Commentary: Biosimilars in the treatment of retinopathy of prematurity.

Abstract

The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity study established the superiority of intravitreal bevacizumab monotherapy over conventional laser therapy in infants with Zone I disease.[1] The current indications for the use of intravitreal antivascular endothelial growth factor (VEGF) injection include aggressive posterior ROP (APROP); Stage 3 ROP with plus disease in Zone I or Zone II posterior; sick or small child not expected to tolerate laser therapy; progression despite laser therapy; and conditions where performing laser is difficult like poorly dilating pupil, cataract, and vitreous haze or hemorrhage. Other anti-VEGF drugs like ranibizumab, aflibercept, and conbercept have also been shown to be efficacious and safe for the treatment of eyes with ROP.[2-4] However, the high cost of these drugs has contributed to reduced patient compliance. Several biosimilars have been developed to help reduce this financial burden. The World Health Organization has defined biosimilars as “biotechnological products comparable in pharmacokinetics, pharmacodynamics, safety, and efficacy to the already approved innovator biologic product.”[5] The cost of a biosimilar is considerably less compared to the innovator molecule as the cost to develop the former is considerably less (US $120–150 million) than the latter ((US $1.2–1.5 billion).[6] This is due to the reduced need for research and development required to develop the biosimilar drug as well as the lower number of clinical trials required to obtain regulatory approval. Razumab is a biosimilar of ranibizumab that has been developed by Intas Pharmaceuticals, India. It received approval from the Drug Controller General of India in 2015 for the treatment of eyes with neovascular age-related macular degeneration. Currently, it has been approved for myopic choroidal neovascularization (CNVM), polypoidal choroidal vasculopathy (PCV), diabetic macular edema (DME), and retinal vein occlusion (RVO). With the expiry of the patents for bevacizumab and ranibizumab in the United States in 2019 and 2020, respectively, as well as in 2022 in Europe, the use of biosimilars is set to increase multifold.[5] Multiple studies have shown that the efficacy as well as the safety profile of the biosimilar drug for the treatment of CNVM, PCV, DME, and RVO is similar to the innovator drug.[5,6] However, none of the studies have evaluated the drug for the treatment of ROP, even though around 5% of members of the Indian ROP Society use biosimilars for the treatment of ROP.[7] We congratulate the authors for their study showing that monotherapy with biosimilar ranibizumab is effective for the treatment of posterior severe ROP.[8] One of the major apprehensions about the use of biosimilars is the high incidence of adverse drug reactions. Several clusters of sterile endophthalmitis were reported in India from 2015–19 with multiple batches of razumab. As a result, the Vitreoretinal Society of India had to issue an advisory that halted its use for a certain period. The inflammation was hypothesized to occur secondary to the immunogenicity against the molecule.[9,10] However, the incidence reported by the authors in the current study is <0.01%.[8] Similarly, other authors have also reported that they are increasingly becoming satisfied with the safety profile of razumab.[11] Further large sample studies are required to study the safety profile of the biosimilar drug for the treatment of ROP. Treatment with anti-VEGF injections leads to regression of the acute phase of ROP as well as enables the normal development of the retinal vasculature. However, a significant number of eyes show disease recurrence. The third edition of the International Classification of Retinopathy of Prematurity has highlighted that the signs of reactivation may range from a new self-limiting demarcation line to stage 3 with plus disease. They also proposed that the reactivated disease may not follow the normal sequence of stages as seen in the acute-phase disease.[12] Reactivation has been seen to occur most commonly at 37–60 weeks postmenstrual age.[13] Similarly, the authors also reported a recurrence rate of 35%.[8] The various reported risk factors for disease reactivation include low gestational age, birth weight or Apgar score; the presence of APROP, Zone I disease, extensive retinal neovascularization or preretinal hemorrhage; multiple births; the use of supplemental oxygen; and longer duration of hospitalization.[13] Currently, there is no clear consensus on the treatment of reactivated disease. While some authors prefer treatment with laser photocoagulation, others support repeat anti-VEGF injection. The authors treated eyes with the recurrent disease with repeat anti-VEGF injection followed by laser photocoagulation, and eyes with peripheral avascular retina in the absence of recurrence with laser photocoagulation.[8] Tandon et al. proposed performing laser 6–8 weeks after anti-VEGF injection in all the eyes irrespective of disease recurrence.[14] Martinez-Castellanos et al. suggested a treatment algorithm according to which the treatment modality is selected depending on the features of reactivation.[15] Further studies are required standardize the treatment protocol for proper management of the reactivated disease.