Ziv-aflibercept may provide another anti-VEGF treatment option

The drug may be a safe, low-cost alternative to treat macular diseases in developing countries and countries that do not have access to aflibercept.

Anti-VEGF therapy has become one of the most common treatments in the field of retinal diseases. Indications for anti-VEGF therapy are expanding every day, ranging from FDA-approved indications such as diabetic macular edema, macular edema secondary to central retinal vein occlusion and wet age-related macular degeneration to non-FDA-approved indications such as Coats’ disease, retinopathy of prematurity and non-AMD choroidal neovascularization.

The biggest burden to the health care system is the cost of this medication and associated expenses, and Avastin (bevacizumab, Genentech) is still more commonly used in practice compared with Lucentis (ranibizumab, Genentech), primarily due to its low cost. According to the 2014 annual Preferences and Trends Survey by the American Society of Retina Specialists, 64.5% of U.S. retina specialists and 41.7% of international retina specialists choose compounded bevacizumab as their primary therapy for neovascular AMD. Switching to a cheaper anti-VEGF agent such as bevacizumab may save almost $29 billion over a 10-year period, according to an analysis by Hutton and colleagues.

Eylea (aflibercept, Regeneron) is a recently approved anti-VEGF therapy for AMD, CRVO and DME. It is a recombinant fusion protein that acts as soluble decoy receptors that bind VEGF and placental growth factor. Aflibercept is gaining popularity for cases that are resistant to other anti-VEGF agents with slightly more benefit in terms of visual gain. Unfortunately, ranibizumab ($1,950 per dose) and aflibercept ($1,850 per dose) are expensive, and the latter is not yet available in many countries, including India.

Ziv-aflibercept

Zaltrap (ziv-aflibercept, Regeneron) is similar to aflibercept. It was approved by the FDA in August 2012 for the treatment of metastatic colorectal carcinoma that is resistant to or has progressed following an oxaliplatin-containing chemotherapeutic regimen. Although structurally identical to intravitreal aflibercept, ziv-aflibercept has a much higher osmolarity. There are concerns that intravitreal injections of ziv-aflibercept solution may be toxic to the retina or uveal tract. Aflibercept is an iso-osmotic solution (300 mOsm/kg), whereas ziv-aflibercept is more concentrated (1,000 mOsm/kg). Animal studies have shown that solutions of less than 500 mOsm cause no retinal pigment epithelium damage. However, 1.25 mg in 0.05 mL of intravitreal ziv-aflibercept achieves vitreous osmolarity of 324 mOsm/kg to 342 mOsm/kg, which is within normal range.

Laboratory studies showed no cytotoxic effects when ARPE-19 cells were exposed to twice the clinical dose of ziv-aflibercept. However, a significant reduction in mitochondrial membrane potential has been shown with a clinical dose of ziv-aflibercept (2 mg in 4 mL of vitreous), although toxicity to Müller cells was not reported. Bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses. Mansour and colleagues suggested that the safety of intravitreal ziv-aflibercept may be attributed to its dilution after injection into 4 mL of vitreous to a final osmolarity of 312 mOsm/kg (within the physiologic range).

Early safety study

In our study, we administered this drug intravitreally (1.25 mg/0.05 mL) in 12 eyes of 12 patients. We evaluated these eyes on day 1, day 7 and day 30 after injection. None of the eyes showed any signs of toxicity on clinical examination during the postoperative period up to 1 month. On electroretinographic studies, we did not find any significant change compared with baseline, suggestive of no functional damage after a single intravitreal injection.

None of the eyes showed any changes in the vitreomacular interface on OCT as signs of toxicity. None of the patients experienced serious ocular or systemic adverse events. In terms of visual gain, among our 12 eyes, visual acuity improved in six eyes, remained the same in five eyes and decreased by one line in one eye. We concluded that the single intravitreal injection of ziv-aflibercept into eyes with neovascular AMD appears to be safe through 1 month.

Ziv-aflibercept may be a safe, low-cost alternate therapy for macular diseases in developing countries and countries where intravitreal aflibercept is not available. The safety of multiple injections with longer follow-up needs to be evaluated further.

