Methods for Treating Neovascular Age-Related Macular Degeneration

Abstract

The present invention relates to a method of treating neovascular age-related macular degeneration (nAMD) in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase; (b) evaluating the patient for disease activity after the second dose of the loading phase; and (c) optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, further comprising administering to the patient a third dose of the VEGF antagonist six weeks after the second dose as part of the loading phase.

Description

[Technical field]

[0001] The present invention relates to a method of treating neovascular age-related macular degeneration (nAMD) in a patient. [Background technology]

[0002] Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the population, affecting 10%-13% of individuals over the age of 65 in North America, Europe and Australia (Kawasaki 2010, Rein et al., Arch Ophthalmol. 2009;127:533-40, Smith 2001). Genetic, environmental and health factors play important roles in the pathogenesis of the disease.

[0003] AMD is classified into two clinical subtypes: non-neovascular (atrophic) or dry and neovascular (exudative) or wet (Ferris et al., Arch Ophthalmol. 1984;102:1640-2, Lim et al., Lancet. 2012;379:1728-38, Miller et al., Am J Ophthalmol. 2013;155:1-35). Neovascular AMD (nAMD) is characterized by the growth of abnormal new blood vessels (angiogenesis) from the underlying choroid under the retinal pigment epithelium (RPE) or subretinal space, called choroidal neovascularization (CNV) (Ferris et al., Arch Ophthalmol. 1984;102:1640-2). These newly formed blood vessels increase the likelihood of leaking blood and serum, damaging the retina by stimulating inflammation and scar tissue formation. This damage to the retina causes progressive, severe, and irreversible vision loss (Shah et al., Am J Ophthalmol. 2007;143:83-89, Shah et al., Am J Ophthalmol. 2009;116:1901-07). Without treatment, most affected eyes will have poor central vision (20 / 200) within 12 months (TAP 2003). Although the neovascular form of the disease is present in only about 10% of all AMD cases, it accounted for approximately 90% of severe vision loss from AMD before the introduction of anti-vascular endothelial growth factor (VEGF) treatment (Ferris et al., Am J Ophthalmol. 1983;118:132-51, Sommer et al., N Engl J Med. 1991;14:1412-17, Wong et al., Ophthalmology. 2008;115:116-26).

[0004] VEGF has been shown to be elevated in patients with nAMD and is thought to play a key role in the neovascular process (Spilsbury et al., Am J Pathol. 2000; 157: 135-44). The use of intravitreal (IVT) drug therapy targeting VEGF has significantly improved visual outcomes in patients with nAMD (Bloch et al., Am J Ophthalmol. 2012; 153: 209-13, Campbell et al., Arch Ophthalmol. 2012; 130: 794-5). Anti-VEGF treatments such as ranibizumab (LUCENTIS®), aflibercept (EYLEA®) and brolucizumab (Beovu®) have been shown to inhibit the VEGF signaling pathway, halt the growth of neovascular lesions and reverse retinal edema.

[0005] In two phase 3 trials of ranibizumab, with a monthly dosing regimen, approximately 95% of subjects treated with ranibizumab experienced stabilization of vision (defined as a loss of <15 ETDRS letters) or improvement in vision at 12 months, compared with 62% and 64% in the control groups (Rosenfeld et al., N Engl J Med. 2006;355:1419-31, Brown et al., N Engl J Med. 2006;355:1432-44). 25-40% of subjects in the ranibizumab group gained ≥15 letters at 12 months, compared with 5-6% in the two control groups. On average, subjects treated with ranibizumab gained 7-11 letters of vision after 12 months, while control subjects lost an average of approximately 10 letters. This increase in visual acuity was essentially maintained during the second year of both Phase 3 studies, while visual acuity, on average, continued to decline in the control group. The benefit in visual acuity, indicating a halt, rather than a slowing, of the progression of nAMD, was supported by corresponding effects on lesion anatomy and subject-reported outcomes. The latter demonstrated statistically and clinically meaningful improvements in near vision, distance vision, and visual acuity-specific dependencies, as measured by the National Eye Institute Visual Functioning Questionnaire-25 (VFQ-25).

[0006] In two parallel phase 3 trials of aflibercept, treatment-naive subjects with nAMD were randomized to two doses (0.5 and 2.0 mg) and two regimens (2.0 mg every 4 weeks and every 8 weeks) or a control arm (ranibizumab 0.5 mg every 4 weeks). At week 52, all aflibercept arms were non-inferior to the ranibizumab arm, independent of dose and regimen, with equivalent visual acuity maintained in 95% of eyes (Heier et al., Ophthalmology. 2012;119:2537-48). Compared with the control arm, which had a mean improvement of 8.7 letters, there was a mean improvement of 9.3 letters in the aflibercept 2 mg every 4 weeks arm and an improvement of 8.4 letters in the aflibercept 2 mg every 8 weeks arm. In the second year of the study, subjects were switched to a capped as-needed (PRN) regimen. The percentage of subjects who maintained BCVA ranged from 91% to 92% for all groups. Mean BCVA improvements ranged from 7.9 (ranibizumab 0.5 mg every 4 weeks), 7.6 (aflibercept 2 mg every 4 weeks and every 8 weeks) to 6.6 (aflibercept 0.5 mg). Across all groups, a mean loss of 0.8 to 1.7 letters was seen after switching from a fixed to a capped PRN regimen. Treatment frequency was similar between the aflibercept and ranibizumab arms during the capped PRN year, with 4.1 injections for the aflibercept 2 mg every 4 weeks arm, 4.2 injections for the aflibercept 2 mg every 8 weeks arm, and 4.7 injections for the ranibizumab 0.5 mg every 4 weeks arm (Schmidt-Erfurth et al.,Br J Ophthalmol 2014;98:1144-1167 2014;98:1144-1167).

[0007] Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, to aflibercept for treating nAMD (Dugel et al., Ophthalmology, Volume 127, Issue 1, January 2020, Pages 72-84). The HAWK (NCT02307682) and HARRIER (NCT02434328) trials were 2-year, double-blind, multicenter, phase 3 studies investigating the efficacy of brolucizumab versus aflibercept in treatment-naive patients with nAMD. Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with three monthly injections, eyes treated with brolucizumab received injections every 12 weeks (q12w) with interval adjustment to every 8 weeks (q8w) if disease activity was present, and eyes treated with aflibercept received injections q8w. Brolucizumab was noninferior to aflibercept for visual function at week 48, with >50% of eyes treated with brolucizumab 6 mg maintained on a q12w dosing interval through week 48. Anatomical outcomes favored brolucizumab over aflibercept. Clinical treatment effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER trials were also compared to modeled placebo data (Agostini et al., Curr Eye Res, 2020 Oct; 45(10): 1298-1301). Compared with modeled placebo, brolucizumab treatment was associated with an increase in overall best-corrected visual acuity of approximately 22 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 48 weeks and 28 letters at 96 weeks.

[0008] Current marketed anti-VEGF treatments usually begin with a loading phase of three monthly doses, followed by maintenance dosing either fixed (e.g., every 4 or 8 weeks or every 12 weeks), or as needed (PRN), or with individualized treatment intervals based on the Treat-and-Extend (T&E) concept (Wykoff et al., 2018). Monthly or bimonthly treatments generally pose a significant burden not only to elderly patients, but also to their caregivers and physicians. Although treatments have also been proven to have a positive benefit / risk ratio, they are not without risks. Each injection is associated with pain, subconjunctival hemorrhage, vitreous hemorrhage, retinal tears, retinal detachment, iatrogenic cataracts, and endophthalmitis (Ohr et al., Expert Opin. Pharmacother. 2012;13:585-591), as well as the potential for persistent increases in intraocular pressure (IOP) with successive injections of anti-VEGF agents (Tseng et al., J Glaucoma. 2012;21:241-47). Moreover, even with monthly IVT injections, 60-70% of patients will gain less than 15 letters of visual acuity. In ranibizumab and aflibercept trials, both interventional (e.g., TREND (Silva et al., Ophthalmology; 2018, 125:57-65), ALTAIR (Bayer AG, 2017, Package leaflet Eylea® - Germany)) and real-life studies (prospective non-interventional trials, e.g., OCEAN (Voegeler and Mueller, Non-interventional Final Study Report CRFB002ADE18, 2017)), when the treatment interval was extended to q6w or more, although there was an early functional and anatomical response after the loading phase (three initial injections), many patients still showed persistent discharge. For these patients, longer-lasting anti-VEGF agents such as brolucizumab (e.g., maintenance dosing every 8 or 12 weeks) may lead to optimized fluid and disease control, i.e., sustained functional and anatomical responses, respectively, and may result in overall improved patient care (e.g., fewer clinic visits, reduced treatment burden).

[0009] Despite the success of existing anti-VEGF treatments, there is still a need for additional treatment options to improve response rates and / or reduce resource use and injection frequency in patients with nAMD.Current dosing regimens include a loading phase of three monthly doses.There is a medical need to improve and optimize the dosing regimen of anti-VEGF in nAMD patients, especially the loading phase dosing regimen, to improve patient care (e.g., reduce frequency of clinic visits, reduce treatment burden). Summary of the Invention

[0010] The present invention provides a method of treating neovascular age-related macular degeneration (nAMD) in a patient, comprising administering to the patient two or three separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase, followed by administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, for example at a dosing interval of once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

[0011] Current marketed anti-VEGF treatments typically begin with a loading phase of three monthly doses, followed by maintenance dosing, either fixed (e.g., every 4 or 8 weeks or every 12 weeks) or individualized treatment intervals based on as-needed (PRN) or treat-and-extend (T&E) concepts (Wykoff et al., 2018). Each injection is associated with the potential for pain, subconjunctival hemorrhage, vitreous hemorrhage, retinal breaks, retinal detachment, iatrogenic cataracts, and endophthalmitis (Ohr et al., Expert Opin. Pharmacother. 2012; 13: 585-591), as well as persistent elevation of intraocular pressure (IOP) with successive injections of anti-VEGF agents (Tseng et al., J Glaucoma. 2012; 21: 241-47). We here conducted a quantitative systems pharmacology model to simulate intraocular brolucizumab PK and VEGF inhibition for alternative dosing regimens. The results of the Beovu arms of the HAWK and HARRIER studies, in which Beovu was administered every 4 weeks (monthly) for the first 3 doses, followed by every 12 or 8 weeks (q12w / q8w), were replicated in a population PK / PD model simulation study in which Beovu was administered every 6 weeks (q6w) for the first 2 doses, followed by every 12 or 8 weeks (q12w / q8w). The inventors surprisingly found that reduced dose intensity within the loading period, i.e., 2 or 3 separate doses of a VEGF antagonist 6 weeks apart, could still maintain robust VEGF inhibition similar to the approved 3-dose loading regimen (3×Q4W followed by a maintenance dose), while reducing the treatment burden and associated risks.

[0012] In one aspect, the invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase; and (b) evaluating the patient for disease activity after the second dose of the loading phase, optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient six weeks after the second dose as part of the loading phase.

[0013] In a further aspect, the invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, wherein the VEGF antagonist is administered to the patient as two separate doses six weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after the second dose of the loading phase, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient six weeks after the second dose, as part of the loading phase.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being administered to the patient as two separate doses six weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after a second dose of the loading phase, and optionally, if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient six weeks after the second dose, as part of the loading phase.

[0015] In another aspect, the invention provides use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, the use comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase; (b) assessing the patient for disease activity after the second dose of the loading phase; and (c) optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering to the patient a third dose of the VEGF antagonist six weeks after the second dose as part of the loading phase.

