DRUG USES IN RETINAL DISEASES

Diseases Retinal in Mechanisms and Drugs • 4 section

REDD14NP and Bevasiranib, 027, SIRNA Technology: RNA Interference• 40-Smallchapter

pegaptanib was used. Ranibizumab therapy was allowed later in the study once it was FDA-approved. The following criteria indicated disease progression: (1) loss of 6 lines or greater best corrected visual acuity and lesion growth documented by fluorescein angiography less than 12 weeks following the first bevasiranib injection; or (2) loss of 3 lines or greater of best corrected visual acuity and lesion growth documented by fluorescein angiography at 12 weeks or greater following the first bevasiranib injection. Lesion growth was defined for both groups as growth of 300% or more in lesions less than 2 disc areas, 200% or more for lesions of 2–4 disc areas, and 100% or more for lesions greater than 4 disc areas at baseline.

The intent-to-treat population consisted of all subjects who were randomized to a treatment, regardless of whether they received the assigned study drug. The modified intent-to-treat population consisted of all randomized subjects who received at least one dose of intravitreal bevasiranib. The per-protocol population consisted of all randomized subjects who received two intravitreal bevasiranib injections and returned for at least one follow-up efficacy evaluation following the second dose. If subjects missed a study visit, the last observed carried forward (LOCF) was used for missing values. If rescue therapy was initiated, the LOCF for the visit prior to the rescue therapy was carried forward. Results were considered statistically significant if P < 0.05.

Positive effects of bevasiranib were defined prior to the initiation of the study by stipulating primary and secondary efficacy endpoints. The primary efficacy endpoint was mean best corrected visual acuity change from baseline to 12-week evaluation for the three dose groups. Another primary efficacy endpoint was the percentage and number of eyes with less than 3 lines decrease in best corrected visual acuity (<15-letter decrease) for each dose group at 12 and 18 weeks posttreatment. Secondary efficacy endpoints were: change in total lesion size; choroidal neovascular membrane size; change in classic component and progression of classic component on fluorescein angiography; change in total lesion thickness (consisting of CNV thickness and pigment epithelial detachment thickness measured by OCT); presence or absence of retinal edema; and presence or absence of other architectural changes such as cysts.

BEVASIRANIB FOR NEOVASCULAR MACULAR DEGENERATION: RESULTS

The intent-to-treat population consisted of 129 eyes, the modified intent-to-treat population consisted of 126 eyes, and the per-protocol analysis consisted of 110 eyes which received both intravitreal bevasiranib injections and at least one follow-up visit. The safety analyses were conducted on the 127 eyes which received at least one bevasiranib injection (one eye was treated with bevasiranib but did not return for required follow-up visits). The efficacy analyses were based on the 110 eyes in the per-protocol analysis. The three groups in the per-protocol analysis were well balanced with respect to visual acuity and lesion type. The numbers of eyes with previous treatment for CNV were also similar between groups. Bevasiranib had an excellent safety profile with no cases of endophthalmitis and only one eye in the 3.0-mg group developed uveitis, which resolved with topical steroids. There were no unexpected systemic adverse events related to the drug and prior pharmacokinetic studies showed no detectable systemic absorption of bevasiranib following intravitreal injection.

The primary efficacy outcomes for change in distance vision are plotted in Figure 40.2. There were no statistically significant differences in visual acuity changes between the three dose groups. The other primary efficacy measure was the number of eyes with <3-line decrease in best corrected visual acuity (Table 40.1).

It is important to recall that bevasiranib blocks the production of VEGF from mRNA, but does not destroy VEGF already produced in the cytoplasm and released into the retina. It became apparent from analysis of this phase II data that treatment of the existing VEGF in the retina prior to injection of bevasiranib using a direct VEGF blocker such as ranibizumab, bevacizumab, or pegaptanib may be important since eyes treated with bevasiranib continued to have decreases in visual acuity, especially following the first intravitreal bevasiranib injection.

Time (weeks)

Figure 40.2  The mean distance visual acuity in eyes with choroidal neovascularization declined 1–2 Early Treatment Diabetic Retinopathy Study (ETDRS) lines in all three dose groups after two injections of the small-interference RNA inhibitor bevasiranib at time 0 and 6 weeks, with no statistically significant difference between the three dose groups.

Figure 40.3  The time to rescue therapy which was triggered by vision loss was substantially greater in the higher-dose bevasiranib groups than the lower-dose bevasiranib group, suggesting a longer duration of action at up to 32 weeks following the first bevasiranib injection. This does suggest a dose-related effect of bevasiranib, with higher doses giving more inhibition of vascular endothelial growth factor production.

The time to rescue therapy was shorter (154 days) for eyes treated with the lower-dose (0.2 mg) compared to the higher-dose (1.5 and 3.0 mg) groups, where the median time to rescue therapy was not reached, suggesting that the higher-dose group exhibited more long-term inhibition of CNV (Figure 40.3). This beneficial difference between the higher and lower doses of bevasiranib did not persist when the entire 2-year data set was analyzed.