Disclosure: Chhablani reports no relevant financial disclosures.

Anti-VEGF therapy has become one of the most common treatments in the field of retinal diseases. Indications for anti-VEGF therapy are expanding every day, ranging from FDA-approved indications such as diabetic macular edema, macular edema secondary to central retinal vein occlusion and wet age-related macular degeneration to non-FDA-approved indications such as Coats’ disease, retinopathy of prematurity and non-AMD choroidal neovascularization.

The biggest burden to the health care system is the cost of this medication and associated expenses, and Avastin (bevacizumab, Genentech) is still more commonly used in practice compared with Lucentis (ranibizumab, Genentech), primarily due to its low cost. According to the 2014 annual Preferences and Trends Survey by the American Society of Retina Specialists, 64.5% of U.S. retina specialists and 41.7% of international retina specialists choose compounded bevacizumab as their primary therapy for neovascular AMD. Switching to a cheaper anti-VEGF agent such as bevacizumab may save almost $29 billion over a 10-year period, according to an analysis by Hutton and colleagues.

Eylea (aflibercept, Regeneron) is a recently approved anti-VEGF therapy for AMD, CRVO and DME. It is a recombinant fusion protein that acts as soluble decoy receptors that bind VEGF and placental growth factor. Aflibercept is gaining popularity for cases that are resistant to other anti-VEGF agents with slightly more benefit in terms of visual gain. Unfortunately, ranibizumab ($1,950 per dose) and aflibercept ($1,850 per dose) are expensive, and the latter is not yet available in many countries, including India.

Ziv-aflibercept

Zaltrap (ziv-aflibercept, Regeneron) is similar to aflibercept. It was approved by the FDA in August 2012 for the treatment of metastatic colorectal carcinoma that is resistant to or has progressed following an oxaliplatin-containing chemotherapeutic regimen. Although structurally identical to intravitreal aflibercept, ziv-aflibercept has a much higher osmolarity. There are concerns that intravitreal injections of ziv-aflibercept solution may be toxic to the retina or uveal tract. Aflibercept is an iso-osmotic solution (300 mOsm/kg), whereas ziv-aflibercept is more concentrated (1,000 mOsm/kg). Animal studies have shown that solutions of less than 500 mOsm cause no retinal pigment epithelium damage. However, 1.25 mg in 0.05 mL of intravitreal ziv-aflibercept achieves vitreous osmolarity of 324 mOsm/kg to 342 mOsm/kg, which is within normal range.

Laboratory studies showed no cytotoxic effects when ARPE-19 cells were exposed to twice the clinical dose of ziv-aflibercept. However, a significant reduction in mitochondrial membrane potential has been shown with a clinical dose of ziv-aflibercept (2 mg in 4 mL of vitreous), although toxicity to Müller cells was not reported. Bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses. Mansour and colleagues suggested that the safety of intravitreal ziv-aflibercept may be attributed to its dilution after injection into 4 mL of vitreous to a final osmolarity of 312 mOsm/kg (within the physiologic range).

Early safety study

In our study, we administered this drug intravitreally (1.25 mg/0.05 mL) in 12 eyes of 12 patients. We evaluated these eyes on day 1, day 7 and day 30 after injection. None of the eyes showed any signs of toxicity on clinical examination during the postoperative period up to 1 month. On electroretinographic studies, we did not find any significant change compared with baseline, suggestive of no functional damage after a single intravitreal injection.

None of the eyes showed any changes in the vitreomacular interface on OCT as signs of toxicity. None of the patients experienced serious ocular or systemic adverse events. In terms of visual gain, among our 12 eyes, visual acuity improved in six eyes, remained the same in five eyes and decreased by one line in one eye. We concluded that the single intravitreal injection of ziv-aflibercept into eyes with neovascular AMD appears to be safe through 1 month.

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Ziv-aflibercept may be a safe, low-cost alternate therapy for macular diseases in developing countries and countries where intravitreal aflibercept is not available. The safety of multiple injections with longer follow-up needs to be evaluated further.

Disclosure: Chhablani reports no relevant financial disclosures.