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    Ziv-Aflibercept: Déjà Vu in Retinal Therapy?

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    Before intravitreal ranibizumab (Lucentis) was commercially available, U.S. ophthalmologists found a way to use anti-VEGF therapy in the eye: off-label repurposing of its cancer-fighting cousin, bevacizumab (Avastin), to treat choroidal neovascu­larization.

    Now, a similar story is unfolding overseas with the VEGF-blocking intravitreal drug aflibercept (Eylea) and the related cancer chemotherapy agent, ziv-aflibercept (Zaltrap). In countries where aflibercept is unavailable or financially prohibitive, researchers have found early evidence that intravitreal ziv-aflibercept might be a safe and effective alternative to the approved drug.1-4

    Clinical experience with ziv-afliber­cept. In Hyderabad, India, researchers at the Smt. Kanuri Santhamma Retina Vitreous Centre of the L.V. Prasad Eye Institute have done hundreds of these off-label injections during the last 2 years, with good clinical outcomes and without retinal toxic­ity, inflammation, or other adverse events, said Jay Chhablani, MS, consulting oph­thalmologist.

    The primary motivation for inves­tigating this option was to help patients who otherwise could not afford therapy with the approved medication, Dr. Chhablani said.

    “In our country, patients generally have to pay out of their pocket for anti-VEGF injections, and Eylea is very ex­pensive, even compared with Lucentis. It is almost double the cost of Lucentis,” he said.

    In Brazil, researchers are studying ziv-aflibercept for treating refractory age-related macular degeneration and diabetic macular edema. They reported positive outcomes at the Academy’s 2015 Retina Subspecialty Day5 and in papers published over the last 2 years.

    How it’s used. For off-label intravitreal administration, standard ziv-aflibercept vials can be divided into 1.25 mg/0.05 mL aliquots without fur­ther mixing or dilution, thus avoiding risks associated with those processes, as reported by Dr. Chhablani and col­leagues in case studies published since mid-2015.1-4

    As Zaltrap, ziv-aflibercept is approved for intravenous use in the United States and Europe to treat patients with met­astatic colorectal cancer. The prepack­aged vials of Eylea and Zaltrap contain identical concentrations of the same active drug, a fusion protein that inhib­its 3 molecules in the angiogenic VEGF family. However, the Eylea formulation is iso-osmolar, and the Zaltrap solu­tion is hyperosmolar (1,000 mOsm/L), relative to the vitreous.

    Safety concerns. Critics commonly express concern about the potential im-pact of the higher osmolarity, Dr. Chhablani said. “Everybody has been worried about the osmolarity issue, but we have extensive experience with this now, and we did not find any problems. We reported the safety of 1.25 mg/0.05 mL in human eyes with no retinal toxicity after a single injection. We have given more than 350, perhaps as many as 500, injections, and we have never seen a problem,” he said.

    Looking ahead. Larger, longer-term studies are necessary to confirm the safety and effectiveness of intravitreal ziv-aflibercept therapy, especially with multiple injections, Dr. Chhablani said. Furthermore, this off-label use is not likely to spread beyond poorer countries like India, where the lack of government insurance coverage puts the approved drug beyond the reach of most patients who need it, he said.

    “There are definitely some patients, such as those with large pigmented epithelial detachments [PED] or polypoidal choroidal vasculopathy [PCV], and patients who are not responding to Avastin or Lucentis, who would benefit from this alternative therapy,” he said. “These are the types of patients whom we now are injecting with ziv-afliber­cept, equally with aflibercept.”

    —Linda Roach


    1 Mansour AM et al. Br J Ophthalmol. Published online March 30, 2016. doi:10.1136/bjophthalmol-2015-308319.

    2 Mansour AM et al. Br J Ophthalmol. Published online May 17, 2016. doi:10.1136/bjophthalmol-2016-308679.

    3 Chhablani J et al. Retina. 2016;36(6):1126-1131.

    4 Mansour AM et al. Br J Ophthalmol. 2015;99(8):1055-1059.

    5 Farah ME. Intravitreal Ziv-Aflibercept. Presented at: AAO Retina Subspecialty Day; Nov. 13, 2015; Las Vegas.

    Further Reading

    These additional references were omitted from the print edition for space considerations.

    Andrade GC et al. Intravitreal injections of ziv-aflibercept for diabetic macular edema: a pilot study. Retina. Published online March 16, 2016. doi:10.1097/IAE.0000000000001000.

    de Oliveira Dias JR et al. Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, and conber­cept. Int J Retina Vitreous. 2016;2:3. doi:10.1186/s40942-016-0026-y.

    de Oliveira Dias JR et al. Intravitreal injection of ziv-af­libercept in patient with refractory age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2015 Jan;46(1):91-94.

    Yogi R et al. Flattening of a treatment-resistant ret­inal pigment epithelial detachment after a single intravitreal injection of ziv-aflibercept. Retin Cases Brief Rep. Published online April 13, 2016. doi: 10.1097/ICB.0000000000000305.

    Relevant financial disclosures: Dr. Chhablani—None.


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