Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1 Presented at the Canadian Ophthalmological Society Annual Meeting & Exhibition 1. Calgary Retina Consultants, Calgary, Alberta, Canada. 2. University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada. 3. Mitchell Eye Center, Calgary, Alberta, Canada. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016.

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Retinopathy of Prematurity (ROP) – Atypical retinal development marked by aberrant vascularity primarily due to prematurity of birth, defined as <32 weeks GA and/or <1500 grams birth weight. The retina is usually fully vascularized by 44 weeks Post-Menstrual Age (PMA). Since the ETROP study(citation), ROP has been categorized into types which includes criteria for zones, stages and plus disease. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Why is this a problem we have to deal with? A recent Canadian study among premature infants in a NICU published in 2013 found: (citation) The incidence was 40.4% for ROP (171/423 infants). 9.2% for severe ROP (39/423) 5.67% that needed laser treatment (24/423) It has also been estimated that worldwide prevalence of blindness from ROP is 50,000 year (citation) 1 in 820 with ROP progress to blindness. As medical providers get better and better at saving the most premature babies, the prevalence of ROP will only increase! Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Zones - 1 to 3 Stages - 1 to 5 Plus disease Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity ROP has been divided into two types for treatment paradigms: Type I ROP Type 2 ROP Zone I, any stage plus disease Zone I, stage 3 no plus disease Zone 2, stage 2 or 3 plus disease Zone I, stage 1 or 2 no plus disease Zone II, stage 3 no plus disease. Within these ROP types, there is an even more aggressive form of ROP defined as Aggressive Posterior Retinopathy of Prematurity. This form can progress to stage 5 retinal detachment very quickly, and was the focus of our study. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Treatment of ROP Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity MABs Monoclonal AntiBodies (MAB’s) can target certain receptors in the body. Of particular importance for us is an MAB that can be used as an anti-VEGF treatment. If ROP is abnormal vascular development due to hypoxic conditions ex-utero, then what if we could slow down that process? Anti-VEGF agents (this comes into the screen animated to the next slide) Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Process for MAB Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Anti-VEGF agents Agent Type Size (kDa) Systemic min conc (nM) Systemic max conc. (nM) Dose Systemic clearance (days) Bevacizumab Humanized MAB 149 .044 0.76 0.625mg (0.025ml) 60 Ranibizumab Fab 48 0.002 0.11 0.2mg (0.02ml) 28 Chart data compiled from multiple sources, see paper ref 32, 34, 38, 39. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Why Ranibizumab cf. to bevacizumab? It’s smaller Stays in vitreous cavity for less time Less of it enters systemic circulation Smaller dose Cleared from systemic circulation faster Suppresses systemic VEGF for less time Because of the concerns of suppressing VEGF systemically, the less that makes it into systemic circulation and the less time an agent stays there on paper means likely a healthier baby with less co-morbidities. (alternate unhealthy and healthy baby images) Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity So what did we do? Selection Criteria Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity How did we do it? Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Results 21 infants and 42 eyes, 20 infants alive at last follow up, 1 died from CMV complications. Mean GA was 24.6 weeks (23 – 28.3, 1.3 weeks) Mean Birth Weight was 613g (425 – 790, 91 grams) 13M:8F (62:38%) PMA at treatment was 37.4 weeks (34.1 – 41.6, 2.2 weeks) 6 infants required laser tx at PMA of 70.4 weeks (37.6 – 120.4, 28.8 weeks). logMAR VA was 1.04 (0.67 – 1.70, 0.37) at clinical resolution of ROP. logMAR average VA was 0.94 (0.2 – 1.53, 0.36) in 28 of 42 eyes (67%) at last follow up visit. All eyes had regression of ROP or were treated with peripheral retinal laser photocoagulation. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Results 21 infants and 42 eyes, 20 infants alive at last follow up, 1 died from CMV complications. Mean GA was 24.6 weeks (23 – 28.3, 1.3 weeks) Mean Birth Weight was 613g (425 – 790, 91 grams) 13M:8F (62:38%) PMA at treatment was 37.4 weeks (34.1 – 41.6, 2.2 weeks) 6 infants required laser tx at PMA of 70.4 weeks (37.6 – 120.4, 28.8 weeks). logMAR VA was 1.04 (0.67 – 1.70, 0.37) at clinical resolution of ROP. logMAR average VA was 0.94 (0.2 – 1.53, 0.36) in 28 of 42 eyes (67%) at last follow up visit. All eyes had regression of ROP or were treated with peripheral retinal laser photocoagulation. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Results In the cases of laser photocoagulation, there was more vascularization of the avascular retina hence less laser was required, mean time from injection to laser for 6 infants 37.5 weeks (0 – 85, 31.3 weeks). There were no adverse ocular events attributable to Ranibizumab injections. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Limitations/Problems Delay in vessel progression to ora serrata, the time to clinical resolution of ROP was higher than other studies. Possibly dose dependent. Future studies are planned to determine: The optimal dose of Ranibizumab. The optimal frequency of treatment. Possible delay or systemic issues with organogenesis from Ranibizumab injection. Although we did not see this in our study it is prudent to monitor the progress of the treated infants long term. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Conclusions Given our findings, we believe that Ranibizumab may prove to be a superior treatment to bevacizumab. Why? Smaller dose (0.2mg vs. 0.625mg) Smaller volume (0.02ml vs. 0.025ml) Less systemic suppression of VEGF Smaller min and max systemic concentration Less time to clear from systemic circulation Outcomes are equivalent or superior to those of bevacizumab studies. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Questions? Contact information; Jason Wesolosky U of C Medicine, class of 2016 403.701.9296 jaysen@ophtho.ca j.wesolosky@ucalgary.ca Copy of this presentation available at http://www.ophtho.ca/cos2015 Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity References References for graphics and papers go here after finalization with Patrick/Anna. Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

Ranibizumab for the Treatment of Severe Retinopathy of Prematurity Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of 2016. Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1