Safety issues related to the long-term use of VEGF inhibitors

Ophthalmologists must consider safety issues when using anti-vascular endothelial growth factor therapy to treat patients with age-related macular degeneration. The inhibition of anti-vascular endothelial growth factor (VEGF) may be theoretically detrimental because VEGF is involved in necessary physiological processes. Thus, ophthalmologists must become aware of safety issues with anti-VEGF therapy to provide optimum treatment for patients.

VEGF in normal physiological processes

The inhibition of anti-vascular endothelial growth factor (VEGF) may be theoretically detrimental because VEGF is involved in necessary physiological processes.

— Andrew P. Schachat, MD

VEGF is required for normal blood vessel development. In addition, it plays a role in pathologic neovascularization. When ophthalmologists use a drug for VEGF blockade, it is aimed at VEGF’s angiogenic, permeability and inflammatory qualities. But VEGF also influences the branching of vessels, survival of vessels and fenestration. Furthermore, it affects neuroprotection, modulation of thrombosis, vasodilation and flow.

When physiologic mechanisms are blocked by VEGF-inhibiting drugs, it is possible that safety concerns will become apparent. This brief article reviews the potential safety concerns with long-term use of VEGF inhibition.

Mechanism of anti-VEGF drugs

Currently, two VEGF-inhibiting drugs have been approved by the Food and Drug Administration for treatment of choroidal neovascularization in AMD—pegaptanib sodium and ranibizumab. At this time, no safety advantage exists for one over the other.

In addition, the oncology drug bevacizumab, which has VEGF-blocking properties similar to those of ranibizumab, has been used by some physicians in an off- label fashion for treatment of CNV in AMD. Well-known safety concerns with intravenous administration of bevacizumab exist. Safety concerns with off-label intraocular injection of bevacizumab have not become apparent; they are theoretical. But bevacizumab has not been methodically studied in prospective randomized trials as have pegaptanib and ranibizumab for ophthalmic use. Although that information is lacking for bevacizumab, it appears safe at this time.

VEGF exists in a number of isoforms. Pegaptanib selectively blocks certain isoforms such as VEGF¹⁶⁵, whereas ranibizumab and bevacizumab block all known isoforms of VEGF-A. Theoretical safety benefits are associated with more specific VEGF blockade.

In experimental animal studies, VEGF¹⁶⁴ has reached elevated levels in experimental proliferative retinopathy. ^1-3 In humans, VEGF¹⁶⁵, which is basically the same isoform, is also selectively involved in ophthalmic disease.

However, VEGF is also involved in normal vessel development. Regression of normal vasculature has been shown with nonselective VEGF blockade in mice.^4,5Loss of functional blood vessels and reduction in endothelial cells were observed after nonselective VEGF inhibition. VEGF also plays a role in other organ systems and pathologies.^6,7 It seems to have a neuroprotective effect as well, in models of stroke, Alzheimer’s disease and epilepsy.^8-10

Nonselective VEGF blockade may have an effect in some of these systems in humans.

Although doses of VEGF-blocking agents used in the eye are infinitesimal, some systemic exposure to these drugs remains.

— Andrew P. Schachat, MD

Nishijima and colleagues¹¹ investigated the effect of nonselective and VEGF¹⁶⁴-specific blockade on neural cell death in mice. With specific VEGF¹⁶⁴ blockade, the TUNEL assay to identify apoptoptic cell death is similar to the control sample without ischemic insult. With nonselective VEGF blockade, the TUNEL assay indicating apoptosis shows more activity.

VEGF also plays a role as a blood clot modulator through many pathways.¹²

Vessel injury from long-term VEGF inhibition manifests through damage to the choriocapillaris, theoretically appearing as geographic atrophy or subretinal hemorrhage. These effects can be masked by the natural history of AMD. Injury to neural cells in the retina as a result of VEGF inhibition can also be missed, as ganglion cell redundancy can mask visual field defects, especially if central vision is spared.

