b Changes in BCVA were attributed to nAMD disease activity (as determined by the investigators).

[0783] c Refers to macular hemorrhage due to nAMD activity (determined by the investigator).

[0784] d Patients whose treatment interval is shortened by 8 weeks from Q16W to Q8W will not be allowed to resume treatment during the study.

[0785] Q16W interval.

[0786] As described above in Table 2 , the algorithm for personalized medication interval decisions is based on the relative change in CST and the absolute change in BCVA compared with the reference CST and BCVA, respectively, and also on the assessment / finding of new macular hemorrhages.

[0787] The algorithm can be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to a web interface of a personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the time of the next dose. The tool can further provide a dosing schedule or notification, monitor and generate a visualization of changes in dosing intervals for a given patient, generate a visualization of changes in dosing intervals for a patient group, aggregate received CST and BCVA data to determine trends, or a combination thereof.

[0788] The dosing schedule or notification may include a display of calendar dates for scheduled dosing visits and calendar reminders notifying the clinician or patient of upcoming dosing visits. A visualization of changes in dosing intervals may include, for example, a schematic display in Table 2. In one instance, a patient's dosing interval adjustment may be displayed in one color, and the patient's previous dosing interval adjustment may be displayed in another color. For example, a patient may first extend their interval by 4 weeks and then maintain their personalized treatment interval. The tool may generate a visualization of a patient's personalized interval progression by displaying the "Interval Maintained" area of ​​the schematic in Table 2 in green and "Interval Extended by 4 Weeks" in yellow. Green may reflect the patient's most recent interval calculation, while yellow may describe the patient's previous interval calculation. With this visualization, a user of the tool can quickly determine that a patient's disease progression is improving, but not improving enough to extend their treatment interval longer.

[0789] The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis can include visualizations of dosing changes for a single patient, similar to the color-coded example described previously. Alternatively, visualizations can show dosing adjustments across patient groups. For example, a visualization can show which patients have interval extensions and which patients have interval shortenings. The visualizations can be organized by various features, such as patient age, previous treatments, disease state, antibodies administered, clinical trial groups, etc. The tool can also aggregate and create visualizations from patient CST and BCVA data. Visualizations can show trends in the data to facilitate or generate longitudinal analysis. These visualizations may include reminders, plots, analysis workflow interfaces, or any graphical interface.

[0790] The tool can generate a dosing plan output or visualization in response to or in conjunction with an ocular assessment and image. In one embodiment, the tool can directly calculate the patient's CST or BVCA. For CST, the tool can receive or directly capture an ocular image. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST from an ocular image. For BCVA, the tool can virtually manage the ocular assessment, prompting and collecting patient user input through a user interface or through an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing plan accordingly.

[0791] The present embodiment may include a method for providing a personalized dosing plan based on a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising: receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; using the computing system, extending, shortening, or maintaining the dosing interval based on the received patient data compared to a corresponding reference CST and BCVA; and generating a PTI from the dosing interval. An exemplary dosing interval will be extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the last 2 study drug dosing visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥5 letters compared to the average of the last two study drug dosing visits, and BCVA has not decreased by ≥10 letters compared to the highest study drug dosing visit measurement, iii) there is no new macular hemorrhage. The exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met or one criterion includes new macular hemorrhage: i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits or an increase of ≥75 μm compared to the lowest dosing visit measurement, ii) BCVA decrease of ≥5 letters compared to the average of the two most recent dosing visits or BCVA decrease of ≥10 letters compared to the highest dosing visit measurement, iii) new macular hemorrhage.

[0792] This method of providing a personalized dosing plan based on a personalized treatment interval (PTI) for treating a patient with nAMD may further include receiving updated patient data at a computing system; continuing to update or maintain the dosing interval, using the computing system, based on the updated patient data; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0793] The present embodiment also includes using a personalized dosing plan according to a personalized treatment interval (PTI) (for treating nAMD), wherein the computing system generates the PTI by receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to the corresponding reference CST and BCVA. The exemplary dosing interval will be extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the last 2 study drug dosing visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥5 letters compared to the average of the last two study drug dosing visits, and BCVA has not decreased by ≥10 letters compared to the highest study drug dosing visit measurement, iii) there is no new macular hemorrhage. The exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met or one criterion includes new macular hemorrhage: i) CST increase of ≥50 μm compared to the average of the two most recent dosing visits or an increase of ≥75 μm compared to the lowest dosing visit measurement; ii) BCVA decrease of ≥5 letters compared to the average of the two most recent dosing visits or BCVA decrease of ≥10 letters compared to the highest dosing visit measurement; iii) new macular hemorrhage.

[0794] Eye assessment

[0795] Ocular assessments include the following and will be performed at designated time points:

[0796] BCVA was measured using a set of three Precision VisionTM or Lighthouse distance visual acuity charts (modified ETDRS charts 1, 2, and R). VA manuals were provided to the investigators. VA examiners and VA examination room certification were obtained prior to any VA examinations. BCVA examiners were blinded to study eye and treatment assignment and would only perform refraction and BCVA assessments (e.g., vision specification manuals). BCVA examiners were also blinded to the patient's BCVA letter score from the previous visit and were only aware of the patient's optometric data from the previous visit. BCVA examiners were not allowed to perform any other tasks involving direct patient care.

[0797] Low-light BCVA is assessed based on the ETDRS chart at the starting distance of the 4-meter low-light best-corrected visual acuity test. The same requirements apply as for best-corrected visual acuity as described in Appendix 4;

[0798] However, low-light best-corrected visual acuity will be measured by placing a 2.0 log-unit neutral density filter (Kodak Wratten 2.0 neutral density filter) over the best correction for that eye and having the participant read a Diabetic Retinopathy Early Treatment Study chart in normal lighting.

[0799] - Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before pupil dilation).

[0800] Slit lamp examination (for grading scales for anterior cells and vitreous cells, see Foster CS, Kothari S, Anesi SD et al. The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016) 1-17).

[0801] ·Dilated binocular indirect high-power ophthalmoscopy.

[0802] • A finger counting test, followed by hand movement and light perception testing (if necessary), was performed in the study eye only within 15 minutes after study treatment by an informed treatment administrator.

[0803] At the time of the study treatment visit, post-treatment IOP measurements will be performed on the study eye only within 30 (± 15) minutes by informed qualified personnel. Patients will be allowed to leave the treatment site if there are no safety concerns after 30 (± 15) minutes after study treatment. If the IOP value is of concern to the treating manager, the patient will remain at the treatment site and will be managed according to the treating manager's clinical judgment. Adverse events will be recorded on the Adverse Event Electronic Case Report Form (eCRF), if applicable.

[0804] The method used to measure IOP in patients must be consistent throughout the study.

[0805] Eye imaging

[0806] The Central Reading Center (CRC(s)) will provide sites with the Central Reading Center Manual and training materials for specific study ocular images. Prior to acquisition of any study images, site personnel, test images, systems, and software (if applicable) will be certified and validated by the Reading Center as specified in the Central Reading Center Manual. All ocular image results will be acquired at the study site by trained site personnel and forwarded to the Central Reading Center for independent analysis and / or storage.

[0807] After randomization, if a patient missed a study visit when ocular images were scheduled or images were not obtained at the scheduled visit (e.g., because of equipment failure), images were obtained at the next scheduled visit that the patient attended.

[0808] Eye images include the following:

[0809] • Color Fundus Photography (CFP) of both eyes. Stereoscopic color fundus photographs will be obtained from both eyes by trained personnel at the study site. Fundus photography will be performed at intervals specified in the activity plan.

[0810] Fundus fluorescein angiography (FFA) of both eyes (performed after obtaining laboratory samples). Fundus fluorescein angiography will be performed on both eyes at the study site by trained personnel certified by the Central Reading Center. Fundus fluorescein angiography will be obtained at the intervals specified in the protocol.

[0811] Spectral domain optical coherence tomography (SD-OCT) or swept-source OCT (SS-OCT) of both eyes

[0812] image.

[0813] • Optional OCT angiography (OCT-A) of both eyes was performed at sites with certified OCT-A capabilities.

[0814] • Optional indocyanine green angiography (ICGA) in both eyes at selected sites with certified ICGA capabilities (performed after obtaining laboratory samples). Indocyanine green angiography (ICGA) will be performed in both eyes at designated intervals by trained personnel certified by a central reading center.

[0815] result

[0816] The primary efficacy analysis included all randomized patients, with patients assigned according to the randomly assigned treatment group.

[0817] The primary efficacy variable is the change in BCVA. The primary efficacy analysis will use, for example, a repeated measures mixed model (MMRM) model.

