MyVisionTest News Archive
Nov 18, 2009
Safety implications of anti-VEGF therapies
Vascular endothelial growth factor (VEGF) ligands and their receptors are essential for development and for a wide variety of physiologic functions through adulthood, including visual function. Given the ubiquitous physiologic role of VEGF, evaluation of potential safety risks associated with nonspecific inhibition of VEGF-A and other VEGF-related targets is imperative.
Safety of systemically administered Anti–VEGF agents
In some patients treated with systemic anti–VEGF-A agents, inhibition of essential VEGF-A functions has been detrimental to systemic health. VEGF-A is believed to function as a homeostatic factor for blood pressure (BP), and inhibition of this function is thought to increase vascular tension. For example, systemic inhibition of VEGF-A has been associated with an increased risk of arterial thromboembolic events (ATEs) in colorectal cancer patients treated with intravenous bevacizumab (Avastin).
An analysis of 5 randomized controlled trials that evaluated safety of bevacizumab in 1,745 patients with colorectal, breast, and lung cancers demonstrated that the addition of bevacizumab to chemotherapy increased the risk for an ATE (hazard ratio, 2.0) compared with chemotherapy alone. Although the precise role of anti–VEGF-A agents in the development of ATEs is not understood fully, it has been suggested that inhibition of VEGF-A may disrupt the regulated expression of proinflammatory genes that promote arteriovascular disease leading to thrombosis.
Pegaptanib Sodium (Macugen)
Pegaptanib sodium is a 28-base ribonucleic aptamer that binds with high affinity to VEGF-165 and larger isoforms. In the phase 3 VISION clinical trial, intravitreal pegaptanib sodium was well tolerated. Serious ocular AEs associated with pegaptanib sodium in the first year of the VISION were endophthalmitis, traumatic cataract, and retinal detachment, which were attributed to the injection preparation or procedure rather than to the drug itself. No AEs related to systemic VEGF-A inhibition were identified; however, patients with a history or evidence of severe cardiac disease or myocardial infarction (MI) within 6 months and stroke within 1 year before the study were excluded from the VISION trial.
Ranibizumab (Lucentis)
Ranibizumab is a humanized antigen-binding fragment with a broader molecular target profile than pegaptanib sodium, binding to all isoforms of VEGF-A and their biologically active degradation products. Ranibizumab is the first and only FDA-approved treatment for neovascular AMD that improves vision in patients.
In the phase 3 ANCHOR and MARINA trials, intravitreal ranibizumab injections were associated with a low rate of ocular AEs, including endophthalmitis, uveitis, and transient increases in intraocular pressure. In these trials, a slightly increased but still low rate of systemic AEs, such as Antiplatelet Trialists' Collaboration (APTC) ATEs and nonocular hemorrhages, were reported.
Two-year data from the phase 3 MARINA trial showed that the rate of APTC ATEs was 4.6% in both ranibizumab dosage groups compared with 3.8% in the sham injection group, and serious nonocular hemorrhages were reported in 2.1% and 1.3% of patients in the 0.5-mg and 0.3-mg ranibizumab groups, respectively, compared with 0.8% of patients in the sham group.
Low rates of MI and stroke were reported in MARINA and ANCHOR. The rates of MI and stroke for all patients enrolled in MARINA were 1.8% and 1.5%, respectively, and in ANCHOR these were 1.5% and 1.2%, respectively (at the 24-month follow-up). The annual rates of MI and stroke in a general inpatient population are 2.2% and 4.1%, respectively.
A meta-analysis of the systemic safety of intravitreal ranibizumab, based on a pooling of first-year data from MARINA, ANCHOR, PIER, FOCUS, and SAILOR and on second-year data from MARINA, ANCHOR, PIER, and FOCUS showed that overall APTC ATE rates for the total patient population are similar across treatment groups. Further analysis of APTC ATE rates for the aforementioned clinical trials is ongoing.
Bevacizumab (Avasatin)
Bevacizumab is a full-length monoclonal antibody that binds to all isoforms of VEGF-A and its bioactive degradation forms. Bevacizumab targets the same VEGF-A isoforms as ranibizumab and, when administered intravitreally, is detected longer in systemic circulation than intravitreal ranibizumab.
