TREATMENT OF AGE RELATED MACULAR DEGENERATION WITH A SMALL ACTIVE CHOROIDAL NEOVASCULARIZATION LESION

Abstract

Methods for treatment of wAMD with an active CNV lesion of less than 50% of the total lesion size and pharmaceutical compositions for the use therein are disclosed.

Claims

1. A method for treating wet age related macular degeneration (wAMD) in a patient, wherein it is first established if the active size of the CNV lesion is smaller than 50% of the total lesion size and then the patient is treated according to usual wAMD treatment schemes in case the active size of the CNV lesion is smaller than 50% of the total lesion size.

2. A method according to claim 1, wherein in case of the active size of the CNV lesion is smaller than 50% of the total lesion size, the patient is treated with an anti-VEGF treatment.

3. A method according to claim 2, wherein the initial anti-VEGF-therapy comprises of a single injection or two, three, four, five, six or more injections of the pharmaceutical composition for anti-VEGF therapy each 4, 8, 12 or more weeks apart.

4. A method according to claim 2, wherein at least 3 doses of the anti-VEGF-therapy are administered every 4 weeks.

5. A method according to claim 2, wherein the evaluation of the treatment response is performed 4, 8, 12 or more weeks after the preceding anti-VEGF-therapy.

6. A method according to claim 2, wherein the anti-VEGF treatment comprises administration of a compound selected from aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

7. A method according to claim 1, wherein in case of the active size of the CNV lesion is smaller than 50% of the total lesion size, the patient is treated with PDT using a photosensitizer.

8. A method according to claim 7, wherein the treatment comprises the administration of verteporfin as photosensitizer.

9. A pharmaceutical composition for the use in the treatment of sCNV wAMD comprising an anti-VEGF agent.

10. A pharmaceutical composition according to claim 9 comprising aflibercept, ranibizumab, bevacizumab, KH-902, or pegaptanip.

11. A pharmaceutical composition for the treatment of sCNV wAMD comprising a photosensitizer agent.

12. A pharmaceutical composition according to claim 11 comprising verteporfin as photosensitizer agent.

Description

EXAMPLE 1

[0062] A total of 304 Chinese subjects with age-related neovascular or wet age-related macular degeneration were enrolled in a randomized, double-blind clinical study to assess the efficacy of intravitreal (IVT) administrated aflibercept compared with V®-PDT on the mean change in BCVA (Best corrected visual acuity) from baseline to Week 28. BCVA of the study eye was assessed according to the standard procedures developed for the ETDRS (Early Treatment Diabetic Retinopathy Study) adapted for Age Related Eye Disease Study (AREDS). The key inclusion criteria were as follows: [0063] Signed and dated written ICF. [0064] Men and women ≧50 years of age. [0065] Active predominantly classic, subfoveal choroidal neovascularization (CNV) lesions secondary to AMD, including juxtafoveal lesions that affect the fovea, as evidenced by fluorescein angiography (FA), in the study eye. [0066] The area of the CNV had to occupy at least 50% of the total lesion. [0067] ETDRS best corrected visual acuity (BCVA) of 73 to 25 letters in the study eye (Snellen activity equivalent of 20/40 to 20/320 in the study eye).

[0068] The following key exclusion criteria applied for the study eye: [0069] Total lesion size is greater than 12 disc areas (30.5 mm.sup.2, including blood, scars and neovascularization), as assessed by FA [0070] Sub-retinal hemorrhages that is >50% of the total lesion area, or if the blood is under the fovea and is 1 or more disc areas in size. (If the blood is under the fovea, then the fovea must be surrounded by 270 degrees by visible CNV.) [0071] Presence of CNV with an origin other than wAMD. History or clinical evidence of diabetic retinopathy, diabetic macular edema or any retinal vascular disease other than wAMD. Particular attention should be made to exclude subjects with polypoidal choroidal vasculopathy (PCV). [0072] Presence of scar, fibrosis, or atrophy involving the center of the fovea that indicates substantial irreversible vision loss. [0073] Presence of retinal pigment epithelial tears or rips involving the macula.

[0074] Eligible patients were randomized 3:1 to receive aflibercept (VTE) 2Q8 or V®-PDT (228 VTE+76 PDT). 194 patients with active CNV lesions >=50% (147 VTE2Q8+47 PDT) and 106 patients with active CNV lesions <50% (78 VTE2Q8+28 PDT) were included. The lesion size was determined by a central reading center based on the MPS protocol [Macular Photocoagulation Study Group, Arch Ophthalmol 1991, 109:1242-1257]. The active CNV size, the area of CNV (mm.sup.2) as well as the total lesion size was measured using the FA. The central retinal thickness was determined by optical coherence tomography. In the VTE2Q8 group patients were treated with 2 mg (0.05 mL) aflibercept administered intravitreally at baseline, week 4, 8, 16, 24, 32, 40 and 48. In the PDT group V®-PDT was performed at baseline and potential PDT retreatment according to the guidelines for the use of PDT treatment in wAMD [Verteporfin Roundtable Participants, Retina. 2005; 25(2):119-34] were performed at week 12 and 24. At Week 28, after assessment of the primary and secondary endpoints, subjects in the PDT.fwdarw.VEGF Trap-Eye group received an IVT injection of 2.0 mg VEGF Trap-Eye, followed by additional 2.0 mg VEGF Trap-Eye injections at Weeks 32, 36, 40, and 48.

