Personalized treatment of ophthalmologic diseases

Abstract

To provide antibodies for use in the treatment of ophthalmic vascular diseases such as diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO).SOLUTION: Provided is a bispecific antibody which binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2), for use in treatment of an ocular vascular diseases selected from neovascular AMD (nAMD) and diabetic macular edema (DME) or of patients suffering from an ocular vascular diseases selected from neovascular AMD (nAMD) and diabetic macular edema (DME). Therein the treatment includes a personalized treatment interval (PTI).SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to antibodies that bind VEGF and ANG2 for use in the treatment of ophthalmic vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] or wet AMD secondary to age-related macular degeneration [AMD]), diabetic retinopathy, in particular diabetic macular edema (DME), or macular edema secondary to retinal vein occlusion (RVO). [Background technology]

[0002] Ophthalmic vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] or wet AMD secondary to age-related macular degeneration [AMD]), diabetic retinopathy, and especially diabetic macular edema (DME) are severe diseases that often lead to vision loss and blindness.

[0003] Neovascular age-related macular degeneration (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD) is a form of advanced AMD that causes rapid and severe vision loss and remains the leading cause of visual impairment in older adults (Bourne et al. Lancet Glob Health 2013;1:e339-49; Wong et al. Lancet Glob Health 2014;2:e106-16).

[0004] 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, causing severe, irreversible loss of central vision if left untreated.

[0005] Prior to anti-vascular endothelial growth factor (anti-VEGF) agents, laser photocoagulation and photodynamic therapy with verteporfin were standard treatments and have been shown to stabilize vision. Although such treatments remain treatment options for selected patients, the treatment of nAMD has been significantly improved with the introduction of biomolecules that target VEGF-A, a key factor in pathological angiogenesis (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 the first approval of Lucentis® (ranibizumab) in 2006, the impressive benefits of anti-VEGF therapy and its ability to restore vision have been widely recognized (American Academy of Ophthalmology 2015).

[0006] A significant challenge with currently available anti-VEGF treatments is the need for frequent and long-term administration to maintain vision gain (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 optimally, and this undertreatment in clinical practice is associated with lower visual acuity (VA) gains compared to those observed in administered 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 frequent burden of treatment on patients, caregivers, and healthcare systems (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), a complication of diabetic retinopathy (DR), can develop at any stage of underlying disease of the retinal microvasculature (Fong et al. Diabetes Care 2004;27:2540-53). DME develops more frequently as the underlying DR worsens, 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 result in a loss of 10 or more letters of visual acuity (VA) within two 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 seen in both type 1 and type 2 diabetes patients (Girach and Lund-Andersen Int J Clin Practice 2007;61:88-97). In 2013, the global patient population with diabetes was approximately 382 million, and is estimated to increase to 592 million by 2035 (International Diabetes Federation 2013).

[0008] With advances in imaging technology, DME is now often diagnosed by optical coherence tomography (OCT) rather than the traditional Early Treatment Diabetic Retinopathy Study (ETDRS) ophthalmoscopy-based criteria. At the molecular level, DME is the result of vascular endothelial growth factor-A (VEGF-A)-mediated increased vascular permeability and loss of pericytes, leading to proangiogenic, hyperpermeable, and hypoxia-mediated release of proinflammatory mediators (Antonetti et al. Semin Ophthalmol 1999;14:240-8). VEGF also upregulates angiopoietin-2 (Ang-2), a homeostatic factor that acts as an antagonist of the Tie2 receptor tyrosine kinase on endothelial cells, preventing vascular stabilization maintained by Ang-1-dependent Tie2 activation. Thus, Ang-2 functions as a vascular destabilizing factor, rendering the vasculature more elastic and prone to endothelial barrier breakdown and sprouting. Excessive Ang-2 and VEGF in retinal tissue promotes vascular instability, vascular leakage, and angiogenesis. Ang-2 is also involved in inflammatory pathways such as lymphocyte recruitment. In summary, both VEGF-A and Ang-2 are recognized as important factors mediating the pathogenesis of diabetic eye disease (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] Macular laser has been the standard of care (SOC) for the treatment of DME, but the development of anti-VEGF drug therapies over the past decade has dramatically improved visual outcomes for patients with DME. Currently available anti-VEGF therapies for DME include ranibizumab and aflibercept. Other approved options available for the treatment of DME include periocular or intravitreal (IVT) steroids and steroid implants.

[0010] Despite the robust efficacy achieved with anti-VEGF therapy in DME, a significant proportion of patients do not experience clinically meaningful improvements in vision in the real world. Frequent IVT administration is necessary to achieve, and in some cases, maintain, the observed early benefits of DME treatment over the long term. The current SOC for administration of anti-VEGF injections requires patients to undergo frequent laboratory testing and IVT injections. This places a significant burden on patients, caregivers, treating physicians, and the healthcare system.

[0011] Large-scale phase III trials of anti-VEGF agents in DME have shown that after the first year of treatment, the number of injections required to maintain visual gains can be reduced (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 the absence of validated predictive biomarkers for treatment frequency to achieve optimal outcomes, standard anti-VEGF approaches in DME still rely on frequent monitoring visits, placing a significant burden on patients and healthcare providers. Furthermore, anti-VEGF monotherapy does not adequately address other pathways that contribute to the deterioration of diabetic eye disease, including inflammation and pericyte destabilization.

[0012] To address the high unmet medical need in DME, novel therapies that target additional pathways and reduce the burden of IVT infusions are needed. Summary of the Invention

[0013] According to one aspect of the present invention, a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation is provided for the treatment of a patient suffering from an ophthalmic 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 binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in a personalized treatment interval (PTI) regimen, the treatment of a patient suffering from an ophthalmic vascular disease selected from nAMD and DME comprising a dosing schedule that extends the dosing interval in the stable absence of disease or shortens the dosing interval in the presence of disease activity. In this way, the patient is optimally treated, ensuring improved and / or maintained vision, while reducing unnecessary treatment burden.

[0014] According to another aspect of the present invention, a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation is provided for the treatment of a patient suffering from certain neovascular AMD (nAMD) (also called wet AMD (wAMD)), 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) in a personalized treatment interval (PTI) regimen, wherein the treatment of the patient suffering from nAMD includes a dosing schedule that extends the dosing interval when the disease is unstable or shortens the dosing interval when there is disease activity. In this way, the patient is optimally treated, ensuring improved and / or maintained vision, while reducing unnecessary treatment burden.

[0015] According to one aspect of the invention, a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation is provided for the treatment of a patient suffering from a disease, 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),

[0016] Treatment of patients with AMD involves a dosing schedule in which, after initiation of treatment, the dosing interval is extended if the disease is stable, or the interval is shortened if disease activity is present.

[0017] One embodiment is such a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for the treatment of a patient suffering from 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) at individualized treatment intervals, a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of 4 doses, every 4 weeks (Q4W); b) Disease activity will be assessed at weeks 20 and 24. Disease activity will be assessed according to the following criteria: i) There is an increase in central subfield thickness (CST) of more than 50 μm compared to the mean CST values ​​of the previous two scheduled visits, which are weeks 12 and 16 for the week 20 assessment and weeks 16 and 20 for the week 24 assessment, or ii) an increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the two previous scheduled visits; iii) A decrease in best corrected visual acuity (BCVA) of 5 or more letters compared with the mean BCVA value at the previous two scheduled visits due to nAMD disease activity; iv) A loss of 10 or more letters of BCVA due to nAMD disease activity compared to the highest BCVA value recorded at any of the two previous scheduled visits, or v) the presence of new macular hemorrhage due to nAMD activity; c) Next, the patient i) Patients who meet disease activity criteria at week 20 will be treated at a dosing interval of every 8 weeks (Q8W) from week 20 onwards (first Q8W dose at week 20); ii) patients who meet disease activity criteria at week 24 will be treated at a dosing interval of every 12 weeks (Q12W) from week 24 onwards (first Q12W dose at week 24); iii) Patients who do not meet disease activity criteria at weeks 20 and 24 will be treated with 16-week (Q16W) dosing intervals beginning at week 28 (first Q16W dose at week 28).

[0018] In one embodiment, the individualized treatment interval is extended, shortened, or maintained after week 60; a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval is reduced by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) The presence of new macular hemorrhage.

[0019] According to another aspect of the present invention, a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation is provided for the treatment of a patient suffering from diabetic retinopathy, in particular diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody binding human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in a personalized treatment interval (PTI) regimen, the treatment of the patient suffering from DME comprising a dosing schedule with extended dosing intervals when the disease is not stable and shortened dosing intervals when disease activity is present. In this way, the patient is optimally treated, ensuring improved and / or maintained vision, while reducing unnecessary treatment burden.

[0020] One embodiment is such a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for the treatment of a patient suffering from 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) at individualized treatment intervals, a) Patients will be initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) until the central subfield thickness (CST) meets a predefined reference CST threshold (measured after week 12) (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT, or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT); b) The dosing interval is then increased by 4 weeks to an initial dosing interval of every 8 weeks (Q8W); c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) if there was a >10% increase in CST value with an associated loss of BCVA of ≥10 letters, the interval was reduced by 8 weeks; Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0021] In one embodiment, such dosing intervals may be adjusted in 4 week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0022] According to another aspect of the present invention, a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation is provided for the treatment of a patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion, comprising administering to the patient an effective amount of a bispecific antibody binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in a personalized treatment interval (PTI) regimen, wherein the treatment of the patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion comprises a dosing schedule in which the dosing interval is extended if the disease is not stable or the interval is shortened if there is disease activity. In this way, the patient is optimally treated, ensuring improved and / or maintained vision, while reducing unnecessary treatment burden.

[0023] One embodiment is such a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for the treatment of a patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal 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) in an individualized treatment interval regimen; a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from Day 1 to Week 20; b) From week 24, patients receive bispecific VEGF / ANG2 antibody at a frequency of Q4W until central subfield thickness (CST) meets a predefined reference CST threshold; c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST score without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increased by >10% with an associated BCVA loss of ≥10 letters, the interval was shortened to Q4W. Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0024] In one embodiment, such dosing intervals may be adjusted in 4 week increments up to every 16 weeks (Q16W) and a minimum of Q4W. In one embodiment of the invention, the bispecific antibody that binds human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) The bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass containing the mutations I253A, H310A, and H435A, and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat).

[0025] In one embodiment of the present invention, the patient suffering from an ophthalmic vascular disease has not been previously treated with an anti-VEGF therapy (eg, monotherapy) (treatment naive).

[0026] In one embodiment of the present invention, the patient suffering from an ophthalmic vascular disease has previously been treated with an anti-VEGF therapy (eg, monotherapy).

[0027] In one embodiment of the present invention, the disclosed bispecific antibodies are administered according to the determination of a software tool. [Brief description of the drawings]

[0028] [Figure 1]Figure 1 outlines the study design for nAMD. a At weeks 20 and 24, patients undergo disease activity assessments. Patients with anatomical or functional signs of disease activity at these time points will receive Q8W or Q12W dosing, respectively, instead of Q16W dosing. b The primary endpoint is the change from baseline in BCVA (assessed with the ETDRS visual acuity chart at a starting distance of 4 meters) based on the average at weeks 40, 44, and 48. c From week 60 onwards (when all patients in group A are scheduled to receive faricimab), patients in group A will be treated according to the PTI dosing regimen (Q8W–Q16W). 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. [Diagram 2]Figure 2 outlines the study design for DME. Arm A (administered Q8W): Patients randomized to Arm A will receive 6 mg IVT RO6867461 (faricimab) infusions Q4W until week 20, followed by 6 mg IVT RO6867461 (faricimab) infusions Q8W until week 96, followed by a final study visit at week 100. Arm B (individualized treatment interval PTI): Patients randomized to Arm B will receive 6 mg IVT RO6867461 (faricimab) infusions Q4W until at least week 12, followed by PTI administration (see PTI dosing criteria below) of 6 mg IVT RO6867461 (faricimab) infusions until week 96, followed by a final study visit at week 100. Arm C (Comparator Arm) (Administered Q8W): Patients randomized to Arm C will receive 2 mg IVT aflibercept infusions Q4W through week 16, followed by 2 mg IVT aflibercept infusions Q8W through week 96, followed by a final study visit at week 100. Patients in all three treatment arms will complete study visits scheduled Q4W throughout the entire study period (100 weeks). To maintain blinding between treatment arms, patients in all three treatment arms will receive a sham procedure at the applicable visit. IVT=intravitreal, Q8W=every 8 weeks, PTI=individualized treatment interval (see section 3.1.2 for additional details), W=week. a The 1-year definition used for the primary efficacy endpoint—defined as the change from baseline in BCVA, measured with the ETDRS visual acuity chart at a starting distance of 4 meters at 1 year—is the mean at weeks 48, 52, and 56. [Diagram 3]Schematic of individualized treatment intervals for DME - Figure 3 outlines the algorithm for interval determination based on relative changes in CST and BCVA compared to reference CST and reference BCVA. Significance of * and ** in Figure 3 * Reference central subfield thickness (CST): CST value when initial CST threshold criteria are met. Reference CST is adjusted if CST decreases by more than 10% from the previous reference CST at two consecutive study drug administration visits and the obtained values ​​are within 30 μm. The CST value obtained at the latter visit serves as the new reference CST starting immediately at that visit. ** Reference best corrected visual acuity (BCVA): average of the three best BCVA scores obtained at the previous study drug administration visits. [Figure 4] Summary comparison of duration of DME and nAMD (time to retreatment) and efficacy (DME) based on published results with other treatment options for DME and nAMD (comparison agents Lucentis® (ranibizumab), Eylea® (aflibercept), brolucizumab, and VA2 (RO6867461 / faricimab). [Diagram 5] Gain in BCVA from baseline in patients with neovascular age-related macular degeneration (nAMD) comparing the bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) at 12 and 16 week intervals with ranibizumab (Lucentis®) at 4 week intervals. [Figure 6] Time to required retreatment for diabetic macular edema (DME) based on disease activity assessed by both: loss of BCVA of ≥ 5 letters, and increase in CST of ≥ 50 μm after discontinuation of treatment (after 20 weeks or 6 months of monthly dosing = time after last intravitreal (IVT) dose). Bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) demonstrated longer time to retreatment compared to ranibizumab (Lucentis®). [Figure 7] Figure 1 provides an overview of the study design for the treatment of macular edema secondary to retinal vein occlusion (RVO). IVT = intravitreal, PTI = individualized treatment interval, Q4W = every 4 weeks, W = week. [Figure 8] Schematic of individualized treatment intervals for the treatment of macular edema secondary to retinal vein occlusion (RVO) - Figure 8 outlines the algorithm for interval determination based on relative changes in CST and BCVA compared to reference CST and reference BCVA. BCVA = best corrected visual acuity, CST = central subfield thickness, Q4W = every 4 weeks. a Initial reference CST = CST value when the initial CST threshold criteria are met, but not later than week 20. The reference CST is adjusted if the CST decreases by more than 10% from the previous reference CST for two consecutive faricimab dosing visits and the obtained values ​​are within 30 μm. The CST value obtained at the later visit serves as the new reference CST starting immediately at that visit. b Reference BCVA = average of the three best BCVA scores obtained at any previous dosing visit. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for use in treating an ophthalmic vascular disease selected from nAMD and DME comprises administering an initial dose consecutively ("treatment initiation").

[0030] In some embodiments, the initial dose may vary, such as monthly administration for 3-7 months, in one embodiment, initiation of treatment includes monthly administration for 3-4 months, in one embodiment, initiation of treatment includes monthly administration for 4-5 months, in one embodiment, initiation of treatment includes monthly administration for 4-6 months, in one embodiment, initiation of treatment includes monthly administration for at least 4 months, in one embodiment, initiation of treatment includes monthly administration for 5-7 months, and in one embodiment, initiation of treatment includes monthly administration for 6 months.

[0031] In one embodiment of the invention, the bispecific antibody, medicament, or pharmaceutical formulation is administered at a dose of about 5-7 mg (in each treatment). In one embodiment, the bispecific antibody is administered at a dose of 6 mg + / - 10% (in each treatment). In one embodiment, the bispecific antibody is administered at a dose of about 6 mg (in each treatment, in one embodiment, a dose of 6 mg (in each treatment)).

[0032] In one embodiment of the invention, the bispecific antibody, medicament, or pharmaceutical formulation is administered at a concentration of bispecific antibody of about 120 mg / ml (+ / - 12 mg / ml).

[0033] Macular degeneration is a condition seen primarily in older people in which the center of the inner layer of the eye, known as the macular region of the retina, thins, atrophies, and in some cases bleeds. This can result in loss of central vision, leading to the inability to see fine detail, read, or recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for people over the age of 50. Although some macular dystrophies that affect younger individuals may be referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD).

[0034] As used herein, "age-related macular degeneration (AMD)" refers to a serious eye condition when a small central portion of the retina, known as the macula, deteriorates.

[0035] AMD includes wet AMD and neovascular AMD. Wet AMD (also called wet AMD, wAMD, or neovascular AMD, nAMD) is characterized by the growth of abnormal blood vessels from the choroid under the macula. This is called choroidal neovascularization. These blood vessels leak blood and fluid onto (and under) the retina, causing (retinal bulging and) distortion of vision, making straight lines appear wavy, and causing blind spots and loss of central vision. These abnormal blood vessels eventually scar, resulting in permanent loss of central vision. Symptoms of AMD include dark, blurry areas in the center of vision, and reduced or changed color perception. AMD can be detected with regular eye exams. One of the most common early signs of macular degeneration is the presence of tiny yellow deposits (drusen) under the retina and pigment clumping.

[0036] There are two forms of advanced AMD that cause severe vision loss: dry and wet. The dry form of advanced AMD, central geographic atrophy, is caused by atrophy of the retinal pigment epithelium layer beneath the retina, which causes vision loss due to loss of photoreceptors (rods and cones) in the central part of the eye. There is no cure for the condition, but vitamin supplements containing high doses of the antioxidants lutein and zeaxanthin have been shown by the National Eye Institute and others to slow the progression of dry macular degeneration and improve vision in some patients.

[0037] "Diabetic macular edema" (DME) as used herein refers to a serious eye condition that affects people with diabetes (type 1 or type 2). Macular edema occurs when blood vessels in the retina leak into the macula, causing fluid and protein deposits to collect on or under the macula of the eye, causing it to thicken and swell (edema). Because the macula is located near the center of the retina at the back of the eyeball, the swelling can distort people's central vision. Primary symptoms of DME include, but are not limited to, blurred vision, floaters, loss of contrast, double vision, and eventual vision loss.