[0016] In one embodiment, the methods and uses of the invention further comprise administering to the patient, after the loading phase, one or more additional separate doses of a VEGF antagonist in a maintenance phase, each additional dose being administered at a dosing interval of at least once every 8 weeks (q8w regimen), such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0017] In one aspect, the invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist spaced 6 weeks apart (q6w regimen); and (b) optionally, assessing the patient for disease activity after a second dose of the VEGF antagonist; (c) optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering to the patient a third dose of the VEGF antagonist 6 weeks after administration of the second dose (q6w regimen); (d) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least 8 weeks after the immediately preceding dose, e.g., at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). The present invention provides a method comprising:

[0018] In a further aspect, the present invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, comprising: (a) administered to patients as two separate doses six weeks apart (q6w regimen); (b) optionally subsequently evaluating the patient for disease activity after a second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after administration of the second dose (q6w regimen); (c) thereafter, followed by one or more additional doses, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0019] In a further aspect, the present invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, comprising: (a) administered to patients as two separate doses six weeks apart (q6w regimen); (b) optionally subsequently assessing the patient for disease activity after a second dose of the pharmaceutical composition, and optionally, if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient 6 weeks after administration of the second dose (q6w regimen); (c) followed by one or more additional doses, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0020] In another aspect, the invention provides a use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen); (b) optionally subsequently evaluating the patient for disease activity after the second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering a third dose of the VEGF antagonist 6 weeks after administration of the second dose (q6w regimen); (c) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least 8 weeks after the immediately preceding dose, e.g., at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). The present invention provides uses including:

[0021] In certain embodiments, the VEGF antagonist used in the methods and uses of the invention is an anti-VEGF antibody, in particular, the anti-VEGF antibody is a single chain antibody (scFv) or a Fab fragment. In certain embodiments, the VEGF antagonist used in the methods and uses of the invention comprises the sequences of SEQ ID NO: 1 and SEQ ID NO: 2, more particularly, the anti-VEGF antibody is brolucizumab. In certain embodiments, the methods and uses of the invention comprise administering to a patient one or more doses of a VEGF antagonist, the VEGF antagonist is brolucizumab, and the dose of the VEGF antagonist is about 3 mg to about 6 mg, in particular about 3 mg or about 6 mg, more particularly 6 mg.

[0022] Non-limiting embodiments of the present disclosure are described in the following embodiments.

[0023] Embodiment 1: A method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase; (b) assessing the patient for disease activity after the second dose of the loading phase, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the loading phase; The method includes:

[0024] Embodiment 2: The method of embodiment 1, further comprising administering to the patient a third dose of the VEGF antagonist 6 weeks after the second dose as part of a loading phase if the presence of disease activity is identified after the second dose of the VEGF antagonist.

[0025] Embodiment 3: The method of embodiment 1 or 2, comprising administering to the patient one or more additional separate doses of a VEGF antagonist following the loading phase, wherein each additional dose is administered at a dosing interval of at least once every 8 weeks (q8w regimen), such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0026] Embodiment 4: The method of embodiment 1 or 2, comprising administering to the patient one or more additional separate doses of a VEGF antagonist in a maintenance phase after the loading phase, wherein each additional dose is administered at a dosing interval of at least once every 12 weeks (q12w regimen).

[0027] Embodiment 5: The method of any one of the preceding embodiments, comprising during the maintenance phase, assessing the patient for disease activity, and if there is observed disease activity, administering to the patient an additional dose at a dosing interval of once every 8 weeks (q8w regimen), and if there is no observed disease activity, administering to the patient an additional dose at a dosing interval of once every 12 weeks (q12w regimen).

[0028] Embodiment 6: A method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist spaced 6 weeks apart (q6w regimen); (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen); The method includes:

[0029] Embodiment 7: (a) administering to a patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen); (b) assessing the patient for disease activity after the second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist; (c) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). 7. The method of embodiment 6, comprising:

[0030] Embodiment 8: The method of embodiment 7, further comprising administering to the patient a third dose of the VEGF antagonist 6 weeks after administration of the second dose (q6w regimen) if the presence of disease activity is identified after the second dose of the VEGF antagonist.

[0031] Embodiment 9: The method of any one of the preceding embodiments, which does not include administering more than 3 doses to the patient with an interval of less than 8 weeks between doses, such as not administering more than 3 doses to the patient with an interval of 6 weeks between doses.

[0032] Embodiment 10: The method of any one of the preceding embodiments, further comprising assessing the patient for disease activity before or after administering the q8w or q12w dose of the VEGF antagonist.

[0033] Embodiment 11: The method of embodiment 10, wherein if the presence of disease activity is identified after a q12w dose of the VEGF antagonist, the patient is switched to a q8w regimen of the VEGF antagonist.

[0034] Embodiment 12: The method of any one of embodiments 1-5 or 7-11, wherein disease activity is assessed based on one or more of best corrected visual acuity (BCVA), visual acuity (VA), central subfield thickness (CSFT) and / or the presence of intraretinal cysts / fluid.

[0035] Embodiment 13: The method of embodiment 12, wherein the presence of disease activity comprises one or more of: (i) a decrease in best corrected visual acuity (BCVA); (ii) a decrease in visual acuity (VA); (iii) a lack of increase or decrease in central subfield thickness (CSFT); (iv) new, persistent, or recurrent intraretinal cysts (IRC), and / or intraretinal fluid (IRF), and / or subretinal fluid (SRF).

[0036] Embodiment 14: The method of any one of the preceding embodiments, wherein the VEGF antagonist is an anti-VEGF antibody, such as a single chain antibody (scFv) or a Fab fragment.

[0037] Embodiment 15: The method of any one of the preceding embodiments, wherein the anti-VEGF antagonist comprises the sequences of SEQ ID NO:1 and SEQ ID NO:2.

[0038] Embodiment 16: The method of embodiment 12, wherein the VEGF antagonist is an anti-VEGF antibody comprising the sequence of SEQ ID NO:3 or SEQ ID NO:4.

[0039] Embodiment 17: The method of embodiment 12 or 13, wherein the anti-VEGF antagonist is brolucizumab.

[0040] Embodiment 18: The method of any one of the preceding embodiments, wherein the VEGF antagonist is administered by injection, for example by intravitreal injection.

[0041] Embodiment 19: The method of any one of the preceding embodiments, wherein the dose of the VEGF antagonist is about 3 mg to about 6 mg, such as about 3 mg or about 6 mg, for example 6 mg.

[0042] Embodiment 20: The method of any one of the preceding embodiments, wherein the patient is a human.

[0043] Embodiment 21: A VEGF antagonist for use as a medicament for treating nAMD in a patient, wherein the VEGF antagonist is administered to the patient as two separate doses six weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after the second dose of the loading phase, such as assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the loading phase, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after the second dose as part of the loading phase.

[0044] Embodiment 22: After the loading phase, one or more additional separate doses of the VEGF antagonist are administered to the patient as a maintenance phase, with each additional dose being administered at an administration interval of at least once every 8 weeks (q8w regimen), such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0045] Embodiment 23: A pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, wherein the pharmaceutical composition is administered to the patient as two separate doses six weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after the second dose of the loading phase, such as assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the loading phase, and optionally, if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient 6 weeks after the second dose, as part of the loading phase.

[0046] Embodiment 24: After the loading phase, one or more additional separate doses of the pharmaceutical composition are administered to the patient as a maintenance phase, with each additional dose being administered at an administration interval of at least once every 8 weeks (q8w regimen), such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0047] Embodiment 25: Use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen) as a loading phase; (b) assessing the patient for disease activity after the second dose of the loading phase, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the loading phase; and (c) optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering to the patient a third dose of the VEGF antagonist 6 weeks after the second dose as part of a loading phase.

[0048] Embodiment 26: The use of embodiment 25, further comprising administering to the patient one or more additional separate doses of a VEGF antagonist after the loading phase, during a maintenance phase, wherein each additional dose is administered at a dosing interval of at least once every 8 weeks (q8w regimen), such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0049] Embodiment 27: A VEGF antagonist for use as a medicament for treating nAMD in a patient, comprising: (a) administered to patients as two separate doses six weeks apart (q6w regimen); (b) optionally subsequently evaluating the patient for disease activity after a second dose of the VEGF antagonist, e.g., evaluating the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after administration of the second dose (q6w regimen); (c) followed by one or more additional doses, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0050] Embodiment 28: A pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, comprising: (a) administered to patients as two separate doses six weeks apart (q6w regimen); (b) optionally subsequently evaluating the patient for disease activity after a second dose of the pharmaceutical composition, e.g., evaluating the patient for disease activity ≧0 to ≦6 weeks after the second dose of the pharmaceutical composition, and optionally, if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient 6 weeks after administration of the second dose (q6w regimen); (c) followed by one or more additional doses, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0051] Embodiment 29: Use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist spaced 6 weeks apart (q6w regimen); (b) optionally subsequently evaluating the patient for disease activity after a second dose of the VEGF antagonist, e.g., evaluating the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering a third dose of the VEGF antagonist 6 weeks after administration of the second dose (q6w regimen); (c) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). Use including.

[0052] Specific preferred embodiments of the present invention will become apparent from the following more detailed description of certain preferred embodiments and the claims. [Brief description of the drawings]

[0053] [Figure 1] Retinal free drug and VEGF concentrations during the 3×Q4W loading phase followed by the Q8W maintenance phase. [Diagram 2] Retinal VEGF concentrations during 3×Q4W and 2×Q6W loading. [Diagram 3] Retinal VEGF concentrations during the 3×Q4W and 2×Q6W loading periods, followed by Q8W and Q12W maintenance periods. [Figure 4]Simulated CSFT change from baseline during the first year of aflibercept 2 mg treatment in the HAWK and HARRIER studies. [Diagram 5] Simulated BCVA change from baseline during the first year of aflibercept 2 mg treatment in the HAWK and HARRIER studies. [Figure 6] FIG. 1 shows the presence of disease activity based on CSFT. [Figure 7] Percentage of patients receiving q12w at week 48 at various thresholds in the simulated brolucizumab 6 mg treatment arms of HAWK and HARRIER. [Figure 8] Mean simulated and observed CSFT change from baseline after three q4w loading injections and individualized q12w / q8w treatment. [Figure 9] Mean simulated and observed BCVA change from baseline after three q4w loading injections and individualized q12w / q8w treatment. [Figure 10] FIG. 1 is a schematic diagram of a simulated DA assessment and treatment schedule. [Figure 11] Mean CSFT change from baseline or observed data following simulated q6w loading and individualized q12w / q8w treatment. [Figure 12] Mean BCVA change from baseline or observed data after simulated q6w stress and individualized q12w / q8w treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. Any references cited herein, including, for example, all patents, published patent applications, and non-patent publications, are incorporated by reference in their entirety. To facilitate understanding of this disclosure, some terms and abbreviations used herein are defined below as follows:

[0055] As used herein, unless otherwise indicated, the terms "a" and "an" are to be construed to mean "one," "at least one," or "one or more." Unless otherwise required by context, singular terms as used herein shall include pluralities and plural terms shall include the singular.

[0056] As used herein, the term "about" includes and describes the value or parameter itself. For example, "about x" includes and describes "x" itself. As used herein, the term "about" when used in connection with a measurement or to modify a value, unit, constant, or range of values, in addition to including the value or parameter itself, refers to a variation of ±1 to 10%. In some embodiments, the term "about" when used in connection with a measurement or to modify a value, unit, constant, or range of values, refers to a variation of ±1, ±2, ±3, ±4, ±5, ±6, ±7, ±8, ±9, or ±10%.

[0057] The term "VEGF" refers to the 165 amino acid vascular endothelial cell growth factor and the related 121 amino acid, 189 amino acid and 206 amino acid vascular endothelial cell growth factors (as described in Leung et al., Science 246:1306 (1989) and Houck et al., Mol. Endocrin. 5:1806 (1991)), as well as naturally occurring allelic and processed forms of those growth factors. The term "VEGF" specifically refers to human VEGF.

[0058] The term "VEGF receptor" or "VEGFr" refers to the cellular receptor for VEGF, which is a cell surface receptor usually found on vascular endothelial cells, and variants thereof that retain the ability to bind hVEGF. One example of a VEGF receptor is the fms-like tyrosine kinase (flt), a transmembrane receptor in the tyrosine kinase family. DeVries et al., Science 255:989 (1992); Shibuya et al., Oncogene 5:519 (1990). The flt receptor contains an extracellular domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The extracellular domain is involved in binding VEGF, while the extracellular domain is involved in signal transduction. Another example of a VEGF receptor is the flk-1 receptor (also called KDR). Matthews et al., Proc. Nat. Acad. Sci. 88:9026 (1991); Terman et al., Oncogene 6:1677 (1991); Terman et al., Biochem. Biophys. Res. Commun. 187:1579 (1992). Binding of VEGF to the flt receptor results in the formation of at least two high molecular weight complexes with apparent molecular weights of 205,000 and 300,000 daltons. The 300,000 dalton complex is believed to be a dimer containing two receptor molecules bound to a single molecule of VEGF.