[0818] Best corrected visual acuity

[0819] BCVA was measured as described. The primary efficacy outcome measure is shown in the graph showing the primary efficacy endpoint: the change in BCVA of the patient over time relative to baseline. According to the above study protocol, the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg as described in Group A using personalized treatment intervals) was compared with, for example, Group B (aflibercept Q8W dosing) comparison.

[0820] Change from Baseline in Central Subfield Thickness (CST) (Study Eye)

[0821] A key secondary endpoint was the change in CST (central subdomain thickness) from baseline. CST (as well as retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in the accompanying figure, in which the change in CST over time is shown for the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg using personalized treatment intervals as described in Group A), according to the above study protocol, compared to, for example, Group B (aflibercept Q8W dosing) comparison.

[0822] Further results of the eye assessment and imaging may be displayed accordingly.

[0823] Example 2:

[0824] Efficacy and durability of bispecific anti-VEGF / ANG2 therapy in patients with diabetic macular edema (DME) using personalized treatment intervals

[0825] In an earlier 36-week Phase II study in patients with diabetic macular edema (DME), some degree of potential longer durability (perhaps requiring longer retreatment time) was seen in all patients involved. The three study groups were treated as follows: Group A: 0.3 mg ranibizumab, intravitreal (IVT); Group B: 1.5 mg RO6867461 (fariximab), IVT; Group C: 6 mg RO6867461 (fariximab), IVT.

[0826] Results on potential longer retreatment time with RO6867461 (fariximab, VA2) Figure 6 as shown in . Figure 6 The time to retreatment of DME patients after cessation of dosing (after 20 weeks or 6 monthly doses = time since last intravitreal (IVT) administration) based on disease activity assessed by two measures: BCVA decrease of ≥5 letters, and CST increase of ≥50 μm (= patients with events). Bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) (administered intravitreally at 6.0 mg or 1.5 mg dose) versus ranibizumab (administered intravitreally at a dose of 0.3 mg) for comparison.

[0827] A Phase III follow-up study has been initiated that will now evaluate the efficacy, safety, and pharmacokinetics of RO6867461 (faliximab) when administered every 8 weeks (Q8W) and at a personalized treatment interval (PTI) schedule compared with aflibercept in patients with DME. Monotherapy comparison. Effects on visual function will be evaluated by measuring the change from baseline in best-corrected visual acuity (BCVA) (i.e., number of ETDRS letters). Effects on retinal anatomy will be evaluated by retinal imaging (spectral-domain optical coherence tomography [SD-OCT], color fundus photographs [CFP], fundus fluorescein angiography [FFA]) and other imaging modalities to assess DME and DR outcomes. In addition, the safety, patient-reported outcomes (PROs), and pharmacokinetics of RO6867461 will be evaluated.

[0828] This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 when given Q8W and in a PTI regimen compared with aflibercept in patients with DME. Monotherapy comparisons. The specific objectives of the studies and the corresponding endpoints are summarized in Table 3 below.

[0829] Table 3 Objectives and corresponding endpoints

[0830]

[0831] a One year was defined as the average of the 48th, 52nd, and 56th week visits.

[0832] Table 3 Objectives and corresponding endpoints (continued)

[0833]

[0834] a One year was defined as the average of the 48th, 52nd, and 56th week visits.

[0835] b The total retinal area was defined as the ultra-wide field (UWF; ) images and was defined as the entire UWF image including the surrounding area measured with Optos FFA in a subset of patients.

[0836] c In a subset of patients, OCT-A measurements were performed.

[0837] Table 3 Objectives and corresponding endpoints (continued)

[0838]

[0839] a One year was defined as the average of the 48th, 52nd, and 56th week visits.

[0840] Table 3 Objectives and corresponding endpoints (continued)

[0841]

[0842] Abbreviations in the table

[0843] ADA = anti-drug antibodies; Ang-2 = angiopoietin-2; ANGPT2 = angiopoietin-2 (gene

[0844] =BCVA = best corrected visual acuity; CST = central subfield thickness; DR = diabetic retinopathy; DRS = diabetic retinopathy severity; DRSS = diabetic retinopathy severity scale; ETDRS = Early Treatment Diabetic Retinopathy Study; FFA = fundus fluorescein angiography;

[0845] IVT = intravitreal; NEI VFQ-25 = National Eye Institute 25-Item Visual Function Questionnaire; OCT-A =

[0846] Optical coherence tomography-angiography; PDR = proliferative diabetic retinopathy; PK = pharmacokinetics; PRP = panretinal photocoagulation; PTI = individualized treatment interval; Q4W = every 4 weeks;

[0847] Q8W = every 8 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; SD-OCT =

[0848] Spectral domain optical coherence tomography; VEGFA=vascular endothelial growth factor-A (gene).

[0849] Patients with DME (e.g., central diabetic macular edema (CI-DME)) are treated with a bispecific antibody that binds to human VEGF and human ANG2, the antibody comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (the antibody VEGFang2-0016 and its production are also described in detail in WO2014 / 009465, which is incorporated by reference). The name of this bispecific anti-VEGF / ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016, or faricimab. As an active comparator in treatment, for example, aflibercept will be used. Patients include anti-VEGF treatment naive patients (who have not previously received anti-VEGF treatment using, for example, aflibercept and / or ranibizumab and / or other anti-VEGF treatments) and a group of patients who have previously received anti-VEGF treatment. Use a vial of sterile, colorless to light brown, preservative-free RO6867461 (Fariximab) solution for intravitreal (IVT) administration at a dose of 6 mg. RO6867461 (Fariximab) will be administered at a concentration of approximately 120 mg / ml.

[0850] Approximately 900 patients will be randomized 1:1:1 to one of three treatment groups at approximately 240 study sites worldwide during the global recruitment phase of the study (see Figure 2 The study will randomize patients with DME whose study eye is naive to anti-VEGF therapy and patients whose study eye has previously received anti-VEGF therapy, provided that the last treatment was at least 3 months before the Day 1 visit (first study treatment). Site investigators will be retinal specialists

[0851] The study treatment groups were as follows (see also Figure 2 ):

[0852] Patients randomized to Group A will receive 6 mg IVT RO6867461 (Fariximab) injections (Q4W) until Week 20, followed by 6 mg IVT RO6867461 (Fariximab) injections (Q8W) until Week 96, followed by a final study visit at Week 100.

[0853] Patients randomized to Arm B (Personalized Treatment Interval PTI) will receive 6 mg IVT RO6867461 (fariximab) injections (Q4W) until at least Week 12, followed by PTI dosing (see PTI dosing criteria below), 6 mg IVT RO6867461 (fariximab) injections until Week 96, followed by a final study visit at Week 100.

[0854] Patients randomized to Group C will receive 2 mg IVT aflibercept injection (Q4W) until Week 16, followed by 2 mg IVT aflibercept injection (Q8W) until Week 96, followed by a final study visit at Week 100.

[0855] Patients in all three treatment groups will complete scheduled study visits Q4W throughout the duration of the study (100 weeks). Patients in all three treatment groups will undergo sham surgery at applicable visits to maintain masking between treatment groups (see Figure 2 - research treatment options).

[0856] Only one eye will be designated as the study eye. If both eyes are eligible, the eye with the worse BCVA assessed at screening will be selected as the study eye unless the investigator determines that the other eye is more suitable for the treatment under study.

[0857] At least two investigators per site will meet the masking requirements of the study. At least one investigator will be designated as the assessing physician who is blinded to each patient's treatment assignment and performs the ocular assessment. At least one other investigator will be aware of and perform the study treatment (see Section 4.2.2 for additional masking details).

[0858] Treatment plans for patients in the personalized treatment interval (PTI) group (Group B)

[0859] This section describes the dosing interval decisions in the PTI group. The study drug dosing visit is the visit when the patient is assigned to receive fariximab (RO6867461).

[0860] Determination of study drug dosing intervals

[0861] Patients randomized to the PTI arm (Arm B) will receive fariximab at a Q4W dosing interval until their CST reaches a predefined reference CST threshold (CST < 325 μm for Spectralis SD-OCT or CST < 315 μm for Cirrus SD-OCT or Topcon SD-OCT) at or after the Week 12 visit. The reference CST will be used for interval decisions at the study drug dosing visit.

[0862] Once a patient's initial reference CST is established, their study drug dosing interval will be increased by 4 weeks to an initial Q8W dosing interval. From this point on, the study drug dosing interval will be extended, shortened, or maintained based on the assessment performed at the study drug dosing visit.

[0863] Figure 3 An interval decision algorithm based on the relative changes in CST and BCVA compared with reference CST and reference BCVA is outlined. Figure 3 The meanings of * and ** are as follows:

[0864] *Reference Central Subfield Thickness (CST): The CST value at which the initial CST threshold criteria are met. If the CST at two consecutive study drug administration visits decreases by >10% from the previous reference CST and the values ​​obtained are within 30 μm, the reference CST is adjusted. Immediately starting from that visit, the CST value obtained at the latter visit will be used as the new reference CST.

