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Educational Initiatives in AMD and Related Retinal Diseases

Educational Initiatives in AMD and Related Retinal Diseases. Causes of CNV. Age-related macular degeneration (AMD) Leading cause of severe vision loss in people over 50 years of age Pathologic myopia One of the most frequent causes of CNV in people under 50 years of age

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Educational Initiatives in AMD and Related Retinal Diseases

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  1. Educational Initiatives in AMD and Related Retinal Diseases

  2. Causes of CNV • Age-related macular degeneration (AMD) • Leading cause of severe vision loss in people over 50 years of age • Pathologic myopia • One of the most frequent causes of CNV in people under 50 years of age • The ocular histoplasmosis syndrome (OHS) • Frequent cause of CNV in mid-central USA • Angioid streaks, idiopathic causes

  3. Proven Treatments • Standard (thermal) laser photocoagulation • Well-demarcated juxtafoveal or extrafoveal lesions due to AMD • Verteporfin (Visudyne™) therapy • Predominantly classic subfoveal CNV due to AMD • Selected patients with AMD with subfoveal occult CNV but no classic CNV • Subfoveal CNV due to pathologic myopia

  4. Clinical Studies of Verteporfin Therapy • Phase I/II dose-finding study • Subfoveal CNV due to AMD and other causes • Phase III TAP Investigation • Subfoveal CNV due to AMD • Phase IIIb VIP Trial • Subfoveal CNV due to AMD or pathologic myopia • Phase I/II VOH Study • Subfoveal CNV due to OHS

  5. Phase I/II Dose-Finding Study • Open-label, non-randomized, multicenter (4), dose-finding study in 142 patients • 128 with CNV due to AMD • 14 with CNV due to other causes • Five treatment regimens • Verteporfin 6 or 12 mg/m2 • Infusion over 5 or 10 min • Light applied 10–30 min after start of infusion • Light-dose escalated from 12.5 to 150 J/cm2 • Retreatment at 2- or 4-week intervals

  6. Phase I/II Dose-Finding StudyTreatment Outcomes • Visual acuity was maintained or improved • Cessation of fluorescein leakage from CNV was temporary, so retreatments were required • Retreatment decreased area of leakage • Higher light doses did not prolong cessation of leakage, but could cause retinal damage

  7. Phase III and IIIbTreatment Protocol Based on the phase I/II results, the regimen chosen was: Verteporfin infusion over 10 min 6 mg/m2 BSA in 30 mL D5W Light application 15 min after start of infusion Follow-up every 3 months Light applied for 83 seconds Wavelength: 689 nm Light intensity: 600 mW/cm2 Light dose: 50 J/cm2 Retreat if there is fluorescein leakage from CNV

  8. Phase III TAP Investigation:Study Objective Does verteporfin therapy reduce the risk of moderate vision loss in patients who present with subfoveal CNV due to AMD? TAP Investigation Verteporfin therapy (n = 402) Placebo (n = 207)

  9. TAP Investigation:Main Eligibility Criteria • AMD patients 50 years of age • Approximate Snellen visual acuity of 20/40 to 20/200 • Subfoveal CNV (new or recurrent) • Evidence of classic CNV (± occult) • Lesion greatest linear dimension (GLD)5400 µm

  10. TAP Investigation:Baseline Characteristics Verteporfin (n = 402) Placebo(n = 207) Mean age 75 years 76 years Women 53% 63% Caucasian 99% 98% Mean visual acuity, 52.8 (20/80-2) 52.6 (20/80-2) letter score (Snellen equivalent)

  11. TAP Investigation:Baseline Lesion Composition Classic CNV Occult CNV Blood Predominantlyclassic (n = 242) Minimally classic (n = 306) No classic (n = 61)

  12. Verteporfin (n = 402) Placebo (n = 207) TAP Investigation:Treatments Administered Patients receivingretreatment (%) Average treatments Year 1 Verteporfin 3.4 Placebo 3.7 Year 2 Verteporfin 2.2 Placebo 2.8 Total Verteporfin 5.6 Placebo 6.5 100 80 60 40 20 0 3 6 9 12 15 18 21 Follow-up visit (months)