[0059] As used herein, "VEGF antagonist" refers to a compound that can reduce or inhibit VEGF activity in vivo. VEGF antagonists can bind to VEGF receptors or block VEGF proteins from binding to VEGF receptors. VEGF antagonists can be, for example, small molecules that can specifically bind to one or more VEGF proteins or one or more VEGF receptors, anti-VEGF antibodies or antigen-binding fragments thereof, fusion proteins (such as aflibercept or other such soluble decoy receptors), aptamers, antisense nucleic acid molecules, interference RNA, receptor proteins, and the like. Some VEGF antagonists are described in WO 2006 / 047325. In one embodiment, the VEGF antagonist is any approved anti-VEGF drug, such as brolucizumab, ranibizumab, or aflibercept. In one embodiment, the VEGF antagonist is an anti-VEGF antibody (such as a bispecific antibody such as brolucizumab or ranibizumab or bevacizumab or faricimab) or an anti-VEGF DARPin (such as abicipar) or a soluble VEGF receptor (e.g. a fusion protein composed of a VEGF receptor domain such as a fusion protein composed of a combination between a VEGF receptor domain with an Fc fragment of a human immunoglobulin and an Fc fragment of a human immunoglobulin, e.g. conbercept, aflibercept) or an AAV containing a sequence encoding an anti-VEGF antibody (such as RGX-314 from Regenxbio), or an AAV containing a sequence encoding a VEGF receptor domain, e.g. conbercept (such as ADVM-022 from Adverum) or any approved anti-VEGF drug (such as brolucizumab, ranibizumab or aflibercept).

[0060] The term "antibody", as used herein, includes full length antibodies and any antigen binding fragment (i.e., "antigen-binding portion", "antigen-binding polypeptide" or "immunobinder") or single chain thereof. An "antibody" comprises a glycoprotein comprising at least two heavy (H) chains and two light (L) chains or antigen binding portions thereof inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (referred to herein as V H Each light chain comprises a light chain variable region (abbreviated herein as VL) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H And each V L is composed of three CDRs and four FRs arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or various cells of the immune system (e.g., effector cells) and factors including the first component (Clq) of the classical complement system.

[0061] The term "single chain antibody", "single chain Fv" or "scFv" refers to an antibody heavy chain variable domain (or region; V H ) and an antibody light chain variable domain (or region; V L Such scFv molecules have the general structure: NH2-VL-linker-VH-VOOH or NH2-VH-linker-VL-COOH.

[0062] The term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., VEGF). It has been shown that fragments of a full-length antibody can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, (ii) a F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region, (iii) an Fd fragment consisting of the VH and CH1 domains, (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a single domain or dAb fragment consisting of the VH domain (Ward et al., (1989) Nature 341:544-546), and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs that can be optionally linked by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked by a synthetic linker that allows them to be produced as a single protein chain using recombinant techniques, with the VL and VH regions pairing to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins. The antibodies can be of different isotypes, for example IgG (e.g., IgG1, IgG2, IgG3 or IgG4 subtypes), IgA1, IgA2, IgD, IgE or IgM antibodies.

[0063] As used herein, the term "subject" or "patient" refers to humans and non-human mammals, including, but not limited to, primates, pigs, horses, dogs, cats, sheep, and cattle. As used herein, "mammal" includes any animal classified as a mammal, including, but not limited to, humans, domestic animals, livestock, and companion animals.

[0064] The terms "treat", "treating" or "treatment" include therapeutic treatments, prophylactic treatments and applications in which a subject reduces the risk of developing a disorder or other risk factors. Treatment does not necessarily cure the disorder, but also encompasses alleviation of symptoms or underlying risk factors. As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression or severity of neovascular (exudative) age-related macular degeneration (nAMD) or the amelioration of one or more symptoms, preferably one or more identifiable symptoms of nAMD. In certain embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of nAMD (such as achieving or at least partially achieving a desired effect (e.g., partial or complete regression of retinal neovascularization, reduction or absence of retinal fluid, e.g., reduction in intraretinal fluid (IRF) and subretinal fluid (SRF), central subfield thickness (CSFT), improved visual acuity, e.g., BCVA >1, >2, >3, >4 or >5 letter change or DRSS score <61)), where the physical parameter is not necessarily discernible by the patient.

[0065] The term "loading phase" refers to the first 2 or 3 doses of a VEGF antagonist administered at q6w intervals. The amount of the dose in the loading phase (2 or 3 doses) can be adjusted based on disease activity assessments as described herein.

[0066] The term "maintenance phase" refers to additional doses at ≥8 week intervals, such as 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 week intervals, which may be adjusted based on disease activity assessments as described herein. Suitably, the term "maintenance phase" refers to additional doses once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen), which may be adjusted based on disease activity assessments as described herein.

[0067] As used herein, a dosing interval may be referred to as qXw, where "X" is the number of weeks between doses administered. For example, q6w is an interval of 6 weeks.

[0068] As used herein, the term "week" means 7 days ± 1 day. As used herein, the term "month" means 25 to 31 days. As used herein, the term "month" also means 4 weeks.

[0069] As used herein, the term "dose" or "therapeutically effective dose" refers to an amount of a therapy (e.g., a VEGF antagonist, e.g., brolucizumab or a pharmaceutical composition provided herein) sufficient to reduce and / or ameliorate the severity and / or symptoms associated with a given condition, disorder or disease. The term "dose" or "therapeutically effective dose" is defined as an amount sufficient to achieve or at least partially achieve a desired effect (e.g., partial or complete regression of retinal neovascularization, reduction or absence of retinal fluid, e.g., reduction in intraretinal fluid (IRF) and subretinal fluid (SRF), central subfield thickness (CSFT), improvement in visual acuity, e.g., BCVA>1, >2, >3, >4, or >5 letter change or DRSS score<61). A therapeutically effective dose is sufficient if it can only result in an incremental change in the symptoms or condition associated with the disease. A therapeutically effective dose does not need to completely cure a disease or completely eliminate symptoms. Preferably, a therapeutically effective dose can at least partially halt the disease and / or its complications in a patient already suffering from the disease. In certain embodiments, a therapeutically effective dose can include repeated administration over a period of time. The amount effective for this use will depend on the severity of the disorder being treated and the general state of the patient's own immune system.

[0070] Treatment regimen The present invention provides a method of treating a patient with nAMD, comprising administering to the patient a VEGF antagonist in a treatment schedule comprising a loading phase and a maintenance phase as described herein.The present invention provides a method of treating neovascular age-related macular degeneration (nAMD) in a patient, comprising administering to the patient two or three separate doses of a VEGF antagonist at 6-week intervals (q6w regimen) as a loading phase, followed by administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least 8 weeks after the immediately preceding dose, for example, at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), for example, once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In one aspect, the present invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen) as a loading phase; and (b) assessing the patient for disease activity after the second dose of the loading phase. In a particular embodiment, the present invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen) as a loading phase; (b) assessing the patient for disease activity after the second dose of the loading phase; and (c) if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering to the patient a third dose of the VEGF antagonist 6 weeks after the second dose as part of the loading phase.

[0071] In a further aspect, the present invention provides a VEGF antagonist for use as a medicament or for treating nAMD in a patient, the VEGF antagonist being administered to the patient as two separate doses 6 weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after the second dose of the loading phase. In a particular embodiment, the present invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, the VEGF antagonist being (a) administered to the patient as two separate doses 6 weeks apart (q6w regimen) in a loading phase, (b) followed by assessing the patient for disease activity after the second dose of the loading phase, and (c) if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after the second dose as part of the loading phase.

[0072] In another aspect, the present invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being administered to the patient as two separate doses 6 weeks apart (q6w regimen) in a loading phase, followed by assessing the patient for disease activity after the second dose of the loading phase. In a particular embodiment, the present invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being (a) administered to the patient as two separate doses 6 weeks apart (q6w regimen) in a loading phase, (b) followed by assessing the patient for disease activity after the second dose of the loading phase, and (c) if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient 6 weeks after the second dose as part of the loading phase.

[0073] In another aspect, the present invention provides a use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen) as a loading phase; and (b) assessing the patient for disease activity after the second dose of the loading phase. In a particular embodiment, the present invention provides a use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen) as a loading phase; (b) assessing the patient for disease activity after the second dose of the loading phase; and (c) administering to the patient a third dose of a VEGF antagonist 6 weeks after the second dose as part of the loading phase if the presence of disease activity is identified after the second dose of the VEGF antagonist.

[0074] In certain embodiments, the loading phase consists of two separate doses administered six weeks apart (q6w), e.g., on day 0 and week 6. In certain embodiments, the loading phase consists of three separate doses administered six weeks apart (q6w), e.g., on day 0, week 6, and week 12. In certain embodiments, if the presence of disease activity is identified after the second dose of the VEGF antagonist, e.g., if the presence of disease activity is identified ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after the second dose as part of the loading phase.

[0075] In certain embodiments, the methods and uses of the present invention further comprise a maintenance phase as described herein. In certain embodiments, the methods and uses of the present invention further comprise administering to the patient, after the loading phase, one or more additional individual doses of a VEGF antagonist in the maintenance phase, each additional dose being administered at least once every 8 weeks (q8w regimen), such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the maintenance phase begins with a dosing regimen in which the VEGF antagonist is administered once every 12 weeks (q12w), with the dosing interval adjusted by plus or minus 4 weeks depending on disease activity assessments performed before the dose is administered. In one embodiment, if disease activity is observed within 8 weeks after the last q12w dose, the patient will receive the next dose 8 weeks after the last q12w dose (q8w dose), and so will be placed in the q8w dosing regimen until disease activity is no longer observed. In one embodiment, if disease activity is observed prior to administration of the q12w dose, the patient will receive the q12w dose as scheduled, and the next dose 8 weeks later, and so will be placed in the q8w dosing regimen until disease activity is no longer observed. If disease activity is no longer observed, the dosing regimen will be adjusted back to the q12w schedule. In another embodiment, if disease activity is not observed at any time during the maintenance phase, the treatment interval may be extended, for example, to q16w by 4 weeks. If disease activity is observed in a patient on a q16w dosing regimen, the treatment interval may be adjusted back to a q12w or q8w dosing regimen.

[0076] In one aspect, the invention provides a method of treating nAMD in a patient, the method comprising: (a) administering to the patient two separate doses of a VEGF antagonist, six weeks apart (q6w regimen); and (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, e.g., once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist spaced 6 weeks apart (q6w regimen); and (b) assessing the patient for disease activity after the second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and if the presence of disease activity is identified after the second dose of the VEGF antagonist, assessing the patient for disease activity after the second dose of the VEGF antagonist. and (b) administering to the patient a third dose of a VEGF antagonist 6 weeks after the previous dose (q6w regimen); and (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least 8 weeks after the immediately preceding dose, e.g., at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a method of treating nAMD in a patient, comprising: (a) administering to the patient three separate doses of a VEGF antagonist spaced six weeks apart (q6w regimen); and (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose administered at least eight weeks after the immediately preceding dose, e.g., at a dosing interval of once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), e.g., once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

[0077] In a further aspect, the invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, the VEGF antagonist being (a) administered to the patient as two separate doses, six weeks apart (q6w regimen), and (b) followed by one or more additional doses, each additional dose being administered at a dosing interval of at least eight weeks after the immediately preceding dose, such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, the VEGF antagonist being (a) administered to the patient as two separate doses six weeks apart (q6w regimen); and (b) subsequently assessing the patient for disease activity after the second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and the presence of disease activity being indicative of a first dose of the VEGF antagonist. If a third dose of the VEGF antagonist is specified after two doses, then (c) a third dose of the VEGF antagonist is administered to the patient 6 weeks after administration of the second dose (q6w regimen), followed by one or more additional doses, each additional dose being administered at least 8 weeks after the immediately preceding dose, for example at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), for example once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a VEGF antagonist for use as a medicament for treating nAMD in a patient, the VEGF antagonist being (a) administered to the patient as three separate doses, six weeks apart (q6w regimen), and (b) followed by one or more additional doses, each additional dose being administered at least eight weeks after the immediately preceding dose, for example at a dosing interval of once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

[0078] In a further aspect, the present invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being (a) administered to the patient as two separate doses, six weeks apart (q6w regimen), and (b) followed by one or more additional doses, each additional dose being administered at a dosing interval of at least eight weeks after the immediately preceding dose, such as once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), such as once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being (a) administered to the patient as two separate doses six weeks apart (q6w regimen); (b) subsequently assessing the patient for disease activity after a second dose of the pharmaceutical composition, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the pharmaceutical composition, and if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient six weeks after administration of the second dose (q6w regimen); and (c) followed by one or more additional doses, each additional dose administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention provides a pharmaceutical composition comprising a VEGF antagonist for use as a medicament for treating nAMD in a patient, the pharmaceutical composition being (a) administered to the patient as three separate doses, six weeks apart (q6w regimen), and (b) followed by one or more additional doses, each additional dose being administered at least eight weeks after the immediately preceding dose, for example at a dosing interval of once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

[0079] In another aspect, the invention provides use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, the use comprising: (a) administering to the patient two separate doses of a VEGF antagonist six weeks apart (q6w regimen); and (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, for example once every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, such as once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), for example once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the invention relates to a use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient two separate doses of a VEGF antagonist spaced 6 weeks apart (q6w regimen); and (b) subsequently assessing the patient for disease activity after the second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and the presence of disease activity indicates a progression from the second use of the VEGF antagonist to the second use of the VEGF antagonist. and (c) administering to the patient one or more additional doses of the VEGF antagonist, where each additional dose is administered at least 8 weeks after the immediately preceding dose, e.g., at a dosing interval of once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).In certain embodiments, the invention provides use of a VEGF antagonist for the manufacture of a medicament for treating nAMD in a patient, comprising: (a) administering to the patient three separate doses of a VEGF antagonist spaced six weeks apart (q6w regimen); and (b) administering to the patient one or more additional doses of a VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, for example at a dosing interval of once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

[0080] In certain embodiments, the methods and uses of the invention do not include administering more than 3 doses to a patient with an interval of less than 8 weeks between doses. In certain embodiments, the methods and uses of the invention do not include administering more than 3 doses to a patient with an interval of 6 weeks between doses.