[0865] ** Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[0866] All comparisons were made relative to a reference CST* and a reference BCVA**. Dosing intervals were determined based on CST and BCVA data obtained from the drug dosing visit.

[0867] Interval extended 4 weeks:

[0868] If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters -

[0869] Maintain interval:

[0870] If CST decreases by >10% or

[0871] An increase or decrease in CST value of ≤10% with an associated decrease in BCVA of ≥10 letters, or

[0872] Increase in CST value between >10% and ≤20% without an associated decrease in BCVA of ≥5 letters -

[0873] Shorten the interval by 4 weeks:

[0874] If the CST value increases by >10% to ≤20% and has an associated BCVA decrease of ≥5 to <10 letters or

[0875] Increase in CST value >20% without associated decrease in BCVA ≥10 letters

[0876] Shorten the interval to 8 weeks:

[0877] If the CST value increases by >10% and has an associated BCVA decrease of ≥10 letters

[0878] *Reference Central Subfield Thickness (CST): The CST value at which the initial CST threshold criteria are met. If the CST at two consecutive study drug administration visits decreases by >10% from the previous reference CST and the values ​​obtained are within 30 μm, the reference CST is adjusted. Immediately starting from that visit, the CST value obtained at the latter visit will be used as the new reference CST.

[0879] ** Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[0880] The personalized dosing interval can be adjusted in 4-week increments to a maximum of once every 16 weeks (Q16W) and a minimum of Q4W. The algorithm for personalized medication treatment interval decisions is based on the relative change in CST and the absolute change in BCVA, compared with the reference CST and BCVA, respectively.

[0881] The algorithm can be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to a web interface of a personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the time of the next dose. The tool can further provide a dosing schedule or notification, monitor and generate a visualization of changes in dosing intervals for a given patient, generate a visualization of changes in dosing intervals for a patient group, aggregate received CST and BCVA data to determine trends, or a combination thereof.

[0882] Dosing schedules or notifications may include display of calendar dates for scheduled dosing visits and calendar reminders notifying the clinician or patient of upcoming dosing visits. Visualizations of changes in dosing intervals may include, for example, Figure 3 . In one case, a patient's dosing interval adjustment might be shown in one color, and the patient's previous dosing interval adjustment might be shown in another color. For example, a patient might first extend their interval by 4 weeks and then maintain their personalized treatment interval. The tool can be used to Figure 3 A visualization of a patient's personalized interval progression is generated by showing the "Interval Maintenance" area of ​​the schematic in the figure and "Interval Extension by 4 Weeks" in yellow. The green color reflects the patient's most recent interval calculation, while the yellow color depicts the patient's previous interval calculation. With this visualization, users of the tool can quickly identify that a patient's disease progression is improving, but not improving enough to extend their treatment interval longer.

[0883] The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis can include visualizations of dosing changes for a single patient, similar to the color-coded example described previously. Alternatively, visualizations can show dosing adjustments across patient groups. For example, a visualization can show which patients have interval extensions and which patients have interval shortenings. The visualizations can be organized by various features, such as patient age, previous treatments, disease state, antibodies administered, clinical trial groups, etc. The tool can also aggregate and create visualizations from patient CST and BCVA data. Visualizations can show trends in the data to facilitate or generate longitudinal analysis. These visualizations may include reminders, plots, analysis workflow interfaces, or any graphical interface.

[0884] The tool can generate a dosing plan output or visualization in response to or in conjunction with an ocular assessment and image. In one embodiment, the tool can directly calculate the patient's CST or BVCA. For CST, the tool can receive or directly capture an ocular image. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST from an ocular image. For BCVA, the tool can virtually manage the ocular assessment, prompting and collecting patient user input through a user interface or through an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing plan accordingly.

[0885] The present embodiment may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient with DME, the method comprising: receiving patient data including a CST and best corrected visual acuity (BCVA) of the patient at a computing system; using the computing system, extending, shortening, or maintaining a dosing interval based on a comparison of the received patient data with a corresponding reference CST and BCVA; and generating a PTI from the dosing interval. If the CST value increases or decreases by ≤10% without an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is extended by 4 weeks. If the CST increases by >10%, the CST value increases or decreases by ≤10% with an associated decrease in BCVA of ≥10 letters, or the CST value increases by >10% to ≤20% without an associated decrease in BCVA of ≥5 letters, the exemplary dosing interval is maintained. If the CST value increases by >10% to ≤20% with an associated decrease in BCVA of ≥5 to <10 letters, or the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is shortened by 4 weeks. If the CST value increases by >10% with an associated BCVA decrease of ≥10 letters, the exemplary dosing interval is shortened by 8 weeks.

[0886] This method of providing a personalized dosing plan based on a personalized treatment interval (PTI) for treating a patient with DME may further include receiving updated patient data at a computing system; continuing to update or maintain the dosing interval, using the computing system, based on the updated patient data; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0887] The present embodiment also includes using a personalized dosing plan according to a personalized treatment interval (PTI) (for treating DME), wherein the computing system generates the PTI by receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to the corresponding reference CST and BCVA. If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters, the exemplary dosing interval is extended by 4 weeks. If the CST decreases by >10%, or the CST value increases or decreases by ≤10% with an associated BCVA decrease of ≥10 letters, or the CST value increases by >10% to ≤20% without an associated BCVA decrease of ≥5 letters, the exemplary dosing interval will be maintained. The exemplary dosing interval is shortened by 4 weeks if the CST value increases by >10% to ≤20% with an associated BCVA decrease of ≥5 to <10 letters, or the CST value increases by >20% without an associated BCVA decrease of ≥10 letters. If the CST value increases by >10% with an associated BCVA decrease of ≥10 letters, the exemplary dosing interval will be shortened by 8 weeks.Similar to Arms A and C, patients randomized to the PTI arm (Arm B) will receive sham surgery at the study visit when they are not receiving fariximab treatment.

[0888] Eye assessment

[0889] The eye assessment will include the following and will be performed on both eyes at designated time points depending on the activity plan:

[0890] Refraction and BCVA were assessed on the ETDRS chart at a starting distance of 4 meters. BCVA was measured using a set of three PrecisionVisionTM or Lighthouse distance visual acuity charts (modified ETDRS charts 1, 2, and R). VA manuals were provided to the investigators. VA examiners and VA examination room certification were obtained prior to any VA examinations. The BCVA examiners were blinded to the study eye and treatment assignment and would only perform refraction and BCVA assessments (e.g., vision specification manuals). The BCVA examiners were also blinded to the patient's BCVA letter score from the previous visit and were only aware of the patient's optometric data from the previous visit. The BCVA examiners were not allowed to perform any other tasks involving direct patient care.

[0891] - Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before pupil dilation).

[0892] Slit lamp examination (for grading scales for anterior cells and vitreous cells, see Foster CS, Kothari S, Anesi SD et al. The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016) 1-17).

[0893] ·Dilated binocular indirect high-power ophthalmoscopy.

[0894] • A finger counting test, followed by hand movement and light perception testing (if necessary), was performed on the study eye only by an informed treatment administrator approximately 15 minutes after study treatment.

[0895] At the study treatment visit, post-treatment IOP measurements will be performed on the study eye only at 30 (±15) minutes by informed qualified personnel. Patients will be allowed to leave the clinic if there are no safety concerns after 30 (±15) minutes following study treatment. If the IOP value is of concern to the treating administrator, the patient will remain at the clinic and will be managed according to the clinical judgment of that physician. Adverse events will be recorded on the Adverse Event Electronic Case Report Form (eCRF), if applicable.

[0896] The method used to measure IOP in patients must be consistent throughout the study.

[0897] Eye imaging

[0898] The Central Reading Center (CRC) will provide sites with the CRC manual and training materials for specific study ocular images. Prior to obtaining any study images, site personnel, test images, systems, and software (if applicable) will be certified and validated by the CRC as specified in the CRC manual. All ocular image results will be obtained at the study site by trained site personnel and forwarded to the CRC for independent analysis and / or storage.

[0899] After randomization, if a patient missed a study visit when ocular CFP and FFA images were scheduled, or if images were not obtained at the scheduled visit (e.g., due to equipment damage), they should be obtained at the next scheduled visit that the patient attended.

[0900] Eye images include the following:

[0901] Forced color fundus photography (CFP) in both eyes (7 or 4 wide fields; one of these methods is performed for patients throughout trial participation). Stereoscopic color fundus photographs are obtained from both eyes by trained personnel at the study site. Fundus photography will be performed at intervals specified in the activity plan.

