1. Retina Centre of Ottawa Clinical Trials
Neovascular age-related macular degeneration (wAMD) (HAWK)
Managing neovascular age-related macular degeneration (wAMD) over 2 years with a treat and extend (T&E) regime of 2mg intravitreal (IVT) aflibercept-a randomized, open-label, active-controlled, parallel-group phase IV/IIIb study (ARIES)
To describe the use of intravitreal aflibercept and to describe follow-up as well as treatment patterns in patients with wet age-related macular degeneration (wAMD) or diabetic macular edema (DME) in routine clinical practice in Canada (PEGASUS)
An open-label, randomized, active-controlled, parallel-group, phase-3b study of the efficacy, safety, and tolerability of 2mg aflibercept administered by intravitreal injections using two different treatment regimes to subjects with neovascular age-related macular degeneration (wAMD) (AZURE)

2. STUDY OF EFFICACY & SAFETY OF PRE-FILLED SYRINGES OF
RANIBIZUMAB PREPARED
BY A COMPOUNDING PHARMACY
FOR wAMD, DME and CVO
(W. Britton, MD; R. Tuli, MD; T. Lee, MD; A. Leslie; A. Vanderlinden; J. Massé)

3. BACKGROUND
Vascular Endothelial Growth Factor (VEGF) is a protein which is a key regulator of angiogenesis + inflammation.
Overproduction (up regulation) results in growth + leakage of abnormal blood vessels.

4. BACKGROUND Up regulation of VEGF is seen in:
Neovascular Age Related Macular Degeneration (wAMD)
Diabetic Macular Edema (DME)
Central Retinal Vein Occlusion (CVO)

5. BACKGROUND
Ranibizumab (Lucentis) is a recombinant, humanized monoclonal antibody specifically designed for intraocular use to neutralize all isoforms of VEGF-A.

6. BACKGROUND
Ranibizumab is highly effective in improving + maintaining vision for patients with:
Neovascular AMD
Diabetic Macular Edema
Cystoid Macular Edema secondary to Central Retinal Vein Occlusion

7. BACKGROUND
Monthly injections of Ranibizumab are the standard of care for:
wAMD
DME
CVO

8. BACKGROUND Ranibizumab is supplied in a sterile vial.
It takes seconds to aspirate the drug into a TB syringe and apply the appropriate needle at the bedside. This is done for every patient.

9. BACKGROUND
EACH retina surgeon at the RETINA CENTRE OF OTTAWA (RCO) does this approximately 50 times per day for each working day in the office.
This means that about 60 minutes per day, per retinal surgeon, is used to prepare Ranibizumab for intraocular injection.

10. BACKGROUND
60 minutes translates into over 12% of a standard work day just to prepare the drug!

11. BACKGROUND
FDA requires that a drug be stable for 2 years in the supplied container.
Makers of Ranibizumab tried for 7 years to develop a syringe which would keep this drug stable for the mandatory 2 year period.

12. PURPOSE OF STUDY
Evaluate efficacy + safety of prefilled syringes of Ranibizumab prepared by a local compounding pharmacy and delivered intravitreally within 24 hours of preparation.

13. METHOD
Patients with wAMD, DME or macular edema secondary to CVO who received intravitreal Ranibizumab (0.5 mg) from prefilled syringes prepared between November 2014 – June 2016 were randomly selected from the patient population of the RETINA CENTRE OF OTTAWA.

14. METHOD Inclusion Criteria wAMD, DME or CVO VA 20/30 – 20/400
OCT on each appointment
Minimum of 6 visits (4-8 weeks apart)

15. METHOD Selected patients were categorized by: Disease process
Treatment naïve vs Previously Treated (actively receiving Anti-VEGF injections prior to prefilled syringes)

16. METHOD 6 separate groups of patients were studied: wAMD Prior Treat
Treat Naïve
wAMD
Prior Treat
DME
CVO

17. wAMD n Values
Treat Naïve n= 77
wAMD
Prior Treat n= 132

18. DME n Values
Treat Naïve n= 37
DME
Prior Treat n= 42

19. CVO n Values
Treat Naïve n= 15
CVO
Prior Treat n= 22

20. METHOD Primary Outcome Secondary Outcomes
Visual acuity (Snellen converted to ETDRS Letter Score)
Secondary Outcomes
OCT central retinal thickness
Percentage of 20/40 or better gainers
Percentage of 20/200 or worse
Percentage gaining ≥ 15 ETDRS letters
Average # injections
Study period was 6 consecutive visits (4-8 weeks apart) for each patient
Serious adverse events (SAE’s) recorded

21. VISUAL ACUITY RESULTS

22. wAMD Visual Acuity
N=77
N=77

23. DME Visual Acuity

24. CVO Visual Acuity

25. CENTRAL RETINAL THICKNESS OCT RESULTS

26. wAMD Central Retinal Thickness OCT Changes

27. DME Central Retinal Thickness OCT Changes

28. CVO Central Retinal Thickness OCT Changes

29. PERCENTAGE 20/40 OR BETTER RESULTS

30. Snellen Equivalent of 20/40 or Better
Percentage of treatment naïve patients with vision of the Snellen equivalent of 20/40 or better at baseline and after 6 months of ranibizumab treatment.

31. PERCENTAGE 20/200 OR WORSE RESULTS

32. Snellen Equivalent of 20/200 or Worse
Percentage of treatment naïve patients with vision of the Snellen equivalent of 20/200 or worse at baseline and after 6 months of ranibizumab treatment.