[0081] In some embodiments, the methods and uses of the disclosure comprise administering a VEGF antagonist described herein to a patient, wherein the patient does not have (i) ocular inflammation, e.g., active ocular inflammation, and / or (ii) retinal vasculitis and / or retinal vascular occlusion, e.g., retinal vasculitis and / or retinal vascular occlusion in the presence of intraocular inflammation.

[0082] In certain embodiments, the methods and uses of the invention comprise assessing the patient for disease activity after the second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist. In certain embodiments, if the presence of disease activity is identified after the second dose of the VEGF antagonist, e.g., if the presence of disease activity is identified ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after the second dose as part of a loading phase.

[0083] In some embodiments, according to the methods or uses of the present disclosure, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist with a dosing interval individualized by the physician based on disease activity assessment, and / or with a dosing interval of at least 8 weeks, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks. In some embodiments, according to the methods or uses of the present disclosure, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist with a dosing interval individualized by the physician based on disease activity assessment, and / or with a dosing interval of ≧8 to ≦24 weeks, e.g., ≧8 to ≦18 weeks (≧q8w to ≦q18w), ≧8 to ≦12 weeks (≧q8w to ≦q12w). Suitably, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist administered to the patient once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). In certain embodiments, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist with an administration interval, e.g., injection interval, of at least about 2 months, e.g., at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months. In preferred embodiments, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist with an administration interval, e.g., injection interval, of at least about 2 months. In more preferred embodiments, the first two or three q6w doses of the VEGF antagonist are followed by one or more doses of the VEGF antagonist with an administration interval, e.g., injection interval, of at least about 3 months.

[0084] In certain embodiments, disease activity assessment (DAA) is performed at every scheduled treatment visit. In some embodiments, the disclosed method or use comprises evaluating the patient for disease activity before or after administering a dose of a VEGF antagonist. In some embodiments, the disclosed method or use comprises evaluating the patient for disease activity before or after administering a dose of a VEGF antagonist every q6w, or q8w, or q12w. The evaluation can determine whether the patient stays on the existing interval or switches to a different interval. In certain embodiments, the disclosed method and use comprises evaluating the patient for disease activity after administering a second q6w dose of a VEGF antagonist or / and before or after administering a dose of a VEGF antagonist every q8w or q12w. In certain embodiments, if the presence of disease activity is identified after the second q6w dose of VEGF antagonist, the third dose of VEGF antagonist is administered 6 weeks after the administration of the second dose.In certain embodiments, if the presence of disease activity is identified after the q12w dose of VEGF antagonist, the patient is switched to the q8w regimen of VEGF antagonist.In certain embodiments, if the presence of disease activity is not identified after the q8w dose of VEGF antagonist, the patient is switched to the q12w regimen of VEGF antagonist.

[0085] Suitably, disease activity may be assessed based on visual function, retinal structure and leakage.Assessment as described herein preferably includes one or more of the following tests to assess the activity of VEGF antagonists (e.g., brolucizumab) on visual function, retinal structure and leakage: (i) best corrected visual acuity (BCVA), (ii) visual acuity (VA), (iii) central subfield thickness (CSFT), (iv) presence of intraretinal cysts / fluid, (v) ETDRS DRSS score based on 7-field stereo color fundus photography (CFP), (vi) anatomical retinal assessment by optical coherence tomography (OCT), standard or wide-field fluorescein angiography (FA), OCT angiography and / or wide-field CFP / FA, (vii) peripheral visual field assessed by perimetry, (viii) contrast sensitivity.

[0086] Visual acuity can be assessed using the best correction determined from the protocol refraction (BCVA). BCVA measurements can be taken in a sitting position, for example, using an ETDRS-like visual acuity test chart.

[0087] Optical coherence tomography (OCT), color fundus photography and fluorescein angiography can be evaluated according to methods known to those skilled in the art.

[0088] CST is the average thickness of a circular 1 mm area centered on the fovea, measured from the retinal pigment epithelium (RPE) to the internal limiting membrane (ILM). CST can be measured, for example, using spectral domain optical coherence tomography (SD-OCT).

[0089] Means for carrying out the above tests are well understood and commonly used by those of skill in the art.

[0090] Advantageously, disease activity may be assessed based on one or more of the following: (i) best corrected visual acuity (BCVA), (ii) visual acuity (VA), (iii) central subfield thickness (CSFT), and (iv) the presence of intraretinal cysts / fluid. The presence of disease activity includes one or more of the following: (i) a decrease in best corrected visual acuity (BCVA), (ii) a decrease in visual acuity (VA), (iii) a lack of increase or decrease in central subfield thickness (CSFT), (iv) new, persistent, or recurrent intraretinal cysts (IRC), and / or intraretinal fluid (IRF), and / or subretinal fluid (SRF). The fluid measured in the eye may be intraretinal fluid and / or subretinal fluid.

[0091] In one embodiment, assessment of disease activity to establish the patient's disease status occurs at baseline (e.g., at week 0; first treatment with a VEGF antagonist; prior to the last dose of a VEGF antagonist). Assessment of disease activity (DAA) during a treatment regimen is at the discretion of the person making the assessment (e.g., the treatment provider) and is based on changes in visual, anatomical, morphological, and clinical parameters relative to the patient's baseline disease status (e.g., at week 0; first treatment with a VEGF antagonist; prior to the last dose of a VEGF antagonist).

[0092] In certain embodiments, the presence of disease activity includes one or more of the following: (i) a decline in BCVA of ≥ 2 letters, e.g., a decline in BCVA of ≥ 3 letters, a decline in BCVA of ≥ 4 letters, and in particular a decline in BCVA of ≥ 5 letters, more specifically, a decline in BCVA observed after the last dose of a VEGF antagonist (e.g., brolucizumab) compared to baseline BCVA, where baseline BCVA was assessed before the last dose of a VEGF antagonist; (ii) a decline in VA of ≥ 1 letter, e.g., a decline in VA of ≥ 2 letters, particularly a decline in VA of ≥ 3 letters, more particularly, the decline in VA is observed after the last dose of a VEGF antagonist (e.g., brolucizumab) compared to baseline VA, where baseline VA was assessed before the last dose of a VEGF antagonist; (iii) an increase in CSFT of ≥ 25 μm, e.g., an increase in CSFT of ≥ 50 μm, in particular, an increase in CSFT of ≥ 75 μm, more particularly, an increase in CSFT is observed after the last administration of a VEGF antagonist (e.g., brolucizumab) compared to baseline CSFT, where baseline CSFT was assessed before the last administration of the VEGF antagonist; (iv) new, persistent, or recurrent intraretinal cysts (IRC), and / or intraretinal fluid (IRF), and / or subretinal fluid (SRF), in particular new, persistent, or recurrent intraretinal cysts (IRC), and / or intraretinal fluid (IRF), and / or subretinal fluid (SRF) observed after the last administration of a VEGF antagonist (e.g., brolucizumab) compared to baseline IRC, and / or IRF, and / or SRF, which baseline IRC, and / or IRF, and / or SRF were assessed prior to the last administration of a VEGF antagonist.

[0093] If disease activity is present (e.g., a loss of letters as measured by BCVA, an increase in CST, increased fluid accumulation and / or increased disease severity compared to the patient's baseline reading or compared to any previous assessment), a more frequent dosing interval is instituted and proceeded with. If improvement in disease activity is observed, a less frequent dosing interval is instituted.

[0094] In certain embodiments, the dosing frequency is adjusted based on the outcome of disease activity assessment, for example, using predefined visual and anatomical criteria. In one embodiment, the dosing frequency of the VEGF antagonist (e.g., brolucizumab) can be adjusted by decreasing the dosing interval from once every 24 weeks (q24w) to once every 18 weeks (q18w). In one embodiment, the dosing frequency of the VEGF antagonist (e.g., brolucizumab) can be adjusted by decreasing the dosing interval from once every 18 weeks (q18w) to once every 12 weeks (q12w). In one embodiment, the dosing frequency of the VEGF antagonist (e.g., brolucizumab) can be adjusted by decreasing the dosing interval from once every 12 weeks (q12w) to once every 8 weeks (q8w) based on disease activity assessment at any scheduled treatment visit. In another embodiment, the dosing frequency of the VEGF antagonist (e.g., brolucizumab) can be adjusted by increasing the dosing interval from once every 8 weeks (q8w) to once every 12 weeks (q12w) based on disease activity assessment at any scheduled treatment visit. In another embodiment, the dosing frequency of the VEGF antagonist (e.g., brolucizumab) can be adjusted by increasing the dosing interval from once every 12 weeks (q12w) to once every 18 weeks (q18w) or once every 24 weeks (q24w) based on disease activity assessment at any scheduled treatment visit. When disease activity is identified as described herein, the treatment regimen can be changed, for example, from every 12 weeks to every 8 weeks (i.e., q8w). In some cases, patients can be on a 12-week regimen for a period of time, then switched to an 8-week interval, then switched back to a 12-week interval. Thus, patients may not remain on one interval regimen but may switch depending on evaluation according to the criteria described herein.

[0095] Anti-VEGF antagonists In one embodiment, the VEGF antagonist of the present disclosure is any approved anti-VEGF drug, such as brolucizumab, ranibizumab, or aflibercept. In one embodiment, the VEGF antagonist of the disclosure is an anti-VEGF antibody (such as a bispecific antibody such as brolucizumab or ranibizumab or bevacizumab or faricimab) or an anti-VEGF DARPin (such as abicipar) or a soluble VEGF receptor (e.g., a fusion protein composed of a VEGF receptor domain, such as a fusion protein composed of a combination between a VEGF receptor domain with an Fc fragment of a human immunoglobulin and an Fc fragment of a human immunoglobulin, e.g., conbercept, aflibercept) or an AAV containing a sequence encoding an anti-VEGF antibody (such as RGX-314 from Regenxbio), or an AAV containing a sequence encoding a VEGF receptor domain, e.g., conbercept (such as ADVM-022 from Adverum), or any approved anti-VEGF drug (such as brolucizumab, ranibizumab or aflibercept).

[0096] In certain embodiments, the VEGF antagonist of the disclosure is an anti-VEGF antibody, such as a single chain antibody (scFv) or a Fab fragment.

[0097] In certain embodiments, the VEGF antagonist of the present disclosure is an anti-VEGF antibody, such as an anti-VEGF antibody described in WO 2009 / 155724, the entire contents of which are incorporated herein by reference.

[0098] In one embodiment, the VEGF antagonist of the disclosure is an anti-VEGF antibody comprising a variable heavy chain having the sequence as set forth in SEQ ID NO:1 and a variable light chain having the sequence as set forth in SEQ ID NO:2. VH: SEQ ID NO: 1 EVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLDIWGQGTLVTVSS VL: SEQ ID NO:2 EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLG

[0099] In another embodiment, the VEGF antagonist of the present disclosure is an anti-VEGF antibody comprising a sequence as set forth in SEQ ID NO:3. [ka]

[0100] In another embodiment, the VEGF antagonist of the present disclosure is an anti-VEGF antibody comprising the sequence set forth in SEQ ID NO: 4 (brolucizumab). The sequence of brolucizumab is set forth in SEQ ID NO: 4, which comprises the sequence of SEQ ID NO: 3. The methionine from the start codon in the expression vector is present in the final protein if it is not cleaved post-translationally as follows: [ka]

[0101] In another embodiment, the VEGF antagonist of the disclosure is an anti-VEGF antibody that comprises three light chain CDRs (CDRL1, CDRL2 and CDRL3) and three heavy chain CDRs (CDRH1, CDRH2, CDRH3).