[0902] Optional ultra-wide field of view (UWF) for both eyes; ) CFP (at sites with UWF CFP capabilities and consent to take these images as well as the mandatory CFP images)

[0903] Fundus fluorescein angiography (FFA) will be performed in both eyes at the study site by trained personnel (UWF (Optos) is the preferred method if the site has the capability)

[0904] FFA; Sites without UWF (Optos)FFA used the same method to capture 7 or 4 wide fields (if applicable, after obtaining blood samples) consistently throughout trial participation. UWF (Optos) is the preferred method for fundus fluorescein angiography (FFA) capture. Study sites without Optos equipment and certification must use 7 or 4-wide field FFA capture.

[0905] Spectral domain optical coherence tomography (SD-OCT) or swept-source OCT (SS-OCT) of both eyes

[0906] image.

[0907] • Optional OCT-angiography (OCT-A) was performed in both eyes at sites with OCT-A capabilities and consent for these images to be taken.

[0908] result

[0909] The primary efficacy analysis included all randomized patients, with patients assigned according to the randomly assigned treatment group.

[0910] The primary efficacy variable is the change in BCVA as described herein. The primary efficacy analysis will use, for example, a repeated measures mixed model (MMRM) model.

[0911] Best corrected visual acuity

[0912] BCVA was measured as described. The primary efficacy outcome measure is shown in the graph showing the primary efficacy endpoint: the change in BCVA of the patient over time relative to baseline. According to the above study protocol, the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg as described in Arm B using an individualized treatment interval) was administered with, for example, Arm A (fariximab Q8W dosing) and / or Arm C (aflibercept) Q8W dosing) comparison.

[0913] Change from Baseline in Central Subfield Thickness (CST) (Study Eye)

[0914] A key secondary endpoint was the change in CST (central subdomain thickness) from baseline. CST (as well as retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in the accompanying figure, in which the change in CST over time is shown for the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg using personalized treatment intervals as described in Group B), according to the above study protocol, compared to, for example, Group A (fariximab Q8W dosing) and / or Group C (aflibercept Q8W dosing) comparison.

[0915] Further results of ocular assessment and imaging can be displayed accordingly

[0916] Example 3:

[0917] Efficacy and durability of bispecific anti-VEGF / ANG2 therapy using personalized treatment intervals in patients with macular edema secondary to retinal vein occlusion (RVO), secondary to central retinal vein occlusion (CRVO), secondary to hemiretinal vein occlusion (HRVO), or secondary to branch vein occlusion (BRVO)

[0918] Nonclinical studies have shown that in vitro, Ang-2 and VEGF act synergistically to modulate the vasculature and increase retinal endothelial cell permeability. In a laser-induced CNV model in non-human primates, simultaneous inhibition of Ang-2 and VEGF using the bispecific monoclonal antibody faricimab resulted in greater reductions in leakage and severity of choroidal neovascularization (CNV) lesions compared with molar equivalents of anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a spontaneous CNV mouse model showed that dual inhibition of Ang-2 and VEGF consistently outperformed monotherapy inhibition of either target alone in terms of reductions in vessel growth, leakage, edema, leukocyte infiltration, and photoreceptor loss (Regula JT, Lundh vonLeithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288).

[0919] In addition, aqueous and vitreous concentrations of Ang-2 and VEGF are upregulated in patients with neovascular age-related macular degeneration (nAMD), DR, and RVO (Tong JP, Chan WM, Liu DT, et al., Am J Ophthalmol 2006; 141:456-462; Penn JS, Madan A, Caldwell RB, et al., Prog Retin Eye Res 2008; 27:331-371.; Kinnunen K ...141:456-462. T, M et al., Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S, Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh vonLeithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288; Ng DS, Yip YW, Bakthavatsalam M et al., Sci Rep 2017;7:45081). Therefore, simultaneous neutralization of both targets, Ang-2 and VEGF, may further normalize pathological ocular vasculature compared to anti-VEGF therapy alone. Data from completed Phase II studies in DME and nAMD (see below) also support the hypothesis that targeting Ang-2 has the potential to extend the durability of the effect beyond anti-VEGF therapy alone in diseases affecting the retinal vasculature.

[0920] Faricimab has been studied for the treatment of nAMD and DME in two Phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME). Four global Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) in DME and GR40306 (TENAYA) and GR40844 (LUCERNE) in nAMD.

[0921] Based on the mechanism of action of faricimab, nonclinical and clinical trial data, and the pathophysiology of macular edema caused by RVO, we hypothesized that faricimab may cause stabilization of the pathological ocular vasculature and improve visual and anatomical outcomes in RVO compared with anti-VEGF monotherapy.

[0922] Macular edema secondary to / due to RVO is the most common retinal vascular disease (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994; 331: 1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016; 8: 1265-1288). The effects of Ang-2 and VEGF inhibition in nonclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288) and from phase I and phase II studies of faricimab in patients with nAMD and DME provide evidence of efficacy against common pathological pathways in all three retinal vascular diseases: nAMD, DME / DR, and macular edema due to RVO (phase I study BP28936 in nAMD; phase II studies AVENUE in nAMD, STAIRWAY in nAMD, and BOULEVARD in DME).

[0923] Because of the similarities in pathophysiology between DME and macular edema due to RVO, data from the phase II BOULEVARD study are reported here. Although the triggers of macular edema in patients with diabetes and RVO are different, the downstream pathophysiology of hypoxia-induced macular edema and subsequent vision loss is similar and driven by the same proangiogenic, proinflammatory, vascular instability, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6). Results regarding the potential for longer retreatment time with RO6867461 (fariximab, VA2) are as follows: Figure 6 as shown in . Figure 6 The time to retreatment of DME patients after cessation of dosing (after 20 weeks or 6 monthly doses = time since last intravitreal (IVT) administration) based on disease activity assessed by two measures: BCVA decrease of ≥5 letters, and CST increase of ≥50 μm (= patients with events). Bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) (administered intravitreally at 6.0 mg or 1.5 mg dose) versus ranibizumab (administered intravitreally at a dose of 0.3 mg) for comparison.

[0924] The BOULEVARD study provides preliminary evidence of a positive benefit / risk profile for fariximab 6 mg IVT injection in patients with DME and supports further evaluation of fariximab in a Phase III DME study. The study met its primary efficacy endpoint, demonstrating a statistically significant improvement in mean change from baseline in BCVA at Week 24 in anti-VEGF therapy-naïve patients treated with fariximab 6 mg compared with ranibizumab 0.3 mg.

[0925] Results from the observation period of the discontinuation study provide evidence that fariximab has a prolonged duration of action compared with anti-VEGF monotherapy.

[0926] Evaluation of the time to disease reactivation up to 16 weeks after the last dose showed that the duration of action of faricimab was superior to ranibizumab, as measured by the time to DME leading to a loss of ≥5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and an increase in central subfield thickness (CST) of ≥50 μm in a dose-dependent manner in the treatment-naive patient population. This improvement in the duration of action of faricimab compared to ranibizumab was also observed in the previously treated group and the entire patient group. Based on this totality of nonclinical and clinical evidence, treatment with faricimab may improve efficacy compared to anti-VEGF standard of care in patients with macular edema caused by RVO. In addition, this study will investigate a less frequent treatment administration schedule (up to every 16 weeks) tailored to individual needs that could provide BCVA results comparable to more frequently used anti-VEGF monotherapy (e.g., every 4 to 8 weeks). Together, these would represent important and meaningful advances over currently available therapies.

[0927] Study Design

[0928] A Phase III, multicenter, randomized, double-blind, active comparator-controlled, parallel-group study evaluating the efficacy, safety, and pharmacokinetics of faricimab (a bispecific antibody that binds to human VEGF and human ANG2, comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 (VEGFang2-0016), WO2014 / 009465, which is incorporated by reference. The name of this bispecific anti-VEGF / ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016, or faricimab) was initiated, which was administered by IVT injection at 4-week intervals until Week 24, followed by a double-blind study period without an active control, to evaluate faricimab administered according to the PTI dosing regimen in patients with macular edema secondary to / due to CRVO or HRVO or BRVO.

[0929] Overview of Study Design

[0930] This study consists of two parts: Part 1 (Day 1 to Week 24) will compare faricimab Q4W with aflibercept (active comparator) Q4W; Part 2 (Weeks 24-72) will evaluate faricimab administered in a blinded treatment interval of Q4W to Q16W according to PTI dosing criteria.

[0931] In Part 1 (Q4W dosing), approximately 680 patients will be randomized in a 1:1 ratio to one of two treatment groups during the global recruitment phase of the study, with treatment defined as follows:

[0932] - Group A (n=340): Patients randomized to Group A will receive fariximab 6 mg IVT Q4W from day 1 to week 20 (6 injections).