  13. Verteporfin (n = 402) Placebo (n = 207) TAP Investigation:Visual Acuity in Total Study Population Eyes with <3-line loss (%) Verteporfin-treated patients were more likely to avoid moderate vision loss at 12 and 24 months than patients who received placebo 80 P<0.001 P<0.001 60 61 53 46 40 38 20 0 12 months 24 months

  14. TAP Investigation:Lesion Composition and Visual Acuity Verteporfin (n = 402) Eyes with <3-line loss (%) Placebo (n = 207) 80 P<0.001 P<0.001 NS NS P=0.051 P=0.055 67 60 63 59 56 56 55 48 40 44 40 31 30 30 20 0 12 months 24 months 12 months 24 months 12 months 24 months Predominantly classic (n = 242) Minimally classic (n = 306) No classic (n = 61)

  15. TAP Investigation:Contrast Sensitivity Follow-up visit (months) In patients with predominantly classic CNV at baseline: • Verteporfin-treated eyes lost fewer letters of contrast sensitivity • Contrast sensitivity remained stable through 24 months Difference 6.2 letters P<0.001 Difference 5.2 letters P<0.001 Mean change frombaseline (letters)

  16. Verteporfin (n = 159) Placebo (n = 83) TAP Investigation:Fluorescein Leakage from Classic CNV At 12 and 24 months, verteporfin-treated patients with predominantly classic CNV at baseline were: Eyes (%) 80 P<0.001 60 65 P<0.001 40 45 • Less likely to have progression of leakage • More likely to have absence of leakage 29 20 21 0 Progression ofleakage Absenceof leakage Outcome at 24 months

  17. TAP Investigation: Conclusions • Verteporfin therapy can safely reduce the risk of moderate and severe vision loss in patients with predominantly classic CNV in AMD • The benefits seen at 12 months were sustained over 24 months • Verteporfin therapy should be considered for patients with predominantly classic subfoveal CNV due to AMD (FDA approved indication: April 2000)

  18. VIP Trial AMD (n = 339) Pathologic Myopia (n = 120) Phase IIIb VIP Trial:Study Objectives Does verteporfin therapy reduce the risk of moderate vision loss in patients who were not eligible for the TAP Investigation?

  19. VIP Trial: AMD PatientsMain Eligibility Criteria • Age 50 years • Lesion with GLD 5400 µm • Subfoveal CNV and one of the following: • Classic CNV and approximate Snellen visual acuity better than 20/40 • Occult CNV, but no classic CNV, with approximate Snellen visual acuity 20/100 or better and hemorrhage, loss of 1 line of visual acuity within 3 months, or growth of lesion GLD 10% within 3 months

  20. VIP Trial: AMD Patients Baseline Characteristics Verteporfin (n = 225) Placebo(n = 114) Mean age 75 years 74 years Women 58% 62% Caucasian 99% 98% Mean visual acuity, 66.3 (20/50+1) 65.4 (20/50)letter score (Snellen equivalent)

  21. Verteporfin (n = 225) Placebo (n = 114) VIP Trial: AMD PatientsBaseline Lesion Composition Eyes (%) 100 80 82 76 60 40 20 7 3 17 16 0 Predominantlyclassic CNV Minimally classic CNV Noclassic CNV Baseline lesion composition

  22. Verteporfin (n = 225) Placebo (n = 114) VIP Trial: AMD PatientsVisual Acuity in Total AMD Population Eyes with <3-line loss (%) 60 Difference in percentage of patients with moderate vision loss: NS P=0.023 49 46 46 40 • No significant difference at month 12 • Significant at month 24 (absolute difference 13%) 33 20 12 months 24 months 0 12 months 24 months

  23. Verteporfin (n = 171) Placebo (n = 93) VIP Trial: AMD PatientsSubgroup with Occult CNV and No Classic CNV Eyes with <3-line loss (%) 60 Difference in percentage of patients with moderate vision loss: NS P=0.032 50 45 45 40 • No significant difference at month 12 • Significant at month 24 (absolute difference 14%) 31 20 0 12 months 24 months

