Ranibizumab Offers New Option in Diabetic Macular Edema
Ranibizumab Offers New Option in Diabetic Macular Edema
Editor's Note:
According to the US Centers for Disease Control and Prevention, 26 million Americans have diabetes type 1 or type 2. Of the complications associated with the disease, perhaps one of the most devastating is diabetic macular edema, which can cause blindness in people with diabetes. With the approval of ranibizumab (Lucentis®; Genentech; South San Francisco, California) intravitreal injection by the US Food and Drug Administration (FDA) on August 10, 2012, for the treatment of diabetic macular edema, a new therapeutic option is now available for patients to help in the fight to preserve vision. Medscape interviewed Baruch D. Kuppermann, MD, PhD, Professor; Chief of Retina Service; Vice Chair of Clinical Research, Department of Ophthalmology, University of California, Irvine, about this important advancement.
Medscape: Diabetic macular edema is a common cause of vision loss in patients with diabetes. Could you describe the pathophysiology of this disease?
Dr. Kuppermann: The primary cause of vision loss associated with diabetes is diabetic macular edema. The mechanisms for its development are quite complex, but ultimately there is a breakdown in the tight junctions between the retinal vascular endothelial cells and the result is both intercellular and intracellular edema.
Medscape: What is the current standard of care for diabetic macular edema?
Dr. Kuppermann: The standard of care has been focal laser for focal diabetic macular edema and grid laser for diffuse diabetic macular edema. However, many physicians have used anti-vascular endothelial growth factor (ant-VEGF) agents that are injected intravitreally, such as bevacizumab (Avastin®, Genentech)and ranibizumab; bevacizumab is an off-label use, as was ranibizumab until its recent approval for this indication. Triamcinolone acetonide is also commonly used intravitreally. Steroid drug delivery implants are also being developed for this indication. Iluvien® (Alimera Sciences; Alpharetta, Georgia) is an extended-release fluocinolone acetonide intravitreal implant that was recently approved in Europe for diabetic macular edema; however, the FDA did not approve it in the United States. Ozurdex® (Allergan, Inc.; Irvine, California) is a dexamethasone implant that has completed 2 pivotal phase 3 trials, although the results are still pending.
Medscape: As you mentioned, ranibizumab is an anti-VEGF agent; it was first approved by the FDA for the treatment of neovascular age-related macular degeneration (AMD). How does its use in the treatment of AMD overlap into its use in macular edema in diabetes?
Dr. Kuppermann: The main chorioretinal vascular disorders -- that is, neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion -- all appear to be significantly mediated by VEGF. VEGF is both an angiogenic factor and a vascular permeability factor, and the pathophysiology of these key diseases can involve one or another or both of these VEGF roles.
Medscape: RISE and RIDE are 2 trials similarly designed to assess the efficacy and safety of ranibizumab for diabetic macular edema. Could you describe these 2 trials and their results?
Dr. Kuppermann: Both trials included patients with diabetic macular edema who were either treatment naive or previously treated. Patients in each trial were randomly assigned to either 0.3-mg or 0.5-mg monthly injections of ranibizumab or to monthly sham injections in a 1:1:1 allocation. All patients received monthly injections for 36 months, although those in the sham group were crossed over to receive 0.5-mg monthly injections of ranibizumab between months 24 and 36. The primary efficacy endpoint was at 24 months; however, the FDA's decision was based on both the 24-month and the 36-month data. Both ranibizumab groups in each trial showed similar results at 24 and 36 months.
In RIDE, the mean change in best corrected visual acuity from baseline at the 24-month time point was 12.0 letters for the 0.5-mg group, 10.9 letters for the 0.3-mg group, and 2.3 letters for the sham group. For RISE, the 24-month improvement in vision was 11.9 letters for the 0.5-mg group, 12.5 letters for the 0.3-mg group, and 2.6 letters for the sham group.
At 36 months, RIDE showed best corrected visual acuity improvements of 11.4 letters for the 0.5-mg group, 10.5 letters for the 0.3-mg group, and 4.7 letters for the sham group (although the sham group crossed over to receive 0.5-mg monthly injections of ranibizumab between 24 and 36 months). At 36 months, RISE showed improvements of 11.0 letters in the 0.5-mg group, 14.2 letters in the 0.3-mg group, and 4.3 letters in the sham/crossover group.
Medscape: What, if any, ocular and nonocular adverse effects can occur with the use of ranibizumab for diabetic macular edema?
Dr. Kuppermann: There were slightly more arteriothrombotic events, principally stroke, in the 0.5-mg group than in the 0.3-mg group. While the study was underpowered to show any differences in these rare events between the groups, based on the slight safety imbalance and the lack of an incremental efficacy benefit between the 0.5-mg and 0.3-mg groups, the company applied for, and the FDA approved, the 0.3-mg dose. This is different from the approval for neovascular AMD and macular edema due to retinal vein occlusion, as the approved dose for those indications is 0.5 mg monthly.
Medscape: With the approval of ranibizumab for diabetic macular edema, what will the impact be on clinical practice?
Dr. Kuppermann: The results from the RIDE and RISE trials are quite significant and set a new standard for the treatment of diabetic macular edema. I anticipate that many patients will benefit from this treatment and that it will become the mainstay of management for diabetic macular edema.
