**8. New anti VEGF agents under investigation**

### **8.1. RNA Interference (SIRNA)**

lar in the ranibizumab-treated patients (4.7%) and in the bevacizumab-treated patients 5.0%; (*P* = 0.89). Venous thrombotic events occurred in 3 (0.5%) ranibizumab-treated patients and

One or more serious systemic adverse events occurred in 255 patients (21.5%), with 53 (17.6%) in the ranibizumab-monthly group, 64 (22.4%) in the bevacizumab-monthly group, 61 (20.5%) in the ranibizumab-as-needed group, and 77 (25.7%) in the bevacizu‐ mab-as-needed group (P = 0.11 by the chi-square test). Hospitalizations accounted for 298 of the 370 individual serious systemic adverse events (80.5%). When dosing-regimen groups were combined, the proportions of patients with serious systemic adverse events were 24.1% for bevacizumab and 19.0% for ranibizumab (P = 0.04). After adjustment for demographic features and coexisting illnesses at baseline, the risk ratio for bevacizumab, as compared with ranibizumab, was 1.29 (95% confidence interval, 1.01 to 1.66; P = 0.04). Patients treated as needed had higher rates than patients treated monthly (risk ratio, 1.20; 95% CI, 0.98 −1.47; *P* =0.08). After excluding all events previously associated with systemic treatment with anti–vascular endothelial growth factor drugs, 170 (28.4%) of ra‐ nibizumab-treated patients and 202 (34.5%) of bevacizumab-treated patients had experi‐

Although event rates for these cerebrovascular or cardiovascular events seem to be low with ranibizumab, ophthalmologists should ensure that patients understand the theoretic poten‐ tial for these risks. Additional studies over time may help to refine understanding of the

In the recently published IVAN trial at 12 months, 6 participants (1.9%) in the ranibizu‐ mab group and 5 (1.7%) in the bevacizumab group (*P* = 0.81) had died; 5 (1.6%) had re‐ ceived continuous and 6 (2.0%) discontinuous treatment (*P* = 0.74) [52]. Fewer participants treated with bevacizumab compared with ranibizumab had an arteriothrom‐ botic event or heart failure (0.7% vs. 2.9%; odds ratio, 0.23; 95% CI, 0.05to 1.07; *P* = 0.03), but no difference between treatment regimens was found (*P* = 0.34). One or more serious systemic adverse events occurred in 30 (9.6%) in the ranibizumab group and 37 (12.5%) in the bevacizumab group (*P* = 0.25). Similarly, 30 (9.7%) in the continuous and 7 (12.3%) in the discontinuous group had ≥1 serious systemic adverse events (*P* = 0.32). More than 10 participant-specific events occurred in 3 MedDRA categories: cardiac disorders, surgi‐ cal or medical procedure, and any other class (available at http://aaojournal.org). Com‐ parisons by drug and regimen for cardiac disorders and surgical or medical procedure showed no differences (*P*≥0.46). One case of severe uveitis developed after 1 injection; there was 1 reported traumatic cataract and 3 retinal pigment epithelial tears. Five "oth‐

Data on the safety of intravitreal bevacizumab are more limited than data on Ranibizumab safety, due to the lack of large multicenter trials performed with Bevacizumab. The results

in 10 (1.7%) bevacizumab-treated patients (*P* = 0.054) [51].

180 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

enced events (*P* = 0.02) [51].

magnitude, if any, of this risk.

er" ocular events were each reported once.

of the CATT and IVAN trials were previously presented.

**7.1. Safety of Bevacizumab**

SIRNA stands for short interfering RNA. SIRNAs are 21 to 25 nucleotide-long double-stranded RNA molecules capable of destroying a corresponding target messenger RNA with high selec‐ tivity and efficacy [71]. This leads to post transcriptional gene silencing (PTGS).

SIRNAs work intracellularly, where they are incorporated into a protein complex called RNA-induced silencing complex (RISC) [71]. The RISC has RNA helicase activity, which un‐ winds the two strands of RNA. The strand of the siRNA that becomes associated to the RISC leads the complex to selectively cleave and degrade messenger RNA molecules containing a complementary sequence. The siRNA is engineered to match the protein encoding nucleo‐ tide sequence of the target messenger RNA. Since the translation of messenger RNA into proteins is an amplification step, destroying it is a very potent method of inhibiting protein function.

