1. 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 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.

2. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

3. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

4. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

5. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

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

7. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

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

9. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

10. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

11. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

12. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

13. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

14. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

15. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

16. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

17. 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 mg)
Smaller volume (0.02ml vs ml)
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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

18. Ranibizumab for the Treatment of Severe Retinopathy of Prematurity
Questions?
Contact information;
Jason Wesolosky
U of C Medicine, class of 2016
Copy of this presentation available at
Jason Wesolosky, University of Calgary Cummings School of Medicine, Class of Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

19. 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 Anna L. Ells, MD1, 2 Patrick C. Mitchell, MD,2,3 Jaysen D. Wesolosky,2 April D. Ingram,1 Alex S. Platt,1

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

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