14 CLINICAL STUDIES

Unless otherwise noted, visual acuity was measured at a distance of 4 meters.

14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of ranibizumab were assessed in three randomized, double-masked, sham- or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (ranibizumab 879, control 444) were enrolled in the three studies.

Studies AMD-1 and AMD-2

In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with ranibizumab in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24.

In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly ranibizumab 0.3 mg intravitreal injections and sham PDT; 2) monthly ranibizumab 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active PDT. Sham PDT (or active PDT) was given with the initial ranibizumab (or sham) intravitreal injection and every 3 months thereafter if FA showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with ranibizumab in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all ranibizumab-treated patients (approximately 95%) maintained their visual acuity. Among ranibizumab-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in Table 3, Table 4, and Figure 1 below.

Table 3 Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-1
Outcome Measure	Month	Sham n=229	Ranibizumab 0.5 mg n=230	Estimated Difference (95% CI) *
* Adjusted estimate based on the stratified model; p < 0.01
Loss of <15 letters in visual acuity (%)	12	60%	91%	30% (23%, 37%)
Loss of <15 letters in visual acuity (%)	24	56%	89%	33% (26%, 41%)
Gain of ≥15 letters in visual acuity (%)	12	6%	31%	25% (18%, 31%)
Gain of ≥15 letters in visual acuity (%)	24	4%	30%	25% (18%, 31%)
Mean change in visual acuity (letters) (SD)	12	-11.0 (17.9)	+6.3 (14.1)	17.1 (14.2, 20.0)
Mean change in visual acuity (letters) (SD)	24	-15.0 (19.7)	+5.5 (15.9)	20.1 (16.9, 23.4)

Table 4 Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-2
Outcome Measure	Month	PDT n=141	Ranibizumab 0.5 mg n=139	Estimated Difference (95% CI) *
* Adjusted estimate based on the stratified model; p < 0.01
Loss of <15 letters in visual acuity (%)	12	66%	98%	32% (24%, 40%)
Loss of <15 letters in visual acuity (%)	24	65%	93%	28% (19%, 37%)
Gain of ≥15 letters in visual acuity (%)	12	11%	37%	26% (17%, 36%)
Gain of ≥15 letters in visual acuity (%)	24	9%	37%	29% (20%, 39%)
Mean change in visual acuity (letters) (SD)	12	-8.5 (17.8)	+11.0 (15.8)	19.8 (15.9, 23.7)
Mean change in visual acuity (letters) (SD)	24	-9.1 (18.7)	+10.9 (17.3)	20 (16.0, 24.4)

* Visual acuity was measured at a distance of 2 meters
Figure 1 Mean Change in Visual Acuity *from Baseline to Month 24 in Study AMD-1 and Study AMD-2

AMD-1		AMD-2
	Ranibizumab 0.5 mg (n=240)		Ranibizumab 0.5 mg (n=139)
	Sham (n=238)		Verteporfin PDT (n=143)

Patients in the group treated with ranibizumab had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas (DA) for ranibizumab versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for ranibizumab versus 2.9-3.1 DA for the control arms.

Study AMD-3

Study AMD-3 was a randomized, double-masked, sham-controlled, 2-year study designed to assess the safety and efficacy of ranibizumab in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for three consecutive doses, followed by a dose administered once every 3 months for 9 months. A total of 184 patients were enrolled in this study (ranibizumab 0.3 mg, 60; ranibizumab 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with ranibizumab in Study AMD-3 received a mean of six total treatments out of a possible 6 from Day 0 through Month 12.

In Study AMD-3, the primary efficacy endpoint was the mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every 3 months with ranibizumab lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all ranibizumab-treated patients (90%) lost fewer than 15 letters of visual acuity at Month 12.

Figure 2 Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3

	Ranibizumab 0.5 mg (n=61)
	Sham (n=63)

Study AMD-4

Study AMD-4 was a randomized, double-masked, active treatment-controlled, two-year study designed to assess the safety and efficacy of ranibizumab 0.5 mg administered monthly or less frequently than monthly in patients with neovascular AMD. Patients randomized to the ranibizumab 0.5 mg less frequent dosing arm received three monthly doses followed by monthly assessments where patients were eligible to receive ranibizumab injections guided by pre-specified re-treatment criteria. A total of 550 patients were enrolled in the two 0.5 mg treatment groups with 467 (85%) completing through Month 24. Data are available through Month 24.

Clinical results at Month 24 remain similar to that observed at Month 12.

