Byooviz (Page 4 of 6)

12.3 Pharmacokinetics

In patients with neovascular AMD, following monthly intravitreal administration of 0.5 mg ranibizumab, mean (±SD) maximum ranibizumab serum concentrations were 1.7 (± 1.1) ng/mL. These concentrations were below the concentration range of ranibizumab (11 to 27 ng/mL) that was necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay (based on human umbilical vein endothelial cells (HUVEC)). No significant change from baseline was observed in the mean plasma VEGF concentrations following three monthly 0.5 mg intravitreal injections. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 2 mg/eye. Serum ranibizumab concentrations in RVO patients were similar to those observed in neovascular AMD patients.

Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations are predicted to be reached at approximately 1 day after monthly intravitreal administration of ranibizumab 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations.

In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab products. Based on the anti-VEGF mechanism of action of ranibizumab products, treatment with ranibizumab products may pose a risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3) ].

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	Ranibizumab0.5 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%)
	24	56%	89%	33%(26%, 41%)
Gain of ≥15 letters in visual acuity (%)	12	6%	31%	25%(18%, 31%)
	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)
	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	PDTn=141	Ranibizumab0.5 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%)
	24	65%	93%	28%(19%, 37%)
Gain of ≥15 letters in visual acuity (%)	12	11%	37%	26%(17%, 36%)
	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)
	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
(click image for full-size original)
AME-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
(click image for full-size original)
	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
(click image for full-size original)
	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

(click image for full-size original)