Editor's Note:
According to the US Centers for Disease Control and Prevention, 26 million Americans have diabetes type 1 or type 2. Of the complications associated with the disease, perhaps one of the most devastating is diabetic macular edema, which can cause blindness in people with diabetes. With the approval of ranibizumab (Lucentis®; Genentech; South San Francisco, California) intravitreal injection by the US Food and Drug Administration (FDA) on August 10, 2012, for the treatment of diabetic macular edema, a new therapeutic option is now available for patients to help in the fight to preserve vision. Medscape interviewed Baruch D. Kuppermann, MD, PhD, Professor; Chief of Retina Service; Vice Chair of Clinical Research, Department of Ophthalmology, University of California, Irvine, about this important advancement.
Medscape: Diabetic macular edema is a common cause of vision loss in patients with diabetes. Could you describe the pathophysiology of this disease?
Dr. Kuppermann: The primary cause of vision loss associated with diabetes is diabetic macular edema. The mechanisms for its development are quite complex, but ultimately there is a breakdown in the tight junctions between the retinal vascular endothelial cells and the result is both intercellular and intracellular edema.
Medscape: What is the current standard of care for diabetic macular edema?
Dr. Kuppermann: The standard of care has been focal laser for focal diabetic macular edema and grid laser for diffuse diabetic macular edema. However, many physicians have used anti-vascular endothelial growth factor (ant-VEGF) agents that are injected intravitreally, such as bevacizumab (Avastin®, Genentech)and ranibizumab; bevacizumab is an off-label use, as was ranibizumab until its recent approval for this indication. Triamcinolone acetonide is also commonly used intravitreally. Steroid drug delivery implants are also being developed for this indication. Iluvien® (Alimera Sciences; Alpharetta, Georgia) is an extended-release fluocinolone acetonide intravitreal implant that was recently approved in Europe for diabetic macular edema; however, the FDA did not approve it in the United States. Ozurdex® (Allergan, Inc.; Irvine, California) is a dexamethasone implant that has completed 2 pivotal phase 3 trials, although the results are still pending.
Medscape: As you mentioned, ranibizumab is an anti-VEGF agent; it was first approved by the FDA for the treatment of neovascular age-related macular degeneration (AMD). How does its use in the treatment of AMD overlap into its use in macular edema in diabetes?
Dr. Kuppermann: The main chorioretinal vascular disorders -- that is, neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion -- all appear to be significantly mediated by VEGF. VEGF is both an angiogenic factor and a vascular permeability factor, and the pathophysiology of these key diseases can involve one or another or both of these VEGF roles.
Medscape: RISE and RIDE are 2 trials similarly designed to assess the efficacy and safety of ranibizumab for diabetic macular edema. Could you describe these 2 trials and their results?
Dr. Kuppermann: Both trials included patients with diabetic macular edema who were either treatment naive or previously treated. Patients in each trial were randomly assigned to either 0.3-mg or 0.5-mg monthly injections of ranibizumab or to monthly sham injections in a 1:1:1 allocation. All patients received monthly injections for 36 months, although those in the sham group were crossed over to receive 0.5-mg monthly injections of ranibizumab between months 24 and 36. The primary efficacy endpoint was at 24 months; however, the FDA's decision was based on both the 24-month and the 36-month data. Both ranibizumab groups in each trial showed similar results at 24 and 36 months.
In RIDE, the mean change in best corrected visual acuity from baseline at the 24-month time point was 12.0 letters for the 0.5-mg group, 10.9 letters for the 0.3-mg group, and 2.3 letters for the sham group. For RISE, the 24-month improvement in vision was 11.9 letters for the 0.5-mg group, 12.5 letters for the 0.3-mg group, and 2.6 letters for the sham group.
At 36 months, RIDE showed best corrected visual acuity improvements of 11.4 letters for the 0.5-mg group, 10.5 letters for the 0.3-mg group, and 4.7 letters for the sham group (although the sham group crossed over to receive 0.5-mg monthly injections of ranibizumab between 24 and 36 months). At 36 months, RISE showed improvements of 11.0 letters in the 0.5-mg group, 14.2 letters in the 0.3-mg group, and 4.3 letters in the sham/crossover group.
Medscape: What, if any, ocular and nonocular adverse effects can occur with the use of ranibizumab for diabetic macular edema?
Dr. Kuppermann: There were slightly more arteriothrombotic events, principally stroke, in the 0.5-mg group than in the 0.3-mg group. While the study was underpowered to show any differences in these rare events between the groups, based on the slight safety imbalance and the lack of an incremental efficacy benefit between the 0.5-mg and 0.3-mg groups, the company applied for, and the FDA approved, the 0.3-mg dose. This is different from the approval for neovascular AMD and macular edema due to retinal vein occlusion, as the approved dose for those indications is 0.5 mg monthly.
Medscape: With the approval of ranibizumab for diabetic macular edema, what will the impact be on clinical practice?
Dr. Kuppermann: The results from the RIDE and RISE trials are quite significant and set a new standard for the treatment of diabetic macular edema. I anticipate that many patients will benefit from this treatment and that it will become the mainstay of management for diabetic macular edema.