SIRNA-027 (SIRNA Therapeutics, Inc.) is a short interfering RNA that targets the VEGF re‐ ceptor 1 (VEGFR-1).Animal experiments have shown that both intravitreous and periocular injections of siRNA directed against VEGFR1 lead to a substantial reduction of VEGFR1 messenger RNA levels [71-72].

The siRNA suppressed the development of CNV at rupture sites in Bruch's membrane and de‐ creased retinal neovascularizationin mice with oxygen-induced ischemic retinopathy [72-73].

Acuity Pharmaceuticals has also produced a siRNA called Cand5 or Bevasiranib that targets the messenger RNA of the VEGF protein itself. Animal models have shown prevention of CNV development after laser-induced injury [72].

Bevasiranib sodium was developed for intravitreal administration. Following intravitreal in‐ jection, bevasiranib is well distributed within the eye and localizes to the retina [72, 73].

Preliminary results of Phases I and II clinical trials of bevasiranib have shown promising re‐ sults for the treatment of nvAMD and diabetic macular edema. There are various studies of different phases underway (the COBALT studies although recruitment was stopped). A phase III study evaluating the combination of bevasiranib and ranibizumab in nvAMD (the CARBON study) is currently underway.

The purpose of this study is to compare intravitreal bevasiranib sodium as maintenance therapy for AMD following initiation with three monthly doses of ranibizumab. Preliminary clinical results indicate that the effects of bevasiranib do not appear until six weeks after the initiation of treatment, which suggests that combination therapy with anti VEGF drug might be justified. The late effect of bevasiranib might be linked to its mechanism of action, since bevasiranib inhibits the synthesis of new VEGF, and does not eliminate existing VEGF, a di‐ rect anti-VEGF agent may be required to neutralize VEGF already present in the eye before inhibition of new VEGF synthesis. Preliminary results of the carbon and cobalt studies sug‐ gested that over 30% of patients on combination ranibizumab-bevasiranib achieve an im‐ provement of at least three additional lines of VA than those on ranibizumab alone. The safety and efficacy of this combination awaits the full results of the ongoing clinical trials.

**8.4. Anti inflammatory mediators**

genic factors such as VEGF.

to further define its efficacy profile.

**8.5. AdPEDF - Fovista (GenVec)**

with wet AMD are under way.

As mentioned before, both angiogenic and inflammatory processes are involved in nvAMD, new therapeutics targeting the inflammatory process, besides steroids are being investigated POT-4 (Potentia Pharmaceuticals)- POT-4 [81] is a peptide capable of binding to human complement factor C3 (C3). As C3 is a central component of all known complement activa‐ tion pathways, its inhibition effectively shuts down all downstream complement activation that could otherwise lead to local inflammation, tissue damage and up-regulation of angio‐

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

183

A phase I single escalating dose study [82] has just released its first results, which indicate that POT-4 IVT is safe, and the data accumulated so far support the continued investigation of POT-4 for the treatment of both dry and wet AMD with a larger randomized phase II trial

ARC1905 (Ophthotech Corp.) -ARC1905 [81] is an anti-C5 aptamer, which prevents the for‐ mation of key terminal fragments (C5a and C5b-9) by inhibiting human complement factor C5 (C5). C5a fragment is an important inflammatory activator inducing vascular permeabili‐ ty, recruitment and activation of phagocytes. C5b-9 is involved in the formation of mem‐ brane attack complex (C5b-9), which initiates cell lysis [81]. Thus by inhibiting these C5-

A phase I study [83] to evaluate the safety, tolerability, and pharmacokinetic profile of mul‐ tiple doses of ARC1905 IVT in combination with multiple doses of Lucentis has been com‐

OT-551 (Othera)- OT-551 [84], an Othera Pharmaceuticals' Othera (OT)-551 antioxidant eye drop has the potential for chronic treatment of the dry form of age-related macular degeneration.