[0038] The pathology of DME is characterized by the breakdown of the inner blood-retinal barrier, which normally prevents the movement of fluid in the retina, allowing fluid to accumulate in the retinal tissue, and the presence of retinal thickening. DME is currently diagnosed during an ophthalmic examination, which consists of a visual acuity test to determine the smallest letter a person can read on a standard eye chart, a dilated eye examination to look for signs of disease, imaging tests such as optical coherence tomography (OCT) or fluorescein angiography (FA) and tonometry, an instrument that measures intraocular pressure. To determine treatment, the following studies are also performed: optical coherence tomography (OCT), fluorescein angiography, and color stereo fundus photography. DME can be characterized into two main classifications: focal and diffuse. Focal DME is characterized by a specific area of ​​separate, differentiated leakage in the macula with sufficient macular blood flow. Diffuse DME is due to leakage throughout the capillary bed surrounding the macula, due to the breakdown of the inner blood-retinal barrier of the eye.

[0039] In addition to focal and diffuse, DME is also classified into clinically significant macular edema (CSME), non-CSME, and CSME with central involvement (CSME-CI) based on clinical examination findings. The present invention includes methods for treating the above classifications of DME.

[0040] Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders and is associated with variable degrees of vision loss (Hayreh and Zimmerman 1994). RVO has been reported as the second leading cause of blindness in patients with retinal vascular disease 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 Ophthalmol Vis Sci 2010;51:3205-3209).

[0041] The main types of RVO include branch vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). The most common symptom of RVO is a sudden, painless decrease in central vision due to macular edema.

[0042] The main types of macular edema secondary to RVO include macular edema secondary to branch vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), and macular edema secondary to central retinal vein occlusion (CRVO). Infrequently, patients present with a history of transient vision loss lasting seconds to minutes, with vision recovering completely. These symptoms may recur over days to weeks, followed by a permanent loss of vision. Metamorphopsia and visual field defects 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).

[0043] The pathogenesis of macular edema in these patients begins with increased intraluminal pressure due to vascular occlusion, which results in areas of reduced perfusion and ischemia. 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 known proangiogenic and vascular permeability enhancing cytokines, with Ang-2 contributing further proinflammatory 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;12:235-239. Epub:5 February 2006). Patients with RVO were found to have the highest vitreous levels of both Ang-2 and VEGF among 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). Increased levels of Ang-2 and VEGF in retinal tissues lead to pathological changes in the retina, and in many patients also to macular edema with reduced vision. RVO is characterized by a characteristic pattern of retinal hemorrhage (one quadrant in BRVO, two quadrants in HRVO, and the entire retina in CRVO), with tortuous and dilated retinal veins throughout the affected area of ​​the retina.

[0044] In more severe cases, patients may develop retinal ischemia with subsequent neovascularization in the anterior segment resulting in retinal neovascularization, hemorrhage, rubeosis or neovascular glaucoma, and some patients may develop optic disc edema.

[0045] Macular edema due to RVO and diabetic macular edema (DME) have different origins but share a common pathophysiology: both are characterized by macular thickening and pathological increase in retinal vascular permeability due to fluid accumulation as a result of breakdown of the blood-retinal barrier, which can lead to irreversible vision loss in both diseases.

[0046] Anti-VEGF pharmacotherapy is the current mainstay of treatment for macular edema due to RVO and has demonstrated efficacy in several key randomized clinical studies, although macular laser and intravitreal (IVT) steroids, particularly steroid implants, are also used in some cases. Despite anti-VEGF being the most effective treatment for macular edema due to RVO, data from anti-VEGF clinical trials have shown that many patients do not achieve optimal best corrected visual acuity (BCVA) and anatomical outcomes, and many patients require frequent, prolonged injections to maintain the gains achieved during initial intensive treatment. Furthermore, real-world data analyses suggest that many patients with RVO fail to achieve the benefits achieved 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 the majority of patients with macular edema due to CRVO will require long-term close monitoring and treatment and that more sustainable and effective treatment options are needed (Bhisitkul RB, Campochiaro PA, Shapiro H, et al. Ophthalmology 2013;120:1057-1063; Scott IU, Neal NL, VanVeldhuisen, et al. JAMA Ophthalmol 2019;E1-E10).

[0047] Preclinical studies have demonstrated that Ang-2 and VEGF act in concert to regulate the vasculature and increase the permeability of retinal endothelial cells in vitro.

[0048] Simultaneous inhibition of Ang-2 and VEGF with the bispecific monoclonal antibody faricimab resulted in a significant reduction in leakage and severity of choroidal neovascularization (CNV) lesions in a non-human primate model of laser-induced CNV compared with molar equivalents of anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a mouse model of spontaneous CNV demonstrated that dual inhibition of Ang-2 and VEGF was consistently superior to monotherapy inhibition of either target alone in terms of reducing vascular proliferation, leakage, edema, leukocyte infiltration, and photoreceptor loss (Regula JT, Lundh von Leithner P, Foxton R, et al. EMBO Mol Med 2016;8:1265-1288).

[0049] Furthermore, aqueous humor and vitreous concentrations of both Ang-2 and VEGF have been shown to be 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, Puustjarvi T, Terasvirta M, et al. Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh von Leithner P, Foxton R, et al. (Ng DS, Yip YW, Bakthavatsalam M, et al. Sci Rep 2017;7:45081). Thus, simultaneous neutralization of both Ang-2 and VEGF targets may further normalize pathological ocular vasculature compared with anti-VEGF therapy alone.

[0050] 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 durability of efficacy over anti-VEGF therapy alone in diseases affecting the retinal vasculature.

[0051] 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 extensive Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) in DME, and GR40306 (TENAYA) and GR40844 (LUCERNE) in nAMD.

[0052] Based on the mechanism of action of faricimab, data from nonclinical and clinical trials, and the pathophysiology of macular edema resulting from RVO, it is hypothesized that faricimab may result in stabilization of the pathological ocular vasculature and improved visual and anatomical outcomes of RVO compared with anti-VEGF monotherapy.

[0053] Macular edema secondary to / resulting from RVO is one of the most common 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).

[0054] The effects of Ang-2 and VEGF inhibition in preclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R, et al. EMBO Mol Med 2016;8:1265-1288), as well as data from phase I and phase II faricimab studies in patients with nAMD and DME, provide evidence of efficacy against pathological pathways common to 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).

[0055] Because of the similarities in pathophysiology between macular edema due to DME and RVO, we report data here from the Phase II BOULEVARD study. Although the induction of macular edema in diabetic and RVO patients is different, the downstream pathology of hypoxia-induced macular edema and subsequent vision loss is similar and is driven by the same proangiogenic, proinflammatory, vascular destabilizing, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6).

[0056] The BOULEVARD study provided preliminary evidence of a positive benefit-risk profile for the use of IVT infusion of 6 mg faricimab for patients with DME, supporting further evaluation of faricimab in Phase III DME studies. 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 treatment-naive patients treated with 6 mg faricimab compared to 0.3 mg ranibizumab. Best corrected visual acuity (BCVA) is determined using a methodology adapted from the 4-meter Early Treatment Diabetic Retinopathy Study [ETDRS] protocol (using an Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity chart) and resulting in a respective letter score. In one embodiment, the determination of BCVA in such a method, use, bispecific antibody (for use), medicine, or pharmaceutical preparation is based on an adapted visual acuity chart for the ETDRS protocol and is evaluated at a starting distance of 4 meters.

[0057] Disease activity is determined, for example, by a decrease in BCVA / ETDR letter score and / or macular thickening, for example, by spectral domain optical coherence tomography (SD-OCT) including the center of the macula as central subfield thickness (CST) (also known as center subfoveal thickness). In one preferred embodiment, the central subfield thickness (CST) is determined using spectral domain optical coherence tomography (SD-OCT). In one preferred embodiment, the CST is measured by spectral domain optical coherence tomography (SD-OCT) with a Spectralis™ device. In one preferred embodiment, the CST is measured by spectral domain optical coherence tomography (SD-OCT) with a Cirrus™ device. In one embodiment, the CST is measured by spectral domain optical coherence tomography (SD-OCT) with a Topcon™ device. In one embodiment, the CST is measured by spectral domain optical coherence tomography (SD-OCT) with an Optovue™ device. As used herein, the term "suffering patient" refers to a human who exhibits and / or has been diagnosed as having one or more symptoms or signs of an ophthalmic vascular disease described herein.

[0058] The term "afflicted patient" may also include, for example, a subject who exhibits (or has exhibited) one or more symptoms of vascular eye disease prior to treatment, such as, for example, retinal neovascularization, neovascularization, vascular leakage, retinal thickening in the center of the fovea, a hard yellow exudate in the center of the fovea with adjacent retinal thickening, and at least one papillary area of ​​retinal thickening, any portion within one papillary diameter of the center of the fovea, blurred vision, floaters, loss of contrast, diplopia, and eventual loss of vision.

[0059] As used herein, the term "patients suffering from" ophthalmic vascular diseases such as nAMD or DME may include a subset of a population that may be susceptible to nAMD or DME or may exhibit high levels of biomarkers associated with nAMD or DME. For example, "patients suffering from DME" may include subjects who have had diabetes for more than 10 years and frequently have high blood glucose levels or high fasting blood glucose levels. In certain embodiments, the term "patients suffering from DME" includes subjects who suffer from or have been diagnosed with diabetes before or at the time of administration of a bispecific anti-VEGF / ANG2 antibody. In certain embodiments, the term "patients suffering from nAMD" includes subjects who are over 50 years old before or at the time of administration of an anti-VEGF / ANG2 antibody.

[0060] In some embodiments, the term "suffering patient" includes subjects who are smokers or who have high blood pressure or high cholesterol.

[0061] As used herein, the term "patient suffering from" ophthalmic vascular disease, such as macular edema secondary to branch vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO), may include a subset of a population that may be susceptible to macular edema secondary to branch vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO), or may exhibit high levels of biomarkers associated with RVO. For example, "patient 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 "patient suffering from" includes subjects who are smokers, or subjects with high blood pressure or high cholesterol. The present invention includes a bispecific antibody, medicament, or pharmaceutical formulation for a method or (for use) for treating, preventing, or reducing the severity of ophthalmic vascular disease, comprising administering a therapeutically effective amount of a bispecific anti-VEGF / ANG2 antibody (or a medicament or pharmaceutical formulation comprising a bispecific anti-VEGF / ANG2 antibody) to a subject in need thereof, where such a bispecific antibody, medicament, or pharmaceutical formulation comprising a bispecific anti-VEGF / ANG2 antibody is administered (intravitreally) to the subject in multiple doses, for example as part of a particular therapeutic dosing regimen.

[0062] One embodiment of the present invention is a method of treatment, use, bispecific antibody, medicament, or pharmaceutical formulation described herein, wherein the patient suffering from an ophthalmic vascular disease has not been previously treated (is treatment naive) with an anti-VEGF therapy (e.g., monotherapy).

[0063] One embodiment of the present invention is a method of treatment, use, bispecific antibody, medicament, or pharmaceutical formulation described herein, where the patient suffering from an ophthalmic vascular disease has previously been treated with an anti-VEGF therapy (e.g., monotherapy, e.g., with ranibizumab, aflibercept, or brolocizumab).

[0064] One embodiment of the present invention is a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for use in treating a patient suffering from neovascular AMD (nAMD), the method comprising administering to the patient an effective amount of a bispecific antibody binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at individualized treatment intervals, a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of 4 doses, every 4 weeks (Q4W); b) Disease activity will be assessed at weeks 20 and 24. Disease activity will be assessed according to the following criteria: i) There is an increase in central subfield thickness (CST) of more than 50 μm compared to the mean CST values ​​of the previous two scheduled visits, which are weeks 12 and 16 for the week 20 assessment and weeks 16 and 20 for the week 24 assessment, or ii) an increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the two previous scheduled visits; iii) a decrease in best-corrected visual acuity (BCVA) of 5 or more letters compared with the mean BCVA value at the previous two scheduled visits due to nAMD disease activity; iv) A loss of 10 or more letters of BCVA due to nAMD disease activity compared to the highest BCVA value recorded at any of the two previous scheduled visits, or v) the presence of new macular hemorrhage due to nAMD activity; c) Next, the patient i) Patients who meet disease activity criteria at week 20 will be treated with a Q8W dosing interval from week 20 onwards (with the first Q8W dose administered at week 20); ii) Patients who meet disease activity criteria at week 24 will be treated with a Q12W dosing interval from week 24 onwards (with the first Q12W at week 24); iii) Patients who do not meet disease activity criteria at weeks 20 and 24 will be treated with a Q16W dosing interval from week 28 onwards (with the first Q16W at week 28).

[0065] In one embodiment, the individualized treatment interval is extended, shortened, or maintained after week 60; a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) an increase in CST of 50 μm or more compared to the average from the last two dosing visits or an increase of 75 μm or more compared to the lowest dosing visit measurement; ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) New macular hemorrhage.

[0066] In one embodiment, the individualized pre-treatment interval disease activity assessments are at weeks 16 and 20, or weeks 24 and 28.

[0067] In one embodiment, the individualized treatment intervals with further extension, reduction or maintenance begin at different time points, e.g., after 50 to 70 weeks, e.g., after 52 or 65 weeks depending on disease activity. Another embodiment of the invention is a method, use, (for use) bispecific antibody, medicament or pharmaceutical formulation for use in treating a patient suffering from diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at individualized treatment intervals, a) Patients will be initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) until the central subfield thickness (CST) meets a predefined reference CST threshold (measured after week 12) (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT, or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT); b) The dosing interval is then increased by 4 weeks to give the initial Q8W dosing interval, c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) if there was a >10% increase in CST value with an associated loss of BCVA of ≥10 letters, the interval was reduced by 8 weeks; Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0068] In one embodiment, such dosing intervals may be adjusted in 4 week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0069] Another embodiment of the invention is a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for use in treating an ophthalmic 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 ophthalmic 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), a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from Day 1 to Week 20; b) From week 24 onwards, patients receive bispecific VEGF / ANG2 antibodies at a frequency of Q4W until the central subfield thickness (CST) meets a predefined reference CST threshold (measured after week 24) (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT), c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST score without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If there was a >10% increase in CST value with an associated BCVA loss of ≥10 letters, the interval was shortened to Q4W. Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0070] In one embodiment, such dosing intervals may be adjusted in 4 week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. As used herein, "antibody" refers to a binding protein that comprises an antigen-binding site.

[0071] The term "binding site" or "antigen-binding site" as used herein refers to the region(s) 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 pair).

[0072] The specificity of an antibody refers to the selective recognition of the antibody for a particular epitope of an antigen. For example, naturally occurring antibodies are monospecific.

[0073] A "bispecific antibody" according to the invention is an antibody that has two different antigen-binding specificities. The antibody of the invention is specific for two different antigens, VEGF as the first antigen, and ANG-2 as the second antigen.

[0074] As used herein, the term "monospecific" antibody refers to an antibody that has one or more binding sites each of which binds to the same epitope of the same antigen.

[0075] The term "valency" as used in this application refers to the presence of a specified number of binding sites in an antibody molecule. Thus, the terms "bivalent", "tetravalent" and "hexavalent" refer to the presence of two, four and six binding sites, respectively, in an antibody molecule. Bispecific antibodies according to the invention are preferably "bivalent".

[0076] As used herein, "bispecific antibodies that bind human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2)," "bispecific anti-VEGF / ANG2 antibodies," and "bispecific <vegf ang2>The terms "antibody" and "antibody" are used interchangeably and refer to an antibody having at least two distinct antigen binding sites, one that binds VEGF and a second that binds ANG2.

[0077] Bispecific anti-VEGF / ANG2 antibodies are described, for example, in WO2010 / 040508, 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 ophthalmic vascular diseases. The bispecific anti-VEGF / ANG2 antibodies of WO2014 / 009465 (incorporated herein in its entirety) are particularly useful in the treatment and treatment schedule of ophthalmic vascular diseases described herein.

[0078] In one embodiment, the bispecific antibody that binds 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 human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) The bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass containing the mutations I253A, H310A, and H435A, and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat).

[0079] In one embodiment, such a bispecific anti-VEGF / ANG2 antibody is bivalent.

[0080] In one embodiment, such a bispecific anti-VEGF / ANG2 antibody comprises: i) the first antigen-binding site that specifically binds to VEGF comprises the heavy chain variable domain VH of the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain VL of the amino acid sequence of SEQ ID NO: 8; ii) The second antigen-binding site that specifically binds to ANG-2 is characterized in that it 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.

[0081] In one aspect of the invention, such a bispecific, bivalent antibody according to the invention comprises: a) the heavy and light chains of a first full-length antibody that specifically binds to VEGF; b) a modified heavy chain and a modified light chain of a second full-length antibody that specifically binds to ANG-2, in which the constant domains CL and CH1 are replaced by each other.

[0082] This bispecific, bivalent antibody format for a bispecific antibody that specifically binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is described in WO2009 / 080253 (including a Knobs-into-Holes modified CH3 domain).

[0083] Antibodies based on the bispecific, bivalent antibody format are designated CrossMAbs.

[0084] In one embodiment, such a bispecific, bivalent anti-VEGF / ANG2 antibody has the following structure: a) the amino acid sequence of SEQ ID NO: 17 as the heavy chain of the first full-length antibody, and the amino acid sequence of SEQ ID NO: 18 as the light chain of the first full-length antibody, and b) comprising the amino acid sequence of SEQ ID NO: 19 as a modified heavy chain of the second full-length antibody, and the amino acid sequence of SEQ ID NO: 20 as a modified light chain of the second full-length antibody.

[0085] In one embodiment, such a bispecific, bivalent anti-VEGF / ANG2 antibody is characterized in that it comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. In one preferred embodiment, the bispecific, bivalent anti-VEGF / ANG2 antibody is faricimab.

[0086] Thus, one embodiment of the present invention is a bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds human VEGF and a second antigen-binding site that specifically binds human ANG-2, characterized in that it comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. In one preferred embodiment, the bispecific, bivalent anti-VEGF / ANG2 antibody is faricimab.

[0087] In one embodiment, the CH3 domains of the bispecific bivalent antibodies according to the invention are modified by the "knob-into-holes" technique, which is described in detail in several examples, e.g. WO96 / 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 modified to increase the heterodimerization of both heavy chains containing these two CH3 domains. Each of the two CH3 domains (of the two heavy chains) can be a "knob" and the other is a "hole". Introduction of disulfide bridges stabilizes the heterodimer (Merchant, AM, et al., Nature Biotech 16 (1998) 677-681; Atwell, S., et al. J. Mol. Biol. 270 (1997) 26-35) and increases the yield.