Bevasiranib was found to be well tolerated with no significant safety concerns up to doses of 3.0 mg/eye at 6-week intervals. The primary endpoints of: (1) mean change in visual acuity; and (2) loss of less than 15 ETDRS letters (3 lines) did not show statistically significant differences between the three groups. There are several explanations for this finding. The first is that the design of the phase II study did not eliminate existing VEGF, which continued to cause vision loss in the early

Diseases Retinal in Mechanisms and Drugs • 4 section

REDD14NP and Bevasiranib, 027, SIRNA Technology: RNA Interference• 40-Smallchapter

a possible latent effect of bevasiranib on DME. At this time, there are no plans to proceed with additional studies to evaluate further the role of bevasiranib in the management of DME. Opko Health is investigating another siRNA compound directed against VEGF which inhibits the angiogenic VEGFA165 isoform but does not inhibit the VEGFA165b antiangiogenic isoform. These compounds have not yet progressed to human clinical trials.

SIRNA-027 FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION

SIRNA-027 is an siRNA which is directed against VEGF receptor 1 rather than VEGF. It showed promising results in preclinical laboratory studies, reducing CNV in mice.35 SIRNA-027 was evaluated in a human phase I trial which was an open-label, dose escalation study of a single intravitreal injection of SIRNA-027. The primary objectives were to study the safety and tolerability of intravitreal SIRNA-027 as well as detecting if the drug was systemically absorbed. The primary efficacy endpoints were changes in visual acuity and macular thickness by OCT. Patients were eligible for the study if they were 50 years or older with subfoveal CNV from AMD of 12 disc areas or less. Any subretinal blood or scarring had to occupy less than 50% of the lesion. The retinal thickness on OCT had to be greater than 250 m. Visual acuity had to be between 20/100 and 20/800 for inclusion. Patients were excluded from the study if CNV was caused by any other ocular or systemic diseases which could interfere with measurements of the efficacy endpoints. Eyes with any standard or experimental therapy for AMD within 3 months of the study were also excluded.

There were 26 eyes divided into five dose groups in the phase I study. The doses of SIRNA-027 varied between 100 and 1600 g (100, 200, 400, 800, 1200, and 1600 g). The ocular and systemic safety of SIRNA-027 was excellent, with most ocular problems related to irritation from the intravitreal injection. There were no serious adverse ocular events and no systemic toxicities were noted. The mean change in visual acuity through 12 weeks is summarized in Figure 40.6. Visual acuity improved in all dose groups tested but there was a tendency for visual acuity to regress toward baseline by 12 weeks (there was only one intravitreal injection at time 0). The mean visual acuity for all dose groups combined is summarized in Figure 40.7, which shows that visual acuity increased to a mean improvement of 6.3 letters by 2 weeks following injection. There was a tendency for visual acuity to deteriorate, but the

Day post injection

Figure 40.6  SIRNA-027, a small-interference RNA directed against vascular endothelial growth factor receptor 1, showed initial mean visual acuity improvements following one intravitreal injection in a dose-ranging study. Visual acuity improvements tended to decrease toward baseline by 80 days following the single injection. The variability in visual acuity results is not surprising since there were only 3–6 eyes in each dose group.

Days post injection

Figure 40.7  The mean visual acuities with SIRNA-027 are plotted, showing the trend toward initial visual acuity improvement by a mean of 6 letters about 2 weeks following injection, followed by decreased vision. There was still a net gain in visual acuity at 80 days.

Figure 40.8  Optical coherence tomography measurements of foveal thickness following intravitreal injection of SIRNA-027 also showed decreases in macular thickness with a trend toward increasing thickness by 80 days following a single injection.

visual acuity had not returned to baseline even by 3 months following injection. Twenty-three percent of eyes gained at least 3 lines or more by 8 weeks following injection and no eyes deteriorated by 3 or more lines. The mean change in foveal thickness by OCT decreased in some groups but not in others, consistent with variability expected in a small sample size of 3–6 eyes per group (Figure 40.8). There was no detectable plasma SIRNA-027, indicating that the drug was not absorbed into the systemic circulation to any measurable degree. Based on the safety data from the phase I study, randomized control studies of SIRNA-027 for neovascular AMD have been conducted by Allergan and Merck. The lack of efficacy and benefits to patients, evaluated through various parameters, has led to discontinuation of further studies with SIRNA-027.

REDD14 NP

REDD14NP is an siRNA that acts via RNA interference to inhibit the expression of the hypoxia-inducible gene, RTP801. Expression of the RTP801 gene is dramatically up-regulated in response to hypoxia and/ or oxidative stress, which leads to the induction of neuronal cell apoptosis. RTP801 is up-regulated in the retina of mice and rats in a model of retinopathy of prematurity, and RTP801 knockout mice exhibited attenuated pathology.36 RTP801 knockout mice also exhibited reduced CNV in a laser-induced model of AMD.