A phase I trial [84] demonstrated that when the compound is added to Lucentis or Avastin treat‐ ment, there is a synergistic effect in patients with wet AMD. A pilot study [85] of participants with bilateral geographic atrophy is designed to characterize the effect of 0.45% concentration of

Pigment epithelium-derived factor (PEDF) is one of the most potent antiangiogenic proteins found in humans, which were shown to inhibit VEGF-induced proliferation, migration of microvascular endothelial cells, reduce VEGF-induced hypermeability and cause vessel re‐ gression in established neovascularization [86]. AdPEDF uses a DNA carrier, to deliver the

A phase I escalating-dose clinical trial [87] in patients with nvAMD was completed. Three to six months after a single injection, it suggested that 50–94% of patients had a stabilization or improvement in lesion size from baseline, suggesting that antiangiogenesis may last for sev‐ eral months after a single IVT. there were no dose-limiting toxicities or drug-related severe adverse events reported. Further studies investigating the efficacy of AdPEDF in patients

OT-551 eye drops on the progression of geographic atrophy area over a two-year period.

mediated inflammatory, ARC1905 might be beneficial in wet AMD.

pleted, but the data have not yet been published in a peer-reviewed journal.

PEDF gene, resulting in the local production of AdPEDF in the treated eye.

However, the lack of available data from randomized placebo-controlled or comparative studies makes it difficult to evaluate the role of bevasiranib in nvAMD therapy. It is clear from experimental and preclinical studies that anti-VEGF siRNA is capable of down regulat‐ ing VEGF production, a key goal of anti-VEGF therapy [72].

In summary, bevasiranib exploits an interesting technology [72, 73] and may be a useful ad‐ dition to the currently available drugs used to treat wet AMD.

### **8.2. Tyrosine kinase inhibitors**

VEGF A signals through two VEGF receptors [7, 10]. VEGF R consist of protein-tyrosine kin‐ ases (VEGFR-1, VEGFR-2, and VEGFR-3) and two non-protein kinase coreceptors (neuropi‐ lin-1 and neuropilin-2) [10]. New drugs targeting these tyrosine kinases are being investigated.

Vatalanib (PTK787; Novartis)- Vatalanib [74] is a potent tyrosine kinase inhibitor with good oral bioavailability and activity against the VEGFR family, PDGFRβ and c-Kit receptor kin‐ ases. Preclinical studies [74] suggest that vatalanib induces dose-dependent inhibition of VEGF-induced angiogenesis. A phase I/II trial, ADVANCE [75], to evaluate the safety and efficacy of oral vatalanib combined with PDT with verteporfin in 50 patients has been com‐ pleted, but the data have not yet been published in a peer-reviewed journal.

Pazopanib (GW786034; GlaxoSmithKline)- Pazopanib [76] is a second-generation tyrosine kinase inhibitor against all VEGFR, PDGFRα, PDGFRβ, and c-kit. A phase I clinical trial us‐ ing pazopanib as eye drops in 38 healthy volunteers has successfully demonstrated its safety and tolerability. Subsequently, a phase II trial [77] to evaluate its pharmacodynamics, phar‐ macokinetics and safety has been completed, but the data have not yet been published in a peer-reviewed journal.

#### **8.3. Anti-VEGFR vaccine therapy**

This is an immunologic approach to combat CNV. A recent report demonstrated CD8+ cyto‐ toxic T lymphocyte (CTL)-mediated regression of physiologic and pathologic retinal neovas‐ cularization [78], thus a possible immunologic therapy for CNV was suggested. It was approved by an animal model [79] which showed that CNV can regress by inducing cellular immunity specific for VEGFR-2.

More recently, a phase I study [80] of anti-VEGFR vaccine therapy has been recruiting par‐ ticipants. The patients will be vaccinated once a week for 12 weeks. On each vaccination day, VEGFR-1 peptide (1 mg) and VEGFR-2 peptide (1 mg) mixed with Montanide ISA 51 will be administered by subcutaneous injection. The study will evaluate the safety and toler‐ ability as well as the immunological and clinical response of the vaccine therapy to treat‐ ment of nvAMD.

#### **8.4. Anti inflammatory mediators**

provement of at least three additional lines of VA than those on ranibizumab alone. The safety and efficacy of this combination awaits the full results of the ongoing clinical trials.