[0088] In a preferred embodiment of the invention, the bispecific anti-VEGF / ANG2 antibody according to the invention comprises: characterized in that the CH3 domain of one heavy chain and the CH3 domain of the other heavy chain, respectively, face each other at an interface that contains the original interface between the CH3 domains of the antibody, The interface is modified to promote the formation of bispecific antibodies, the modification comprising: a) Within the original interface of the CH3 domain of one heavy chain facing the original interface of the CH3 domain of the other heavy chain in the bispecific antibody, the CH3 domain of one heavy chain is modified such that amino acid residues are replaced with amino acid residues having a larger side chain volume, thereby generating a protrusion within the interface of the CH3 domain of one heavy chain that is positionable in a cavity within the interface of the CH3 domain of the other heavy chain; and, b) in the original interface of a second CH3 domain facing the original interface of a first CH3 domain in the bispecific antibody, The CH3 domain of the other heavy chain is characterized in that amino acid residues are replaced with amino acid residues having a smaller side chain volume, thereby creating a cavity in the interface of the second CH3 domain into which a protrusion in the interface of the first CH3 domain can be positioned. Thus, the bispecific anti-VEGF / ANG2 antibodies for use as described herein preferably comprise: the CH3 domain of the heavy chain of the full-length antibody of a) and the CH3 domain of the heavy chain of the full-length antibody of b) each face at an interface that contains an alteration in the original interface between the antibody CH3 domains; i) in the CH3 domain of one heavy chain an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protrusion in the interface of the CH3 domain of one heavy chain which can be positioned in a cavity in the interface of the CH3 domain of the other heavy chain; and ii) in the CH3 domain of the other heavy chain, The second CH3 domain is characterized in that amino acid residues are replaced with amino acid residues having smaller side chain volumes, thereby creating a cavity in the interface of the second CH3 domain into which a protrusion in the interface of the first CH3 domain can be positioned.

[0089] Preferably, said amino acid residues having larger side chain volumes are selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W).

[0090] Preferably, said amino acid residues having smaller side chain volumes are selected from the group consisting of alanine (A), serine (S), threonine (T) and valine (V).

[0091] In one embodiment of the invention, both CH3 domains are further modified by introducing a cysteine ​​(C) as an amino acid at the corresponding position of each CH3 domain such that a disulfide bridge can be formed between both CH3 domains.

[0092] 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 the CH3 domains can also be used, for example by introducing a S354C mutation in one CH3 domain and a Y349C mutation in the other CH3 domain (Merchant, AM, et al., Nature Biotech 16 (1998) 677-681).

[0093] In another preferred embodiment, the bispecific antibody comprises the S354C and T366W mutations in one of the two CH3 domains and the Y349C, T366S, L368A, Y407V mutations in the other of the two CH3 domains. In another preferred embodiment, the bispecific antibody comprises a Y349C, T366W mutation in one of the two CH3 domains and a S354C, T366S, L368A, Y407V mutation in the other of the two CH3 domains (containing an additional Y349C or S354C mutation in one CH3 domain and an additional S354C or Y349C mutation in the other CH3 domain forming an interchain disulfide bridge) (numbering is always according to the EU index of Kabat (Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

[0094] Other techniques of CH3 modification to achieve heterodimerization are contemplated as alternatives to the present invention and are described, for example, in WO96 / 27011, WO98 / 050431, EP1870459, WO2007 / 110205, WO2007 / 147901, WO2009 / 089004, WO2010 / 129304, WO2011 / 90754, WO2011 / 143545, WO2012 / 058768, WO2013 / 157954, and WO2013 / 096291.

[0095] In one embodiment, the heterodimerization approach described in EP1870459A1 is used instead. This approach is based on the introduction of substitutions / mutations of charged amino acids with opposite charges at specific amino acid positions in the CH3 / CH3 domain interface between both heavy chains. One preferred embodiment of said 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 the other heavy chain of the multispecific antibody (numbering according to the Kabat EU index).

[0096] In another embodiment, said multispecific antibody comprises the amino acid T366W mutation in the CH3 domain of the "knob chain" and the amino acid T366S, L368A and Y407V mutations in the CH3 domain of the "hole chain", and further comprises the amino acid R409D and K370E mutations in the CH3 domain of the "knob chain" and the amino acid D399K and E357K mutations in the CH3 domain of the "hole chain".

[0097] In one embodiment, the heterodimerization approach 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 the other heavy chain comprises an amino acid L351D mutation. In a further embodiment, the CH3 domain of one heavy chain further comprises an amino acid L351K mutation. In a further embodiment, the CH3 domain of the other heavy chain further comprises an amino acid mutation selected from Y349E, Y349D, and L368E (L368E in one embodiment).

[0098] In one embodiment, the heterodimerization approach 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 the other heavy chain comprises amino acid T366A and K409F mutations. In a further embodiment, the CH3 domain of the other heavy chain further comprises amino acid mutations at positions T411, D399, S400, F405, N390, or K392. In one embodiment, the amino acid mutations are: a) T411N, T411R, T411Q, T411K, T411D, T411E, and T411W, b) D399R, D399W, D399Y, and D399K, c) S400E, S400D, S400R, and S400K, d) F405I, F405M, F405T, F405S, F405V, and F405W, e) N390R, N390K, and N390D, f) selected from the group consisting of K392V, K392M, K392R, K392L, K392F, and K392E.

[0099] In a further embodiment, the CH3 domain of one heavy chain comprises the amino acid L351Y and Y407A mutations, and the CH3 domain of the other heavy chain comprises the amino acid T366V and K409F mutations. In a further embodiment, the CH3 domain of one heavy chain comprises the amino acid Y407A mutation, and the CH3 domain of the other heavy chain comprises the amino acid T366A and K409F mutations. In a further embodiment, the CH3 domain of the other heavy chain further comprises the amino acid K392E, T411E, D399R, and S400R mutations.

[0100] In one embodiment, the heterodimerization approach described in WO2011 / 143545 is used instead. In one embodiment, the amino acid modifications according to WO2011 / 143545 are introduced into the CH3 domain of the heavy chain at positions selected from the group consisting of 368 and 409.

[0101] In one embodiment, the heterodimerization approach described in WO2011 / 090762 is used instead, in which the knob-into-hole technique described above is also used. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366W mutation and the CH3 domain of the other heavy chain comprises an amino acid Y407A mutation. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366Y mutation and the CH3 domain of the other heavy chain comprises an amino acid Y407T mutation.

[0102] In one embodiment, the multispecific antibody is of the IgG2 isotype and the heterodimerization approach described in WO2010 / 129304 is alternatively used.

[0103] In one embodiment, the heterodimerization approach described in WO2009 / 089004 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid substitution of K392 or N392 with a negatively charged amino acid (in one embodiment, glutamic acid (E) or aspartic acid (D)); in a further embodiment, a K392D or N392D mutation), and the CH3 domain of the other heavy chain comprises an amino acid substitution of D399, E356, D356, or E357 with a positively charged amino acid (in one embodiment, lysine (K) or arginine (R); in a further embodiment, a D399K, E356K, D356K, or E357K mutation; in yet a further embodiment, a D399K or E356K mutation). In a further embodiment, the CH3 domain of one heavy chain further comprises an amino acid substitution of K409 or R409 with a negatively charged amino acid (in one embodiment, glutamic acid (E) or aspartic acid (D); in a further embodiment, a K409D or R409D mutation). In a further embodiment, the CH3 domain of one heavy chain further or alternatively comprises an amino acid substitution of K439 and / or K370 with a negatively charged amino acid (in one embodiment, glutamic acid (E) or aspartic acid (D)).

[0104] In one embodiment, the heterodimerization approach described in WO2007 / 147901 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises the amino acid mutations K253E, D282K, and K322D, and the CH3 domain of the other heavy chain comprises the amino acid mutations D239K, E240K, and K292D.

[0105] In one embodiment, the heterodimerization approach described in WO2007 / 110205 is alternatively used.

[0106] In one embodiment, the bispecific antibody that binds 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 human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) the bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass, comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat), iv) In the constant heavy chain region, the T366W mutation is contained in one CH3 domain and the T366S, L368A, Y407V mutations are contained in the other CH3 domain (numbering according to EU index of Kabat).

[0107] In one embodiment, the bispecific antibody that binds 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 human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) the bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass, comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat), iv) In the constant heavy chain region, the S354C and T366W mutations are contained in one CH3 domain and the Y349C, T366S, L368A and Y407V mutations are contained in the other CH3 domain (numbering according to EU index of Kabat).

[0108] In one embodiment, such a bispecific anti-VEGF / ANG2 antibody is bivalent.

[0109] In one embodiment, such a bispecific anti-VEGF / ANG2 antibody comprises: i) the first antigen-binding site that specifically binds to VEGF comprises a heavy chain variable domain VH having the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain VL having the amino acid sequence of SEQ ID NO: 8; ii) The second antigen-binding site that specifically binds to ANG-2 is characterized in that it 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.

[0110] In one aspect of the invention, such a bispecific, bivalent antibody according to the invention comprises: a) the heavy and light chains of a first full-length antibody that specifically binds to VEGF; b) characterized in that it comprises a modified heavy chain and a modified light chain of a second full-length antibody that specifically binds to ANG-2, in which the constant domains CL and CH1 are replaced by each other.

[0111] The term "VEGF" as used herein refers to human vascular endothelial growth factor (VEGF / VEGF-A), the 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 well as naturally occurring alleles and processed forms of those growth factors, as described in 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. VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors and intraocular disorders (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 isolated from several sources and includes several isoforms. VEGF exhibits highly specific mitogenic activity on endothelial cells. VEGF antagonists / inhibitors inhibit the binding of VEGF to its receptor VEGFR. Known VEGF antagonists / inhibitors include bispecific anti-VEGF / ANG2 antibodies described in WO2014 / 009465.

[0112] The term "ANG-2" as used herein refers to human angiopoietin-2 (ANG-2) (alternatively abbreviated as ANGPT2 or ANG2) (SEQ ID NO: 25), described, for example, in 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 discovered as ligands for Ties, a family of tyrosine kinases selectively expressed in vascular endothelium (Yancopoulos, GD, et al., Nature 407 (2000) 242-48). There are currently four definitive members of the angiopoietin family. Angiopoietin-3 and -4 (Ang-3 and Ang-4) may represent widely diverged 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 first identified in tissue culture experiments as agonists and antagonists, respectively (ANG-1 Davis, S., et al., Cell 87 (1996) 1161-69; and 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 the receptor TIE2. Known ANG2 antagonists / inhibitors include the bispecific anti-VEGF / ANG2 antibodies described in WO2014 / 009465.

[0113] The antigen-binding site of the bispecific antibody of the present invention contains six complementarity determining regions (CDRs) that contribute to different degrees to the affinity of the binding site for the antigen. 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 to a compiled database of amino acid sequences, and the regions are defined according to the variations between the sequences.

[0114] The antibodies of the present invention comprise immunoglobulin constant regions derived from human origin of one or more immunoglobulin classes, including the IgG, IgM, IgA, IgD, and IgE classes, and in the case of IgG and IgA, their subclasses, in particular IgG1 and IgG4.

[0115] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of a single amino acid composition.

[0116] The term "chimeric antibody" refers to antibodies, usually prepared by recombinant DNA techniques, that contain a variable region, i.e., a binding region, from one source or species and at least a portion of a constant region from a different source or species.

[0117] Chimeric antibodies comprising murine variable regions and human constant regions are preferred. Other preferred forms of "chimeric antibodies" encompassed by the present invention are those in which the constant regions have been modified or altered from the constant regions of the original antibody to produce properties according to the invention, particularly 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 comprising DNA segments encoding immunoglobulin variable regions and DNA segments encoding immunoglobulin constant regions. Methods for producing chimeric antibodies include conventional recombinant DNA and gene transfection techniques well known in the art. See, for example, Morrison, SL, et al., Proc. Natl. Acad. Sci. USA 81 (1984) 6851-6855; US 5,202,238 and US 5,204,244.

[0118] The term "humanized antibody" refers to an antibody in which the framework or "complementarity determining regions" (CDRs) have been modified to include CDRs of an immunoglobulin with different specificity compared to the parent immunoglobulin. In a preferred embodiment, murine CDRs are grafted onto the framework regions of a human antibody to prepare a "humanized antibody". See 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 representing sequences recognizing the antigens indicated above for chimeric antibodies. Other forms of "humanized antibodies" encompassed by the present invention are those in which the constant regions have been further modified or altered from the constant regions of the original antibody to create properties according to the invention, particularly with respect to C1q binding and / or Fc receptor (FcR) binding.

[0119] 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, upon immunization, can produce a full repertoire or set of human antibodies in the absence of endogenous immunoglobulin production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice results in the production of human antibodies upon antigen challenge (e.g., Jakobovits, A., et al., Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A., et al., Nature 362 (1993) 255-258; Brueggemann, M., et al., Year Immunol. 7 (1993) 33-40). Human antibodies can be produced in phage display libraries (see Hoogenboom, HR, and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, JD, et al., J. Mol. Biol. 222 (1991) 581-597).

[0120] The techniques of Cole, A., et al. and Boerner, P., et al. are also available for the preparation of human monoclonal antibodies (Cole, A., et al., Monoclonal Antibodies and Cancer Therapy, Liss, AL, p. 77 (1985); and Boerner, P., et al., J. Immunol. 147 (1991) 86-95). As already mentioned for the chimeric and humanized antibodies according to the invention, the term "human antibody" as used herein also includes such antibodies which are modified in the constant region to create the properties according to the invention, for example by "class switching", i.e. alteration or mutation of the Fc part (e.g. IgG1 to IgG4 mutation and / or IgG1 / IgG4 mutation), in particular with regard to C1q binding and / or FcR binding.

[0121] The term "recombinant antibody" as used herein is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from host cells, such as NS0 or CHO cells, or animals (e.g., mice), that are transgenic for human immunoglobulin genes or antibodies expressed using recombinant expression vectors transfected into the host cells. Such recombinant antibodies have variable and constant regions in rearranged form. The recombinant antibodies according to the invention have been subjected to somatic hypermutation in vivo. Thus, the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that are derived from and related to human germline VH and VL sequences, but may not naturally exist within the human antibody germline repertoire in vivo.

[0122] As used herein, the term "variable domain" (variable domain of the light chain (VL), variable domain of the heavy chain (VH)) refers to each of the pair of light and heavy chains that are directly involved in binding the antibody to the antigen.

[0123] Variable human light and heavy chain domains have the same general structure, each domain containing four framework (FR) regions whose sequences are widely conserved and connected by three "hypervariable regions" (or complementarity determining regions, CDRs). The CDRs may form a β-sheet conformation and loops that connect the β-sheet structure. The CDRs in each chain are held in a three-dimensional structure by the framework regions and form the antigen-binding site together with the CDRs from the other chain. The heavy and light chain CDR3 regions of an antibody play a particularly important role in the binding specificity / affinity of the antibody according to the invention and therefore provide a further object of the invention.

[0124] The terms "hypervariable region" or "antigen-binding portion of an antibody" when used herein refer to the amino acid residues of an antibody that are responsible for antigen-binding.

[0125] The hypervariable region comprises amino acid residues from the "complementarity determining region" or "CDR". The "framework" or "FR" regions are those variable domain regions other than the hypervariable region residues as defined herein. Thus, the light and heavy chains of an antibody comprise, from N-terminus to C-terminus, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The CDRs on each chain are separated by such framework amino acids. In particular, the CDR3 of the heavy chain is the region that contributes most to antigen binding. The CDR and FR regions are determined according to the standard definition in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0126] 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, from the N-terminus to the C-terminus, 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), abbreviated as VH-CH1-HR-CH2-CH3, and optionally, in the case of an antibody of the subclass IgE, an antibody heavy chain constant domain 4 (CH4). Preferably, a "full-length antibody heavy chain" is a polypeptide consisting of, from the N-terminus to the C-terminus, VH, CH1, HR, CH2 and CH3. A "full-length antibody light chain" is a polypeptide consisting of, from the N-terminus to the C-terminus, an antibody light chain variable domain (VL), and an antibody light chain constant domain (CL), abbreviated as VL-CL. The antibody light chain constant domain (CL) can be κ (kappa) or λ (lambda). The two full-length antibody chains are linked together via interpolypeptide disulfide bonds between the CL and CH1 domains and between the hinge regions of the full-length antibody heavy chains. Typical examples of full-length antibodies are natural antibodies such as IgG (e.g., IgG1 and IgG2), IgM, IgA, IgD, and IgE. The full-length antibody according to the invention can be from a single species, e.g., human, or can be a chimerized or humanized antibody. The full-length antibody according to the invention comprises two antigen-binding sites formed by a pair of VH and VL, respectively, that specifically bind to the same antigen. The C-terminus of the heavy or light chain of a full-length antibody refers to the last amino acid at the C-terminus of the heavy or light chain. The N-terminus of the heavy or light chain of said full-length antibody refers to the last amino acid at the N-terminus of said heavy or light chain.

[0127] The term "constant region" as used in this application refers to the sum of the domains of an antibody other than the variable region. The constant region is not directly involved in antigen binding, but exhibits various effector functions. Depending on the amino acid sequence of the constant region of the heavy chain, antibodies are classified into the following classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further classified into subclasses, such as IgG1, IgG2, IgG3, and IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The light chain constant regions found in all five antibody classes are called κ (kappa) and λ (lambda).

[0128] The term "constant region of human origin" or "human constant region" as used in this application refers to the constant heavy chain region of a human antibody of subclass IgG1, IgG2, IgG3, or IgG4, and / or the constant light chain kappa or lambda region. Such constant regions are known in the art and are described, for example, in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, for example, 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). For numbering of positions and mutations, the EU numbering system (EU index), Kabat, E. A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), is used within this application and is referred to as "Kabat EU Index numbering."

[0129] In one embodiment, the bispecific antibody according to the invention has a constant region of the human IgG1 subclass (derived from the 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.

[0130] In one embodiment, the bispecific antibody described herein is of the IgG1 isotype / subclass and comprises a constant heavy chain domain of SEQ ID NO: 23, or the constant portion of 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, a C-terminal glycine (Gly446) is additionally present. In one embodiment, a C-terminal glycine (Gly446) and a C-terminal lysine (Lys447) are additionally present.

[0131] Unless otherwise specified herein, numbering of amino acid residues in the constant region is according to the EU numbering system (also called the EU index of Kabat), as described in Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0132] In one embodiment, the bispecific antibody according to the invention is of human IgG1 subclass with the mutations L234A (Leu235Ala), L235A (Leu234Ala) and P329G (Pro329Gly). Such antibodies have reduced FcR binding (in particular, they do not show binding to FcRgammaI, FcRgammaII and FcRgammaIII). This is useful, for example, to reduce potential side effects such as thrombosis (Meyer, T., et al., J. Thromb. Haemost. 7 (2009) 171-81).

[0133] The Pro329Ala mutation already described removes only two-thirds of the FcgammaRIIIa sandwich interaction, whereas the Pro329Gly in the antibody according to the present invention fully confers the binding of the Fc part to FcgammaRIII. This is particularly useful because the binding to FcgammaRIII is involved in ADCC (antibody-dependent cellular cytotoxicity), which causes cell death and may be useful in the treatment of cancer diseases, but may cause serious side effects in antibody-based treatment of other vascular or immune diseases. Thus, the antibody according to the present invention with IgG1 subclass with mutations L234A, L235A, and P329G, and IgG4 subclass with mutations S228P, L235E, and P329G, is particularly useful, since they both do not show binding to FcRgammaI, FcRgammaII, and FcRgammaIII.

[0134] 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.

[0135] In one embodiment of the invention, the bispecific antibodies, medicaments, or pharmaceutical formulations described herein are administered by intravitreal application, e.g., by intravitreal injection (administered "intravitreally").

[0136] 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.