[0102] [Table 1]

[0103] Brolucizumab is a humanized single-chain Fv (scFv) antibody fragment inhibitor of VEGF with a molecular weight of approximately 26 kDa. It is an inhibitor of VEGF-A and functions by binding to the receptor binding site of the VEGF-A molecule, thereby preventing the interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of endothelial cells. Increased levels of signaling through the VEGF pathway are associated with pathological ocular neovascularization and retinal edema. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions and reverse retinal edema in patients with nAMD.

[0104] In certain embodiments, the VEGF antagonist of the present disclosure is administered by injection. In certain embodiments, the VEGF antagonist of the present disclosure is administered by intravitreal injection.

[0105] In some embodiments, the VEGF antagonist of the present disclosure is brolucizumab and is administered as an intravitreal injection at a dose of about 1, about 2, about 3, about 4, about 5, or about 6 mg (e.g., about 6 mg / 0.05 mL). In certain embodiments, the VEGF antagonist of the present disclosure is brolucizumab and is administered as an intravitreal injection at a dose of 1, 2, 3, 4, 5, or 6 mg (e.g., 6 mg / 0.05 mL).

[0106] Pharmaceutical Preparations In one aspect, the method or use of the present disclosure includes the use of a pharmaceutical formulation or composition comprising a VEGF antagonist, such as an anti-VEGF antibody. The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the antagonist, such as an antibody or antibody derivative, to be demonstrably effective and does not contain additional components that are toxic to the subject to which the formulation or composition will be administered. A "pharmaceutical acceptable" excipient (vehicle, additive) is one that can be reasonably administered to a target mammal to provide an effective dose of the active ingredient utilized.

[0107] A "stable" formulation is one in which the therapeutic agent, e.g., a VEGF antagonist, e.g., an anti-VEGF antibody or antibody derivative thereof, essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability may be measured at a selected temperature for a selected period of time. Preferably, the formulation is stable at room temperature (about 30°C) or 40°C for at least one week and / or at about 2-8°C for at least three months to two years. Furthermore, the formulation is preferably stable after freezing (e.g., to -70°C) and thawing the formulation.

[0108] An antagonist, e.g., an antibody or antibody derivative, "retains its physical stability" in a pharmaceutical formulation if it meets the defined release specifications for aggregation, decomposition, precipitation, and / or denaturation, as measured upon visual inspection of color and / or clarity or by UV light scattering or size exclusion chromatography or other suitable art-recognized methods.

[0109] An antagonist, e.g., an antibody or antibody derivative, "retains its chemical stability" in a pharmaceutical formulation if the chemical stability at a given time is such that the compound, e.g., a protein, is still considered to retain its biological activity as defined below. Chemical stability can be assessed by detecting and quantifying chemically modified forms of the protein. Chemical modifications can include size modifications (e.g., clipping), which can be assessed, for example, using size exclusion chromatography, SDS-PAGE and / or matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). Other types of chemical modifications include charge modifications (e.g., resulting from deamidation), which can be assessed, for example, by ion exchange chromatography.

[0110] An antagonist, e.g., an antibody or antibody derivative, "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody at a given time is within about 10% (within the error of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined, e.g., in an antigen binding assay. Other "biological activity" assays for antibodies are detailed herein below.

[0111] "Isotonic" means that the formulation of interest has essentially the same osmotic pressure as human blood. An isotonic formulation will generally have an osmotic pressure of about 250-350 mOsm. Isotonicity can be measured, for example, using a vapor pressure or ice osmometer.

[0112] A "polyol" is a substance having multiple hydroxyl groups, and includes sugars (reducing and non-reducing sugars), sugar alcohols, and sugar acids. Preferred polyols herein have a molecular weight that is less than about 600 kD (e.g., in the range of about 120 to about 400 kD). A "reducing sugar" is one that contains a hemiacetal group that can reduce metal ions or covalently react with lysine and other amino groups in proteins, and a "non-reducing sugar" is one that does not have these properties of a reducing sugar. Examples of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, and glucose. Non-reducing sugars include sucrose, trehalose, sorbose, melezitose, and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol, and glycerol are examples of sugar alcohols. With respect to sugar acids, these include L-gluconate and its metal salts. Where it is desired that the formulation be freeze-thaw stable, the polyol is preferably one that does not crystallize at freezing temperatures (e.g., −20° C.) which would destabilize the antibody in the formulation. Non-reducing sugars such as sucrose and trehalose are preferred polyols herein, with trehalose being preferred over sucrose due to the superior solution stability of trehalose.

[0113] As used herein, "buffer" refers to a buffered solution that resists changes in pH through the action of its acid-base conjugate components. Buffers of the present disclosure have a pH in the range of about 4.5 to about 8.0; preferably about 5.5 to about 7. Examples of buffers that will control the pH in this range include acetate (e.g., sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers. If a freeze-thaw stable formulation is desired, the buffer is preferably not phosphate.

[0114] In the pharmacological sense, in the context of this disclosure, a "therapeutically effective amount" of a therapeutic agent, e.g., a VEGF antagonist, e.g., an anti-VEGF antibody or antibody derivative, refers to an amount effective in the prevention or treatment of the disorder for which the antagonist, e.g., an antibody or antibody derivative, is effective in the treatment. This includes chronic and acute disorders or diseases, including those pathological conditions that predispose a mammal to the disorder in question.

[0115] A "preservative" is a compound that can be included in a formulation to essentially reduce bacterial activity therein, thereby facilitating the production of, for example, a multi-use formulation. Examples of possible preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl group is a long-chain compound) and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol. The most preferred preservative herein is benzyl alcohol.

[0116] The pharmaceutical composition used in the present disclosure comprises a VEGF antagonist, preferably an anti-VEGF antibody (e.g., an anti-VEGF antibody comprising the variable light chain sequence of SEQ ID NO: 1 and the variable heavy chain sequence of SEQ ID NO: 2, such as brolucizumab), together with at least one physiologically acceptable carrier or excipient. The pharmaceutical composition may comprise, for example, one or more of water, buffer (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrate (e.g., glucose, mannose, sucrose or dextran), mannitol, protein, adjuvant, polypeptide or amino acid such as glycine, antioxidant, chelating agent such as EDTA or glutathione, and / or preservative. As noted above, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.

[0117] Carriers are often substances that can be associated with the antibody or antibody derivative prior to administration to a patient for controlling stability or bioavailability of the compound. Carriers for use in such formulations are generally biocompatible and can also be biodegradable. Carriers include, for example, monovalent or polyvalent molecules such as serum albumin (e.g., human or bovine), egg albumin, peptides, polylysine, and polysaccharides such as aminodextran and polyamidoamine. Carriers also include solid support materials such as beads and microparticles including, for example, polyacetate polyglycolate, poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose, or dextran. Carriers can hold the compound in various ways, including covalent binding (directly or through a linker group), non-covalent interaction, or admixture.

[0118] The pharmaceutical compositions may be formulated for any suitable mode of administration, including, for example, topical, ocular, oral, nasal, rectal or parenteral administration. In certain embodiments, compositions in a form suitable for intraocular injection, such as intravitreal injection, are preferred.

[0119] Pharmaceutical compositions can be prepared as sterile injectable aqueous or oleaginous suspensions in which the active agent (i.e., VEGF antagonist) is suspended or dissolved in the vehicle, depending on the vehicle and concentration used. Such compositions can be formulated according to known techniques using suitable dispersing, wetting and / or suspending agents, such as those mentioned above. Among the acceptable vehicles and solvents that can be used are water, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable compositions, and adjuvants such as local anesthetics, preservatives and / or buffers can be dissolved in the vehicle.

[0120] Aqueous formulations of VEGF antagonists, such as anti-VEGF antibodies (e.g., brolucizumab) used in the methods or uses of the present disclosure are prepared in a pH-buffered solution. Preferably, the buffer of such aqueous formulations has a pH in the range of about 4.5 to about 8.0, preferably about 5.5 to about 7.0, and most preferably about 6.75. In one embodiment, the pH of the aqueous pharmaceutical composition of the present disclosure is about 7.0 to 7.5 or about 7.0 to 7.4, about 7.0 to 7.3, about 7.0 to 7.2, about 7.1 to 7.6, about 7.2 to 7.6, about 7.3 to 7.6, or about 7.4 to 7.6. In one embodiment, the aqueous pharmaceutical composition of the present disclosure has a pH of about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of ≧7.0. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.2. Examples of buffers that will control the pH within this range include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate), gluconate, histidine, citrate (e.g., sodium citrate) and other organic acid buffers. The buffer concentration can be, for example, about 1 mM to about 50 mM, preferably about 5 mM to about 30 mM, depending on the buffer and the desired isotonicity of the formulation. In a preferred embodiment, the aqueous pharmaceutical composition comprises a 15 mM sodium citrate buffer.

[0121] Polyols acting as isotonicity agents may be used to stabilize antibodies in aqueous formulations. In a preferred embodiment, the polyol is a non-reducing sugar such as sucrose or trehalose, preferably sucrose. If desired, the polyol is added to the formulation in an amount that may vary with respect to the desired isotonicity of the formulation. Preferably, the aqueous formulation is isotonic, in which case a suitable concentration of the polyol in the formulation is, for example, in the range of about 1% to about 15% w / v, preferably in the range of about 2% to about 10% w / v. However, hypertonic or hypotonic formulations may also be suitable. The amount of polyol added may also vary with respect to the molecular weight of the polyol. For example, a smaller amount of a monosaccharide (e.g., mannitol) may be added compared to a disaccharide (e.g., trehalose).

[0122] Surfactants are also added to the aqueous antibody formulation. Exemplary surfactants include non-ionic surfactants such as polysorbates (e.g., polysorbate 20, 80, etc.) or poloxamers (e.g., poloxamer 188). The amount of surfactant is such that it reduces aggregation of the formulated antibody / antibody derivative and / or minimizes particle formation and / or reduces adsorption in the formulation. For example, the surfactant may be present in the formulation in an amount of about 0.001% to about 0.5%, preferably about 0.005% to about 0.2%, preferably about 0.01% to about 0.02%, and most preferably about 0.02%.

[0123] In one embodiment, the aqueous antibody formulation used in the methods or uses of the present disclosure is essentially free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol, and benzethonium Cl. In another embodiment, a preservative may be included in the formulation, particularly where the formulation is a multi-dose formulation. The concentration of the preservative may range from about 0.1% to about 2%, most preferably from about 0.5% to about 1%. One or more other pharma- ceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 21st edition, Osol, A. Ed. (2006), may be included in the formulation, provided they do not adversely affect the desired characteristics of the formulation. Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include additional buffers, cosolvents, antioxidants including ascorbic acid and methionine, chelating agents such as EDTA, metal complexes (e.g., Zn-protein complexes), biodegradable polymers such as polyesters, and / or salt-forming counterions such as sodium.

[0124] The formulations to be used for in vivo administration must be sterile, which is readily accomplished by filtration through sterile filtration membranes, either prior to or following preparation of the formulation.

[0125] In one embodiment, the VEGF antagonist of the present disclosure is administered to the eye of the subject who needs treatment according to known methods for ocular delivery.Preferably, the subject is a human, and VEGF antagonist A is an anti-VEGF antibody (preferably brolucizumab), and the antibody is administered directly to the eye.Administration to the patient can be achieved, for example, by intravitreal injection.

[0126] The VEGF antagonists in the methods and uses of the present disclosure may be administered as the sole treatment or in combination with other drugs or therapies useful in treating the subject's condition.

[0127] A preferred formulation of brolucizumab for intravitreal injection comprises about 4.5% to 11% (w / v) sucrose, 5 to 20 mM sodium citrate, and 0.001% to 0.05% (w / v) polysorbate 80, with the pH of the formulation being about 7.0 to about 7.4. One such formulation comprises 5.9% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 6 mg of brolucizumab. Another such formulation comprises 6.4% (w / v) or 5.8% sucrose, 12 mM or 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, a pH of 7.2, and 3 mg of brolucizumab. One such formulation includes 6.75% (w / v) sucrose, 15 mM sodium citrate, 0.02% (w / v) polysorbate 80, pH of 7.2, and 6 mg of brolucizumab. Preferred concentrations of brolucizumab are about 120 mg / ml and about 60 mg / ml. Doses can be delivered, for example, as concentrations of 6 mg / 50 μL and 3 mg / 50 μL.