In a small, nonrandomized clinical study, intravenous bevacizumab for the treatment of neovascular AMD resulted in a significant elevation of systolic and diastolic BP, evident at 3 weeks. Although the safety of intravitreal bevacizumab for neovascular AMD has not been investigated in large, randomized, masked clinical trials, retrospective case series evaluating intravitreal bevacizumab have shown that bevacizumab is well tolerated in most patients with neovascular AMD and other retinal and choroidal vascular diseases.
A prospective, nonrandomized clinical study demonstrated the ocular and systemic safety of intravitreal bevacizumab for the treatment of neovascular AMD.
The International Intravitreal Bevacizumab Safety Survey, which collected self-reported safety data from retinal physicians through the Internet between November 2005 and April 2006 from patients from 12 countries, showed that bevacizumab generally was safe: for 5,228 patients, a total of 7,113 injections were reported. The most common potential drug-related ocular AE was inflammation or uveitis (0.14%), and the most common potential drug-related systemic AE was BP elevation (0.21%). The rates of AEs reported in this survey were lower than those reported for ranibizumab in the MARINA and ANCHOR trials, which raises the possibility that self-reporting methods may not be reliable to determine true safety rates.
The safety of intravitreal bevacizumab, as well as its efficacy, compared with ranibizumab currently are being evaluated in the National Eye Institute-sponsored randomized, phase 3 Comparison of AMD Treatment Trials (CATT) Study.
VEGF Trap
VEGF Trap is a soluble fusion protein containing the extracellular sequences for VEGF receptors 1 and 2 that consequently acts as a VEGF decoy receptor. Based on its molecular structure, VEGF Trap has very broad targeting, binding to all VEGF family members. VEGF Trap binds VEGF-A with higher affinity than antibodies (it has an approximately 140-fold higher affinity than that of ranibizumab), which may make it active at lower concentrations and may reduce the frequency of dosing relative to other anti-VEGF agents. It is unclear whether the higher affinity of VEGF Trap for its targets, its relatively broad molecular targeting, and predicted intravitreal half-life will be associated with greater systemic safety risks.
In a randomized, double-masked, escalating-dose, placebo-controlled phase 1 trial of 25 patients with neovascular AMD treated with intravenous VEGF Trap, a dose-dependent increase in hypertension was observed, and the clinical trial and clinical development of systemic VEGF Trap for neovascular AMD were halted. Systemic VEGF Trap no longer is being evaluated for ocular disease.
The CLEAR-IT AMD 1 phase 1 study evaluated intravitreal injection of VEGF Trap (0.15 or 4 mg), which was well tolerated, with no ocular inflammation. In the CLEAR-IT AMD two randomized, controlled phase 2 study of the safety and efficacy of VEGF Trap at different doses and dosing regimens, VEGF Trap also generally was well tolerated, with no drug-related systemic AEs. VIEW 1 and VIEW 2 are ongoing phase 3 trials designed to investigate different dosing intervals of VEGF Trap and should help to elucidate the ocular and systemic safety profiles of VEGF Trap in neovascular AMD patients.
Conclusion
In summary, the specificity of molecular targeting of a therapeutic agent can impact its efficacy and safety profiles: in general, the more broadly acting an agent, the greater is its potential for efficacy, but so, too, is its potential for causing AEs. Two main potential determinants of systemic AEs with intravitreal anti-VEGF therapies include degree of systemic exposure (blood levels) and the degree of systemic anti-VEGF blockade. Data from animal studies suggest that systemic levels after intravitreal injection of 0.5 mg ranibizumab are similar to those after an intravitreal injection of 0.3 mg pegaptanib. However, the exact isoforms that may play a role in maintaining systemic tissue health are unknown. Therefore, it is reasonable to hypothesize that a more selective VEGF blocker (such as pegaptanib) may elicit fewer systemic side effects than a pan-VEGF blocker (such as ranibizumab).