Systemic cardiovascular factors are of concern in patients with AMD. The risk for cardiovascular events is elevated in patients with neovascular AMD. Heart attacks, high blood pressure, stroke and lipid disorders are more common in patients with neovascular AMD than in other patients.^13,14

Although doses of VEGF-blocking agents used in the eye are infinitesimal, some systemic exposure to these drugs remains.¹⁵ The normal circulating level of VEGF in the blood, 100 pg/mL, is necessary for normal health. A single intravitreal injection of 0.3 mg pegaptanib results in 10 to 100 times more pegaptanib circulating in the bloodstream than VEGF. Case reports have described an effect on neovascularization in the nontreated eye after injection of anti-VEGF agent in one eye only. These drugs are entering the systemic circulation and may have systemic effects.

Bevacizumab

Bevacizumab is administered systemically for treating cancer. The drug label states that intravenous infusion of bevacizumab 5 mg/kg has been associated with systemic hypertension and with elevated rates of arterial thromboembolic events, both cerebrovascular and cardiovascular, compared to controls. Other concerns with systemic administration of the drug include gastrointestinal perforations, nasal septum perforations and reports of reversible posterior leukoencephalopathy, a rare neurological disorder, with an incidence of less than 0.1% in postmarketing experience.

Ranibizumab

In studies of intravitreal injection of ranibizumab, no increase in atherosclerotic or cardiovascular events has been observed compared to control subjects receiving sham injections.

Two large clinical studies of ranibizumab for the treatment of CNV in AMD have been reported.

The MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody RhuFab V2 in the Treatment of Neovascular AMD) study, which included patients with minimally classic or occult with no classic CNV lesions, has reported 1-year and 2-year results.¹⁶

At the 1-year follow-up interval, in patients receiving sham injections or treatment with 0.3 mg or the FDA-approved 0.5-mg dose, no statistically significant difference was seen in the frequency of hypertension; in nonfatal arterial thromboembolic events, whether myocardial infarction or stroke; or in the number of deaths (Figure).

The 2-year MARINA safety data were similar, with no statistically significant differences between groups in serious vascular events, nonocular hemorrhage, systemic immunoreactivity or death (Figure).

In the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) study, in patients with predominantly classic CNV in AMD, similarly, no statistical differences in safety were seen.¹⁷ Risks combined for atherosclerotic thromboembolic events, vascular deaths, nonfatal myocardial infarction and nonfatal hemorrhagic stroke are statistically similar in treatment and sham groups (Figure).

Similarly, the 2-year ANCHOR safety data showed a low rate of serious adverse effects. Nonocular hemorrhage occurred in seven patients, and no safety issues occurred in terms of hypertension.¹⁸

Figure: MARINA and ANCHOR results chart
Figure. MARINA and ANCHOR results show that patients treated with ranibizumab experienced only minimal adverse effects.

Source: Schachat AP

Pegaptanib

Systemic safety data are available for pegaptanib for up to 3 years for 298 patients in the sham treatment group, 596 patients who received pegaptanib in year 1 and 161 patients who received pegaptanib for all 3 years.^19,20 No statistically significant differences occurred between the sham and the two treatment groups in number of deaths, discontinuation due to adverse events, report of hypertension in year 3 or serious hemorrhagic adverse events. In patients treated with pegaptanib throughout the 3 years, mean systolic pressure was approximately 140 mm Hg and mean diastolic pressure was approximately 80 mm Hg at all visits.

No differences were seen between groups in ischemic coronary artery disorders in year 3 including angina, myocardial infarction, myocardial ischemia, age-indeterminate myocardial infarction or acute myocardial infarction. Similarly, no differences between groups were seen in central nervous system hemorrhages and cerebrovascular accidents.

Conclusion

Of the two VEGF-inhibiting drugs approved for treatment of CNV in AMD, ranibizumab has an efficacy advantage over pegaptanib, with a higher number of patients maintaining stable VA, or improving VA. Pegaptanib has a cost advantage and a dose-interval advantage. It is administered every 6 weeks as opposed to every 4 weeks. And it has 3 years of safety compared to 2 years for pegaptanib.

No safety differences are apparent, but theoretical safety benefits are associated with specific blockade of VEGF¹⁶⁵. The results of a trial in which ranibizumab is administered for induction of VEGF inhibition and then the patient is maintained on pegaptanib are not yet available. If the data show that pegaptanib maintains stable vision after ranibizumab induction, then this may be a reasonable treatment strategy.

Regarding the off-label use of bevacizumab, more safety and efficacy data are needed to support a continued role. For the future, longer acting versions of the available drugs or combination strategies may help to decrease the frequency of treatment and increase safety for patients with AMD.

References

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