33. GAINERS OF ≥ 15 LETTERS RESULTS

34. Gains of ≥ 15 ETDRS Letters
Percentage of treatment naïve patients who gained 15 or more ETDRS letters from baseline to 6 months of ranibizumab treatment.

35. AVERAGE # INJECTIONS

36. AVERAGE # INJECTIONS (6 VISITS)
GROUP Tx Naïve Prev. Tx
wAMD
DME
CVO

37. SERIOUS ADVERSE EVENTS

38. SERIOUS ADVERSE EVENTS
wAMD
DME
CVO
TX Naïve
Previous TX
Endophthalmitis
Myocardial Infarction 1
Stroke
Death

39. DISCUSSION

40. DISCUSSION
To put our data into perspective, we compared our TREATMENT NAÏVE groups with published results from key pivotal clinical trials.

41. wAMD VISUAL ACUITY RESULTS (Tx NAÏVE)
STUDY Mean ∆ ETDRS Letters
RCO
HARBOR
(RCO n= 77, HARBOR n= 275)

42. DME VISUAL ACUITY RESULTS (Tx NAÏVE)
STUDY Mean ∆ ETDRS Letters RCO RISE (RCO n= 37, RISE n= 125)

43. CVO VISUAL ACUITY RESULTS (Tx NAÏVE)
STUDY Mean ∆ ETDRS Letters
RCO
CRUISE
(RCO n= 15, CRUISE n= 130)

44. wAMD CENTRAL RETINAL THICKNESS (Tx NAÏVE)
STUDY CRT (µm)
RCO
HARBOR
(RCO n= 77, HARBOR n= 275)

45. DME CENTRAL RETINAL THICKNESS (Tx NAÏVE)
STUDY CRT (µm) RCO RISE -210 (RCO n= 37, RISE n= 125)

46. CVO CENTRAL RETINAL THICKNESS (Tx NAÏVE)
STUDY CRT (µm) RCO -179 CRUISE (RCO n= 15, CRUISE n= 130)

47. wAMD % ≥ 20/40 (Tx Naïve)
STUDY STUDY BASELINE END % CHANGE RCO 18.2% 36.4% +18.2% HARBOR N/A 52.4% N/A (RCO n= 77, HARBOR n= 275)

48. DME % ≥ 20/40 (Tx Naïve)
STUDY STUDY BASELINE END % CHANGE RCO 16.2% 43.2% +27% RISE 19.2% 39.2% +20% (RCO n= 37, RISE n= 125)

49. CVO % ≥ 20/40 (Tx Naïve)
STUDY STUDY BASELINE END % CHANGE RCO 6.7% 20% +13.3% CRUISE 5.4% 46.9% +41.5% (RCO n= 15, CRUISE n= 130)

50. wAMD % ≤ 20/200 (Tx Naïve)
STUDY STUDY BASELINE END % CHANGE RCO 35.1% 10.4% -24.7% HARBOR N/A 7.3% N/A (RCO n= 77, HARBOR n= 275)

51. DME % ≤ 20/200 (Tx Naïve) STUDY STUDY BASELINE END % CHANGE
RCO 27% 8.1% %
RISE 8% N/A N/A
(RCO n= 37, RISE n= 125)

52. CVO % ≤ 20/200 (Tx Naïve) STUDY STUDY BASELINE END % CHANGE
RCO 46.7% 20% %
CRUISE 30% 11.5% -18.5%
(RCO n= 15, CRUISE n =130)

53. wAMD ≥ 15 ETDRS LETTER GAINERS
STUDY ≥ 15 LETTER GAINERS RCO 29% HARBOR 34.5% (RCO n= 77, HARBOR n= 275)

54. DME ≥ 15 ETDRS LETTER GAINERS
STUDY ≥ 15 LETTER GAINERS
RCO %
RISE %
(RCO n= 37, RISE n= 42)

55. CVO ≥ 15 ETDRS LETTER GAINERS
STUDY ≥ 15 LETTER GAINERS
RCO %
CRUISE %
(RCO n= 15, CRUISE n= 130 )

56. wAMD AVERAGE # INJECTIONS (Tx Naïve)
AVERAGE # STUDY INJECTIONS RCO 5.08 HARBOR 7

57. DME AVERAGE # INJECTIONs (Tx Naïve)
AVERAGE # STUDY INJECTIONS RCO 5.22 RISE 7

58. CVO AVERAGE # INJECTIONS (Tx Naïve)
AVERAGE # STUDY INJECTIONS RCO 5.27 CRUISE 7

59. CONCLUSIONS

60. CONCLUSIONS
Visual acuity results demonstrated that the efficacy of Ranibizumab placed in syringes by compounding pharmacy within 24 hours of use is equal to that achieved when the drug is drawn up immediately prior to delivery for wAMD, DME and CVO.
Visual acuity improvements were achieved with fewer # injections than in key pivotal trials.

61. CONSLUSIONS
CRT reduction was less robust than that achieved in pivotal clinical trials.
This could be explained by REAL WORLD treatment regimes.
This also highlights the relative disconnect between Visual Acuity improvements and reduction in leakage as measured by Central Retinal Thickness on OCT.

62. CONSLUSIONS
SAE’s were consistent with comparable Ranibizumab trials and in keeping with age and underlying systemic disorders of our patient population. Most importantly, there were no cases of endophthalmitis in any of our patients.