[0933] - Group B (comparator group, n=340): Patients randomized to Group B will receive aflibercept 2 mg IVT Q4W from day 1 to week 20 (6 injections).

[0934] In Part 2 (PTI regimen), patients in Arm A and Arm B will receive fariximab 6 mg IVT from Week 24 to Week 68 according to the PTI dosing regimen.

[0935] All patients will complete the planned study visit Q4W for the entire study duration (72 weeks). To maintain blinding to the fariximab treatment interval from Week 24 to Week 68, sham surgery will be performed during the study visit without fariximab treatment (according to the PTI dosing schedule).

[0936] Figure 7 Present an overview of the research design.

[0937] Only one eye will be designated as the study eye. If both eyes are eligible, the eye with the worse BCVA assessed at screening will be selected as the study eye unless the investigator determines that the other eye is more suitable for the study treatment. There will be at least two investigators at each site to meet the study masking requirements. At least one investigator will be designated as the assessing physician who is blinded to the treatment assignment for each patient and will make the ocular assessment. At least one other investigator will be aware of and perform the study treatment.

[0938] The study will include a screening period of up to 28 days (Days -28 to -1) and a treatment period of approximately 68 weeks, followed by a final study visit at Week 72.

[0939] Goals and End Points

[0940] This study will evaluate the efficacy, safety, and pharmacokinetics of fariximab versus aflibercept in patients with macular edema secondary to (due to) CRVO or HRVO or BRVO, up to the primary endpoint at Week 24. The efficacy, safety, and pharmacokinetics of fariximab administered according to the PTI dosing schedule (i.e., from Q4W to Q16W) will be evaluated during the study period from Week 24 to Week 72. The specific objectives and corresponding endpoints of the study are outlined below. In this protocol, "study drug" refers to fariximab or aflibercept, and "study treatment" refers to fariximab, aflibercept, or sham.

[0941] Efficacy target

[0942] For efficacy endpoint assessments, BCVA will be assessed on the ETDRS visual acuity chart at an initial testing distance of 4 meters.

[0943] Main efficacy target

[0944] The primary efficacy objective of this study was to evaluate the efficacy of fariximab 6 mg IVT Q4W compared with aflibercept 2 mg IVT Q4W based on the following endpoints:

[0945] - Change in BCVA from baseline at Week 24

[0946] Secondary efficacy targets

[0947] The secondary efficacy objectives of part 1 of this study (ie, through week 24) were to evaluate the efficacy of faricimab according to the following endpoints: Efficacy compared with aflibercept:

[0948] - Change from baseline in BCVA at designated time points through Week 24

[0949] - Proportion of patients with a BCVA gain of ≥15 letters from baseline

[0950] Week 24

[0951] - Increase in BCVA from baseline by ≥15, ≥

[0952] 10. Proportion of patients with ≥5 or >0 letters

[0953] - Avoidance of BCVA loss from baseline at specified time points through Week 24

[0954] 15. Proportion of patients with ≥10, ≥5, or >0 letters

[0955] -Proportion of patients achieving BCVA ≥84 letters (equivalent to 20 / 20 Snellen) at the specified time point through Week 24

[0956] - Proportion of patients with BCVA equivalent to Snellen 20 / 40 or better at the specified time points through Week 24

[0957] - Proportion of patients with BCVA equivalent to Snellen 20 / 200 or worse at the specified time points through Week 24

[0958] - Change from baseline in CST at designated time points through Week 24

[0959] - Change from baseline in the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) composite score at specified time points through Week 24

[0960] The secondary efficacy objectives of Part 2 of this study (i.e., Week 24 to Week 72) were based on the following endpoints: Efficacy of fariximab administered with the PTI dosing regimen:

[0961] - Change in BCVA from baseline at specified time points from Week 24 to Week 72

[0962] - Proportion of patients achieving a BCVA gain of ≥15 letters from baseline at Week 24

[0963] - Increase in BCVA from baseline at specified time points from Week 24 to Week 72

[0964] Proportion of patients with ≥15, ≥10, ≥5, or >0 letters

[0965] - Proportion of patients who achieved freedom from BCVA loss of ≥15, ≥10, ≥5, or >0 letters from baseline at specified time points from Week 24 to Week 72

[0966] - Proportion of patients achieving BCVA ≥84 letters (equivalent to 20 / 20 Snellen) at specified time points from Week 24 to Week 72

[0967] - BCVA equivalent to Snellen at specified time points from week 24 to week 72

[0968] Percentage of patients with 20 / 40 or better

[0969] - BCVA equivalent to Snellen at specified time points from week 24 to week 72

[0970] Proportion of patients with 20 / 200 or worse

[0971] - Change in BCVA relative to Week 24 at specified time points through Week 72

[0972] - Avoid BCVA loss ≥15,

[0973] Proportion of patients with ≥10, ≥5, or >0 letters

[0974] -Proportion of patients dosing on a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W treatment interval at Week 72

[0975] - Number of study drug injections received from Week 24 to Week 72

[0976] - Change from baseline in CST at specified time points from Week 24 to Week 72

[0977] - Change from baseline in NEI VFQ-25 composite score at specified time points from Week 24 to Week 72

[0978] Exploratory efficacy goals

[0979] The exploratory efficacy objectives of this study were to evaluate the efficacy of fariximab based on the following endpoints:

[0980] - Over time (at specified time points), on fundus fluorescein angiography (FFA) and

[0981] Absence of retinal ischemia on optical coherence tomography angiography (OCT-A) (optional)

[0982] The proportion of patients

[0983] - Comparison of retinal ischemic areas on FFA and OCT-A (optional) over time

[0984] Changes from baseline

[0985] - Patients with vascular leak on FFA and optionally on OCT-A over time

[0986] Proportion

[0987] - Vascular leakage on FFA and OCT-A (optional) relative to baseline over time

[0988] Line changes

[0989] - OCT-A (optional) over time, as defined in the SAP (Statistical Analysis Plan)

[0990] Change from baseline in the foveal avascular zone and other exploratory outputs—the proportion of patients without retinal neovascularization over time (according to the investigators'

[0991] Evaluate)

[0992] - Proportion of patients without vitreous, preretinal, or subretinal hemorrhage over time (based on investigator assessment)

[0993] - Proportion of patients free of anterior segment (iris and anterior chamber angle) neovascularization over time - Proportion of patients requiring panretinal photocoagulation at any time during the study - Proportion of patients free of macular edema (defined as CST ≤ 325 μm for Spectralis SD-OCT or CST ≤ 315 μm for Cirrus SD-OCT or Topcon SD-OCT) over time

[0994] - Proportion of patients without intraretinal fluid over time

[0995] - Proportion of patients without subretinal fluid over time

[0996] - Proportion of patients free of both intraretinal and subretinal fluid over time - Proportion of patients free of intraretinal cysts over time - NEI VFQ-25 near-field activities-subscale scores and remote activities-subscale scores over time

[0997] Table 1. Changes in scores from baseline

[0998] Treatment plan for part 1 (Q4W dosing)

[0999] In Part 1 of the study, patients will receive:

[1000] - Patients randomized to Arm A will receive fariximab Q4W from Day 1 to Week 20

[1001] - Patients randomized to Arm B will receive aflibercept Q4W Part 2 treatment schedule from Day 1 to Week 20 (Personalized Treatment Interval (PTI) regimen)

[1002] In part 2 of the study, all patients will visit Q4W from Week 24 to Week 68 and receive either sham treatment or fariximab 6 mg IVT, depending on their PTI dosing regimen.

[1003] The fariximab PTI decision will be automatically calculated based on the PTI criteria described in this section.

[1004] The study drug dosing interval decision in the PTI group was based on the algorithm described in this section. The fariximab dosing visit was defined as the visit when the patient received fariximab 6 mg IVT.

[1005] Starting at Week 24, patients will receive faricimab Q4W until the CST reaches a predefined reference CST threshold (<325 mm for Spectralis SD-OCT or <315 mm for Cirrus SD-OCT and Topcon SD-OCT) as determined by CRC. Figure 8 After the patient's initial reference CST is established, if the CST value is stable (i.e., has not increased or decreased by >10%) and there is no associated visual acuity change relative to the reference BCVA (e.g., Figure 8 If the patient loses ≥10 letters in the sera (described in the instructional text and defined below), the patient is eligible to increase the fariximab dosing interval in 4-week increments.

[1006] Reference CST and reference BCVA (in Figure 8 and in the captions of the accompanying drawings, see letter a and b ) have the following meanings:

[1007] aReference Central Subfield Thickness (CST): The CST value at which the initial CST threshold criteria are met. If the CST at two consecutive study drug administration visits decreases by >10% from the previous reference CST and the values ​​obtained are within 30 μm, the reference CST is adjusted. Immediately starting from that visit, the CST value obtained at the latter visit will be used as the new reference CST.