The systemic safety of VEGF-targeted therapies currently is under investigation, with predominantly circumstantial evidence from clinical trials linking VEGF inhibition to systemic AEs. Additional data are needed to ascertain whether intravitreal administration of more broadly targeted antiangiogenic agents is associated more frequently with systemic AEs than the intravitreal administration of more VEGF isoform-selective agents.
Read more...
Am J Ophthalmol. 2009 Nov;148(5):647-56
Vascular endothelial growth factor (VEGF) ligands and their receptors are essential for development and for a wide variety of physiologic functions through adulthood, including visual function. Given the ubiquitous physiologic role of VEGF, evaluation of potential safety risks associated with nonspecific inhibition of VEGF-A and other VEGF-related targets is imperative. Safety of systemically administered Anti–VEGF agents
An analysis of 5 randomized controlled trials that evaluated safety of bevacizumab in 1,745 patients with colorectal, breast, and lung cancers demonstrated that the addition of bevacizumab to chemotherapy increased the risk for an ATE (hazard ratio, 2.0) compared with chemotherapy alone. Although the precise role of anti–VEGF-A agents in the development of ATEs is not understood fully, it has been suggested that inhibition of VEGF-A may disrupt the regulated expression of proinflammatory genes that promote arteriovascular disease leading to thrombosis.
Pegaptanib Sodium (Macugen)
Pegaptanib sodium is a 28-base ribonucleic aptamer that binds with high affinity to VEGF-165 and larger isoforms. In the phase 3 VISION clinical trial, intravitreal pegaptanib sodium was well tolerated. Serious ocular AEs associated with pegaptanib sodium in the first year of the VISION were endophthalmitis, traumatic cataract, and retinal detachment, which were attributed to the injection preparation or procedure rather than to the drug itself. No AEs related to systemic VEGF-A inhibition were identified; however, patients with a history or evidence of severe cardiac disease or myocardial infarction (MI) within 6 months and stroke within 1 year before the study were excluded from the VISION trial.
Ranibizumab (Lucentis)
Ranibizumab is a humanized antigen-binding fragment with a broader molecular target profile than pegaptanib sodium, binding to all isoforms of VEGF-A and their biologically active degradation products. Ranibizumab is the first and only FDA-approved treatment for neovascular AMD that improves vision in patients.
In the phase 3 ANCHOR and MARINA trials, intravitreal ranibizumab injections were associated with a low rate of ocular AEs, including endophthalmitis, uveitis, and transient increases in intraocular pressure. In these trials, a slightly increased but still low rate of systemic AEs, such as Antiplatelet Trialists' Collaboration (APTC) ATEs and nonocular hemorrhages, were reported.
Two-year data from the phase 3 MARINA trial showed that the rate of APTC ATEs was 4.6% in both ranibizumab dosage groups compared with 3.8% in the sham injection group, and serious nonocular hemorrhages were reported in 2.1% and 1.3% of patients in the 0.5-mg and 0.3-mg ranibizumab groups, respectively, compared with 0.8% of patients in the sham group.
Low rates of MI and stroke were reported in MARINA and ANCHOR. The rates of MI and stroke for all patients enrolled in MARINA were 1.8% and 1.5%, respectively, and in ANCHOR these were 1.5% and 1.2%, respectively (at the 24-month follow-up). The annual rates of MI and stroke in a general inpatient population are 2.2% and 4.1%, respectively.
A meta-analysis of the systemic safety of intravitreal ranibizumab, based on a pooling of first-year data from MARINA, ANCHOR, PIER, FOCUS, and SAILOR and on second-year data from MARINA, ANCHOR, PIER, and FOCUS showed that overall APTC ATE rates for the total patient population are similar across treatment groups. Further analysis of APTC ATE rates for the aforementioned clinical trials is ongoing.
Bevacizumab (Avasatin)
Bevacizumab is a full-length monoclonal antibody that binds to all isoforms of VEGF-A and its bioactive degradation forms. Bevacizumab targets the same VEGF-A isoforms as ranibizumab and, when administered intravitreally, is detected longer in systemic circulation than intravitreal ranibizumab.