[0137] In some embodiments, therapeutic kits of the invention can include one or more doses of the described bispecific antibodies present in a medicament or pharmaceutical formulation, a suitable device for intravitreal injection of the medicament or pharmaceutical formulation, and instructions detailing suitable targets and protocols for performing the injections.

[0138] In these embodiments, the pharmaceutical agent or pharmaceutical preparation is typically administered to the subject in need of treatment by intravitreal injection.This can be carried out 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.

[0139] Regardless of the route of administration selected, the bispecific antibodies described herein are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0140] One embodiment is a method of treatment or a bispecific antibody (medicament or pharmaceutical formulation) for use in the treatment of an ophthalmic vascular disease according to any one of the preceding claims, wherein the antibody is administered according to a determination of a software tool.

[0141] Another embodiment is a method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from nAMD, the method comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an evaluation of new macular hemorrhage; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the dosing interval based on the criteria described herein for various ophthalmic vascular diseases, such as macular edema secondary to nAMD, DME, or RVO.

[0142] Another embodiment is a computer device / computing system for use / implementation of such methods. [Table 1]

[0143] The embodiments of the present invention are listed below.

[0144] 1. A bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) for use in the treatment of an ophthalmic vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), or in the treatment of a patient suffering from an ophthalmic vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), (or a medicament or pharmaceutical formulation comprising the bispecific antibody, or a bispecific antibody for use in the preparation of a medicament), wherein the treatment comprises a personalized treatment interval (PTI).

[0145] 2. A bispecific antibody (medicament or pharmaceutical formulation) according to embodiment 1 (for use) for use in the treatment of neovascular age-related macular degeneration (nAMD) or for the treatment of patients suffering from nAMD.

[0146] 3. The treatment includes individualized treatment intervals; a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of 4 doses, every 4 weeks (Q4W); b) Disease activity will be assessed at weeks 20 and 24. Disease activity will be assessed according to the following criteria: i) An increase in central subfield thickness (CST) of more than 50 μm compared to the mean CST values ​​at the previous two scheduled visits, which are weeks 12 and 16 for the week 20 assessment and weeks 16 and 20 for the week 24 assessment; or ii) an increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the two previous scheduled visits; iii) A decrease in best corrected visual acuity (BCVA) of 5 or more letters compared with the mean BCVA value at the previous two scheduled visits due to nAMD disease activity; iv) A loss of 10 or more letters of BCVA due to nAMD disease activity compared to the highest BCVA value recorded at any of the two previous scheduled visits, or v) the presence of new macular hemorrhage due to nAMD activity; c) Next, the patient i) Patients who meet disease activity criteria at week 20 are treated with a Q8W dosing interval from week 20 onwards (first Q8W dose at week 20); ii) patients who meet disease activity criteria at week 24 are treated with a Q12W dosing interval from week 24 onwards (first Q12W dose at week 24); iii) Patients who do not meet the disease activity criteria at weeks 20 and 24 are treated with a Q16W dosing interval from week 28 onwards (first Q16W dose at week 28).

[0147] 4. Individualized treatment intervals are extended, shortened, or maintained after week 60, a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) the presence of new macular hemorrhage; A bispecific antibody (for use) according to embodiment 3 (medicament or pharmaceutical formulation).

[0148] 5. A bispecific antibody (medicament or pharmaceutical formulation) according to embodiment 1 (for use) for use in the treatment of diabetic macular edema (DME) or for the treatment of patients suffering from DME.

[0149] 6. The treatment includes individualized treatment intervals (PTIs); a) Patients will be initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) until the central subfield thickness (CST) meets a predefined reference CST threshold (measured after week 12) (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT, or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT); b) The dosing interval is then increased by 4 weeks to give the initial Q8W dosing interval, c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) if there was a >10% increase in CST value with an associated loss of BCVA of ≥10 letters, the interval was reduced by 8 weeks; Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; The bispecific antibody (medicament or pharmaceutical formulation) (for use) according to embodiment 5, wherein the reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

[0150] 7. The bispecific antibody (for use) (medicament or pharmaceutical formulation) according to embodiment 6, wherein the dosing interval may be adjusted in 4 week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0151] 8. A bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) for use in the treatment of an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, or in the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein the treatment comprises individualized treatment intervals (PTIs); a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from Day 1 to Week 20; b) From week 24 onwards, patients will receive bispecific VEGF / ANG2 antibody at a frequency of Q4W until the central subfield thickness (CST) meets a predefined reference CST threshold (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT or 315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured after week 24); c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST score without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increased by >10% with an associated BCVA loss of ≥10 letters, the interval was shortened to Q4W. Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visits, bispecific antibody.

[0152] 9. The bispecific antibody (for use) (medicament or pharmaceutical formulation) according to embodiment 8, wherein the administration interval may be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0153] 10. The bispecific antibody that binds human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) A bispecific antibody (for use) according to any one of embodiments 1 to 9 (medicament or pharmaceutical formulation), wherein the bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass comprising the mutations I253A, H310A, and H435A, and the mutations L234A, L235A, and P329G (numbering according to the EU index as in Kabat).

[0154] 11. i) the first antigen-binding site that specifically binds to VEGF comprises the heavy chain variable domain VH of the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain VL of the amino acid sequence of SEQ ID NO: 8; ii) A bispecific antibody (for use) according to embodiment 10 (medicament or pharmaceutical formulation), wherein the second antigen-binding site which 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.

[0155] 12. A bispecific antibody (for use) according to any one of embodiments 1 to 9 (medicament or formulation), wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20.

[0156] 13. A bispecific antibody (for use) according to any one of embodiments 1 to 9 (medicament or pharmaceutical formulation), wherein the bispecific antibody is faricimab.

[0157] 14. The bispecific antibody (for use) (medicament or pharmaceutical formulation) according to any one of embodiments 10 to 13, wherein the bispecific antibody is administered in a dose of about 5 to 7 mg (in each treatment).

[0158] 15. The bispecific antibody (for use) (medicament or pharmaceutical formulation) according to any one of embodiments 8 to 13, wherein the bispecific antibody is administered in a dose of about 6 mg (in each treatment).

[0159] 16. The bispecific antibody (for use) of embodiment 14 or 15 (medicament or pharmaceutical formulation), wherein the bispecific antibody is administered at a concentration of about 120 mg / ml.

[0160] 17. The bispecific antibody (for use) according to any one of the preceding embodiments, wherein the patient suffering from an ophthalmic vascular disease has not been previously treated with an anti-VEGF therapy.

[0161] 18. The bispecific antibody (for use) according to any one of the preceding embodiments, wherein the patient suffering from an ophthalmic vascular disease has previously been treated with an anti-VEGF therapy.

[0162] 19. A bispecific antibody (medicament or pharmaceutical formulation) for use according to any one of the preceding embodiments, wherein the antibody is administered according to a determination of a software tool.

[0163] 20. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from nAMD, the method comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an evaluation of new macular hemorrhage; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) The presence of new macular hemorrhage, method.

[0164] 21. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from DME, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) If the CST value increases by more than 10% with an associated loss of BCVA of 10 letters or more, the interval is shortened by 8 weeks.

[0165] 22. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or Increase in CST value of >10% to <20% without associated loss of BCVA of ≥5 letters iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST value without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increases by more than 10% with an associated BCVA loss of 10 letters or more, the interval will be shortened to Q4W.

[0166] twenty three. receiving updated patient data at a computing system; using a computing system to continually update or maintain the dosing interval based on updated patient data; 23. The method of any one of embodiments 20, 21 or 22, further comprising generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0167] 24. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of nAMD), comprising: a computing system comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an evaluation of new macular hemorrhage; Generate a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) Presence of new macular hemorrhage, use.

[0168] 25. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of DME), comprising: a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; Generate a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) If the CST value increases by >10% with an associated loss of BCVA of ≥10 letters, the interval will be shortened by 8 weeks.

[0169] 26. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion), comprising a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; generating a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or Increase in CST value of >10% to <20% without associated loss of BCVA of ≥5 letters iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST value without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increases by more than 10% with an associated BCVA loss of 10 letters or more, the interval is shortened to Q4W.

[0170] The embodiments of the present invention are listed below.

[0171] 1. A method of treating a patient suffering from an ophthalmic vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), 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), wherein the treatment comprises a personalized treatment interval (PTI).

[0172] 2. The method of embodiment 1, wherein the ophthalmic vascular disease is neovascular age-related macular degeneration (nAMD).

[0173] 3. The treatment includes individualized treatment intervals; a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of 4 doses, every 4 weeks (Q4W); b) Disease activity will be assessed at weeks 20 and 24. Disease activity will be assessed according to the following criteria: i) There is an increase in central subfield thickness (CST) of more than 50 μm compared to the mean CST values ​​of the previous two scheduled visits, which are weeks 12 and 16 for the week 20 assessment and weeks 16 and 20 for the week 24 assessment, or ii) an increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the two previous scheduled visits; iii) a decrease in best-corrected visual acuity (BCVA) of 5 or more letters compared with the mean BCVA value at the previous two scheduled visits due to nAMD disease activity; iv) A loss of 10 or more letters of BCVA due to nAMD disease activity compared to the highest BCVA value recorded at any of the two previous scheduled visits, or v) the presence of new macular hemorrhage due to nAMD activity; c) Next, the patient i) Patients who meet disease activity criteria at week 20 will be treated with a Q8W dosing interval from week 20 onwards (with the first Q8W dose administered at week 20); ii) Patients who meet disease activity criteria at week 24 will be treated with a Q12W dosing interval from week 24 onwards (with the first Q12W at week 24); The method of embodiment 2, wherein iii) patients who do not meet disease activity criteria at weeks 20 and 24 are treated with a Q16W dosing interval from week 28 onwards (with the first Q16W at week 28).

[0174] 4. The individualized treatment interval is extended, shortened, or maintained after week 60; a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) an increase in CST of 50 μm or more compared to the average from the last two dosing visits or an increase of 75 μm or more compared to the lowest dosing visit measurement; ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) the presence of new macular hemorrhage; 4. The method of embodiment 3.

[0175] 5. The method of embodiment 1 for use in treating diabetic macular edema (DME) or treating a patient suffering from DME.

[0176] 6. The treatment includes individualized treatment intervals (PTIs); a) Patients will be initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) until the central subfield thickness (CST) meets a predefined reference CST threshold (measured after week 12) (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT, or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT); b) The dosing interval is then increased by 4 weeks to give the initial Q8W dosing interval, c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) if there was a >10% increase in CST value with an associated loss of BCVA of ≥10 letters, the interval was reduced by 8 weeks; Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; The method of embodiment 5, wherein the reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0177] 7. The method of embodiment 6, wherein the dosing interval may be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0178] 8. A method of treating a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal 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), the treatment comprising individualized treatment intervals (PTIs); a) Patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from Day 1 to Week 20; b) From week 24, patients will receive bispecific VEGF / ANG2 antibody at a frequency of Q4W until central subfield thickness (CST) meets a predefined reference CST threshold (CST<325 μm for Spectralis Spectral Domain-Central Subfield Thickness SD-OCT, or CST<315 μm for Cirrus SD-OCT or Topcon SD-OCT) (measured after week 24), c) From this point onwards, the dosing interval will be extended, shortened or maintained based on assessments made at the dosing visit based on the relative change in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA, If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST score without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increased by >10% with an associated BCVA loss of ≥10 letters, the interval was shortened to Q4W. Each reference central subfield thickness (CST) is the CST value at which the initial CST threshold criteria were met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreased by more than 10% from the previous reference CST and the resulting values ​​were within 30 μm, the CST value obtained at the later visit served as the new reference CST; Reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

[0179] 9. The method of embodiment 8, wherein the dosing interval may be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

[0180] 10. The bispecific antibody that binds human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) The method according to any one of the preceding embodiments, wherein the bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass comprising the mutations I253A, H310A, and H435A, and the mutations L234A, L235A, and P329G (numbering according to the EU index as per Kabat).

[0181] 11. i) the first antigen-binding site that specifically binds to VEGF comprises the heavy chain variable domain VH of the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain VL of the amino acid sequence of SEQ ID NO: 8; ii) The method of embodiment 10, wherein 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.

[0182] 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 sequences of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20.

[0183] 13. The method of any one of embodiments 1-9, wherein the bispecific antibody is faricimab.

[0184] 14. The method of any one of embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 5-7 mg (in each treatment).

[0185] 15. The method of any one of embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 6 mg (in each treatment).

[0186] 16. The method of embodiment 14 or 15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml.

[0187] 17. The method of any one of the preceding embodiments, wherein the patient suffering from ophthalmic vascular disease has not been previously treated with an anti-VEGF therapy.

[0188] 18. The method of any one of the preceding embodiments, wherein the patient suffering from ophthalmic vascular disease has previously been treated with an anti-VEGF therapy.

[0189] 19. The method of any one of the preceding embodiments, wherein the antibody is administered according to a determination of a software tool.

[0190] 20. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from nAMD, the method comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an evaluation of new macular hemorrhage; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval will be shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) The presence of new macular hemorrhage.

[0191] 21. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from DME, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) If the CST value increases by more than 10% with an associated loss of BCVA of 10 letters or more, the interval is shortened by 8 weeks.

[0192] 22. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using a computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating a PTI from the administration interval, i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with associated loss of BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST value without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increases by more than 10% with an associated BCVA loss of 10 letters or more, the interval will be shortened to Q4W.

[0193] twenty three. receiving updated patient data at a computing system; using a computing system to continually update or maintain the dosing interval based on updated patient data; 23. The method of any one of embodiments 20, 21 or 22, further comprising generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0194] 24. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of nAMD), comprising: a computing system comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an evaluation of new macular hemorrhage; Generate a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; a) The interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of more than 50 μm compared to the lowest in-study drug administration visit measurement; ii) no loss of 5 or more letters of BCVA compared to the average of the last two study drug administration visits and no loss of 10 or more letters of BCVA compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) An increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement, ii) A loss of 5 or more letters of BCVA compared to the average of the last two administration visits or a loss of 10 or more letters of BCVA compared to the highest administration visit measurement; iii) Presence of new macular hemorrhage, use.

[0195] 25. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of DME), comprising: a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; generating a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; i) - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 letters or more, the interval will be extended by 4 weeks. ii) -CST decreases by more than 10%; or - 10% or less increase or decrease in CST value with associated loss of BCVA of 10 letters or more; or - If CST increases by >10% - ≤20% without associated loss of BCVA of ≥5 letters, the interval will be maintained. iii) - A 10%-20% increase in CST value with associated 5-10 letter loss in BCVA, or - If CST value increases by >20% without associated loss of BCVA of ≥10 letters, the interval is reduced by 4 weeks iv) If the CST value increases by >10% with an associated loss of BCVA of ≥10 letters, the interval will be shortened by 8 weeks.

[0196] 26. Use of an individualized dosing schedule according to individualized treatment intervals (PTIs) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion), comprising a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; generating a PTI by extending, shortening, or maintaining the dosing interval based on the received patient data compared to the respective reference CST and BCVA; i) If the CST value increases or decreases by 10% or less without an associated loss of 10 or more letters of BCVA, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more, or If the CST value increased by >10% to <20% without an associated loss of BCVA of ≥5 letters, the interval was maintained. iii) Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or A >20% increase in CST score without an associated loss of 10 or more letters of BCVA, or If the CST value increased by 10% or less with an associated BCVA loss of 10 letters or more, the interval was shortened by 4 weeks. iv) If the CST value increases by more than 10% with an associated BCVA loss of 10 letters or more, the interval is shortened to Q4W. EXAMPLES

[0197] Treating patients with vascular eye disease with a bispecific antibody that binds human VEGF and human ANG2 Example 1: Efficacy and Duration of Treatment in Patients with Neovascular Age-Related Macular Degeneration (nAMD) Using Individualized Treatment Intervals Notably, an earlier Phase II 52-week study to investigate the efficacy of RO6867461 (faricimab) administered at 12- and 16-week intervals in treatment-naïve patients with nAMD showed longer duration (potentially longer time to retreatment) for all patients involved. Three arms were studied: - Arm A (Q12W): 6 mg RO6867461 intravitreal (IVT) every 4 weeks up to week 12 (4 injections), followed by 6 mg RO6867461 IVT every 12 weeks up to week 48 (injections at weeks 24, 36, and 48; 3 injections)…………………………………… - Arm B (Q16W): 6mg RO6867461 IVT every 4 weeks up to week 12 (4 infusions), followed by 6mg RO6867461 IVT every 16 weeks up to week 48 (infusions at weeks 28 and 44; 2 infusions)……… ……………………………………. - Group C (control group): Ranibizumab IVT 0.5 mg every 4 weeks for 48 weeks (13 injections). Only one eye will be selected as the study eye.

[0198] The results for BCVA are shown in Figure 5. Figure 5 shows the BCVA improvement from baseline in patients with neovascular age-related macular degeneration (nAMD) comparing bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) at 12 and 16 week intervals and ranibizumab (Lucentis® (intravitreally administered at a dose of 0.3 mg)) at 4 week intervals.

[0199] A follow-up Phase III study was initiated to evaluate the efficacy, safety, duration, and pharmacokinetics of a 6 mg dose of faricimab administered at intervals of up to 16 weeks (on a specific individualized treatment interval (PTI) schedule) compared with aflibercept monotherapy Q8W in patients with CNV secondary to AMD, also known as nAMD.

[0200] Faricimab is administered at a concentration of approximately 120 mg / ml.

[0201] The specific objectives and corresponding endpoints of the study are outlined in Table 1. [Table 2] [Table 3] [Table 4]

[0202] Patients suffering from neovascular age-related macular degeneration (nAMD), also called age-related macular degeneration (wet AMD), are treated with 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 (this antibody VEGFang2-0016 and its production are also described in detail in WO2014 / 009465, which is incorporated by reference). This bispecific anti-VEGF / ANG2 antibody is referred to herein as RO6867461 or RG7716 or VEGFang2-0016 or faricimab. For example, aflibercept is used as a positive control drug in the treatment. Patients include anti-VEGF treatment-naive patients (e.g., not previously treated with anti-VEGF treatment with aflibercept and / or ranibizumab and / or other anti-VEGF treatments). Use a vial of sterile, colorless to brownish, preservative-free solution of RO6867461 (faricimab) for intravitreal (IVT) administration at a 6 mg dose.

[0203] research design This is a multicenter, randomized, positive-controlled, double-blind, parallel-group, 112-week study to investigate the efficacy, safety, duration, and pharmacokinetics of faricimab administered at intervals of up to 16 weeks in patients with treatment-naive nAMD.

[0204] Overall, approximately 640 patients will be enrolled and randomized in a 1:1 ratio to one of two treatment arms.