[1008] b Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[1009] The maximum and minimum treatment intervals that can be assigned will be Q16W and Q4W, respectively. Patients who have previously had their dosing interval extended and who experience an exacerbation that results in a shortening of the interval will not be allowed to have their dosing interval extended again, except for patients whose dosing interval is shortened to Q4W; their interval may be extended again, but only to an interval that is 4 weeks shorter than the original maximum extension. For example, if a patient's interval is shortened from Q12W to Q8W, that patient's interval will not be extended beyond Q8W for the remainder of the treatment period. If a patient's interval is shortened from Q16W to Q4W, that patient's interval may be extended to a maximum of Q12W, but not back to Q16W.

[1010] Determination of the interval of fariximab (RO6867461 / RG7716 / VEGFang2-0016)

[1011] The following and Figure 8 An algorithm for interval decision making based on the relative change in CST and BCVA at the fariximab dosing visit compared to the reference CST and reference BCVA is outlined. The fariximab dosing interval will be extended, maintained, or shortened as follows.

[1012] - Extended interval by 4 weeks

[1013] If the CST value increases or decreases by ≤10% without an associated decrease in BCVA by ≥10 letters

[1014] - The interval is maintained if any of the following criteria are met:

[1015] If the CST value decreases by >10%

[1016] If the CST value decreases ≤10% with an associated BCVA decrease of ≥10 letters If the CST value increases between >10% and ≤20% without an associated BCVA decrease of ≥5 letters

[1017] - The interval is shortened by 4 weeks if any of the following criteria are met:

[1018] If the CST value increase is between >10% and ≤20% and there is an associated BCVA decrease of ≥5 to <10 letters

[1019] If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters

[1020] If the CST value increases by ≤10% and has an associated BCVA decrease of ≥10 letters

[1021] -Interval shortened to Q4W

[1022] If the CST value increases by >10% and has an associated BCVA decrease of ≥10 letters

[1023] As described above, the algorithm for personalized medication interval decisions is based on the relative change in CST and the absolute change in BCVA compared with the reference CST and BCVA, respectively.

[1024] The algorithm can be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to a web interface of a personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the time of the next dose. The tool can further provide a dosing schedule or notification, monitor and generate a visualization of changes in dosing intervals for a given patient, generate a visualization of changes in dosing intervals for a patient group, aggregate received CST and BCVA data to determine trends, or a combination thereof.

[1025] Dosing schedules or notifications may include display of calendar dates for scheduled dosing visits and calendar reminders notifying the clinician or patient of upcoming dosing visits. Visualizations of changes in dosing intervals may include, for example, Figure 8 . In one case, a patient's dosing interval adjustment might be shown in one color, and the patient's previous dosing interval adjustment might be shown in another color. For example, a patient might first extend their interval by 4 weeks and then maintain their personalized treatment interval. The tool can be used to Figure 8 A visualization of a patient's personalized interval progression is generated by showing the "Interval Maintenance" area of ​​the schematic in the figure and "Interval Extension by 4 Weeks" in yellow. The green color reflects the patient's most recent interval calculation, while the yellow color depicts the patient's previous interval calculation. With this visualization, users of the tool can quickly identify that a patient's disease progression is improving, but not improving enough to extend their treatment interval longer.

[1026] The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis can include visualizations of dosing changes for a single patient, similar to the color-coded example described previously. Alternatively, visualizations can show dosing adjustments across patient groups. For example, a visualization can show which patients have interval extensions and which patients have interval shortenings. The visualizations can be organized by various features, such as patient age, previous treatments, disease state, antibodies administered, clinical trial groups, etc. The tool can also aggregate and create visualizations from patient CST and BCVA data. Visualizations can show trends in the data to facilitate or generate longitudinal analysis. These visualizations may include reminders, plots, analysis workflow interfaces, or any graphical interface.

[1027] The tool can generate a dosing plan output or visualization in response to or in conjunction with an ocular assessment and image. In one embodiment, the tool can directly calculate the patient's CST or BVCA. For CST, the tool can receive or directly capture an ocular image. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST from an ocular image. For BCVA, the tool can virtually manage the ocular assessment, prompting and collecting patient user input through a user interface or through an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing plan accordingly.

[1028] The present embodiment may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient with an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving patient data including the patient's CST and best corrected visual acuity (BCVA) at a computing system; using the computing system, extending, shortening, or maintaining the dosing interval based on a comparison of the received patient data with a corresponding reference CST and BCVA; and generating a PTI from the dosing interval. An exemplary dosing interval is extended by 4 weeks if the CST value increases or decreases by ≤10% without an associated decrease in BCVA of ≥10 letters. An exemplary dosing interval is maintained if any of the following criteria are met: if the CST value increases by >10%; or if the CST value decreases by ≤10% with an associated decrease in BCVA of ≥10 letters; or if the CST value increases by >10% to ≤20% without an associated decrease in BCVA of ≥5 letters. The exemplary dosing interval is shortened to 4 weeks if any of the following criteria are met: if the CST value increases by >10% to ≤20% with an associated decrease in BCVA of ≥5 to <10 letters, or if the CST value increases by >20% with an associated decrease in BCVA of ≥10 letters, or if the CST value increases by ≤10% with an associated decrease in BCVA of ≥10 letters. If the CST value increases by >10% with an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is shortened to Q4W.

[1029] This method of providing a personalized dosing plan based on a personalized treatment interval (PTI) for treating a patient having an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion can further include receiving updated patient data at a computing system; continuing to update or maintain the dosing interval, using the computing system, based on the updated patient data; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[1030] The present embodiment also includes using a personalized dosing plan according to a personalized treatment interval (PTI) (for treating macular edema selected from secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion, or secondary to branch vein occlusion), wherein the computing system generates the PTI by receiving patient data including the patient's CST and best corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to the corresponding reference CST and BCVA. If the CST value increases or decreases by ≤10% without an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is extended by 4 weeks. The exemplary dosing interval is maintained if any of the following criteria are met: if the CST value increases by >10%; or if the CST value decreases by ≤10% and has an associated decrease in BCVA of ≥10 letters; or if the CST value increases by >10% to ≤20% without an associated decrease in BCVA of ≥5 letters. The exemplary dosing interval is shortened to 4 weeks if any of the following criteria are met: if the CST value increases by >10% to ≤20% with an associated decrease in BCVA of ≥5 to <10 letters, or if the CST value increases by >20% with an associated decrease in BCVA of ≥10 letters, or if the CST value increases by ≤10% with an associated decrease in BCVA of ≥10 letters. If the CST value increases by >10% with an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is shortened to Q4W.

[1031] Eye assessment

[1032] Unless otherwise specified, ocular assessments will be performed on both eyes at designated time points according to the activity plan. The assessment will include:

[1033] - Refraction and BCVA assessed on the ETDRS eye chart at a starting test distance of 4 meters (performed prior to pupil dilation)

[1034] - Predose IOP measurement in both eyes (performed before mydriasis)

[1035] -Slit lamp examination (grading scale for anterior cells and vitreous cells)

[1036] -Dilated binocular indirect high-power ophthalmoscopy

[1037] - Finger counting test, followed by hand movement and light perception testing (if necessary), performed in the study eye only, during approximately 15 minutes of study treatment

[1038] - Post-dose IOP in the study eye only 30 (±15) minutes after study treatment administration

[1039] Intraocular pressure measurement

[1040] Patients will be allowed to leave the clinic if there are no safety concerns after 30 (± 15) minutes after study treatment administration. If the IOP value is of concern to the treating administrator / informed investigator, the patient will remain in the clinic and be managed according to the clinical judgment of the treating administrator / informed investigator. Adverse events will be recorded on the Adverse Event Electronic Case Report Form (eCRF), if applicable.

[1041] - The IOP measurement method used for patients must be consistent throughout the study eye imaging

[1042] After randomization, if a patient missed a study visit when color fundus photography (CFP) and fundus fluorescein angiography (FFA) masked images were scheduled, or if the images were not obtained at the scheduled visit (e.g., because of equipment damage), they should be obtained at the next scheduled visit that the patient attended.

[1043] Eye images include the following:

[1044] -FFA of the study eye

[1045] - CFP of the study eye

[1046] - Spectral domain optical coherence tomography (SD-OCT) or swept source OCT (SS-OCT) of the study eye

[1047] OCT images

[1048] - Optional OCT-A of the study eye at a site with OCT-A capability (provided the site approves optional sampling)

[1049] For patients diagnosed with bilateral RVO at screening, CFP and OCT images of the fellow eye were also captured and stored at the CRC.

[1050] result

[1051] The primary efficacy analysis included all randomized patients, with patients assigned according to the randomly assigned treatment group.