[0128] Dosage The dosage used in the disclosed method or use is a therapeutically effective dosage based on the particular disease or condition being treated. The amount effective for this use will depend on the severity of the disorder being treated and the general state of the patient's own immune system. The dosage can be readily determined by a physician of ordinary skill in treating diseases or conditions using known dosage adjustment techniques. The therapeutically effective amount of the VEGF antagonist used in the disclosed method or use is determined, for example, by considering the desired dose volume and mode of administration. Typically, the therapeutically effective composition is administered at a dosage ranging from 0.001 mg / ml to about 200 mg / ml per dose.

[0129] In one embodiment of the present disclosure, the VEGF antagonist used in the method or use of the present disclosure is brolucizumab, and the dosage used in the method or use of the present disclosure is about 60 mg / ml to about 120 mg / ml (e.g., the dosage is 60, 70, 80, 90, 100, 110 or 120 mg / ml). In a preferred embodiment, the dosage of the VEGF antagonist used in the method or use of the present disclosure is 60 mg / ml or 120 mg / ml. Suitably, each dosage is 50 μL, e.g., each dosage is 6 mg / 50 μL or 3 mg / 50 μL.

[0130] In certain embodiments, the dose of the VEGF antagonist is administered directly to the patient's eye. In one embodiment, the dose of the VEGF antagonist per eye is at least about 0.5 mg to about 6 mg. Preferred doses per eye include about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6.0 mg. In one embodiment, the dose per eye is at least about 3 mg to about 6 mg, particularly about 3 mg or about 6 mg. The dose can be administered in various volumes suitable for ocular administration, such as, for example, 50 μl or 100 μl, including 3 mg / 50 μl or 6 mg / 50 μl. Smaller volumes may also be used, including 20 μl or less, for example, about 20 μl, about 10 μl, or about 8.0 μl. In certain embodiments, a dose of 2.4 mg / 20 μl, 1.2 mg / 10 μl, or 1 mg / 8.0 μl (e.g., 1 mg / 8.3 μl) is delivered to the patient's eye to treat or ameliorate one or more of the above diseases and disorders. Delivery may be, for example, by injection, for example, intravitreal injection.

[0131] In certain embodiments, the VEGF antagonist of the disclosure is brolucizumab and is administered as an injection, e.g., an intravitreal injection, at a dose of about 1, about 2, about 3, about 4, about 5, or about 6 mg (e.g., about 6 mg / 0.05 mL), e.g., 1, 2, 3, 4, 5, or 6 mg (e.g., 6 mg / 0.05 mL).

[0132] kit The disclosure also provides a kit comprising a drug container (e.g., a vial or a prefilled syringe) containing a VEGF antagonist (e.g., brolucizumab) and instructions for using the VEGF antagonist to treat a patient diagnosed with nAMD.

[0133] In one embodiment, the instructions indicate that the VEGF antagonist (e.g., brolucizumab) is to be administered to the patient as two separate doses six weeks apart (q6w regimen), followed by one or more additional doses, each additional dose being administered at least eight weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks apart, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0134] In a more specific embodiment, the instructions include administering a VEGF antagonist (e.g., brolucizumab) to the patient as two separate doses six weeks apart (q6w regimen), optionally followed by assessing the patient for disease activity after a second dose of the VEGF antagonist, e.g., assessing the patient for disease activity ≧0 to ≦6 weeks after the second dose of the VEGF antagonist, and if the presence of disease activity is identified after the second dose of the VEGF antagonist, administering a third dose of the VEGF antagonist. is administered to the patient 6 weeks after administration of the second dose (q6w regimen), followed by one or more additional doses, with each additional dose being administered at a dosing interval of at least 8 weeks after the immediately preceding dose, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, e.g., once every 8 weeks (q8w regimen) to once every 12 weeks (q12w regimen), e.g., once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

[0135] In a more specific embodiment, the instructions indicate that the VEGF antagonist (eg, brolucizumab) should be administered to the patient at a dose of 3 mg or 6 mg, preferably 6 mg, and more preferably 6 mg / 50 μL.

[0136] The disclosure also provides a kit comprising a drug container (e.g., a vial or a prefilled syringe) containing a VEGF antagonist (e.g., brolucizumab) and instructions for using the VEGF antagonist to treat a patient diagnosed with nAMD.

[0137] In one embodiment, the kit comprises one or more doses of 3 mg or 6 mg of brolucizumab, each dose provided in a single-use container, e.g., a vial, containing sufficient brolucizumab to deliver a dose of 3 mg or 6 mg, preferably 6 mg, when administered in a volume of 0.05 mL, or a pre-filled syringe containing 3 mg or 6 mg, e.g., 3 mg / 50 μL or 6 mg / 50 μL, preferably 6 mg, e.g., 6 mg / 50 μL of brolucizumab.

[0138] In one embodiment, the instructions further indicate that the treatment provider (e.g., a physician or other qualified medical professional) can adjust the dosing interval from once every 12 weeks to once every 8 weeks if disease activity is observed in the treated eye.

[0139] In another embodiment, the instructions further indicate that the treatment provider (e.g., a physician or other qualified medical professional) can extend the dosing interval from once every 8 weeks to once every 12 weeks if no disease activity is observed in the treated eye.

[0140] In yet another embodiment, the instructions further indicate that during the maintenance phase, the VEGF antagonist is to be administered as needed, i.e., when needed (PRN), at the discretion of the treatment provider (e.g., a physician or other qualified medical professional) based on visual and / or anatomical outcomes to determine disease activity.

[0141] The various features, aspects and embodiments of the invention referred to in individual sections above apply mutatis mutandis to other sections and embodiments, as appropriate. Thus, features specified in one section may be combined with features specified in other sections, as appropriate.

[0142] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific aspects and embodiments of the invention described herein which equivalents are intended to be encompassed by the scope of the following claims.

[0143] All references cited herein, including patents, patent applications, articles, publications, textbooks, and the like, and the references cited therein, are incorporated herein by reference in their entirety to the extent they are not already incorporated.

[0144] The following examples are included to demonstrate preferred embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the invention and therefore may be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of this disclosure, understand that many modifications can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the invention. EXAMPLES

[0145] Example 1: Predicted human intraocular drug PK and posology simulations of VEGF inhibition Background and Objectives Brolucizumab is a humanized, single-chain variable fragment (scFv) antibody developed for the treatment of wet age-related macular degeneration (wet AMD). Similar to other anti-VEGF biologics approved for use in wet AMD, brolucizumab is administered locally by intravitreal injection. The approved dosing regimen for brolucizumab consists of a loading phase (three monthly injections of 6 mg), followed by a maintenance phase (injections every 8 or 12 weeks; Q8W or Q12W).

[0146] The objective of modeling activity was to predict retinal VEGF inhibition for alternative dosing regimens, including altered loading and / or maintenance phases. A quantitative systems pharmacology (QSP) modeling approach was used to predict human ocular pharmacokinetics (PK) and VEGF inhibition of brolucizumab for alternative dosing regimens. A model was adapted from a series of models relating IVT administration of anti-VEGF biologics to intraocular PKPD and clearance from the eye (Hutton-Smith LA, et al (2016) Molecular Pharmaceutics; 13(9): 2941-2950; Hutton-Smith LA, et al (2017) Molecular Pharmaceutics; 14(8): 2690-2696; Hutton-Smith LA, et al (2018) Molecular Pharmaceutics; 15(7): 2770-2784; Caruso A, et al (2020) Molecular Pharmaceutics; 17(2): 695-709). Application of the model to brolucizumab considered the rapid distribution of this scFv antibody in the eye due to its small size (hydrodynamic radius) and the formation of an inhibitory complex with VEGF. The simulated clearance of free and VEGF-bound brolucizumab from the eye (i.e., an ocular half-life of 4.4 days) is consistent with the absorption rates identified in a clinical pharmacology analysis of brolucizumab serum concentrations in patients. The analysis considered intra-patient variability in ocular VEGF levels by repeating the simulation with varying retinal VEGF synthesis rates.

[0147] A simulation was performed to compare the approved brolucizumab dosing regimen (a 3 × Q4W loading dose phase followed by a Q8W or Q12W maintenance dose) with an alternative regimen consisting of a 2 × Q6W loading dose phase followed by a Q8W or Q12W maintenance dose.

[0148] Materials and Methods Model Structure The following three-compartment PKPD model, describing the distribution of drugs in the eye after IVT administration (pharmacokinetics; PK) and the kinetics of VEGF production and inhibition by the drug (pharmacodynamics; PD), was constructed using MATLAB SimBiology software (MathWorks®, Natick, MA USA).

number

[0149] Simulations were performed using computational modeling techniques common in the art according to the manufacturer's instructions. The PKPD model was adapted from a published model in the literature describing the PKPD of ranibizumab in the human eye (Hutton-Smith LA, et al (2018) Molecular Pharmaceutics; 15 (7): 2770-2784). The applied model allows the simulation of a VEGF antagonist (e.g., brolucizumab) being administered at a specified dose and time. VEGF exists in the eye in a dimeric form consisting of two VEGF monomers, and therefore can form a complex with one VEGF antagonist or two VEGF antagonists.

[0150] The model includes three compartments (Table 1).

[0151] [Table 2]

[0152] After IVT administration of a drug to the vitreous compartment, the drug distributes between the retina, vitreous and aqueous compartments, and irreversibly distributes to the outside of the eye via the retina and aqueous compartments. The term "ocular half-life" may generally refer to the combined rate at which a drug distributes to the outside of the aqueous and retinal compartments of the eye (i.e., disappears from the eye). VEGF is generally understood to distribute into the eye via the retina, and is described in the model as a zero-order reaction in which new VEGF is generated in the retina (i.e., "VEGF synthesis" or "VEGF production"). The distribution of VEGF in and out of the eye follows the same format as for VEGF antagonists.

[0153] The species represented in the figures in the retina, vitreous and aqueous compartments are presented respectively in Tables 2, 3 and 4. The values ​​of the parameters presented in the figures are given in Table 5.

[0154] [Table 3]

[0155] [Table 4]

[0156] [Table 5]

[0157] [Table 6]

[0158] [Table 7]

[0159] [Table 8]

[0160] [Table 9]

[0161] [Table 10]

[0162] [Table 11]

[0163] [Table 12]

[0164] [Table 13]

[0165] [Table 14]

[0166] [Table 15]

[0167] [Table 16]

[0168] [Table 17]

[0169] Model parameters Of all the parameters utilized in the model (Tables 5-7), some are related to the drug being modeled, i.e., brolucizumab. These are the brolucizumab:VEGF binding parameter values ​​(dissociation rate constant "koff", association rate constant "kon" and equilibrium binding constant "Kd") and the hydrodynamic radius values ​​of the drug ("rh_R") and associated drug:VEGF complex ("rh_VR" and "rh_RVR").

[0170] Brolucizumab:VEGF binding parameter values ​​(Table 8) were defined based on surface plasmon resonance (SPR) in vitro binding experiments with the drug and recombinant VEGF165 protein at 37°C. These in vitro measured Brolucizumab:VEGF binding parameter values ​​were then scaled similarly to ranibizumab to obtain in vivo estimates. A scaling factor of 20.5 was utilized based on the in vitro measured Kd of ranibizumab, with the model fit (in vivo) Kd given by Hutton-Smith et al., 2018, using the hydrodynamic radius of 3.0 nm and ocular half-life of 5.8 days for ranibizumab given by Caruso et al., 2020. Scaling is performed such that koff is held constant and kon is divided by the scaling factor.

[0171] [Table 18]

[0172] The hydrodynamic radius values ​​of the drug ("rh_R") and VEGF ("rh_V") and the associated ocular half-lives of the drug ("thalf_R") and VEGF ("thalf_V") are established according to the correlations given by Caruso et al., 2020, in a large meta-analysis of published data. These correlations give a relationship between hydrodynamic radius and ocular half-life, which are used herein to calculate either of these parameters when the other is known. In particular, we rely on the ocular half-life value of 4.4 days for the drug provided by clinical pharmacology analysis and the hydrodynamic radius of 2.39 nm for VEGF estimated by Hutton-Smith et al., 2018. The hydrodynamic radius values ​​of the associated drug:VEGF complex ("rh_VR" and "rh_RVR") were taken from the calculated structural models of the drug and VEGF. All hydrodynamic radius and half-life values ​​are presented in Table 9.

[0173] [Table 19]

[0174] Drug-independent parameters used are used to describe VEGF production and distribution inside and outside the eye, as well as the overall biophysical properties of the eye, such as the permeability coefficients of the internal limiting membrane (ILM) and retinal pigment epithelium (RPE) and the clearance rate from the ocular chamber. These values ​​are shown in Table 5. Simulations are performed with varying retinal VEGF synthesis rates to consider the intrapatient variability of ocular VEGF levels (Table 10). To represent low, average and high retinal VEGF synthesis rates, we utilize the population distribution terms of mean ± 2 × SD reported in Hutton-Smith et al., 2018.