  24. Verteporfin (n = 123) Placebo (n = 64) VIP Trial: AMD Patients Visual Acuity <65 Letters or Lesion Size 4 MPS DA Eyes with <3-line loss (%) 60 P=0.058 Difference in percentage of patients with moderate vision loss: P<0.001 54 51 40 39 • No significant difference at month 12 • Significant at month 24 (absolute difference 26%) 26 20 0 12 months 24 months

  25. VIP Trial: AMD PatientsConclusions • Modest benefits for the primary visual acuity outcome at 24 months • Verteporfin therapy should be considered for AMD patients with subfoveal CNV composed of occult CNV with no classic CNV with recent lesion growth or visual acuity deterioration • Additional studies are underway to investigate the therapeutic potential of verteporfin therapy in AMD populations with other types of subfoveal CNV

  26. VIP Trial: Patients with Pathologic Myopia • Fundus manifestations consistent with pathologic myopia: • Lacquer cracks • Staphylomatous abnormalities • ‘Tilted’ optic nerves • One of the following: • Spherical equivalent equal to or more negative than –6 D • Spherical equivalent less negative than–6 D and axial length 26.5 mm

  27. VIP Trial: Patients with Pathologic Myopia Main Eligibility Criteria • Age 18 years • Approximate Snellen visual acuity 20/100 or better • Subfoveal CNV (classic or occult or both) • Lesion GLD 5400 µm

  28. VIP Trial: Patients with Pathologic Myopia Baseline Characteristics Verteporfin (n = 81) Placebo(n = 39) Median age 51 years 46 years Women 70% 59% Caucasian 91% 92% Asian 4% 5% Hispanic 5% 3% Median visual acuity, 62 (20/64+2) 58 (20/64-2)letter score (Snellen equivalent)

  29. VIP Trial: Patients with Pathologic Myopia Baseline Lesion Composition Eyes (%) 100 Verteporfin (n = 81) Placebo (n = 39) 80 60 40 20 0 Predominantlyclassic CNV Minimally classic CNV Noclassic CNV Baseline lesion composition

  30. VIP Trial: Patients with Pathologic Myopia Primary Visual Acuity Outcome Eyes with <1.5-line loss (%) Verteporfin-treated patients were more likely to have stabilized vision (defined as losing <1.5 lines) at month 12 80 P=0.003 60 40 20 0 Verteporfin (n = 81) Placebo (n = 39)

  31. VIP Trial: Patients with Pathologic Myopia Secondary Visual Acuity Outcome Eyes with <3-line loss (%) Verteporfin-treated patients were more likely to avoid moderate vision loss at month 12 100 P=0.011 80 60 40 20 0 Verteporfin (n = 81) Placebo (n = 39)

  32. VIP Trial: Patients with Pathologic Myopia Conclusions • Verteporfin therapy can safely increase the chance of stable or improved vision in patients with subfoveal CNV due to pathologic myopia • Verteporfin therapy should be considered for subfoveal CNV secondary to pathologic myopia

  33. VOH Study:Study Objectives Determine the safety and tolerability of verteporfin therapy in patients with subfoveal CNV secondary to OHS

  34. VOH Study:Main Eligibility Criteria • Age 18 years (mean 50 years) • Approximate Snellen visual acuity 20/40 to 20/200 • Subfoveal CNV • Lesion GLD 5400 µm

  35. VOH Study: Visual Acuity Outcomes at Month 12 Among the 25 patients followed up at 12 months: • Median visual acuity improved by 7.0 letters • Visual acuity improved by: • At least 1 line in 56% of patients • At least 3 lines in 7% of patients • 16% of patients lost at least 1 line of visual acuity

  36. VOH Study:Conclusions • Median visual acuity improved and most patients avoided vision loss through 12 months • Two-year data from these patients are being compiled • To date, no conclusive data to indicate if verteporfin therapy, or any other therapy, is more effective than no treatment • Further investigation with appropriate controls would be needed to make definitive treatment recommendations