[0205] Arm A (faricimab up to Q16W) (n=320): Patients randomized to Arm A will receive 6 mg IVT faricimab Q4W (4 infusions) up to Week 12. At Week 20, a protocol-defined disease activity assessment will require that patients in Arm A with active disease (see below for criteria) are treated at that visit and continue on the Q8W dosing regimen of faricimab. At a second protocol-defined disease activity assessment at Week 24, patients in Arm A with active disease (excluding patients with active disease at Week 20 and therefore receiving a Q8W dosing regimen of faricimab) are treated at that visit and continue on the Q12W dosing regimen of faricimab. Patients receiving faricimab without active disease according to protocol-defined criteria at Weeks 20 and 24 will be treated with the Q16W dosing regimen of faricimab. Patients will continue to receive faricimab on a fixed regimen every 8, 12, or 16 weeks until week 60, according to disease activity assessments performed at weeks 20 and 24. After week 60 (when all patients in arm A are scheduled to receive faricimab), all patients in arm A will be treated according to an individualized treatment interval (PTI) dosing regimen (see Table 2 for PTI dosing criteria) for up to 108 weeks.

[0206] Arm B (Comparator arm) (Q8W): Patients randomized to Arm B will receive 2 mg IVT aflibercept Q4W (3 infusions) up to week 8, followed by 2 mg IVT aflibercept Q8W up to week 108.

[0207] Patients in both treatment arms will complete scheduled study visits Q4W throughout the study period (112 weeks). Placebo will be administered to patients in both treatment arms at study visits without study treatment administration to maintain blinding between treatment arms.

[0208] Figure 1 provides an overview of the study design.

[0209] 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, instead of Q16W dosing.

[0210] bThe primary endpoint was change from baseline in BCVA (assessed with the ETDRS visual acuity chart at a starting distance of 4 meters) based on the average at weeks 40, 44, and 48.

[0211] cFrom week 60 onwards (when all patients in arm A are scheduled to receive faricimab), patients in arm A will be treated according to the PTI dosing regimen (between Q8W and Q16W).

[0212] 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=weeks.

[0213] Only one eye will be assigned as the study eye. If both eyes are deemed 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 based on medical reasons, the investigator deems the other eye more suitable for treatment in the study).

[0214] To meet the blinding requirements of the study, there will be a minimum of two investigators per site. At least one investigator will be blinded to each patient's treatment assignment and designated as the evaluator who will evaluate the ocular assessments. At least one other investigator will be unblinded and will administer the study treatment.

[0215] The study will consist of a screening period of up to 28 days (day -28 to day -1) and a treatment period of approximately 108 weeks, followed by a final study visit at week 112 (at least 28 days after the last study treatment administration).

[0216] Disease activity criteria at weeks 20 and 24 Determination of active disease will be made at weeks 20 and 24 if any of the following criteria are met: An increase in CST of more than 50 μm compared to the mean CST values ​​over the two previous scheduled visits (Weeks 12 and 16 for the Week 20 assessment, and Weeks 16 and 20 for the Week 24 assessment), or An increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the previous two scheduled visits, or A decrease in BCVA of ≥5 letters compared to the mean BCVA value over the previous two scheduled visits due to nAMD disease activity (as determined by the investigator), or A decrease in BCVA of 10 or more letters compared to the highest BCVA value recorded at any of the two previous scheduled visits due to nAMD disease activity (as determined by the investigator), or · Presence of new macular hemorrhage due to nAMD activity (determined by the investigator).

[0217] Additional considerations at Week 24: If at Week 24 the above criteria are not met but there is significant nAMD disease activity that in the investigator's opinion requires treatment, patients randomized to Arm A will receive 6 mg faricimab at Week 24 and continue to receive repeat weekly treatment for 12 weeks. Patients randomized to Arm A who meet the disease activity criteria at Week 20 will remain on the Q8W dosing schedule and will not receive treatment at Week 24. Patients randomized to Arm B will remain on the Q8W dosing schedule and will receive aflibercept at Week 24.

[0218] Individualized Treatment Interval (PTI) Disease Activity Criteria Beginning at week 60, when all patients in group A are scheduled to receive faricimab, the study drug administration interval for patients in group A will be extended based on assessments made at the study drug administration visit. The determination of the study drug administration interval during the PTI regimen phase for group A (and the respective algorithm) is shown in Table 2. The determination is made based on data from visits in which patients received the drug. Patients will receive a sham procedure at the study visit if they are not receiving treatment with faricimab. [Table 5]

[0219] As outlined above in Table 2, the algorithm for individualized drug treatment interval determination is based on the relative change in CST and phase absolute change in BCVA compared to the reference CST and BCVA, respectively, as well as the assessment / detection of new macular hemorrhage. The algorithm may be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile app, a software program, or any clinical decision support tool. For example, the patient's CST and BCVA scores may be uploaded to the web interface of a personalized dosing interval software tool.

[0220] Using the uploaded CST and BVCA, the tool may automatically calculate and output the timing of the following doses: The tool may further provide a dosing schedule or notification, monitor and generate visualizations of dosing interval changes for a given patient, generate visualizations of dosing interval changes for patient populations, aggregate received CST and BCVA data to determine trends, or provide a combination thereof.

[0221] The dosing schedule or notification may include a display of calendar dates of scheduled dosing visits, and calendar alerts notifying the clinician or patient of upcoming dosing visits. Visualization of dosing interval changes may include, for example, displaying a schematic diagram of Table 2. In some cases, a patient's dosing interval adjustments may be shown in one color and the patient's immediately preceding dosing interval adjustments in another color.

[0222] To illustrate, a patient may first extend the interval by 4 weeks and then maintain the individualized treatment interval. The tool may visualize the patient's individualized interval progression by showing the "interval maintained" area of ​​the schematic in Table 2 in green and "interval extended by 4 weeks" in yellow. The green may reflect the patient's most recent interval calculation, while the yellow may indicate the results of the patient's most recent interval calculation. This visualization may allow a user of the tool to quickly see that the patient's disease progression is improving, but not improving enough to warrant further extension of the treatment interval.

[0223] The tool may further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis may include visualization of dosing changes for a single patient, similar to the color-coding example above. Alternatively, the visualization may show dosing adjustments across a group of patients. For example, a visualization may show which patients have extended intervals and which have shortened intervals.

[0224] The visualizations may be organized by various characteristics such as patient age, previous treatments, medical condition, antibodies administered, clinical trial arms, etc. The tool may also aggregate and create visualizations from the patient's CST and BCVA data. Visualizations may show trends in the data and facilitate or generate longitudinal analyses. These visualizations may include alerts, plots, analysis workflow interfaces, or any graphical interface.

[0225] The tool may generate an output or visualization of the dosing schedule in response to or together with the ocular assessment and images. In one embodiment, the tool may directly calculate the patient's CST or BVCA. For CST, the tool receives or directly captures ocular images. The tool may further calculate the CST from the ocular images using image segmentation, image recognition, or machine learning techniques. For BCVA, the tool may perform the ocular assessment virtually and facilitate and collect the patient's user input through a user interface or eye tracking mechanism. Alternatively, the tool may receive, store, and track the ocular assessment data. In this way, the tool may track the disease progression of each patient and adjust the dosing schedule accordingly.

[0226] The present embodiment may include a method for providing an individualized dosing schedule according to a personalized treatment interval (PTI) for the treatment of a patient suffering from nAMD, comprising: receiving patient data including the patient's CST and best corrected visual acuity (BCVA) in a computing system; using the computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA; and generating the PTI from the dosing interval. An exemplary dosing interval is extended by 4 weeks (up to Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm compared to the lowest study drug administration visit measurement and no increase in CST of 50 μm or more; ii) no decrease in BCVA of 5 letters or more compared to the average of the last two study drug administration visits and no decrease in BCVA of 10 letters or more compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage.

[0227] An exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or an exemplary dosing interval is shortened to an 8 week interval if two or more of the following criteria are met or one criterion includes new macular hemorrhage: i) there is an increase in CST of 50 μm or more compared to the average from the last two dosing visits or there is an increase in CST of 75 μm or more compared to the lowest dosing visit measurement; ii) there is a loss of BCVA of 5 letters or more compared to the average of the last two dosing visits or there is a loss of BCVA of 10 letters or more compared to the highest dosing visit measurement; iii) there is a new macular hemorrhage.

[0228] Such a method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for treatment of a patient suffering from nAMD may further include receiving, in a computing system, updated patient data, continuously updating or maintaining, using the computing system, a dosing interval based on the updated patient data, and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0229] The present embodiment also includes the use of a personalized dosing schedule according to a personalized treatment interval (PTI) (for the treatment of nAMD), where the computing system generates the PTI by receiving patient data including the patient's CST and best corrected visual acuity (BCVA), and extends, shortens, or maintains the dosing interval based on the received patient data compared to the respective reference CST and BCVA. An exemplary dosing interval is extended by 4 weeks (up to Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the last two study drug administration visits, where stability is defined as a change in CST of less than 30 μm compared to the lowest study drug administration visit measurement and no increase in CST of 50 μm or more; ii) no decrease in BCVA of 5 letters or more compared to the average of the last two study drug administration visits and no decrease in BCVA of 10 letters or more compared to the highest study drug administration visit measurement; iii) no new macular hemorrhage. An exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or an exemplary dosing interval is shortened to an 8 week interval if two or more of the following criteria are met or one criterion includes new macular hemorrhage: i) there is an increase in CST of 50 μm or more compared to the average from the last two dosing visits or there is an increase in CST of 75 μm or more compared to the lowest dosing visit measurement; ii) there is a loss of BCVA of 5 letters or more compared to the average of the last two dosing visits or there is a loss of BCVA of 10 letters or more compared to the highest dosing visit measurement; iii) there is a new macular hemorrhage.

[0230] Ocular evaluation Ocular evaluations will be performed at designated time points and will include the following: ·BCVA will be measured using a set of three Precision Vision™ or Lighthouse distance acuity charts (modified ETDRS acuity charts 1, 2, and R). The VA manual was provided to the investigator. Certification of the VA examiner and VA examination office was secured prior to performing the VA examination. The BCVA examiner was blinded to study eye and treatment assignment and only performed refraction and BCVA assessments (e.g., visual acuity specification manual). The BCVA examiner was also blinded to the BCVA letter scores of the patient's previous visits and was only aware of the patient's refraction data from the previous visit. The BCVA examiner was not permitted to perform any other tasks involving direct patient care. Low-luminance BCVA assessed with the ETDRS eye chart at the low-luminance best-corrected visual acuity starting distance of 4 meters. Same requirements as best-corrected visual acuity as listed in Appendix 4. However, low-luminance best-corrected visual acuity is measured by placing a 2.0 log-unit neutral density filter (Kodak Wratten 2.0 neutral density filter) over the best correction of that eye and having the participant read the Early Treatment Diabetic Retinopathy Study eye chart at normal luminance. · Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before dilatation of the eyes). Slit lamp examination (for anterior and vitreous cell grading scales see CS, Kothari S, Anesi SD, et al. The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61(2016)1-17). - Binocular indirect ophthalmoscopy with high magnification Index test, followed by hand movement and light perception tests (if required), were performed within 15 minutes after study treatment in the study eye by the open-label treatment administerer only. Post-treatment IOP measurement in the study eye only within 30 (± 15) minutes by qualified personnel assigned to an unblinded role at the study treatment visit. If there are no safety concerns after 30 minutes (± 15) of study treatment, patients will be allowed to leave the clinic. If the IOP value is of concern to the treatment administerer, patients will remain in the clinic and will be managed according to the clinical judgment of the treatment administerer. Adverse events will be recorded on the electronic Adverse Event Case Report Form (eCRF) as appropriate.

[0231] The method of IOP measurement used on patients should be consistent throughout the study.

[0232] Eye Imaging The Central Reading Center (CRC) will provide sites with Central Reading Center manuals and training materials for specific study ocular imaging. Prior to acquisition of any study images, site personnel, test images, systems, and software (if applicable) will be certified and verified by the Reading Center as specified in the Central Reading Center manuals. All ocular imaging 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.

[0233] After randomization, if a patient misses a study visit when ocular images are scheduled, or if images are not taken at the scheduled visit (e.g., due to equipment malfunction), the patient should have images obtained at the next scheduled visit.

[0234] Eye images include: · Color Fundus Photography (CFP) of both eyes. Stereo color fundus photographs will be taken of both eyes by trained personnel at the study site. Fundus photography will occur at intervals specified in the activity schedule. Fluorescein angiography (FFA of both eyes, performed after obtaining the specimen). Fluorescein angiography will be performed on both eyes at the study site by trained personnel certified by the central reading center. Fluorescein angiograms will be obtained at intervals specified in the protocol. Spectral-domain optical coherence tomography (SD OCT) or swept-source OCT (SS-OCT) images of both eyes. · Optional optical OCT angiography (OCT-A) of both eyes at sites with agreed OCT-A capabilities. Optional indocyanine green angiography (ICGA) of both eyes at selected sites with agreed ICGA capabilities (performed after laboratory samples are obtained). Indocyanine green angiography (ICGA) will be performed in both eyes by trained personnel certified by the Central Reading Center at specified intervals.

[0235] result The primary efficacy analysis included all randomized patients, grouped according to treatment assigned at randomization.

[0236] The primary efficacy variable is the change in BCVA. The primary efficacy analysis will be performed using, for example, a mixed model with repeated measures (MMRM) model.

[0237] Best corrected visual acuity BCVA is measured as described. The main efficacy outcome measurements are shown in the figure representing the primary efficacy endpoint. BCVA changes from patient baseline over time. The bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg as described in group A using individualized treatment intervals) containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 is compared with group B (administered aflibercept (Eylea®) Q8W) according to the above study scheme, for example.

[0238] Central Subfield Thickness (CST) Change from Baseline (Study Eye) The key secondary endpoint is the change from baseline in central subfield thickness CST. CST (and retinal thickness) is measured by optical coherence tomography (OCT). The results are shown in the figure, in which the change in CST is shown over time for bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg, as described in group A, using individualized treatment intervals) that includes the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, and is compared with group B (administered aflibercept (Eylea®) Q8W) according to the above study scheme.

[0239] Further results and imaging of the eye evaluation can be displayed accordingly.

[0240] Example 2: Efficacy and Duration of Bispecific Anti-VEGF / ANG2 Treatment in Patients with Diabetic Macular Edema (DME) Using Individualized Treatment Intervals An early Phase II 36-week study in patients with diabetic macular edema (DME) saw some potential for longer duration (potentially longer time to retreatment) across all patients involved. The three study arms were treated as follows: Arm A: 0.3 mg ranibizumab intravitreal (IVT); Arm B: 1.5 mg RO6867461 (faricimab) IVT; Arm C: 6 mg RO6867461 (faricimab) IVT.

[0241] Results regarding the potentially longer time to retreatment of RO6867461 (faricimab, VA2) are shown in Figure 6. Figure 6 shows the time to retreatment in patients with DME after dosing has been discontinued (after 20 weeks or 6 months of dosing = time after last intravitreal (IVT) dose) based on disease activity assessed by both: BCVA loss of ≥ 5 letters and CST increase of ≥ 50 μm (= patients with an event). The bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at a dose of 6.0 mg or 1.5 mg) was compared to ranibizumab (Lucentis®) (administered intravitreally at a dose of 0.3 mg).

[0242] We have initiated a follow-up Phase III study to evaluate the efficacy, safety, and pharmacokinetics of RO6867461 (faricimab) when administered to patients every 8 weeks (Q8W) and individualized treatment interval (PTI) regimens compared to aflibercept (Eylea®) monotherapy in patients with DME. We will assess the impact on visual function by measuring the change from baseline in best corrected visual acuity (BCVA) (i.e., number of ETDRS letters). We will evaluate the effect on retinal anatomy by retinal imaging (spectral domain optical coherence tomography [SD-OCT], color fundus photography [CFP], fluorescein angiography [FFA]), as well as other imaging modalities to evaluate outcomes for both DME and DR. Additionally, we will evaluate the safety, patient-reported outcomes (PROs), and pharmacokinetics of RO6867461.

[0243] This study evaluates the efficacy, safety, and pharmacokinetics of RO6867461 when administered in a Q8W and PTI regimen compared with aflibercept (Eylea®) monotherapy in patients with DME. The specific objectives and corresponding endpoints of the study are outlined in Table 3. [Table 6] [Table 7] [Table 8] [Table 9]

[0244] Patients suffering from DME (e.g., center-involving diabetic macular edema (CI-DME)) are treated with 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 (this antibody VEGFang2-0016 and its production are also described in detail in WO2014 / 009465, which is also incorporated by reference). This bispecific anti-VEGF / ANG2 antibody is referred to herein as RO6867461 or RG7716 or VEGFang2-0016 or faricimab. For example, aflibercept is used as a positive control drug in the treatment. Patients include anti-VEGF treatment-naive patients (not previously treated with anti-VEGF treatment, e.g., aflibercept and / or ranibizumab and / or other anti-VEGF treatment) and patients previously treated with anti-VEGF treatment. Use a vial of sterile, colorless to brownish, preservative-free solution of RO6867461 (faricimab) for intravitreal (IVT) administration at a dose of 6 mg. RO6867461 (faricimab) is administered at a concentration of approximately 120 mg / ml.

[0245] Approximately 900 patients will be randomized in a 1:1:1 ratio to one of three treatment arms across approximately 240 study sites overall during the entire enrollment phase of the study (see Figure 2). The study will randomize patients with DME who are anti-VEGF therapy naive in the study eye, and patients who have been previously treated with anti-VEGF therapy in the study eye, provided that their last treatment was at least 3 months prior to Visit Day 1 (first study treatment). Site investigators will be retina specialists.

[0246] The study treatment arms were as follows (see also Figure 2):

[0247] Arm A (Q8W dosing): Patients randomized to Arm A will receive 6 mg IVT RO6867461 (faricimab) infusions Q4W through week 20, followed by 6 mg IVT RO6867461 (faricimab) infusions Q8W through week 96, followed by a final study visit at week 100.

[0248] Arm B (Individualized Treatment Interval PTI): Patients randomized to Arm B will receive 6 mg IVT RO6867461 (faricimab) infusions Q4W until at least Week 12, followed by PTI dosing of 6 mg IVT RO6867461 (faricimab) infusions (see PTI dosing criteria below) until Week 96, followed by a final study visit at Week 100.

[0249] Arm C (Comparator arm) (Q8W dosing): Patients randomized to Arm C will receive 2 mg IVT aflibercept infusions Q4W until week 16, followed by 2 mg IVT aflibercept infusions Q8W until week 96, followed by a study endpoint at week 100.

[0250] Patients in all three treatment groups will complete study visits scheduled Q4W throughout the entire study period (100 weeks). To maintain blinding between treatment groups, a sham procedure will be administered to patients in all three treatment groups at applicable visits (see Figure 2 - Study Treatment Scheme).

[0251] Only one eye will be assigned as the study eye. If both eyes are deemed eligible, the eye with the worse BCVA assessed at screening will be selected as the study eye, unless the investigator deems the other eye more suitable for treatment in the study.

[0252] To fulfill the blinding requirements of the study, there will be a minimum of two investigators per site. At least one investigator will be blinded to each patient's treatment assignment and designated as the evaluator who will evaluate the ocular assessments. At least one other investigator will be unblinded and will administer the study treatment (see Section 4.2.2 for additional blinding details).