From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm (see Figure 3). Over this 21-month period, patients in the 0.5 mg less frequent dosing and the 0.5 mg monthly arms averaged 10.3 and 18.5 injections, respectively. The distribution of injections received in the less frequent dosing arm is shown in Figure 4.

Figure 3 Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-4

	Ranibizumab 0.5 mg Monthly (n=275)
	Ranibizumab 0.5 mg Less Frequent than Monthly (n=275)

Figure 4
Distribution of Injections from Month 3 to Month 24 in the Less Frequent Dosing Arm in Study AMD-4

14.2 Macular Edema Following Retinal Vein Occlusion (RVO)

The safety and efficacy of ranibizumab were assessed in two randomized, double-masked, 1-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (ranibizumab 0.3 mg, 266 patients; ranibizumab 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive ranibizumab injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12.

In Study RVO-1, patients with macular edema following branch or hemi-RVO, received monthly ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 6-month treatment period. Macular focal/grid laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg ranibizumab and 71 of 132 (54%) patients treated with sham.

In Study RVO-2, patients with macular edema following central RVO received monthly ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months.

At Month 6, after monthly treatment with 0.5 mg ranibizumab, the following clinical results were observed:

Table 5 Visual Acuity Outcomes at Month 6 in Study RVO-1 and Study RVO-2
Outcome Measure	Study *	Sham	Ranibizumab 0.5 mg	Estimated Difference (95% CI) †
* RVO-1: Sham, n=131; Ranibizumab 0.5 mg, n=132 RVO-2: Sham, n=130; Ranibizumab 0.5 mg, n=130 † Adjusted estimate based on stratified model; p < 0.01
Gain of ≥15 letters in visual acuity (%)	RVO-1	29%	61%	31% (20%, 43%)
Gain of ≥15 letters in visual acuity (%)	RVO-2	17%	48%	30% (20%, 41%)

Figure 5 Mean Change in Visual Acuity from Baseline to Month 6 in Study RVO-1 and Study RVO-2

		RVO-1:	RVO-2:
		Ranibizumab 0.5 mg (n=131)	Ranibizumab 0.5 mg (n=130)
		Sham (n=132)	Sham (n=130)
	p < 0.01 for all time points

14.3 Myopic Choroidal Neovascularization (mCNV)

The efficacy and safety data of ranibizumab were assessed in a randomized, double-masked, active-controlled 3- month study in patients with mCNV. Patients age ranged from 18 to 87 years, with a mean age of 55 years. A total of 276 patients (222 patients in the ranibizumab treated Groups I and II; 55 patients in the active control PDT group) were enrolled. Patients randomized to the ranibizumab groups received injections guided by pre- specified re-treatment criteria. The retreatment criteria in Group I were vision stability guided, with the Best Corrected Visual Acuity (BCVA) at the current visit being assessed for changes compared with the two preceding monthly BCVA values. The retreatment criteria in Group II were disease activity guided, based on BCVA decrease from the previous visit that was attributable to intra- or sub-retinal fluid or active leakage secondary to mCNV as assessed by OCT and/or FA compared to the previous monthly visit.

Visual gains for the two ranibizumab 0.5 mg treatment arms were superior to the active control arm. The mean change in BCVA from baseline at Month 3 was: +12.1 letters for Group I, +12.5 letters for Group II and +1.4 letters for the PDT group. (Figure 6; Table 6). Efficacy was comparable between Group I and Group II.

Table 6 Mean Change in Visual Acuity and Proportion of Patients who Gained ≥15 letters from Baseline at Month 3
Study Arms	Mean change in BCVA from baseline (Letters)		Proportion of patients who gained ≥15 letters from baseline
Study Arms	Mean (SD)	Estimated Difference (95% CI) *	Percent	Estimated Difference (95% CI) *
* Adjusted estimates based on stratified models; p < 0.01
Group I	12.1 (10.2)	10.9 (7.6, 14.3)	37.1	22.6 (9.5, 35.7)
Group II	12.5 (8.8)	11.4 (8.3, 14.5)	40.5	26.0 (13.1, 38.9)
Control (PDT)	1.4 (12.2)		14.5

Figure 6
Mean Change in Visual Acuity from Baseline to Month 3 in mCNV Study

The proportion of patients who gained ≥15 letters (ETDRS) by Month 3 was 37.1% and 40.5% for ranibizumab Groups I and II, respectively and 14.5% for the PDT group. The mean number of injections between baseline and Month 3 was 2.5 and 1.8 for Groups I and II, respectively. 41% of patients received 1, 2 or 3 injections between baseline and Month 3 with no injections afterwards.