In a small, nonrandomized clinical study, intravenous bevacizumab for the treatment of neovascular AMD resulted in a significant elevation of systolic and diastolic BP, evident at 3 weeks. Although the safety of intravitreal bevacizumab for neovascular AMD has not been investigated in large, randomized, masked clinical trials, retrospective case series evaluating intravitreal bevacizumab have shown that bevacizumab is well tolerated in most patients with neovascular AMD and other retinal and choroidal vascular diseases.
A prospective, nonrandomized clinical study demonstrated the ocular and systemic safety of intravitreal bevacizumab for the treatment of neovascular AMD.
The International Intravitreal Bevacizumab Safety Survey, which collected self-reported safety data from retinal physicians through the Internet between November 2005 and April 2006 from patients from 12 countries, showed that bevacizumab generally was safe: for 5,228 patients, a total of 7,113 injections were reported. The most common potential drug-related ocular AE was inflammation or uveitis (0.14%), and the most common potential drug-related systemic AE was BP elevation (0.21%). The rates of AEs reported in this survey were lower than those reported for ranibizumab in the MARINA and ANCHOR trials, which raises the possibility that self-reporting methods may not be reliable to determine true safety rates.
The safety of intravitreal bevacizumab, as well as its efficacy, compared with ranibizumab currently are being evaluated in the National Eye Institute-sponsored randomized, phase 3 Comparison of AMD Treatment Trials (CATT) Study.
VEGF Trap
VEGF Trap is a soluble fusion protein containing the extracellular sequences for VEGF receptors 1 and 2 that consequently acts as a VEGF decoy receptor. Based on its molecular structure, VEGF Trap has very broad targeting, binding to all VEGF family members. VEGF Trap binds VEGF-A with higher affinity than antibodies (it has an approximately 140-fold higher affinity than that of ranibizumab), which may make it active at lower concentrations and may reduce the frequency of dosing relative to other anti-VEGF agents. It is unclear whether the higher affinity of VEGF Trap for its targets, its relatively broad molecular targeting, and predicted intravitreal half-life will be associated with greater systemic safety risks.
In a randomized, double-masked, escalating-dose, placebo-controlled phase 1 trial of 25 patients with neovascular AMD treated with intravenous VEGF Trap, a dose-dependent increase in hypertension was observed, and the clinical trial and clinical development of systemic VEGF Trap for neovascular AMD were halted. Systemic VEGF Trap no longer is being evaluated for ocular disease.
The CLEAR-IT AMD 1 phase 1 study evaluated intravitreal injection of VEGF Trap (0.15 or 4 mg), which was well tolerated, with no ocular inflammation. In the CLEAR-IT AMD two randomized, controlled phase 2 study of the safety and efficacy of VEGF Trap at different doses and dosing regimens, VEGF Trap also generally was well tolerated, with no drug-related systemic AEs. VIEW 1 and VIEW 2 are ongoing phase 3 trials designed to investigate different dosing intervals of VEGF Trap and should help to elucidate the ocular and systemic safety profiles of VEGF Trap in neovascular AMD patients.
Conclusion
In summary, the specificity of molecular targeting of a therapeutic agent can impact its efficacy and safety profiles: in general, the more broadly acting an agent, the greater is its potential for efficacy, but so, too, is its potential for causing AEs. Two main potential determinants of systemic AEs with intravitreal anti-VEGF therapies include degree of systemic exposure (blood levels) and the degree of systemic anti-VEGF blockade. Data from animal studies suggest that systemic levels after intravitreal injection of 0.5 mg ranibizumab are similar to those after an intravitreal injection of 0.3 mg pegaptanib. However, the exact isoforms that may play a role in maintaining systemic tissue health are unknown. Therefore, it is reasonable to hypothesize that a more selective VEGF blocker (such as pegaptanib) may elicit fewer systemic side effects than a pan-VEGF blocker (such as ranibizumab).
The systemic safety of VEGF-targeted therapies currently is under investigation, with predominantly circumstantial evidence from clinical trials linking VEGF inhibition to systemic AEs. Additional data are needed to ascertain whether intravitreal administration of more broadly targeted antiangiogenic agents is associated more frequently with systemic AEs than the intravitreal administration of more VEGF isoform-selective agents.
Read more...
Am J Ophthalmol. 2009 Nov;148(5):647-56