  37. SafetyClinically Relevant Ocular Events Verteporfin n (%) Placebon (%) Event Any visual disturbance TAP Investigation 50 (12.4) 14 (6.8) VIP Trial 73 (17.9) 12 (5.8) Acute documented visual acuity decrease* TAP Investigation 3 (0.7) 0 (0.0) VIP Trial 10 (3.3) 0 (0.0) * >20-letter loss within 7 days of treatment

  38. SafetyClinically Relevant Systemic Events Verteporfin (n = 734)n (%) Placebo(n = 360)n (%) Event Infusion-related 15 (2.0) 0 (0.0) back pain Injection-site 80 (10.9) 16 (4.4) adverse events Photosensitivity 16 (2.2) 1 (0.3)reactions

  39. Management of Clinically Relevant Adverse Events • Extravasation • Avoidable with proper precautions • Infusion-related back pain • No adverse sequelae known at this time • Resolves within a short time • Photosensitivity reactions • Treat as sunburn (sunscreen is ineffective) • Avoidable with proper precautions • Acute visual acuity decrease within 7 days • Observation, no retreatment recommended

  40. Outcomes in Clinical Trials of Verteporfin Therapy • Safely reduces risk of moderate and severe vision loss • Most patients lose some vision over 2 years after initiating therapy due to natural course of disease • Modest improvements in vision can occur in some patients, but are unusual • Verteporfin therapy should be considered in selected patients with subfoveal CNV: • Predominantly classic CNV secondary to AMD • Occult CNV with no classic CNV secondary to AMD • CNV secondary to pathologic myopia

  41. Patient Selection for Verteporfin Therapy Diagnostic assessment should include: • Best-corrected visual acuity • Fundus biomicroscopy via a dilated pupil • Color fundus photography • Fluorescein angiography

  42. Treatment spot size GLD Verteporfin Therapy: Determining GLD and Treatment Spot Size • Determine size of lesion on photographic image • Calculate actual GLD on retina • Add 1000 µm to allow a500 µm border around lesion • Treatment spot should be no closer than 200 µm to edge of optic disc

  43. Zeiss Visulas690s andVisulinkPDT adapter Coherent OpalPhotoactivatorand LaserLinkadapter Verteporfin Therapy: Setting Laser and Administering Infusion • Enter contact lens magnification • Enter the spot size (GLD + 1000 µm) • Start the timer at the beginning of the infusion • Physician or nurse must monitor the patient throughout the 10-minute infusion

  44. Treatment: Positioning Patient and Applying Laser Light • The patient is positioned at the slit lamp immediately after the end of infusion Light at 689 nm is delivered via a fiber optic and slit lamp using a contact lens Light dose • 600 mW/cm2 • 83 seconds 50 J/cm2

  45. Concurrent Bilateral Treatment If the patient has received previous verteporfin treatment with an acceptable safety profile: • The first eye is treated 15 min after the start of infusion • Immediately after treatment of the first eye, the laser is reset to the parameters of the second eye • The second eye is treated no later than 20 min after the start of infusion

  46. Follow-up • Follow-up visits after a treatment should be scheduled at least as often as every 10–14 weeks • Fluorescein angiography is required to determine whether leakage has recurred • Retreatment is often necessary during the first2 years

  47. Retreatment Patients are retreated as often as every 10–14 weeks if: • Evidence of leakage from classic or occult CNV • No serious adverse events believed to be associated with prior therapy Early phase of angiogram showing recurrent leakage within a hypofluorescent region 3 months after verteporfin therapy

  48. Patient Education Physician needs to manage patient expectations: • Treatment is designed to reduce the risk of vision loss • Vision improves in few cases • Retreatment is often required at 3-month intervals during the first 2 years

  49. Summary • Verteporfin therapy is a safe and effective treatment for selected patients with subfoveal CNV • Introducing verteporfin therapy will impact retinal practices • Need to identify and educate people at risk of developing CNV • Need to be able to identify CNV and determine if treatment is indicated • May be a large increase in treatments and reductions in the magnitude of vision loss

  50. This activity was made possible by an unrestricted educational grant from Novartis Ophthalmics, Inc.

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