[0175] [Table 20]

[0176] Modeling steps and process overview Simulations were performed with the drug dosing regimens shown in each of the figures. The PK / PD profiles of the concentration of drug over time in the vitreous (PK) and the concentration of free VEGF in the retina (PD) were simulated and the results were plotted as graphs. Simulations were performed with varying retinal VEGF synthesis rates to consider inter-patient variability in ocular VEGF levels. Intraocular PK / PD and retinal VEGF inhibition are first simulated for the clinical dosing regimen defined by the HAWK and HARRIER studies (3×Q4W loading phase followed by a Q8W or Q12W maintenance phase). As a second step, retinal VEGF inhibition is simulated for an alternative dosing regimen of 2×Q6W loading phase followed by a Q8W or Q12W maintenance phase.

[0177] result Simulated retinal free drug and retinal free VEGF concentrations for the dosing regimen of 3×Q4W loading phase followed by a Q8W maintenance phase are shown in FIG.

[0178] Simulated retinal VEGF inhibition of the 3xQ4W and 2xQ6W loading dose regimens is shown in Figure 2. The results demonstrate that both regimens provide near complete VEGF inhibition (retinal VEGF concentrations close to zero) over the first 12-13 weeks. Recovery of free VEGF begins to be observed approximately 6-7 weeks after the last dose of each regimen, coinciding with clearance of the drug from the eye.

[0179] Retinal VEGF inhibition of both loading dose regimens (3 × Q4W and 2 × Q6W) followed by a maintenance dose of either Q8W or Q12W was simulated and depicted in Figure 3. No obvious differences in VEGF inhibition were observed during the maintenance phase after either loading dose regimen (3 × Q4W or 2 × Q6W).

[0180] Several observations are evident in the results. First, the 2×Q6W loading regimen is predicted to elicit substantially similar (almost complete) retinal VEGF inhibition as 3×Q4W, regardless of baseline VEGF levels. Second, there are no apparent differences in drug PK or VEGF inhibition during the maintenance phase following either loading dose regimen (3×Q4W or 2×Q6W). Third, the extent of free retinal VEGF recovery with Q8W and Q12W maintenance dosing is more evident under conditions of high VEGF synthesis.

[0181] conclusion With respect to the loading phase, 3×Q4W and 2×Q6W provide near complete VEGF inhibition (retinal VEGF concentrations close to 0), with recovery of free VEGF observed to begin approximately 6-7 weeks after the last dose. Full recovery to baseline levels of VEGF is expected to occur approximately 12 weeks after the last dose. Pharmacodynamic responses during the maintenance phase are expected to be identical for both loading dose regimens. The Q8W maintenance regimen results in partial recovery of retinal VEGF prior to administration of successive doses, while Q12W allows for near complete recovery of VEGF levels to pre-dose steady-state levels prior to administration of successive doses. These observations hold in conditions of low, intermediate, and high levels of VEGF, which is expected given the large excess of brolucizumab over VEGF (approximately >100,000-fold).

[0182] Taken together, these posology simulations suggest that reduced dose intensity during the loading period may still maintain robust VEGF inhibition and that patient factors such as intraocular VEGF levels may affect the ability to maintain VEGF inhibition with longer dosing intervals during the maintenance phase. The simulations further suggest that switching to a two-dose loading regimen (2×Q6W followed by a maintenance dose) may achieve similar VEGF inhibition to the approved three-dose loading regimen (3×Q4W followed by a maintenance dose).

[0183] Example 2: Clinical trial simulation of q6w load and individualized q12w / q8w brolucizumab treatment effects on retinal thickness and visual acuity in patients with wet AMD the purpose: The objective was to simulate a reduced loading of brolucizumab 6 mg administered as two or three injections six weeks apart followed by individualized q12w / q8w maintenance in the patient populations of the HAWK and HARRIER trials and compare BCVA gains and CSFT declines with results from the brolucizumab 6 mg treatment arms of the HAWK and HARRIER trials with three monthly loading doses followed by individualized q12w / q8w maintenance.

[0184] data: Clinical trial simulation of 2 or 3 q6w loading doses and 3 q4w loading doses followed by q12w / q8w maintenance in the patient populations of the HAWK and HARRIER trials.

[0185] The HAWK study was a 2-year, randomized, double-blind, 3-arm phase 3 registration study comparing the efficacy and safety of brolucizumab (3 mg and 6 mg) versus aflibercept 2 mg in 1078 patients with nAMD.

[0186] The HARRIER trial was a 2-year, randomized, double-blind, two-arm phase 3 registration study comparing the efficacy and safety of 6 mg brolucizumab versus 2 mg aflibercept in 739 patients with nAMD.

[0187] In the HAWK and HARRIER trials, patients in the brolucizumab arm were initially assigned to the q12w regimen after three monthly loading doses and switched to the q8w regimen according to individualized treatment needs after disease activity assessments (DAAs) at prespecified visits. DAA visits during the first year of the HAWK trial were at weeks 16, 20, 32, and 44; the HARRIER trial had additional DAAs at weeks 28 and 40.

[0188] method: A nonlinear mixed-effects PK / PD model was developed and used to simulate the longitudinal dynamics of CSFT and BCVA change from baseline in wet AMD patients treated with anti-VEGF. The PK of the anti-VEGF drugs was described by a one-compartment model in which the vitreous clearance half-life of brolucizumab was fixed at a typical value of 8.6 days obtained from the population PK analysis, and the typical aflibercept half-life of 5.9 days was estimated using the K-PD approach. Central subfield thickness (CSFT) was calculated as a function of the time-independent normal thickness R norm and the disease-induced thickness R(t) that can be reduced by anti-VEGF treatment. The effect of anti-VEGF on R(t) was described using a generalized growth model (1), while BCVA improvement was dominated by delayed CSFT reduction using a drug effect compartment. The model included IIV on normal CSFT Rnorm, baseline disease-related CSFT Rdis, drug effect on CSFT Emax, CSFT increase velocity k, effect of CSFT reduction on BCVA Vmax, and BCVA k eff The delayed effect of CSFT reduction on Rdis was included. The covariate effects and individual residuals of baseline CSFT on Rdis and baseline BCVA on Vmax were included in the model. The efficacy parameter Emax was modeled as drug specific, whereas EC50 was modeled as common to all three drugs. The full joint model of CSFT(t) and BCVA change from baseline V(t) is specified by the following set of equations:

[0189] In the penalty kick,

number

[0190] In CSFT,

number

[0191] BCVA change from baseline V(t) with delayed effect

number

number

[0192] The inter-individual variability of the model parameters and covariate effects is of the following form:

number

[0193] Model evaluation of 1 year of q8w treatment The PK / PD model was developed using HAWK and HARRIER data up to the first treatment individualization visit at week 16 in the brolucizumab treatment arm. The aflibercept treatment arm data was also fitted by the model up to week 16 to avoid imbalances. The 1-year aflibercept 2mg treatment arm of HAWK and HARRIER was simulated using the patient covariates of the aflibercept arm and three q4w loadings followed by q8w maintenance. The results are presented in Figures 4 and 5. It was observed that the CSFT change from baseline reproduced the observed data well. The BCVA change from baseline was slightly underestimated by the model in the HARRIER study, but the mean of the observed data was within the SE of the simulated mean BCVA change from baseline.

[0194] Disease activity assessment simulation Brolucizumab treatment in the HAWK and HARRIER studies was individualized for q12w or q8w intervals based on disease activity (DA) assessments at week 16 and at the end of 12-week intervals (weeks 16, 20, 32, and 44 visits in the first year) in HAWK. In the HARRIER study, DA assessments were additionally performed at the end of 8-week intervals (weeks 16, 20, 28, 32, 40, and 44 visits in the first year). Disease activity assessment criteria were not defined, but guidelines were provided for reducing the treatment interval from q12w to q8w. At week 16, they were: ≥ 5 letter loss in BCVA compared to baseline A decrease in BCVA of ≥3 letters and an increase in CSFT of ≥75 μm compared to week 12 ≥ 5 letter loss in BCVA with nAMD DA compared to Week 12 -New or worsening IRF / intraretinal cysts compared to week 12.

[0195] After 16 weeks, the guidelines were: Loss of ≥ 5 letters of BCVA with nAMD DA compared to Week 12.

[0196] These guidelines allow investigators to make decisions regarding treatment. Current standards for anti-VEGF treatment individualization are largely guided by OCT (Fung, AE, et al., 2007. American journal of ophthalmology, 143(4), pp. 566-583). Therefore, DA assessment and treatment interval individualization are estimated using simulated dynamics of CSFT, which is the best available surrogate for quantifying retinal fluid in OCT images.

[0197] In the single-dose brolucizumab SEE study, switching to standard care was recommended if CSFT exceeded the 340 μm threshold. In the phase IIIb SUSTAIN study of ranibizumab administered in a PRN regimen, retreatment criteria were a BCVA loss of 6 letters or a retinal thickness increase of more than 100 μm compared to the best value obtained in the first 4 months (Holz, FG, et al., 2011. Ophthalmology, 118(4), pp. 663-671). The SUSTAIN criteria may be too lenient, because the mean BCVA improvement from baseline to month 12 was 3.6 letters, which is lower than the typical visual acuity improvement of 5 to 6 letters in anti-VEGF clinical trials with similar mean baseline BCVA values ​​(Khanna, S., et al., 2019. BMJ open ophthalmology, 4(1), p. e000398). The HAWK and HARRIER studies used a threshold of 75um CSFT increase from the maximum treatment effect visit at week 12 as guidance for DA assessment. Thresholds of 50um and 75um increase from the mean and minimum CSFT at the two previous visits, respectively, were recommended for DA assessment in a recent trial of neovascular AMD (Heier, JS, et al., 2022. The Lancet).

[0198] Different treatment scenarios were simulated: if a patient was switched to q8w based on DA presence, DA presence was simulated as either CSFT above a specific CSFT threshold or CSFT increase from week 12 (maximum loading effect visit) higher than a CSFT increase threshold. Figure 6 is a diagram of the simulated disease activity presence. The CSFT value threshold aims to simulate DA presence in slow responders, while the CSFT increase threshold aims to detect relapse of active disease.

[0199] The percentage of patients remaining on q12w treatment after three q4w loading doses in the HAWK and HARRIER brolucizumab 6 mg arm patient populations was estimated. Each study was simulated 20 times to estimate standard errors. Patient dropout in the 6 mg brolucizumab arm of the HAWK and HARRIER studies was approximately 9% and was not simulated. The DA assessment visits where DA assessment and regimen switching were simulated correspond to the DA assessment visits in the HAWK study (weeks 16, 20, 32 and 44 visits). Figure 7 shows the percentage of patients remaining on the q12w regimen at week 48 for various CSFT and CSFT gain thresholds. In the HAWK trial, the actual percentage (95% CI) was 55.6 (50.2, 60.8), whereas in the HARRIER study it was 51.0 (45.7, 56.1).

[0200] From Figure 7, it follows that a CSFT threshold of 340 μm and a CSFT increase threshold of 75 μm reproduce within the confidence interval the percentage of patients remaining in q12w in HAWK and HARRIER. These thresholds have been used in clinical trials and are therefore clinically meaningful.

[0201] For the applicability of these thresholds to the simulation of different loading regimens, they should also reproduce the CSFT and BCVA efficacy results of the brolucizumab 6 mg arms of the HAWK and HARRIER trials.

[0202] Simulations of mean CSFT and BCVA change from baseline with three q4w loading brolucizumab 6 mg doses followed by individualized q12w / q8w treatment are presented in Figures 8 and 9. Although there is good agreement between the simulated CSFT and BCVA in the HAWK study and the observed CSFT and BCVA, the simulated efficacy results of the HARRIER study show some deviations from the observed data: the simulated mean CSFT improvement is slightly lower than the mean of the observed data, and the simulated mean BCVA improvement appears better than the mean observed data over the first few months of treatment. The simulated and observed mean BCVA improvements are within their confidence intervals only towards the end of the first year of treatment. The brolucizumab 6 mg simulations in the aflibercept arms of both studies and in the HAWK study were in good agreement with the observed data for both efficacy metrics, and therefore these simulations were considered to be an appropriate representation of the treatment effect in the treated population.

[0203] Thus, a positive DA assessment followed by a switch to q8w treatment, when simulated as either an increase in CSFT of >340 μm or an increase in CSFT from week 12 of >75 μm, well reproduces the HAWK and HARRIER efficacy data in terms of CSFT reduction, BCVA improvement and percent of patients receiving q12w at week 48.