[1052] The primary efficacy variable is the change in BCVA. The primary efficacy analysis will use, for example, a repeated measures mixed model (MMRM) model.

[1053] Best corrected visual acuity

[1054] BCVA was measured as described. The primary efficacy outcome measure is shown in the graph showing the primary efficacy endpoint: the change in BCVA of the patient over time relative to baseline. According to the above study protocol, the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg as described in Group A using personalized treatment intervals) was compared with, for example, Group B (aflibercept In part 1 of the study) comparison.

[1055] Change from Baseline in Central Subfield Thickness (CST) (Study Eye)

[1056] A key secondary endpoint was the change in CST (central subdomain thickness) from baseline. CST (as well as retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in the accompanying figure, in which the change in CST over time is shown for the bispecific anti-VEGF / ANG2 antibody RO6867461 (fariximab) comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (administered intravitreally at 6.0 mg using personalized treatment intervals as described in Group A), according to the above study protocol, compared to, for example, Group B (aflibercept In part 1 of the study) comparison.

[1057] Further results of the eye assessment and imaging may be displayed accordingly.

[1058] Example 4

[1059] Binding of anti-VEGF / ANG2 antibodies to VEGF, Ang2, FcγR, and FcRn

[1060] VEGF isoform kinetic affinity, including species cross-reactivity assessment

[1061] Approximately 12,000 resonance units (RU) of the capture system (10 μg / ml goat anti-human F(ab)'2; product number: 28958325; GE Healthcare Bio-Sciences AB, Sweden) were coupled to a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 using an amine coupling kit provided by GE Healthcare. The sample and system buffers were PBS-T (10 mM phosphate-buffered saline containing 0.05% 20) pH 7.4. The flow cell was set to 25°C, while the sample block was set to 12°C and perfused twice with running buffer. The antibodies were captured by injecting a 50 nM solution at a flow rate of 5 μl / min, with an injection time of 30 seconds. The association was measured by injecting human hVEGF121, mouse mVEGF120 or rat rVEGF164 in solutions of various concentrations starting from 300 nM at a 1:3 dilution at a flow rate of 30 μl / min, with an injection time of 300 seconds. The dissociation phase was monitored for up to 1200 seconds and triggered by switching from the sample solution to the running buffer. The surface was regenerated by washing with a glycine (pH 2.1) solution at a flow rate of 30 μl / min for 60 seconds. Large refractive index deviations were corrected by subtracting the response obtained from the goat anti-human F(ab')2 surface. Blank injections (= double reference) were also subtracted. In order to calculate the apparent K D For other kinetic parameters, the Langmuir 1:1 model was used. The results are shown in Table 5.

[1062] Ang2 solution affinity, including species cross-reactivity assessment

[1063] Solution affinity measures the affinity of an interaction by determining the concentration of the free interaction partner in an equilibrium mixture. Solution affinity assays involve holding a constant concentration of <vegf-ang-2>The bispecific antibody was mixed with different concentrations of ligand (=Ang2). The antibody was immobilized on the surface of a CM5 chip (GE Healthcare BR-1005-30) at maximum possible resonance units (e.g. 17000 resonance units (RU)) using an amine coupling kit provided by GE Healthcare at pH 5.0. The sample and system buffer was HBS-P pH 7.4. The flow cell was set to 25°C, while the sample block was set to 12°C and perfused twice with running buffer. To generate a calibration curve, increasing concentrations of Ang2 were injected into a BIAcore containing immobilized VEGF-ANG-2> bispecific antibody. TM flow cell. The amount of bound Ang2 was determined as resonance units (RU) and plotted against concentration. Solutions of each ligand (11 concentrations of VEGF-ANG-2>bispecific antibody, 0 to 200 nM) were incubated with 10 nM Ang2 and allowed to equilibrate at room temperature. The free Ang2 concentration was determined from a calibration curve generated before and after measuring the response of known amounts of Ang2 solutions. Using model 201, a 4-parameter fit was set up using XLfit4 (IDBS software), with the concentration of free Ang2 used as the y-axis and the concentration of the antibody used for inhibition used as the x-axis. The affinity was calculated by determining the inflection point of the curve. The surface was regenerated by washing with 0.85% H3PO4 solution at a flow rate of 30 μl / min for 30 seconds. The bulk refractive index difference was corrected by subtracting the response obtained from the blank coupled surface. The results are shown in the table below.

[1064] FcRn steady-state affinity

[1065] For FcRn measurements, steady-state affinity was used to compare bispecific antibodies against each other. Human FcRn was diluted into coupling buffer (10 μg / ml, sodium acetate pH 5.0) and quantified by using BIAcore TM The targeted immobilization program of the guide was immobilized on a C1 chip (GE Healthcare BR-1005-35) to a final response of 200 RU. The flow cell was set at 25°C, while the sample block was set at 12°C and perfused twice with running buffer. The sample and system buffers were PBS-T (10 mM phosphate buffered saline containing 0.05% 20) pH 6.0. In order to evaluate different IgG concentrations of each antibody, concentrations of 62.5nM, 125nM and 250nM, 500nM were prepared. The flow rate was set to 30μl / min, and different samples were continuously injected onto the chip surface, and an association time of 180 seconds was selected. The surface was regenerated by injecting PBS-T pH 8 at a flow rate of 30μl / min, and the injection time was 60 seconds. The bulk refractive index difference was corrected by subtracting the response obtained from the blank surface. Buffer injection (= double reference) was also subtracted. In order to calculate steady-state affinity, a method from Bia-Evaluation software was used. In short, the RU value (RU maximum) was plotted against the analyzed concentration to generate a dose response curve. Based on a 2-parameter fit, the upper asymptote was calculated, allowing the determination of the half-maximum RU value to determine the affinity. The results are shown in the table below. Similarly, the affinity for cynomolgus monkey, mouse and rabbit FcRn can be determined.

[1066] FcγRIIIa measurement

[1067] For FcγRIIIa measurement, direct binding assay was used. At pH 5.0, the capture system (1 μg / ml Penta-His; Qiagen) of about 3000 resonance units (RU) was coupled to a CM5 chip (GE Healthcare BR-1005-30) using an amine coupling kit provided by GE Healthcare. The sample and system buffer were HBS-P+pH 7.4. The flow cell was set to 25°C, while the sample block was set to 12°C and perfused twice with running buffer. The FcγRIIIa-His-receptor was captured by injecting 100nM solution at a flow rate of 5μl / min, and the injection time was 60 seconds. Combination was measured by injecting 100nM bispecific antibodies or monospecific control antibodies (anti-Dig for IgG1 subclass and IgG4 subclass antibodies) at a flow rate of 30μl / , and the injection time was 180 seconds. The surface was regenerated by washing with a glycine (pH2.5) solution at a flow rate of 30μl / min for 120 seconds. Since FcγRIIIa binding is different from the Langmuir 1:1 model, this assay only determines binding / no binding. In a similar manner, binding of FcγRIa and binding of FcγRIIa can be determined. The results are shown in the table below. As a result, if the mutation P329GLALA is introduced, binding to FcγRIIIa can no longer be detected.

[1068] VEGF and Ang2 are independently associated with <vegf-ang-2>Evaluation of bispecific antibody binding

[1069] Approximately 3500 resonance units (RU) of the capture system (10 μg / ml goat anti-human IgG; GE Healthcare Bio-Sciences AB, Sweden) were coupled to a CM4 chip (GE Healthcare BR-1005-34) at pH 5.0 using an amine coupling kit provided by GE Healthcare. The sample and system buffers were PBS-T (10 mM phosphate-buffered saline containing 0.05% 20) pH 7.4. The temperature of the flow cell was set to 25° C., while the temperature of the sample block was set to 12° C. Prior to capture, the flow cell was primed twice with running buffer.

[1070] The antibody was captured by injecting a 10 nM solution at a flow rate of 5 μl / min for 60 seconds. The binding of each ligand to the bispecific antibody was analyzed independently by determining the active binding capacity of each ligand, added sequentially or simultaneously (flow rate of 30 μl / min):

[1071] 1. Inject human VEGF at a concentration of 200 nM for 180 seconds (to identify a single binding of the antigen).

[1072] 2. Injection of human Ang2 at a concentration of 100 nM for 180 seconds (identification of single binding of antigen).

[1073] 3. Inject human VEGF at a concentration of 200 nM for 180 seconds, and then inject human Ang2 at a concentration of 100 nM for 180 seconds (to identify the binding of Ang2 in the presence of VEGF).

[1074] 4. Inject human Ang2 at a concentration of 100 nM for 180 seconds, followed by an injection of human VEGF at a concentration of 200 nM (to identify VEGF binding in the presence of Ang2).