[0253] Treatment schedule for patients in the individualized treatment interval (PTI) group (Group B) This section describes the determination of the administration interval for the PTI group.

[0254] The on-study drug administration visit was the visit when the patient was assigned to receive faricimab (RO6867461).

[0255] Determination of study drug administration interval Patients randomized to the PTI group (arm B) will be treated with faricimab at Q4W dosing intervals until their CST at week 12 or later 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).

[0256] The reference CST will be used at in-study drug administration visits for interval determination.

[0257] After a patient's initial reference CST is established, the study drug dosing interval will be increased by 4 weeks to the initial Q8W dosing interval. From this point onwards, the study drug dosing interval will be lengthened, shortened or maintained based on assessments made at the drug administration visit.

[0258] Figure 3 outlines the algorithm for determining intervals based on relative changes in CST and BCVA compared to reference CST and reference BCVA. In Figure 3, * and ** mean the following: * Reference Central Subfield Thickness (CST): The CST value when the initial CST threshold criteria are met. If the CST decreases by more than 10% from the previous reference CST for two consecutive study drug administration visits and the obtained values ​​are within 30 μm, the reference CST is adjusted. The CST value obtained at the latter visit serves as the new reference CST starting immediately at that visit. ** Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[0259] All comparisons are made against a reference CST* and reference BCVA**. Determination of drug administration intervals based on CST and BCVA data obtained from drug administration visits.

[0260] 4-week interval extension: A ≥10% increase or decrease in CST value without an associated loss of ≥10 letters of BCVA.

[0261] Maintain spacing: If the CST decreases by more than 10%, or A 10% or less increase or decrease in CST value with an associated loss of 10 or more letters of BCVA, or Increase in CST value of >10%-<20% without associated loss of BCVA of ≥5 letters.

[0262] Reduced 4 week interval: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA, or Increase in CST value of >20% without associated loss of BCVA of ≥10 letters.

[0263] Reduced 8 week interval: Increase in CST value of >10% with associated loss of BCVA of ≥10 letters * Reference Central Subfield Thickness (CST): The CST value when the initial CST threshold criteria were met. If the CST decreases by more than 10% from the previous reference CST for two consecutive study drug administration visits and the obtained values ​​are within 30 μm, the reference CST is adjusted. The CST value obtained at the later visit serves as the new reference CST starting immediately at that visit. ** Reference Best Corrected Visual Acuity (BCVA): The average of the three best BCVA scores obtained at any prior study drug administration visit.

[0264] The individualized drug administration interval may be adjusted in 4-week increments up to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. The algorithm for determining the individualized drug treatment interval is based on the relative change in CST and the absolute change in BCVA compared to the reference CST and BCVA, respectively.

[0265] The algorithm may be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile app, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores may be uploaded to a web interface of a personalized dose interval software tool. Using the uploaded CST and BVCA, the tool may automatically calculate and output the timing of the following doses. The tool may further provide a dosing schedule or notification, monitor and generate visualizations of dose interval changes for a given patient, generate visualizations of dose interval changes for a group of patients, aggregate received CST and BCVA data to determine trends, or a combination thereof.

[0266] The dosing schedule or notification may include a display of calendar dates of scheduled dosing visits, and calendar alerts notifying the clinician or patient of upcoming dosing visits. The visualization of dosing interval changes may include, for example, a display of the schematic diagram of FIG. 3. In some cases, a patient's dosing interval adjustments may be shown in one color and the patient's immediately preceding dosing interval adjustments in another color. To illustrate, a patient may first extend the interval by 4 weeks and then maintain the individualized treatment interval. The tool may visualize the patient's individualized interval progression by displaying the "interval maintained" area of ​​the schematic diagram of FIG. 3 in green and the "interval extended by 4 weeks" in yellow. The green may reflect the patient's most recent interval calculation, and the yellow may indicate the results of the patient's immediately preceding interval calculation. This visualization may allow a user of the tool to quickly see that the patient's disease progression is improving, but not improving enough to warrant further extension of the treatment interval.

[0267] The tool may further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis may include visualization of dosing changes for a single patient, similar to the color-coding example discussed above. Alternatively, the visualization may show dosing adjustments across a group of patients. For example, a visualization may show which patients have extended intervals and which have shortened intervals. The visualization may be organized by various characteristics such as patient age, previous treatments, medical condition, antibodies administered, clinical study groups, etc. The tool may also aggregate and create visualizations from the patient's CST and BCVA data. Visualizations may show trends in the data and facilitate or generate longitudinal analyses. These visualizations may include alerts, plots, analysis workflow interfaces, or any graphical interface.

[0268] The tool may generate an output or visualization of the dosing schedule in response to or together with the ocular assessment and images. In one embodiment, the tool may directly calculate the patient's CST or BVCA. For CST, the tool receives or directly captures ocular images. The tool may further calculate the CST from the ocular images using image segmentation, image recognition, or machine learning techniques. For BCVA, the tool may virtually administer the ocular assessment and facilitate and collect patient user input via a user interface or eye tracking mechanism. Alternatively, the tool may receive, store, and track ocular assessment data. In this way, the tool may track each patient's disease progression and adjust the dosing schedule accordingly.

[0269] The present embodiment may include a method of providing an individualized dosing schedule according to a personalized treatment interval (PTI) for the treatment of a patient suffering from DME, comprising receiving patient data including the patient's CST and best corrected visual acuity (BCVA) in a computing system, and using the computing system to extend, shorten, or maintain the dosing interval based on the received patient data compared to the respective reference CST and BCVA, and generating the PTI from the dosing interval. If the CST value increases or decreases by 10% or less and is not accompanied by an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is extended by 4 weeks. If the CST decreases by more than 10%, or if the CST value increases or decreases by 10% or less and is accompanied by an associated decrease in BCVA of 10 or more letters, or if the CST value increases by more than 10% to 20% or less and is not accompanied by an associated decrease in BCVA of 5 or more letters, the exemplary dosing interval is maintained. If the CST value increases by more than 10% to less than 20% with an associated decrease in BCVA of 5 to less than 10 letters, or if the CST value increases by more than 20% without an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is reduced by 4 weeks. If the CST value increases by more than 10% with an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is reduced by 8 weeks.

[0270] Such a method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for treatment of a patient suffering from DME may further include receiving, in a computing system, updated patient data, continuously updating or maintaining, using the computing system, a dosing interval based on the updated patient data, and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0271] The present embodiment also relates to the use of an individualized dosing schedule according to a personalized treatment interval (PTI) (for the treatment of DME), in which a computing system receives patient data including a patient's CST and best corrected visual acuity (BCVA), and produces the PTI by extending, shortening, or maintaining the dosing interval based on the received patient data, compared to the respective reference CST and BCVA. An exemplary dosing interval is extended by 4 weeks if the CST value increases or decreases by 10% or less and is not accompanied by an associated decrease in BCVA of 10 letters or more. If the CST decreases by more than 10%, or if the CST value increases or decreases by 10% or less and is accompanied by an associated decrease in BCVA of 10 letters or more, or

[0272] If CST values ​​increase by >10%-<20% without an associated decrease in BCVA of ≥5 letters, the exemplary dosing interval is maintained. -If the CST value increases by more than 10% to less than 20% with an associated BCVA decrease of 5 to less than 10 letters, or if the CST value increases by more than 20% without an associated BCVA decrease of 10 or more letters, the exemplary dosing interval is reduced by 4 weeks. If the CST value increases by more than 10% with an associated BCVA decrease of 10 or more letters, the exemplary dosing interval is reduced by 8 weeks. Similar to groups A and C, patients randomized to the PTI group (group B) will receive a sham procedure at the study visit if the patient is not receiving treatment with faricimab.

[0273] Ocular evaluation Ocular evaluations will be performed on both eyes at designated times according to the schedule of activities and will include the following: Refraction and BCVA assessed with ETDRS acuity charts at a starting distance of 4 meters. BCVA is measured using a set of three Precision Vision™ or Lighthouse distance acuity charts (modified ETDRS acuity charts 1, 2, and R). The VA manual was provided to the investigators. Certification of the VA examiners and VA examination office was secured prior to performing the VA examination. BCVA examiners were blinded to study eye and treatment assignments and only performed refraction and BCVA assessments (e.g., visual acuity specification manual). BCVA examiners were also blinded to the BCVA letter scores of the patient's previous visits and were only aware of the patient's refraction data from the previous visit. BCVA examiners were not allowed to perform other tasks involving direct patient care. Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before dilatation of the eyes). Slit lamp examination (for anterior and vitreous cell grading scales see CS, Kothari S, Anesi SD, et al. The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61(2016)1-17) - Binocular indirect ophthalmoscopy with high magnification Index test performed within approximately 15 minutes after study treatment in the study eye by the unblinded treatment recipient only, followed by hand movement and light perception testing (if indicated). Post-treatment IOP measurement in the study eye at 30 (± 15) minutes by qualified personnel assigned to an unblinded role at the study treatment visit. If there are no safety concerns 30 (± 15) minutes after study treatment, the patient will be allowed to leave the clinic. If the IOP value is of concern to the treatment administerer, the patient will remain in the clinic and treatment will be administered according to this physician's clinical judgment. Adverse events will be recorded on the electronic Adverse Event Case Report Form (eCRF) as appropriate.

[0274] The method of IOP measurement used on patients should be consistent throughout the study.

[0275] Eye Imaging The Central Reading Center (CRC) will provide sites with CRC manuals and training materials for specific study ocular imaging. Prior to acquisition of any study images, site personnel, study images, systems, and software (if applicable) will be qualified and verified by the CRC as specified in the CRC manual. All ocular imaging results will be acquired at the study site by trained site personnel and forwarded to the CRC for independent analysis and / or storage.

[0276] After randomization, if a patient misses a study visit when CFP and FFA images are scheduled, or if images are not taken at the scheduled visit (e.g., due to equipment failure), the patient should have images obtained at the next scheduled visit.

[0277] Eye images include: · Mandatory color fundus photography (CFP) of both eyes (7 or 4 widefield; patients will have one of these methods consistently throughout study participation). Stereo color fundus photographs will be taken of both eyes by trained personnel at the study site. Fundus photography will occur at intervals specified in the activity schedule. Binocular optional ultra-wide field (UWF; Optos®) CFP (at sites that have UWF CFP capability and have agreed to capture these images in addition to the required CFP images) · Fluorescein Angiography (FFA) of both eyes (preferred method is UWF(Optos) FFA if site has capability. Sites without UWF(Optos) FFA to capture 7 or 4 widefields using the same method consistently throughout study participation) (performed after blood sample collection, if applicable) will be performed on both eyes at the study site by trained personnel. UWF(Optos) is the preferred method for Fluorescein Angiography (FFA) capture. Study sites without Optos equipment and certification should use 7 or 4 widefield FFA capture. Spectral-domain optical coherence tomography (SD-OCT) or swept-source OCT (SS-OCT) images of both eyes. Optional OCT Angiograms (OCT-A) of both eyes at sites with OCT-A capability and agreement by the site to take these images.

[0278] result The primary efficacy analysis included all randomized patients, grouped according to treatment assigned at randomization.

[0279] The primary efficacy variable is the change in BCVA as described herein. The primary efficacy analysis is performed, for example, using a mixed model with repeated measures (MMRM) model.

[0280] Best corrected visual acuity BCVA is measured as described. The main efficacy outcome measurements are shown in the figure representing the primary efficacy endpoint. BCVA changes from patient baseline over time. The bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg as described in group B using individualized treatment intervals) containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 is compared, for example, with group A (faricimab administered Q8W) and / or group C (aflibercept (Eylea® administered Q8W) according to the study scheme above.

[0281] Central Subfield Thickness (CST) Change from Baseline (Study Eye) The key secondary endpoint is the change from baseline in central subfield thickness CST. CST (and retinal thickness) is measured by optical coherence tomography (OCT). The results are shown in the figure, in which the change in CST is shown over time for bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg as described in group B, using individualized treatment intervals) that includes the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, compared with, for example, group A (Q8W administration of faricimab) and / or group C (Q8W administration of aflibercept (Eylea®)) according to the above study scheme.

[0282] Further results of ocular evaluation and imaging can be presented accordingly.

[0283] Example 3: Efficacy and duration of bispecific anti-VEGF / ANG2 treatment in patients with macular edema secondary to retinal vein occlusion (RVO), including macular edema secondary to central retinal vein occlusion (CRVO), secondary to hemiretinal vein occlusion (HRVO), or secondary to branch vein occlusion (BRVO), using individualized treatment intervals Preclinical studies have shown that Ang-2 and VEGF act in concert to regulate the vasculature and increase retinal endothelial cell permeability in vitro. Simultaneous inhibition of Ang-2 and VEGF with the bispecific monoclonal antibody faricimab resulted in a significant reduction in leakage and severity of choroidal neovascularization (CNV) lesions in a non-human primate laser-induced CNV model compared with molar equivalents of anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a mouse model of spontaneous CNV showed that dual inhibition of Ang-2 and VEGF was consistently superior to monotherapy inhibition of either target alone in terms of reducing vascular proliferation, leakage, edema, leukocyte infiltration, and photoreceptor loss (Regula JT, Lundh von Leithner P, Foxton R, et al. EMBO Mol Med 2016;8:1265-1288).

[0284] Furthermore, aqueous humor and vitreous concentrations of both Ang-2 and VEGF have been shown to be 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, Puustjarvi T, Terasvirta M, et al. Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh von Leithner P, Foxton R, et al. al.EMBO Mol Med 2016;8:1265-1288; Ng DS, Yip YW, Bakthavatsalam M, et al.Sci Rep 2017;7:45081). Thus, simultaneous neutralization of both Ang-2 and VEGF targets may result in greater normalization of 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 efficacy over anti-VEGF therapy alone in diseases affecting the retinal vasculature.

[0285] 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 extensive Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) in DME, and GR40306 (TENAYA) and GR40844 (LUCERNE) in nAMD.

[0286] Based on the mechanism of action of faricimab, data from nonclinical and clinical trials, and the pathophysiology of macular edema resulting from RVO, it is hypothesized that faricimab may result in stabilization of the pathological ocular vasculature and improved visual and anatomical outcomes of RVO compared with anti-VEGF monotherapy.

[0287] Macular edema secondary to / resulting from RVO is one of the most common 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). The effects of Ang-2 and VEGF inhibition in preclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R, et al. EMBO Mol Med 2016;8:1265-1288), as well as data from phase I and phase II faricimab studies in patients with nAMD and DME, provide evidence of efficacy against pathological pathways common to 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).

[0288] Due to the similarities in pathophysiology between macular edema due to DME and RVO, data from the Phase II BOULEVARD study are reported here. Although the induction of macular edema in diabetic and RVO patients is different, the downstream pathology of hypoxia-induced macular edema and subsequent vision loss is similar and is caused by the same proangiogenic, proinflammatory, vascular destabilizing, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6). Results regarding the potential longer time to retreatment with RO6867461 (faricimab, VA2) are shown in Figure 6. Figure 6 shows the time to retreatment in patients with DME after dosing was discontinued (after 20 weeks or 6 months of dosing = time after last intravitreal (IVT) dose) based on disease activity assessed by both: BCVA loss of ≥ 5 letters and CST increase of ≥ 50 μm (= patients with events). The bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab), administered intravitreally at a dose of 6.0 mg or 1.5 mg, was compared to ranibizumab (Lucentis®), administered intravitreally at a dose of 0.3 mg.

[0289] The BOULEVARD study provided preliminary evidence of a positive benefit / risk profile for the use of a 6 mg IVT infusion of faricimab for patients with DME and supported further evaluation of faricimab in phase III DME studies.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 treatment-naive patients treated with 6 mg faricimab compared with 0.3 mg ranibizumab.

[0290] Results from the treatment-free observational period of the study provided evidence of a longer duration of response with faricimab compared with anti-VEGF monotherapy.

[0291] Evaluation of time to disease reactivity up to 16 weeks after the last dose demonstrated improved duration of effect of faricimab over ranibizumab, as measured by time to loss of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters due to DME, and an increase in central subfield thickness (CST) of 50 μm or more, in a dose-dependent manner in a treatment-naive patient population.

[0292] This improvement in the duration of effect of faricimab over ranibizumab was also seen in previously treated and overall patient populations. Based on the totality of this non-clinical and clinical evidence, treatment with faricimab may provide improved efficacy over anti-VEGF standard of care in patients with macular edema due to RVO. Furthermore, this study examines less frequent (up to every 16 weeks) treatment dosing schedules tailored to individual needs that may provide BCVA results comparable to more frequently administered anti-VEGF monotherapy (e.g., every 4-8 weeks). Together, these would represent an important and meaningful advancement compared to currently available treatments.

[0293] research design A Phase III, multicenter, randomized, double-blind, positive control, parallel group study to evaluate the efficacy, safety, and pharmacokinetics of faricimab (a bispecific antibody that binds 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 (incorporated by reference). This bispecific anti-VEGF / ANG2 antibody is referred to herein as RO6867461 or RG7716 or VEGFang2-0016, or faricimab) administered by IVT infusion every 4 weeks for up to 24 weeks in patients with macular edema due to CRVO or HRVO or BRVO.

[0294] Subsequently, a double-blind study period without a positive control was initiated to evaluate faricimab administered according to the PTI dosing regimen.

[0295] Overview of study design The study consists of two parts: Part 1 (Days 1-24) compares faricimab Q4W with aflibercept (positive control) Q4W; Part 2 (Days 24-72) evaluates faricimab administered at a blinded treatment interval of Q4W to Q16W based on the PTI dosing criteria.

[0296] In Part 1 (Q4W dosing), approximately 680 patients will be randomized in a 1:1 ratio to one of two treatment arms during the entire enrollment phase of the study, with treatments defined as follows: -Arm A (n=340) Patients randomized to Arm A will receive faricimab 6 mg IVT Q4W from Day 1 through Week 20 (6 infusions). -Arm B (control group, n=340): Patients randomly assigned to Arm B received aflibercept 2 mg IVT Q4W from Day 1 to Week 20 (6 infusions).

[0297] In part 2 (PTI regimen), patients in both arms A and B will receive faricimab 6 mg via IVT according to the PTI dosing regimen from weeks 24 to 68.

[0298] All patients will complete scheduled study visits Q4W throughout the entire study period (72 weeks). To maintain blinding of the faricimab treatment interval from Week 24 to Week 68, sham treatment will be administered during the study visits and no faricimab treatment (per the PTI dosing regimen) will be administered at the study visits.

[0299] Figure 7 shows an overview of the study design.

[0300] Only one eye will be assigned as the study eye. If both eyes are deemed eligible, the eye with the worse BCVA, as assessed at screening, will be selected as the study eye, unless the investigator determines that the other eye is more suitable for treatment in the study. There will be a minimum of two investigators per site to meet the blinding requirements of the study. At least one investigator will be blinded to each patient's treatment assignment and designated as the assessor to evaluate the ocular assessments. At least one other investigator will be unblinded and will administer the study treatment.

[0301] The study will consist of a screening period lasting up to 28 days (-28 days to -1 days) and a treatment period of approximately 68 weeks, followed by a final study visit at week 72.