[0075] Intravitreal injections of 2 mg aflibercept was superior to V®-PDT with a mean change from baseline BCVA letter score at week 28 of 14.0 (−29 to 59) VTE2Q8 group versus 3.9 (−36 to 43) PDT group (P<0.0001) in the whole study population irrespective of the active CNV lesion size. Intravitreal injection of 2 mg aflibercept provided an effective treatment for patients with an active CNV lesion <50% of total lesion size (mean change of BCVA from baseline at week 28: 16.7 (−21 to 59) see FIG. 2/2) which was comparable to the treatment outcome of patients with an active CNV lesion >=50% of total lesion size (mean change of BCVA from baseline at week 28:12.7 (−29 to 40) see FIG. 1/2). V®-PDT treatment effect is numerically higher in patients with an active CNV lesion <50% of total lesion size (mean change of BCVA from baseline at week 28: 8.0 (−18 to 43), see FIG. 2/2) than in patients with an active CNV lesion >=50% of total lesion size (mean change of BCVA from baseline at week 28: 1.5 (−36 to 27) see FIG. 1/2).

[0076] In general, for most of the other efficacy parameters a more favorable outcome in patients with an active CNV lesion <50% of the total lesion size compared to those with an active CNV lesion >=50% of the total lesion size was observed for patients both treated with VTE2Q8 and V®-PDT (table 1).

TABLE-US-00002 TABLE 1 Efficacy outcome for VTE2Q8 and V ®-PDT in patients with active CNV lesion size <50% and >=50% of total lesion size at week 28 VTE2Q8 Active CNV V ®-PDT Active CNV lesion Active CNV Active CNV Efficacy parameter (unit) lesion <50%* >=50%* lesion <50%* lesion >=50%* Mean change of BCVA (letters) 16.7 12.7 8.0 1.5 Proportion of patients who maintained 97.4 99.3 92.9 91.7 vision (letter loss <15 letters) (%) Proportion of patients who gained 5 or 85.9 77.6 50.0 41.7 more letters (%) Proportion of patients who gained 10 73.1 66.7 32.1 27.1 or more letters (%) Proportion of patients who gained 15 57.7 45.6 25.0 12.5 or more letters (%) Proportion of patients who lost 5 or 5.1 6.8 17.9 31.3 more letters (%) Proportion of patients who lost 10 or 3.8 2.7 14.3 18.8 more letters (%) Proportion of patients who lost 15 or 2.6 0.7 7.1 8.3 more letters (%) Mean change in central retinal −180.6 −180.4 −109.5 −91.6 thickness (um) Mean change in CNV lesion size −0.688 −1.009 −0.286 −0.201 (mm.sup.2) *Active CNV lesion of total lesion size

TABLE-US-00003 TABLE 2 Efficacy outcome for VTE2Q8 and V ®-PDT in patients with active CNV lesion size <50% and >=50% of total lesion size at week 52 VTE2Q8 Active CNV V ®-PDT Active CNV lesion Active CNV Active CNV Efficacy parameter (unit) lesion <50%* >=50%* lesion <50%* lesion >=50%* Mean change of BCVA (letters) 18.1 14.0 13.4 6.4 Proportion of patients who maintained 96.2 98.0 96.4 87.5 vision (letter loss <15 letters) (%) Proportion of patients who gained 5 or 88.5 78.9 67.9 60.4 more letters (%) Proportion of patients who gained 10 78.2 67.3 57.1 50.0 or more letters (%) Proportion of patients who gained 15 69.2 53.1 46.4 39.6 or more letters (%) Proportion of patients who lost 5 or 6.4 8.2 21.4 29.2 more letters (%) Proportion of patients who lost 10 or 3.8 4.1 10.7 16.7 more letters (%) Proportion of patients who lost 15 or 3.8 2.0 3.6 12.5 more letters (%) Mean change in central retinal −185.5 −192.1 −176.0 −166.6 thickness (um) Mean change in CNV lesion size −0.688 −1.173 −0.286 −1.213 (mm.sup.2) *Active CNV lesion of total lesion size

DESCRIPTION OF THE FIGURES

[0077] FIG. 1/2: Mean change from baseline in ETDRS BCVA letter score by visit in subjects with an active CNV lesion >50% of total lesion size at baseline. The mean change in BCVA score (no. of letters) as measured by ETDRS from baseline at week 1 (V3) week 4 (V4), week 8 (V5), week 12 (V6), week 16 (V7), week 20 (V8), week 24 (V9), week 28 (V10), Week 32 (Visit 11), Week 36 (Visit 12), Week 40 (Visit 13), Week 44 (visit 14), Week 28 (Visit 15), Week 52 (Visit 16) is shown for the VTE2Q8 group (solid line with diamonds) and the PDT->VTE group (dashed line with squares). At week 28 (V10) the mean change in BCVA score from baseline is 12.7 for the VTE2Q8 group and 1.5 for the PDT->VTE group. At week 52, the mean change in BCVA score from baseline is 14.0 for the VTE2Q8 group and 6.4 for the PDT->VTE group.

[0078] FIG. 2/2: Mean change from baseline in ETDRS BCVA letter score by visit in subjects with an active CNV lesions <50% of total lesion size at baseline. The mean change in BCVA score (no. of letters) as measured by ETDRS from baseline at week 1 (V3) week 4 (V4), week 8 (V5), week 12 (V6), week 16 (V7), week 20 (V8), week 24 (V9), week 28 (V10), Week 32 (Visit 11), Week 36 (Visit 12), Week 40 (Visit 13), Week 44 (visit 14), Week 28 (Visit 15), Week 52 (Visit 16) is shown for the VTE2Q8 group (solid line with diamonds) and the PD->VTET group (dashed line with squares). At week 28 (V10) the mean change in BCVA score from baseline is 16.7 for the VTE2Q8 group and 8.0 for the PDT->VTE group. At week 52 (V10) the mean change in BCVA score from baseline is 18.1 for the VTE2Q8 group and 13.4 for the PDT->VTE group.