However, the lack of available data from randomized placebo-controlled or comparative studies makes it difficult to evaluate the role of bevasiranib in nvAMD therapy. It is clear from experimental and preclinical studies that anti-VEGF siRNA is capable of down regulat‐

In summary, bevasiranib exploits an interesting technology [72, 73] and may be a useful ad‐

VEGF A signals through two VEGF receptors [7, 10]. VEGF R consist of protein-tyrosine kin‐ ases (VEGFR-1, VEGFR-2, and VEGFR-3) and two non-protein kinase coreceptors (neuropi‐ lin-1 and neuropilin-2) [10]. New drugs targeting these tyrosine kinases are being

Vatalanib (PTK787; Novartis)- Vatalanib [74] is a potent tyrosine kinase inhibitor with good oral bioavailability and activity against the VEGFR family, PDGFRβ and c-Kit receptor kin‐ ases. Preclinical studies [74] suggest that vatalanib induces dose-dependent inhibition of VEGF-induced angiogenesis. A phase I/II trial, ADVANCE [75], to evaluate the safety and efficacy of oral vatalanib combined with PDT with verteporfin in 50 patients has been com‐

Pazopanib (GW786034; GlaxoSmithKline)- Pazopanib [76] is a second-generation tyrosine kinase inhibitor against all VEGFR, PDGFRα, PDGFRβ, and c-kit. A phase I clinical trial us‐ ing pazopanib as eye drops in 38 healthy volunteers has successfully demonstrated its safety and tolerability. Subsequently, a phase II trial [77] to evaluate its pharmacodynamics, phar‐ macokinetics and safety has been completed, but the data have not yet been published in a

This is an immunologic approach to combat CNV. A recent report demonstrated CD8+ cyto‐ toxic T lymphocyte (CTL)-mediated regression of physiologic and pathologic retinal neovas‐ cularization [78], thus a possible immunologic therapy for CNV was suggested. It was approved by an animal model [79] which showed that CNV can regress by inducing cellular

More recently, a phase I study [80] of anti-VEGFR vaccine therapy has been recruiting par‐ ticipants. The patients will be vaccinated once a week for 12 weeks. On each vaccination day, VEGFR-1 peptide (1 mg) and VEGFR-2 peptide (1 mg) mixed with Montanide ISA 51 will be administered by subcutaneous injection. The study will evaluate the safety and toler‐ ability as well as the immunological and clinical response of the vaccine therapy to treat‐

pleted, but the data have not yet been published in a peer-reviewed journal.

ing VEGF production, a key goal of anti-VEGF therapy [72].

182 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

dition to the currently available drugs used to treat wet AMD.

**8.2. Tyrosine kinase inhibitors**

investigated.

peer-reviewed journal.

**8.3. Anti-VEGFR vaccine therapy**

immunity specific for VEGFR-2.

ment of nvAMD.

As mentioned before, both angiogenic and inflammatory processes are involved in nvAMD, new therapeutics targeting the inflammatory process, besides steroids are being investigated

POT-4 (Potentia Pharmaceuticals)- POT-4 [81] is a peptide capable of binding to human complement factor C3 (C3). As C3 is a central component of all known complement activa‐ tion pathways, its inhibition effectively shuts down all downstream complement activation that could otherwise lead to local inflammation, tissue damage and up-regulation of angio‐ genic factors such as VEGF.

A phase I single escalating dose study [82] has just released its first results, which indicate that POT-4 IVT is safe, and the data accumulated so far support the continued investigation of POT-4 for the treatment of both dry and wet AMD with a larger randomized phase II trial to further define its efficacy profile.

ARC1905 (Ophthotech Corp.) -ARC1905 [81] is an anti-C5 aptamer, which prevents the for‐ mation of key terminal fragments (C5a and C5b-9) by inhibiting human complement factor C5 (C5). C5a fragment is an important inflammatory activator inducing vascular permeabili‐ ty, recruitment and activation of phagocytes. C5b-9 is involved in the formation of mem‐ brane attack complex (C5b-9), which initiates cell lysis [81]. Thus by inhibiting these C5 mediated inflammatory, ARC1905 might be beneficial in wet AMD.