[1075] 5. Human VEGF at a concentration of 200 nM and human Ang2 at a concentration of 100 nM were co-injected for 180 seconds (the binding of VEGF and the binding of Ang2 were determined simultaneously).

[1076] The surface was regenerated by washing with 3 mM MgCl2 solution at a flow rate of 30 μl / min for 60 seconds. Large refractive index deviations were corrected by subtracting the response obtained from a goat anti-human IgG surface.

[1077] If the resulting final signals of methods 3, 4 and 5 are equal to or similar to the sum of the individual final signals of methods 1 and 2, the bispecific antibody is able to bind to both antigens independently of each other. The results are shown in the table below, where VEGFang2-0016 (=RO6867461) is shown to be able to bind to VEGF and ANG2 independently of each other

[1078] Simultaneous expression of VEGF and Ang2 <vegf-ang-2>Evaluation of bispecific antibody binding

[1079] First, approximately 1600 resonance units (RU) of VEGF (20 μg / ml) were coupled to a CM4 chip (GE Healthcare BR-1005-34) at pH 5.0 using an amine coupling kit provided by GE Healthcare. The sample and system buffers were PBS-T (10 mM phosphate buffered saline containing 0.05% 20) pH 7.4. The flow cell was set to 25°C and the sample block was set to 12°C and primed twice with running buffer. Second, a 50 nM bispecific antibody solution was injected at a flow rate of 30 μl / min for 180 seconds. Third, hAng-2 was injected at a flow rate of 30 μl / min for 180 seconds. The binding response of hAng-2 depended on the amount of bispecific antibody bound to VEGF and showed simultaneous binding. The surface was regenerated by washing with 0.85% H3PO4 solution at a flow rate of 30 μl / min for 60 seconds. Simultaneous binding of hAng2 to previously bound VEGF <vegf-ang-2>Additional specific binding signals of the bispecific antibodies were shown.

[1080] Table: Results: Kinetic affinity for VEGF isoforms from different species

[1081] VEGFang2-0016-apparent affinity Human VEGF 121 ≤1pM (outside Biacore specification) Mouse VEGF 120 No combination Rat VEGF 164 14nM

[1082] Table: Results: Solution affinity to Ang2

[1083] VEGFang2-0016 KD[nM] humanAng2 20 cynoAng2 13 mouseAng2 13 rabbitAng2 11

[1084] Table: Results: <vegf-ang-2>Affinity of bispecific antibodies for FcRn

[1085] VEGFang2-0016[Affinity] Human FcRn No combination Cynomolgus FcRn No combination Mouse FcRn No combination

[1086] Table: Results of binding to FcgammaIIIa

[1087] VEGFang2-0016 FcRIIIa No combination

[1088] Table: Results: VEGF and Ang2 and <vegf-ang-2>Independent binding of bispecific antibodies

[1089] < / vegf>

Claims

1. Use of a unit dose comprising 6 mg of faricimab in the preparation of a medicament for treating an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), or for treating a patient suffering from an ocular vascular disease selected from nAMD and DME, wherein the treatment comprises a personalized treatment interval (PTI).

2. The use according to claim 1, wherein the ocular vascular disease is nAMD.

3. The method according to claim 2, wherein the personalized treatment interval comprises: a) Patients were first treated with faciliximab 4 times at a dosing interval of every 4 weeks (Q4W) b) At Weeks 20 and 24, disease activity was assessed, whereby disease activity was determined if one of the following criteria was met: i) Central subfield thickness (CST) increases by >50 μm compared to the average CST values ​​of the two previous scheduled visits, with the scheduled visits at Weeks 12 and 16 used for the Week 20 assessment and the scheduled visits at Weeks 16 and 20 used for the Week 24 assessment, or ii) CST increased by ≥75 μm compared with the lowest CST value recorded in any of the first two planned examinations; iii) The best corrected visual acuity (BCVA) is reduced by ≥5 letters compared with the average BCVA of the previous two scheduled examinations, iv) a decrease in BCVA of ≥10 letters from the highest BCVA recorded at either of the two previous scheduled visits, or v) New macular hemorrhages due to nAMD activity c) Then, the patient i) Patients who meet disease activity criteria at Week 20 will be treated at an 8-week (Q8W) dosing interval starting at Week 20 (with the first Q8W dose at Week 20); ii) Patients who meet disease activity criteria at Week 24 will be treated at a 12-week (Q12W) dosing interval starting at Week 24 (with the first Q12W dose at Week 24); as well as iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated at a every 16 weeks (Q16W) dosing interval starting from Week 28 (with the first Q16W dose at Week 28).

4. The use according to claim 3, wherein the personalized treatment interval will be extended, shortened or maintained after week 60, wherein a) In cases where all of the following criteria are met, the interval is extended by 4 weeks (to a maximum of Q16W): i) CST is stable compared to the average of the 2 most recent study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥50 μm compared to the lowest study drug administration visit measurement, ii) no decrease in BCVA of ≥5 letters compared to the mean of the two most recent study drug visit measurements and compared to the highest study drug visit measurement, No decrease in BCVA of ≥10 letters, iii) No new macular hemorrhage b) If one of the following criteria is met, the interval is shortened by 4 weeks (to a minimum of Q8W), or The interval is shortened to 8 weeks if two or more of the following criteria are met, or if one criterion includes a new macular hemorrhage: i) CST increased by ≥50 μm compared to the average of the two most recent dosing examinations, or CST increased by ≥75 μm compared to the lowest dosing examination measurement; ii) BCVA decrease of ≥5 letters compared with the average of the two most recent dosing visits; or a decrease in BCVA of ≥10 letters compared with the highest dosing examination measurement; iii) New macular hemorrhage.

5. The use according to claim 1, wherein the ocular vascular disease is DME.

6. The method according to claim 5, wherein the personalized treatment interval (PTI) comprises: a) patients are initially treated with the fariximab at a 4-week (Q4W) dosing interval until the central subdomain thickness (CST) reaches a predetermined reference CST threshold, as measured at or after Week 12; b) Then, the dosing interval is increased by 4 weeks to an initial Q8W dosing interval; c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment performed at the dosing visit, which is based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA; in i) The said interval is extended by 4 weeks in the following cases: - If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters; ii) The interval will be maintained if: - If the CST decreases by >10%, or - If the CST value increases or decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or - If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters; iii) The interval is shortened by 4 weeks in the following cases: - if the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or - An increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters; iv) if the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, the interval is shortened by 8 weeks; wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

7. The use according to claim 6, wherein the dosing interval can be adjusted in increments of 4 weeks to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

8. Use of a unit dose comprising 6 mg of fariximab for the preparation of a medicament for treating an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, or for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemi-retinal vein occlusion or secondary to branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI), wherein a) Patients were first treated with the fariximab at a 4-week (Q4W) dosing interval from day 1 to week 20 b) From week 24, patients received the fariximab at a frequency of Q4W until the central subdomain thickness (CST) reached the predetermined reference CST threshold; c) extending, shortening or maintaining the dosing interval from this time point onwards based on the assessment made at the dosing visit, the assessment being based on the relative change in CST and best corrected visual acuity (BCVA) compared to the corresponding reference CST and BCVA; in i) The interval is extended by 4 weeks in the following cases If the CST value increases or decreases by ≤10% without an associated BCVA decrease of ≥10 letters; or ii) The interval is maintained if any of the following criteria is met: If the CST value decreases by >10%; or If the CST value decreases by ≤10% and the associated BCVA decreases by ≥10 letters; or If the CST value increased by >10% and ≤20% without an associated BCVA decrease of ≥5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: If the CST value increases by >10% and ≤20% with an associated BCVA decrease of ≥5 to <10 letters; or If the CST value increases by >20% without an associated decrease in BCVA of ≥10 letters; or If the CST value increased by ≤10% and the associated BCVA decreased by ≥10 letters; iv) In the following cases, the interval is shortened to Q4W If the CST value increases by >10% and the associated BCVA decreases by ≥10 letters, wherein the corresponding reference central subdomain thickness (CST) is the CST value at which the initial CST threshold criteria are met, and if the CST decreases by >10% from the previous reference CST between two consecutive dosing visits and the values ​​obtained are within 30 μm, then the reference CST is adjusted so that the CST value obtained at the later visit will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) was the mean of the three best BCVA scores obtained at any prior dosing visit.

9. The use according to claim 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

10. The use according to any one of claims 1 to 9, wherein the fariximab is administered at a concentration of about 120 mg / ml.

11. Use according to any one of the preceding claims, wherein the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy.

12. Use according to any one of the preceding claims, wherein the patient suffering from an ocular vascular disease has previously been treated with an anti-VEGF therapy.

13. Use according to any one of the preceding claims, wherein the antibody is administered according to a determination made by a software tool.

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