[0302] Objectives and Endpoints This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared with aflibercept in patients with macular edema secondary to CRVO or HRVO or BRVO through the primary endpoint of 24 weeks. The efficacy, safety, and pharmacokinetics of faricimab administered according to a PTI dosing regimen (i.e., Q4W to Q16W) will be evaluated over the study period from 24 weeks to 72 weeks. The specific objectives and corresponding endpoints of the study are outlined below. In this protocol, "study drug" refers to faricimab or aflibercept and "study treatment" refers to faricimab, aflibercept, or sham treatment.

[0303] Efficacy purpose To assess efficacy endpoints, BCVA will be assessed using the ETDRS visual acuity chart at a starting test distance of 4 meters.

[0304] Primary efficacy objective The primary efficacy objective of this study is to evaluate the efficacy of faricimab 6 mg IVT Q4W compared with aflibercept 2 mg IVT Q4W based on the following endpoints: - Change from baseline in BCVA at week 24

[0305] Secondary efficacy objectives Secondary efficacy objectives of Part 1 (through 24 weeks) of this study are to evaluate the efficacy of faricimab compared with aflibercept based on the following endpoints: - Change from baseline in BCVA at designated time points through Week 24 - Proportion of patients with an increase in BCVA of ≥15 letters from baseline at Week 24 - Proportion of patients with an increase in BCVA from baseline of ≥15 letters, ≥10 letters, ≥5 letters, or ≥0 letters at specified time points through Week 24 - Proportion of patients who had not lost ≥15, ≥10, ≥5, or ≥0 letters of BCVA from baseline at a specified time point through Week 24 - Proportion of patients who achieved BCVA of 84 letters or greater (20 / 20 Snellen equivalent) at a specified time point through week 24 - Proportion of patients with BCVA Snellen score ≥ 20 / 40 at designated time points through Week 24 - Proportion of patients with BCVA Snellen equivalent of 20 / 200 or less from the designated time point through Week 24 - Change from baseline in CST from the designated time point through week 24 - Change from baseline to Week 24 on the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) composite score from the designated time point

[0306] The secondary efficacy objectives of Part 2 of this study (i.e., weeks 24 to 72) are to evaluate the efficacy of faricimab administered according to the PTI dosing regimen based on the following endpoints: - Change from baseline in BCVA at selected time points from Week 24 to Week 72 - Proportion of patients with an increase in BCVA of ≥15 letters from baseline at Week 24 - Proportion of patients with an increase in BCVA from baseline of ≥15 letters, ≥10 letters, ≥5 letters, or ≥0 letters at any given time point between Weeks 24 and 72 - Proportion of patients who did not lose 15 or more letters of BCVA, 10 or more letters, 5 or more letters, or 0 or more letters of BCVA from baseline at designated time points between Weeks 24 and 72 - Proportion of patients who achieved BCVA of 84 letters or greater (20 / 20 Snellen equivalent) at a specified time point between Weeks 24 and 72 -Proportion of patients with BCVA Snellen score ≥ 20 / 40 at specific time points from Week 24 to Week 72 - Proportion of patients with BCVA Snellen equivalent of 20 / 200 or less at a given time point from Week 24 to Week 72 -Changes in BCVA at specific time points from Week 24 to Week 72 - Proportion of patients who did not lose BCVA of ≥15 letters, ≥10 letters, ≥5 letters, or ≥0 letters from Week 24 to Week 72 - Proportion of patients with Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W treatment intervals at Week 72 - Number of study drug infusions received between Weeks 24 and 72 -Change from baseline in CST at selected time points from Week 24 to Week 72 -Change from baseline in NEI VFQ-25 composite score at selected time points from Week 24 to Week 72

[0307] Exploratory Efficacy Objectives The exploratory efficacy objectives of this study are to evaluate the efficacy of faricimab based on the following endpoints: - Proportion of patients over time (at specified time points) who are free of retinal ischemia on fluorescein fundus angiography (FFA) and optical coherence tomography angiography (OCT-A) (optional) - Change in retinal ischemic area from baseline over time on FFA and OCT-A (optional) - Proportion of patients with vascular leakage on FFA and / or OCT-A over time - Change from baseline in vascular leakage area on FFA and OCT-A (optional) over time - Changes over time from baseline in foveal avascular area on OCT-A (optional) and other exploratory outcomes defined by SAP (Statistical Analysis Plan) - Proportion of patients without retinal neovascularization over time (as assessed by the investigator) - Proportion of patients over time without vitreous, preretinal, or subretinal hemorrhage (as assessed by the investigator) - Proportion of patients without anterior segment (iris and anterior chamber angle) neovascularization over time - Proportion of patients requiring panretinal photocoagulation at any time during the study - The proportion of patients without macular edema, defined as a CST ≤ 325 μm for Spectralis SD-OCT or a CST ≤ 315 μm for Cirrus SD-OCT or Topcon SD-OCT. - Proportion of patients without intraretinal fluid over time - Proportion of patients without subretinal fluid over time - Proportion of patients free of both intraretinal and subretinal fluid over time - Proportion of patients without intraretinal cysts over time - Changes from baseline over time in NEI VFQ-25 near activities subscale score and distance activities subscale score

[0308] Part 1 treatment schedule (Q4W administration) In part 1 of the study, patients will be treated as follows: -Patients randomly assigned to Arm A will receive faricimab Q4W from Day 1 through Week 20. -Patients randomly assigned to Arm B will receive aflibercept Q4W from Day 1 through Week 20.

[0309] Treatment schedule for Part 2 (individualized treatment interval (PTI) regimen) In part 2 of the study, all patients will visit the clinic Q4W from weeks 24 to 68 and receive either sham treatment or faricimab 6 mg IVT depending on their PTI dosing regimen.

[0310] Faricimab PTI determination is calculated automatically based on the PTI criteria described in this section.

[0311] Determination of study drug administration intervals in the PTI group was based on the algorithm described in this section. Faricimab administration visits were defined as the visits when patients received faricimab 6 mg IVT.

[0312] Beginning at week 24, patients will receive faricimab at a frequency of Q4W until their CST meets a predefined reference CST threshold (<325mm for Spectralis SD-OCT or <315mm for Cirrus SD-OCT and Topcon SD-OCT) as determined by the CRC. The reference CST (Figure 8 description and defined below) will be used at the faricimab administration visit to determine the faricimab administration interval. After the patient's initial reference CST is established, patients are eligible to increase their faricimab administration interval in 4-week increments if their CST value is stable (i.e., not increasing or decreasing by >10%) and there is no associated visual acuity loss of 10 letters or more with respect to the reference BCVA (Figure 8 description and defined below).

[0313] Reference CST and reference BCVA (in Figure 8 and in the figure legend, the letters a and b ) means: *Reference central subfield thickness (CST): CST value when the initial CST threshold criteria were met. If the CST decreases by more than 10% from the previous reference CST for two consecutive study drug administration visits and the obtained values ​​are within 30 μm, the reference CST is adjusted. The CST value obtained at the later visit serves as the new reference CST starting immediately at that visit. b **Reference Best Corrected Visual Acuity (BCVA): the average of the three best BCVA scores obtained at any prior study drug administration visit. The maximum and minimum treatment intervals that may be assigned are Q16W and Q4W, respectively. Patients whose dosing intervals have previously been extended and who experience a disease exacerbation that causes an interval shortening cannot have their intervals extended again, except for patients whose dosing intervals are shortened to Q4W. Their intervals 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, this patient's interval may not be extended beyond Q8W for the remainder of the treatment period. If a patient's interval is shortened from Q16W to Q4W, this patient's interval may be extended to Q12W, but may not be reverted back to Q16W.

[0314] Determination of faricimab (RO6867461 / RG7716 / VEGFang2-0016) interval The algorithm used for interval determination, based on the relative change in CST and BCVA at the faricimab dosing visit compared to the reference CST and reference BCVA, is outlined below and in Figure 8. Faricimab dosing intervals will be extended, maintained, or shortened as follows: - If CST values ​​increase or decrease by 10% or less without an associated loss of BCVA of 10 or more letters, the dosing interval will be extended by 4 weeks. -Any of the following conditions are met: If the CST value decreases by more than 10%, A decrease in CST score of 10% or less with an associated decrease in BCVA of 10 letters or more was If the CST value increases by >10%–≤20% without an associated loss of BCVA of ≥5 letters, the interval is maintained. -Any of the following criteria are met: A 10% to 20% increase in CST value with an associated 5 to 10 letter loss in BCVA >20% increase in CST value without associated loss of 10 or more letters of BCVA If the CST value increases by 10% or less with an associated loss of BCVA of 10 letters or more, the interval will be shortened by 4 weeks. -If the CST value increases by >10% with an associated loss of BCVA of ≥10 letters, the interval will be shortened to Q4W.

[0315] As outlined above, the algorithm for determining individualized drug treatment intervals is based on the relative change in CST and the absolute change in BCVA compared to the reference CST and BCVA, respectively.

[0316] The algorithm may be implemented by a computing system or device. Such a computing system or device may include a web interface, a mobile app, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores may be uploaded to a web interface of a personalized dose interval software tool. Using the uploaded CST and BVCA, the tool may automatically calculate and output the timing of the following doses. The tool may further provide a dosing schedule or notification, monitor and generate visualizations of dose interval changes for a given patient, generate visualizations of dose interval changes for a group of patients, aggregate received CST and BCVA data to determine trends, or a combination thereof.

[0317] The dosing schedule or notification may include a display of calendar dates of scheduled dosing visits, and calendar alerts notifying the clinician or patient of upcoming dosing visits. The visualization of dosing interval changes may include, for example, a display of the schematic of FIG. 8. In some cases, a patient's dosing interval adjustments may be shown in one color and the patient's immediately preceding dosing interval adjustments in another color. To illustrate, a patient may first extend the interval by 4 weeks and then maintain the individualized treatment interval. The tool may visualize the patient's individualized interval progression by displaying the "interval maintained" area of ​​the schematic of FIG. 8 in green and the "interval extended by 4 weeks" in yellow. The green may reflect the patient's most recent interval calculation, and the yellow may indicate the results of the patient's immediately preceding interval calculation. This visualization may allow a user of the tool to quickly see that the patient's disease progression is improving, but not improving enough to warrant further extension of the treatment interval.

[0318] The tool may further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Such data analysis may include visualization of dosing changes for a single patient, similar to the color-coding example discussed above. Alternatively, the visualization may show dosing adjustments across a group of patients. For example, a visualization may show which patients have extended intervals and which have shortened intervals. The visualization may be organized by various characteristics such as patient age, previous treatments, medical condition, antibodies administered, clinical study groups, etc. The tool may also aggregate and create visualizations from the patient's CST and BCVA data. Visualizations may show trends in the data and facilitate or generate longitudinal analyses. These visualizations may include alerts, plots, analysis workflow interfaces, or any graphical interface.

[0319] The tool may generate an output or visualization of the dosing schedule in response to or together with the ocular assessment and images. In one embodiment, the tool may directly calculate the patient's CST or BVCA. For CST, the tool receives or directly captures ocular images. The tool may further calculate the CST from the ocular images using image segmentation, image recognition, or machine learning techniques. For BCVA, the tool may virtually administer the ocular assessment and facilitate and collect patient user input via a user interface or eye tracking mechanism. Alternatively, the tool may receive, store, and track ocular assessment data. In this way, the tool may track each patient's disease progression and adjust the dosing schedule accordingly.

[0320] The present embodiment may include a method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method including receiving patient data including the patient's CST and best corrected visual acuity (BCVA) in a computing system; using the computing system to extend, shorten, or maintain a dosing interval based on the received patient data compared to a respective reference CST and BCVA; and generating a PTI from the dosing interval.

[0321] If the CST value increases or decreases by 10% or less and is not accompanied by an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is extended by 4 weeks. If any of the following criteria are met: if the CST value decreases by more than 10%, or if the CST value decreases by 10% or less and is accompanied by an associated decrease in BCVA of 10 or more letters, or if the CST value increases by more than 10% to 20% or less and is accompanied by an associated decrease in BCVA of 5 or more letters, the exemplary dosing interval is maintained. If any of the following criteria are met: if the CST value increases by more than 10% to 20% or less and is accompanied by an associated decrease in BCVA of 5 or more letters to less than 10 letters, or if the CST value increases by more than 20% and is accompanied by an associated decrease in BCVA of 10 or more letters, or if the CST value increases by 10% or less and is accompanied by an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is shortened by 4 weeks. If the CST value increases by more than 10% and is accompanied by an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is shortened to Q4W.

[0322] Such a method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion may further include receiving, at a computing system, updated patient data; continuously updating or maintaining, using the computing system, a dosing interval based on the updated patient data; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

[0323] The present embodiment also includes the use of a personalized dosing schedule according to a personalized treatment interval (PTI) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion), where the computing system receives patient data including the patient's CST and best corrected visual acuity (BCVA), and generates the PTI by extending, shortening, or maintaining the dosing interval compared to the respective reference CST and BCVA based on the received patient data. If the CST value increases or decreases by 10% or less and is not accompanied by an associated decrease in BCVA of 10 or more letters, the exemplary dosing interval is extended by 4 weeks. If any of the following criteria are met: if the CST value decreases by more than 10%, or if the CST value decreases by 10% or less and is accompanied by an associated decrease in BCVA of 10 or more letters, or if the CST value increases by more than 10% to 20% and is not accompanied by an associated decrease in BCVA of 5 or more letters, the exemplary dosing interval is maintained. If any of the following criteria are met: CST value increases by >10%-20% with associated BCVA loss of 5-10 letters, or CST value increases by >20% without associated BCVA loss of 10 or more letters, or CST value increases by 10% or less with associated BCVA loss of 10 or more letters, the exemplary dosing interval is reduced by 4 weeks. If CST value increases by >10% with associated BCVA loss of 10 or more letters, the exemplary dosing interval is reduced to Q4W.

[0324] Ocular evaluation Ocular evaluations will be performed on both eyes at designated times according to the activity schedule unless otherwise noted. Evaluations will include: -Refraction and BCVA assessed with the ETDRS chart at a starting test distance of 4 meters (performed before dilation of the eyes) - Pre-dose IOP measurement in both eyes (performed before dilatation of the eyes) -Slit lamp examination (for anterior and vitreous cell grading scale) -Binocular indirect ophthalmoscopy with high magnification - Index test, followed by hand movement and light perception testing (if required), was performed within approximately 15 minutes of study treatment in the study eye only. - Post-dose IOP (intraocular pressure) measurements in the study eye only taken 30 (± 15) minutes after study treatment administration

[0325] If there are no safety concerns 30 (± 15) minutes after study treatment administration, patients will be allowed to leave the clinic. If IOP values ​​are of concern to the Treatment Administerer / Unblinded Investigator, patients will remain in the clinic and treatment will be administered according to the clinical judgment of the Treatment Administerer / Unblinded Investigator. Adverse events will be recorded on the electronic Adverse Event Case Report Form (eCRF) as appropriate. --The method of IOP measurement used for patients should be consistent across study eye images.

[0326] After randomization, if a patient misses a study visit when color fundus photography (CFP) or fluorescein angiography (FFA) ocular images are scheduled, or if images are not taken at the scheduled visit (e.g., because the equipment broke), ocular images should be obtained at the next scheduled visit the patient attends.

[0327] Eye images include: -FFA of research eyes -CFP of research eye --Spectral-domain optical coherence tomography (SD-OCT) or swept-source OCT (SS-OCT) images of the research eye --Optional OCT-A of research eyes at sites with OCT-A capabilities (provided the site approves optional sampling)

[0328] For patients diagnosed with bilateral RVO at screening, CFP and OCT images will also be captured in the fellow eye and stored in the CRC.

[0329] result The primary efficacy analysis included all randomized patients, grouped according to treatment assigned at randomization.

[0330] The primary efficacy variable is the change in BCVA. The primary efficacy analysis will be performed using, for example, a mixed model with repeated measures (MMRM) model.

[0331] Best corrected visual acuity BCVA is measured as described. The main efficacy outcome measurements are shown in the figures representing the main efficacy endpoints. BCVA changes over time from patient baseline. The bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg as described in group A using individualized treatment intervals) containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 is compared with aflibercept (Eylea®) in group B (part 1 of the study) according to the above study scheme, for example.

[0332] Central Subfield Thickness (CST) Change from Baseline (Study Eye) The key secondary endpoint is the change from baseline in central subfield thickness CST. CST (and retinal thickness) is measured by optical coherence tomography (OCT). The results are shown in the figure, in which the change in CST is shown over time for bispecific anti-VEGF / ANG2 antibody RO6867461 (faricimab) (administered intravitreally at 6.0 mg as described in group A, using individualized treatment intervals) that includes the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, and is compared with group B (aflibercept (Eylea®) in part 1 of the study) according to the above study scheme.

[0333] Further results and imaging of the eye evaluation can be displayed accordingly.

[0334] Example 4 Binding of anti-VEGF / ANG2 antibodies to VEGF, Ang2, FcgammaR, and FcRn Kinetic affinity of VEGF isoforms including assessment of species cross-reactivity Approximately 12000 resonance units (RU) of the capture system (10 μg / ml goat anti-human F(ab)'2; order code: 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 supplied by GE Healthcare. Sample and system buffer was PBS-T (10 mM phosphate buffered saline with 0.05% Tween® 20) pH 7.4. The flow cell was set at 25° C. and the sample block was set at 12° C. and primed twice with running buffer. Bispecific antibodies were captured by injecting a 50 nM solution at a flow rate of 5 μl / min for 30 seconds. Association was measured by injecting various concentrations of human hVEGF121, mouse mVEGF120, or rat rVEGF164 in solution for 300 s, starting at 300 nM in a 1:3 dilution, at a flow rate of 30 μl / min. The dissociation phase was monitored for up to 1200 s and was triggered by switching from sample solution to running buffer. The surface was regenerated by washing with glycine pH 2.1 solution for 60 s at a flow rate of 30 μl / min. Bulk refractive index differences were corrected by subtracting the response obtained from a goat anti-human F(ab')2 surface. A blank injection was also subtracted (double referenced). The apparent K D The Langmuir 1:1 model was used to calculate the kinetic parameters and other parameters. The results are shown in Table 5.