A phase I study [83] to evaluate the safety, tolerability, and pharmacokinetic profile of mul‐ tiple doses of ARC1905 IVT in combination with multiple doses of Lucentis has been com‐ pleted, but the data have not yet been published in a peer-reviewed journal.

OT-551 (Othera)- OT-551 [84], an Othera Pharmaceuticals' Othera (OT)-551 antioxidant eye drop has the potential for chronic treatment of the dry form of age-related macular degeneration.

A phase I trial [84] demonstrated that when the compound is added to Lucentis or Avastin treat‐ ment, there is a synergistic effect in patients with wet AMD. A pilot study [85] of participants with bilateral geographic atrophy is designed to characterize the effect of 0.45% concentration of OT-551 eye drops on the progression of geographic atrophy area over a two-year period.

#### **8.5. AdPEDF - Fovista (GenVec)**

Pigment epithelium-derived factor (PEDF) is one of the most potent antiangiogenic proteins found in humans, which were shown to inhibit VEGF-induced proliferation, migration of microvascular endothelial cells, reduce VEGF-induced hypermeability and cause vessel re‐ gression in established neovascularization [86]. AdPEDF uses a DNA carrier, to deliver the PEDF gene, resulting in the local production of AdPEDF in the treated eye.

A phase I escalating-dose clinical trial [87] in patients with nvAMD was completed. Three to six months after a single injection, it suggested that 50–94% of patients had a stabilization or improvement in lesion size from baseline, suggesting that antiangiogenesis may last for sev‐ eral months after a single IVT. there were no dose-limiting toxicities or drug-related severe adverse events reported. Further studies investigating the efficacy of AdPEDF in patients with wet AMD are under way.

**9. Conclusion**

ment strategies will be essential.

**Author details**

**References**

and regain vision in this potentially blinding disease.

Shani Golan1,2, Michaella Goldstein1,2 and Anat Loewenstein1,2

1 Department of Ophthalmology Tel Aviv Medical Center, Israel

Louis, USA: Mosby Year Book; 1992. p. 198 – 227.

mology. 2001;108:697 – 704.

Pharmacological Reports, vol. 58, no. 3, pp. 353–363, 2006.

2 Sackler Faculty of Medicine, Tel Aviv University, Tel- Aviv, Israel

[1] Alm A. Ocular circulation. In: Hart WM, editor. Adler's Physiology of the Eye. St

[3] J. Z. Nowak, "Age-related macular degeneration (AMD): pathogenesis and therapy,"

[4] Smith W, Assink J, Klein R, Mitchell P, Klaver CCW,Klein BEK, et al. Risk factors for age-related macular degeneration: Pooled fi ndings from three continents. Ophthal‐

[2] Folkman J, Ingber D. Inhibition of angiogenesis. Semin Cancer Biol. 1992;3:89 – 96.

Over the past decade, the treatment of nvAMD improved dramatically with the discovery of anti-VEGF agents that have enabled patients not only to stabilize the vision but to improve

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

185

With the goal of maximizing VA and minimizing the frequency of intravitreal injections and associated risks of treatment, evidence-based management of wet AMD has evolved into in‐ dividualized anti-VEGF therapy with frequent follow up and retreatment. As a safer and more cost-effective alternative to the traditional monthly treatments used in the ANCHOR and MARINA trials, two individualized anti-VEGF treatment regimens have been descri‐ bed, but neither has been proven superior to date: as-needed (or "PRN") therapy and the treat-and-extend strategy. Despite a paucity of evidence comparing the as-needed versus the treat-and extend treatment regimens, a possibility exists that the treat and extend regimen will prove to be the most efficacious, cost-saving, and preferred protocol. The current evi‐ dence based treatment strategy for the management of wet AMD supports the use of either bevacizumab or ranibizumab either monthly or with a more individualized treatmentstrat‐ egy with close followup. As second generation anti-VEGF agents become available and the stress on our healthcaresystems intensifies, increasingly efficacious and costconscioustreat‐


**Table 1.** Summary of main clinical trials on anti VEGF treatment for AMD