[0204] result: Simulation of 2 or 3 q6w loading doses and q12w / q8w maintenance Two q6w loading doses of brolucizumab 6 mg followed by individualized q12w / q8w maintenance were simulated in the brolucizumab 6 mg treatment arm population of the HAWK and HARRIER studies. At week 12, 6 weeks after the second loading injection, a DA assessment was simulated. If a DA was present, the patient was given an injection and then treated with q8w. If a DA was not present, the patient was scheduled for a visit at week 18, 12 weeks after the last loading dose, and DA was assessed again. At this visit, the patient was treated regardless of DA, but if a DA was present, the patient was switched to q8w, otherwise the patient was treated with q12w, with DA assessments at the end of each 12-week interval. If there was a subsequent positive DA assessment, the patient was switched to q8w treatment. DA presence was simulated as a CSFT greater than 340 μm or a CSFT increase from week 12 greater than 75 μm. A schematic diagram of the simulated DA assessment and treatment schedule is presented in Figure 10.

[0205] Each study was simulated 20 times to assess the standard error of the mean of simulated values ​​- BCVA change from baseline, CSFT change from baseline, and percent of patients on q12w treatment at week 48. Patient dropout in the 6 mg brolucizumab arms of the HAWK and HARRIER studies was approximately 9%, which was not simulated.

[0206] The simulated CSFT change from baseline and BCVA change from baseline after two q6w loading injections and individualized q12w / q8w treatment were close to the HAWK and HARRIER study data, but slower than expected BCVA improvement was observed in the brolucizumab 6 mg treatment arm of HARRIER as previously described. We compared the simulated BCVA and CSFT change from baseline at week 48, the primary endpoint visit of these studies, and the mean BCVA and CSFT change from baseline from weeks 36 to 48 with values ​​reported in the HAWK and HARRIER clinical trials.

[0207] There were no statistically significant differences between the simulated results and the observed data (Figures 11 and 12, Tables 11 and 12). The percentage of patients in a q12w treatment interval at the end of the simulated study (week 48) in the brolucizumab 6 mg HAWK and HARRIER populations was 50% (2% SE), only slightly lower than the 55.6% and 51.0% reported in HAWK and HARRIER, respectively.

[0208] [Table 21]

[0209] [Table 22]

[0210] Discussion: Figures 4 and 5 demonstrate that the joint PK / PD model for CSFT and BCVA can adequately simulate the data of aflibercept treatment with a q8w regimen for one year. Furthermore, after selecting a clinically meaningful CSFT threshold of the simulated DA assessment for treatment interval individualization, the model successfully reproduced the CSFT and BCVA efficacy results of individualized q8w / q12w treatment after three q4w loading doses of the brolucizumab 6 mg treatment arm of the HAWK and HARRIER trials (Figures 8, 9). Two q6w loading doses and an optional third dose at week 12, followed by q12w / q8w maintenance, were simulated, all controlled by the same DA assessment rules as the simulation reproducing the brolucizumab 6 mg treatment arm of the HAWK and HARRIER trials. This resulted in similar efficacy results in terms of BCVA improvement and CSFT reduction as observed in the trials. Compared with the HARRIER and HAWK trials, we calculated that either the same proportion or only about 5% fewer patients, respectively, were receiving q12w maintenance at week 48. The percent (SE) of simulated patients who required a third loading dose at week 12 was 20.4 (1).

[0211] Conclusion: Reducing brolucizumab 6 mg treatment from three q4w doses to two or three q6w doses during the loading phase is predicted to result in similar efficacy at the expense of a <5% reduction in patients receiving q12w maintenance treatment.

Claims

1. A method for treating neovascular age-related macular degeneration (nAMD) in patients, (a) As a loading phase, administer two separate doses of VEGF antagonist to the patient at 6-week intervals (q6w regimen), (b) Evaluating the patient for disease activity after the second dose of the loading period, for example, evaluating the patient for disease activity ≥ 0 to ≤ 6 weeks after the second dose of the loading period. A method that includes this.

2. The method according to claim 1, further comprising administering a third dose of the VEGF antagonist to the patient six weeks after the second dose as part of the loading period, if the presence of disease activity is identified after the second dose of the VEGF antagonist.

3. The method according to claim 1 or 2, comprising administering to the patient one or more additional individual doses of the VEGF antagonist during the maintenance phase after the loading phase, wherein each additional dose is administered at intervals of at least once every eight weeks (q8w regimen), for example once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

4. The method according to claim 1 or 2, comprising administering to the patient one or more additional individual doses of the VEGF antagonist during the maintenance phase after the loading phase, wherein each additional dose is administered at intervals of at least 12 weeks (q12w regimen).

5. The method according to claim 1, comprising: evaluating the patient for disease activity during the maintenance period; administering an additional dose to the patient at intervals of once every eight weeks (q8w regimen) if disease activity is observed; and administering an additional dose to the patient at intervals of once every twelve weeks (q12w regimen) if no disease activity is observed.

6. A method for treating neovascular age-related macular degeneration (nAMD) in patients, (a) The patient shall be administered two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen), (b) Administering the patient one or more additional doses of the VEGF antagonist, each additional dose being administered at least eight weeks after the most recent dose, for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen). A method that includes this.

7. (a) The patient shall be administered two separate doses of a VEGF antagonist at 6-week intervals (q6w regimen), (b) Evaluating the patient for disease activity after a second dose of the VEGF antagonist, for example, evaluating the patient for disease activity ≥0 to ≤6 weeks after the second dose of the VEGF antagonist, (c) Administering the patient an additional dose of one or more doses of the VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen). The method according to claim 6, including the method described in claim 6.

8. The method according to claim 7, further comprising administering a third dose of the VEGF antagonist to the patient six weeks after the administration of the second dose (q6w regimen) if the presence of disease activity is identified after the second dose of the VEGF antagonist.

9. The method according to claim 1 or 6, which does not include administering more than three doses to the patient at intervals of less than eight weeks, for example, not including administering more than three doses to the patient at intervals of six weeks.

10. The method according to claim 1 or 6, further comprising evaluating the patient for disease activity before or after administering the VEGF antagonist in doses every q8w or q12w.

11. The method according to claim 10, wherein if the presence of disease activity is identified after a q12w dose of the VEGF antagonist, the patient is switched to a q8w regimen of the VEGF antagonist.

12. The aforementioned disease activity is, (i) best corrected visual acuity (BCVA); (ii) Visual acuity (VA); (iii) Center subfield thickness (CSFT), and / or (iv) Presence of intraretinal cysts / fluid The method according to claim 1 or 7, which is evaluated based on one or more of the following.

13. The presence of the aforementioned disease activity indicates that (i) Decrease in best corrected visual acuity (BCVA), (ii) Decline in visual acuity (VA), (iii) Lack of increase or decrease in central subfield thickness (CSFT), (iv) New, persistent, or recurrent intraretinal cysts (IRCs), and / or intraretinal fluid (IRFs), and / or subretinal fluid (SRFs) The method according to claim 12, comprising one or more of the above.

14. The method according to claim 1 or 6, wherein the VEGF antagonist is an anti-VEGF antibody, such as a single-chain antibody (scFv) or a Fab fragment.

15. The method according to claim 1 or 6, wherein the anti-VEGF antagonist comprises the sequences of SEQ ID NO: 1 and SEQ ID NO:

2.

16. The method according to claim 12, wherein the VEGF antagonist is an anti-VEGF antibody comprising the sequence of SEQ ID NO: 3 or SEQ ID NO:

4.

17. The method according to claim 12, wherein the anti-VEGF antagonist is brolucizumab.

18. The method according to claim 1 or 6, wherein the VEGF antagonist is administered by injection, for example, intravitreal injection.

19. The method according to claim 1 or 6, wherein the dose of the VEGF antagonist is about 3 mg to about 6 mg, for example, about 3 mg or about 6 mg, for example, 6 mg.

20. The method according to claim 1 or 6, wherein the patient is human.

21. A VEGF antagonist for use as a pharmaceutical for treating neovascular age-related macular degeneration (nAMD) in a patient, wherein the patient is administered two separate doses at 6-week intervals (q6w regimen) during a loading phase, and thereafter, the patient is evaluated for disease activity after the second dose of the loading phase, for example, the patient is evaluated for disease activity ≥0 to ≤6 weeks after the second dose of the loading phase. Optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient six weeks after the second dose as part of the loading phase.

22. The VEGF antagonist for use according to claim 21, wherein, after the loading period, one or more additional individual doses of the VEGF antagonist are administered to the patient as a maintenance phase, each additional dose being administered at intervals of at least once every eight weeks (q8w regimen), for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

23. A pharmaceutical composition comprising a VEGF antagonist for use as a pharmacopoeia for the treatment of neovascular age-related macular degeneration (nAMD) in a patient, wherein the patient is administered two separate doses at 6-week intervals (q6w regimen) during a loading phase, and thereafter the patient is evaluated for disease activity after the second dose of the loading phase, for example, the patient is evaluated for disease activity ≥0 to ≤6 weeks after the second dose of the loading phase. If, optionally, the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient six weeks after the second dose as part of the loading period.

24. The pharmaceutical composition for use according to claim 23, wherein, after the loading period, one or more additional individual doses of the pharmaceutical composition are administered to the patient as a maintenance period, and each additional dose is administered at intervals of at least once every eight weeks (q8w regimen), once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

25. The use of VEGF antagonists for the manufacture of pharmaceuticals for the treatment of neovascular age-related macular degeneration (nAMD) in patients, (a) As a loading phase, administer two separate doses of the VEGF antagonist to the patient at 6-week intervals (q6w regimen), (b) Evaluating the patient for disease activity after the second dose of the loading period, for example, evaluating the patient for disease activity ≥ 0 to ≤ 6 weeks after the second dose of the loading period. including, and (c) optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, the use further comprises administering a third dose of the VEGF antagonist to the patient six weeks after the second dose as part of the loading period.

26. The use according to claim 25, further comprising administering to the patient one or more additional individual doses of the VEGF antagonist during the maintenance phase after the loading phase, each additional dose being administered at intervals of at least once every eight weeks (q8w regimen), for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

27. A VEGF antagonist for use as a pharmaceutical for treating neovascular age-related macular degeneration (nAMD) in patients, (a) The patient is administered two separate doses at 6-week intervals (q6w regimen), (b) Optionally, the patient is subsequently evaluated for disease activity after a second dose of the VEGF antagonist, for example, after ≥0 to ≤6 weeks following the second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered to the patient 6 weeks after the administration of the second dose (q6w regimen). (c) A VEGF antagonist, administered at least eight weeks after the previous dose, with intervals ranging from every eight weeks (q8w regimen) to every twelve weeks (q12w regimen), for example, every eight weeks (q8w regimen) or every twelve weeks (q12w regimen).

28. A pharmaceutical composition comprising a VEGF antagonist for use as a pharmaceutical for treating neovascular age-related macular degeneration (nAMD) in patients, (a) The patient is administered two separate doses at 6-week intervals (q6w regimen), (b) Optionally, the patient is subsequently evaluated for disease activity after a second dose of the pharmaceutical composition, for example, after ≥0 to ≤6 weeks following the second dose of the pharmaceutical composition, and optionally, if the presence of disease activity is identified after the second dose of the pharmaceutical composition, a third dose of the pharmaceutical composition is administered to the patient 6 weeks after the administration of the second dose (q6w regimen). (c) A pharmaceutical composition wherein one or more additional doses are subsequently administered, each additional dose at least eight weeks after the immediately preceding dose, for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), or at intervals of once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen).

29. The use of VEGF antagonists for the manufacture of pharmaceuticals for the treatment of neovascular age-related macular degeneration (nAMD) in patients, (a) Administering the patient two separate doses of the VEGF antagonist at 6-week intervals (q6w regimen), (b) Optionally, the patient is subsequently evaluated for disease activity after a second dose of the VEGF antagonist, for example, after ≥0 to ≤6 weeks following the second dose of the VEGF antagonist, and optionally, if the presence of disease activity is identified after the second dose of the VEGF antagonist, a third dose of the VEGF antagonist is administered 6 weeks after the administration of the second dose (q6w regimen). (c) Administering the patient an additional dose of one or more doses of the VEGF antagonist, each additional dose being administered at least eight weeks after the immediately preceding dose, for example, once every eight weeks (q8w regimen) to once every twelve weeks (q12w regimen), for example, once every eight weeks (q8w regimen) or once every twelve weeks (q12w regimen). Use including.

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