[0335] Affinity of Ang2 solutions including assessment of species cross-reactivity Solution affinity measures the affinity of an interaction by determining the concentration of the free interaction partner in the equilibrium mixture. Solution affinity assays are performed using a mixture of two free interaction partners held at a constant concentration. <vegf-ang-2>It involves mixing the bispecific antibody with various concentrations of ligand (=Ang2). The maximum possible resonance units of the antibody (e.g., 17000 resonance units (RU)) were immobilized on a CM5 chip (GE Healthcare BR-1005-30) surface at pH 5.0 using an amine coupling kit supplied by GE Healthcare. Sample and system buffer was HBS-P pH 7.4. The flow cell was set at 25°C and the sample block was set at 12°C and primed twice with running buffer. To generate a calibration curve, increasing concentrations of Ang2 were injected into the BIAcore™ flow cell containing immobilized VEGF-ANG-2>bispecific antibody. The amount of bound Ang2 was determined as resonance units (RU) and plotted against concentration. A solution of each ligand (11 concentrations from 0 to 200 nM for VEGF-ANG-2>bispecific antibody) was incubated with 10 nM Ang2 and allowed to reach equilibrium at room temperature. Free Ang2 concentration was determined from a calibration curve constructed before and after measuring the response of solutions containing known amounts of Ang2. A four-parameter fit was set up in XLfit4 (IDBS software) using model 201, with the free Ang2 concentration as the y-axis and the concentration of the inhibitory antibody as the x-axis. The affinity was calculated by determining the inflection point of this curve. The surface was regenerated by washing once with 0.85% H3PO4 solution for 30 seconds at a flow rate of 30 μl / min. Bulk refractive index differences were corrected by subtracting the response obtained from a blank coupled surface. The results are shown in the table below.

[0336] FcRn steady-state affinity For FcRn measurements, the bispecific antibodies were compared against each other using steady-state affinity. Human FcRn was diluted in coupling buffer (10 μg / ml, sodium acetate pH 5.0) and immobilized on a C1 chip (GE Healthcare BR-1005-35) by targeted immobilization procedure using the BIAcore™ wizard for a final response of 200 RU. The flow cell was set at 25° C., the sample block was set at 12° C., and primed twice with running buffer. Sample and system buffer was PBS-T (10 mM phosphate buffered saline with 0.05% Tween® 20) pH 6.0. To evaluate different IgG concentrations for each antibody, concentrations of 62.5 nM, 125 nM, and 250 nM, 500 nM were prepared. The flow rate was set at 30 μl / min, and an association time of 180 seconds was selected to sequentially inject the different samples over the chip surface. The surface was regenerated by injecting PBS-T pH 8 for 60 seconds at a flow rate of 30 μl / min. Bulk refractive index differences were corrected by subtracting the response obtained from a blank surface. Buffer injections were also subtracted (= double referencing). The steady-state affinity was calculated using the method of the Bia-Evaluation software. Briefly, the RU values ​​(RUmax) were plotted against the analyzed concentrations to generate dose-response curves. Based on a two-parametric fit, the upper asymptote can be calculated to determine the half-maximal RU value and therefore the affinity. The results are shown in the table below. Similarly, the affinity for monkey, mouse and rabbit FcRn can be determined.

[0337] FcgammaRIIIa measurement For FcgammaRIIIa measurements, a direct binding assay was used. Approximately 3000 resonance units (RU) of the capture system (1 μg / ml Penta-His; Qiagen) were coupled to a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 by using an amine coupling kit supplied by GE Healthcare. Sample and system buffer was HBS-P+pH 7.4. The flow cell was set at 25°C, the sample block at 12°C and primed twice with running buffer. FcgammaRIIIa-His receptors were captured by injecting a 100 nM solution at a flow rate of 5 μl / min for 60 seconds. Binding was measured by injecting 100 nM of bispecific or monospecific control antibodies (anti-Dig for IgG1 and IgG4 subclass antibodies) at a flow rate of 30 μl / min for 180 seconds. The surface was regenerated by washing with glycine pH 2.5 solution at a flow rate of 30μl / min for 120 seconds.Because the binding of FcgammaRIIIa is different from the Langmuir 1:1 model, this assay was used to determine binding only / no binding.In a similar manner, the binding of FcgammaRIa and FcgammaRIIa can be determined.The results are shown in the following table, in which the binding to FcgammaRIIIa could not be detected by introducing the mutation P329G LALA.

[0338] <vegf-ang-2>Assessment of independent VEGF and Ang2 binding to bispecific antibodies 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 by using an amine coupling kit provided by GE Healthcare. Sample and system buffer was PBS-T (10 mM phosphate buffered saline with 0.05% Tween® 20) pH 7.4. The temperature of the flow cell was set to 25° C. and the temperature of the sample block was set to 12° C. Before capture, the flow cell was primed twice with running buffer.

[0339] Bispecific antibodies were captured by injecting a 10 nM solution for 60 seconds at a flow rate of 5 μl / min. Independent binding of each ligand to the bispecific antibodies was analyzed by determining the active binding capacity of each ligand added sequentially or simultaneously (flow rate of 30 μl / min). 1. Human VEGF at a concentration of 200 nM is injected for 180 seconds (to identify single binding of antigen). 2. Human Ang2 at a concentration of 100 nM is injected for 180 seconds (to identify single binding of antigen). 3. Human VEGF at a concentration of 200 nM is injected for 180 seconds, followed by an additional injection of human Ang2 at a concentration of 100 nM for 180 seconds (to identify binding of Ang2 in the presence of VEGF). 4. Human Ang2 at a concentration of 100 nM is injected for 180 seconds, followed by an additional injection of human VEGF at a concentration of 200 nM (to identify binding of VEGF in the presence of Ang2). 5. Co-injection of human VEGF at a concentration of 200 nM and human Ang2 at a concentration of 100 nM for 180 seconds (to simultaneously identify the binding of VEGF and Ang2).

[0340] The surface was regenerated by washing with 3 mM MgCl2 solution for 60 seconds at a flow rate of 30 μl / min. Bulk refractive index differences were corrected by subtracting the response obtained from a goat anti-human IgG surface.

[0341] If the final signal resulting from methods 3, 4, and 5 is equal or similar to the sum of the individual final signals from methods 1 and 2, then the bispecific antibody is capable of binding both antigens independently of each other. The results are shown in the table below, which shows that VEGFang2-0016 (=RO6867461) is capable of binding to VEGF and ANG2 independently of each other.

[0342] <vegf-ang-2>Assessment of simultaneous binding of VEGF and Ang2 to bispecific antibodies First, about 1600 resonance units (RU) of VEGF (20 μg / ml) were coupled to a CM4 chip (GE Healthcare BR-1005-34) at pH 5.0 by using an amine coupling kit supplied by GE Healthcare. Sample and system buffer was PBS-T (10 mM phosphate buffered saline with 0.05% Tween® 20) pH 7.4. The flow cell was set at 25° C. and the sample block was set at 12° C. and primed twice with running buffer. Second, a 50 nM solution of bispecific antibody 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 depends on the amount of bispecific antibody bound to VEGF, indicating 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 is consistent with prior VEGF binding. <vegf-ang-2>As shown by the additional specific binding signal of hAng2 to the bispecific antibody. [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] < / vegf>

Claims

1. 1. A bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) for use in the treatment of an ophthalmic vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), or in the treatment of a patient suffering from an ophthalmic vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), wherein said treatment comprises a personalized treatment interval (PTI).

2. 2. The bispecific antibody (for use) according to claim 1 for use in the treatment of neovascular age-related macular degeneration (nAMD) or for the treatment of a patient suffering from nAMD.

3. wherein the treatment comprises individualized treatment intervals; a) patients are initially treated with a bispecific VEGF / ANG2 antibody at a dosing interval of four doses, every four weeks (Q4W); b) Disease activity is assessed at weeks 20 and 24, and said disease activity meets the following criteria: i) an increase in central subfield thickness (CST) of more than 50 μm compared to the mean CST values ​​at the previous two scheduled visits, which are weeks 12 and 16 for the week 20 assessment and weeks 16 and 20 for the week 24 assessment; or ii) an increase in CST of 75 μm or more compared to the lowest CST value recorded at any of the previous two scheduled visits; iii) a reduction in best corrected visual acuity (BCVA) of 5 or more letters compared to the mean BCVA value at the previous two scheduled visits; iv) A decrease in BCVA of 10 letters or more compared to the highest BCVA value recorded at any of the previous two scheduled visits, or v) the presence of new macular hemorrhage due to nAMD activity; c) then, i) patients meeting the disease activity criteria at week 20 are treated with a dosing interval of every 8 weeks (Q8W) starting at week 20 (first Q8W dose at week 20); ii) patients who meet the disease activity criteria at week 24 are treated with a dosing interval of every 12 weeks (Q12W) after week 24 (first Q12W dose at week 24); iii) The bispecific antibody (for use) of claim 2, wherein patients not meeting disease activity criteria at weeks 20 and 24 are treated with dosing intervals of every 16 weeks (Q16W) from week 28 onwards (first Q16W dose at week 28).

4. the individualized treatment interval is extended, shortened, or maintained after week 60; a) the interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two 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 or more compared to the lowest in-study drug administration visit measurement; ii) no decrease in BCVA of 5 or more letters compared to the average of the last two study drug administration visits and no decrease in BCVA of 10 or more letters compared to the highest on-study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval will be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) an increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement; ii) A decrease in BCVA of 5 or more letters compared to the average of the last two dosing visits or a decrease in BCVA of 10 or more letters compared to the highest dosing visit measurement; iii) the presence of new macular hemorrhage; A bispecific antibody for use according to claim 3.

5. 2. The bispecific antibody for use according to claim 1 for use in the treatment of diabetic macular edema (DME) or for the treatment of patients suffering from DME.

6. the treatment comprises a personalized treatment interval (PTI); a) a patient is initially treated with the bispecific VEGF / ANG2 antibody at a dosing interval of every four weeks (Q4W) until the central subfield thickness (CST) meets a predefined reference CST threshold measured at or after week 12; b) the dosing interval is then increased by 4 weeks to an initial Q8W dosing interval; c) from this point onwards, the dosing interval is extended, shortened or maintained based on assessments made at the dosing visit based on relative changes in CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; i) - if the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; ii) - if the CST is reduced by more than 10%, or - an increase or decrease in the CST value of 10% or less with an associated decrease in BCVA of 10 letters or more; or - if the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) - an increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 letters to less than 10 letters; or - if the CST value increases by more than 20% without an associated decrease in BCVA of 10 or more letters, the interval is reduced by 4 weeks; iv) if the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more, the interval is shortened by 8 weeks; the respective reference central subfield thickness (CST) is the CST value at which an initial CST threshold criterion is met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreases by more than 10% from the previous reference CST and the resulting values ​​are within 30 μm, the CST value obtained at the subsequent visit serves as the new reference CST; 6. The bispecific antibody for use according to claim 5, wherein said reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

7. 7. The bispecific antibody for use according to claim 6, wherein the dosing interval may be adjusted in increments of 4 weeks, up to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

8. 1. A bispecific antibody that binds human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) for use in the treatment of an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, or in the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein said treatment comprises individualized treatment intervals (PTI); a) a patient is initially treated with said bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from day 1 to week 20; b) From week 24, patients receive the bispecific VEGF / ANG2 antibody at a frequency of Q4W until the central subfield thickness (CST) meets a predefined reference CST threshold; c) from this point onwards, the dosing interval is extended, shortened or maintained based on assessments made at the dosing visit based on the relative changes in the CST and best corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; i) If the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in the CST value of 10% or less accompanied by an associated decrease in BCVA of 10 letters or more; or If the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) Any of the following criteria are met: An increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 to less than 10 letters; or If the CST value increases by more than 20% without an associated decrease in BCVA of 10 letters or more, or If the CST value increases by 10% or less with an associated decrease in BCVA of 10 letters or more, the interval is shortened by 4 weeks; iv) If the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more, the interval is shortened to Q4W; the respective reference central subfield thickness (CST) is the CST value at which an initial CST threshold criterion is met, and the reference CST is adjusted such that if the CST for two consecutive administration visits decreases by more than 10% from the previous reference CST and the resulting values ​​are within 30 μm, the CST value obtained at the subsequent visit serves as the new reference CST; A bispecific antibody, wherein said reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.

9. 9. The bispecific antibody (for use) according to claim 8, wherein the administration interval may be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

10. said bispecific antibody that binds human VEGF and human ANG2 is a bispecific, bivalent anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds human VEGF and a second antigen-binding site that specifically binds human ANG-2; i) the first antigen-binding site that specifically binds to VEGF comprises, in the heavy chain variable domain, 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, and, in the light chain variable domain, 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; ii) the 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; iii) A bispecific antibody for use according to any one of claims 1 to 9, wherein said bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass comprising the mutations I253A, H310A and H435A, and the mutations L234A, L235A and P329G, the numbering being according to the EU index of Kabat.

11. i) the first antigen-binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as a heavy chain variable domain VH and the amino acid sequence of SEQ ID NO: 8 as a light chain variable domain VL; ii) The bispecific antibody for use according to claim 10, wherein the second antigen-binding site which specifically binds to ANG-2 comprises as heavy chain variable domain VH the amino acid sequence of SEQ ID NO: 15 and as light chain variable domain VL the amino acid sequence of SEQ ID NO:

16.

12. 10. The bispecific antibody for use according to any one of claims 1 to 9, wherein said bispecific antibody binding to human VEGF and human ANG2 comprises the amino acid sequences of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:

20.

13. The bispecific antibody for use according to any one of claims 1 to 9, wherein the bispecific antibody is faricimab.

14. The bispecific antibody for use according to any one of claims 10 to 13, wherein the bispecific antibody is administered in a dose of about 5 to 7 mg.

15. The bispecific antibody for use according to any one of claims 10 to 13, wherein the bispecific antibody is administered in a dose of about 6 mg.

16. 16. The bispecific antibody for use according to claim 14 or 15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml.

17. The bispecific antibody for use according to any one of claims 1 to 16, wherein the patient suffering from an ophthalmic vascular disease has not been previously treated with an anti-VEGF therapy.

18. The bispecific antibody for use according to any one of claims 1 to 17, wherein the patient suffering from an ophthalmic vascular disease has previously been treated with an anti-VEGF therapy.

19. The bispecific antibody for use according to any one of claims 1 to 18, wherein said antibody is administered according to the determination of a software tool.

20. 1. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from nAMD, the method comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an assessment of new macular hemorrhage; using said computing system to extend, shorten or maintain a dosing interval based on said received patient data compared to a respective reference CST and BCVA; generating a PTI from the dosing interval; a) the interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two 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 or more compared to the lowest in-study drug administration visit measurement; ii) no decrease in BCVA of 5 or more letters compared to the average of the last two study drug administration visits and no decrease in BCVA of 10 or more letters compared to the highest on-study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval is reduced by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) an increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement; ii) A decrease in BCVA of 5 or more letters compared to the average of the last two dosing visits or a decrease in BCVA of 10 or more letters compared to the highest dosing visit measurement; iii) the presence of new macular hemorrhage; method.

21. 1. A method for providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from DME, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using said computing system to extend, shorten or maintain a dosing interval based on said received patient data compared to a respective reference CST and BCVA; generating a PTI from the dosing interval; i) - if the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; ii) - if the CST is reduced by more than 10%, or - an increase or decrease in the CST value of 10% or less with an associated decrease in BCVA of 10 letters or more; or - if the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) - an increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 letters to less than 10 letters; or - if the CST value increases by more than 20% without an associated decrease in BCVA of 10 or more letters, the interval is reduced by 4 weeks; iv) if the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more, the interval is shortened by 8 weeks.

22. 1. A method of providing an individualized dosing schedule according to an individualized treatment interval (PTI) for the treatment of a patient suffering from an ophthalmic vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving, at a computing system, patient data including a CST and a best corrected visual acuity (BCVA) of the patient; using said computing system to extend, shorten or maintain a dosing interval based on said received patient data compared to a respective reference CST and BCVA; generating a PTI from the dosing interval; i) If the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in the CST value of 10% or less accompanied by an associated decrease in BCVA of 10 letters or more; or If the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) Any of the following criteria are met: An increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 to less than 10 letters; or If the CST value increases by more than 20% without an associated decrease in BCVA of 10 letters or more, or If the CST value increases by 10% or less with an associated decrease in BCVA of 10 letters or more, the interval is shortened by 4 weeks; iv) If the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more, the interval is shortened to Q4W.

23. receiving updated patient data at the computing system; using the computing system to continually update or maintain the dosing interval based on the updated patient data; 23. The method of any one of claims 20, 21, or 22, further comprising generating a visualization, user interface, or notification based on the updated or maintained dosing interval.

24. 1. Use of an individualized dosing schedule according to individualized treatment intervals (PTI) (for the treatment of nAMD), comprising: a computing system comprising: receiving, at a computing system, patient data including information regarding the patient's CST and best corrected visual acuity (BCVA), and optionally an assessment of new macular hemorrhage; generating said PTI by extending, shortening or maintaining a dosing interval based on said received patient data compared to respective reference CST and BCVA; a) the interval is extended by 4 weeks (up to a maximum of Q16W) if all of the following criteria are met: i) Stable CST compared to the average of the last two 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 or more compared to the lowest in-study drug administration visit measurement; ii) no decrease in BCVA of 5 or more letters compared to the average of the last two study drug administration visits and no decrease in BCVA of 10 or more letters compared to the highest on-study drug administration visit measurement; iii) no new macular hemorrhage; b) The interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met: or If two or more of the following criteria are met, or if one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) an increase in CST of 50 μm or more compared to the average from the last two dosing visits, or an increase of 75 μm or more compared to the lowest dosing visit measurement; ii) A decrease in BCVA of 5 or more letters compared to the average of the last two dosing visits or a decrease in BCVA of 10 or more letters compared to the highest dosing visit measurement; iii) the presence of new macular hemorrhage; use.

25. 1. Use of an individualized dosing schedule according to individualized treatment intervals (PTI) (for the treatment of DME), comprising: a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; generating said PTI by extending, shortening or maintaining a dosing interval based on said received patient data compared to respective reference CST and BCVA; i) - if the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; ii) - if the CST is reduced by more than 10%, or - an increase or decrease in the CST value of 10% or less with an associated decrease in BCVA of 10 letters or more; or - if the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) - an increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 letters to less than 10 letters; or - if the CST value increases by more than 20% without an associated decrease in BCVA of 10 or more letters, the interval is reduced by 4 weeks; iv) The interval is reduced by 8 weeks if the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more.

26. 1. Use of an individualized dosing schedule according to individualized treatment intervals (PTI) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion), comprising: a computing system comprising: receiving patient data including a CST and a best corrected visual acuity (BCVA) of the patient; generating said PTI by extending, shortening or maintaining a dosing interval based on said received patient data compared to respective reference CST and BCVA; i) If the CST value increases or decreases by 10% or less without an associated decrease in BCVA of 10 or more letters, the interval is extended by 4 weeks; or ii) Any of the following criteria are met: If the CST value decreases by more than 10%, or A decrease in the CST value of 10% or less accompanied by an associated decrease in BCVA of 10 letters or more; or If the CST value increases by more than 10% to no more than 20% without an associated decrease in BCVA of 5 or more letters, the interval is maintained; iii) Any of the following criteria are met: An increase in the CST value of more than 10% to less than 20% with an associated decrease in BCVA of 5 to less than 10 letters; or If the CST value increases by more than 20% without an associated decrease in BCVA of 10 letters or more, or If the CST value increases by 10% or less with an associated decrease in BCVA of 10 letters or more, the interval is shortened by 4 weeks; iv) If the CST value increases by more than 10% with an associated decrease in BCVA of 10 letters or more, the interval is shortened to Q4W.

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