COVER STORY
`
`Anti-VEGF Therapy
`for Diabetic Macular
`Edema: An Update
`
`Ranibizumab as an adjunct to laser photocoagulation for DME
`will be evaluated in a phase 3 clinical trial.
`
`BY PASCALE G. MASSIN, MD, PHD
`
`I n the past decade, the introduction of drugs that
`
`inhibit the action of vascular endothelial growth fac-
`tor (VEGF) has had a significant impact on the field
`of ophthalmology. Groundbreaking research in the
`1990s identified the key roles VEGF plays in pathologic
`angiogenesis as well as in normal vessel development.1,2
`Subsequently, it was recognized that levels of VEGF are
`elevated in many ocular neovascular diseases, including
`age-related macular degeneration (AMD), diabetic
`retinopathy (DR), diabetic macular edema (DME), central
`retinal vein occlusion, and iris neovascularization.3-7
`Aiello and colleagues3 found that levels of VEGF were
`elevated in a number of ocular neovascular diseases,
`including DR and retinal vein occlusion. In ocular fluid
`samples taken from patients undergoing surgery, they
`detected VEGF in 69 of 136 patients with DR, compared
`with two of 31 patients with no neovascular disorder.
`VEGF concentration was higher in patients with prolifer-
`ative DR than in patients with nonproliferative DR or
`nondiabetic patients.
`Diabetic retinopathy is the most common microvas-
`cular complication of diabetes, affecting approximately
`half of patients with diabetes.8 DME, which is brought
`on by vascular permeability, is the principal cause of
`central vision loss in patients with DR. In patients who
`have been diagnosed with diabetes for 15 years, the
`prevalence of DME is 20% in those with type 1 diabetes,
`25% in those with insulin-dependent type 2 diabetes,
`and 15% in those with type 2 diabetes not taking
`insulin.9,10
`
`54 I RETINA TODAY I SEPTEMBER/OCTOBER 2008
`
`Laser photocoagulation, the current
`reference standard treatment,
`reduces but does not eliminate the
`risk of vision loss from DR.
`
`Current treatment options for DME are suboptimal.
`Laser photocoagulation, the current reference standard
`treatment, reduces but does not eliminate the risk of
`vision loss from DR. In addition, laser does not reverse
`existing vision loss.
`While laser photocoagulation is effective in halting the
`progression of focal DME, it is less effective in patients
`with diffuse DME, a generalized breakdown of the blood-
`retinal barrier. Randomized studies have shown that laser
`photocoagulation reduces visual loss due to DME, but
`despite laser treatment 15% of patients still lose
`vision.11,12 For this reason, a number of alternative treat-
`ments for treatment of DME are under investigation,
`including the use of VEGF inhibitors.
`
`R ATIONALE FOR VEGF INHIBITION IN DME
`The rationale for the use of a VEGF inhibitor in the
`treatment of DME is strong. Funatsu and colleagues4
`found elevated levels of VEGF in the aqueous humor in
`eyes of patients with DME. Qaum and colleagues13
`showed in mice that blood–retinal-barrier breakdown in
`experimental diabetes is VEGF dependent, creating an
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`COVER STORY
`
`imbalance in vascular permeability and a capillary per-
`meability similar to that in AMD. They concluded that
`VEGF inhibition should be a useful approach to treat-
`ment of blood–retinal-barrier breakdown in diabetes.
`A phase 1/2 study was conducted to investigate the
`efficacy of the VEGF-inhibiting drug ranibizumab
`(Lucentis, Genentech) in the treatment of DME. The
`RESOLVE (A Randomized, Double-Masked, Multicenter,
`Phase 2 Study Assessing the Safety and Efficacy of Two
`Concentrations of Ranibizumab [Intravitreal Injections]
`Compared With Non-Treatment Control for the
`Treatment of Diabetic Macular Edema With Center
`Involvement) study, was sponsored by Novartis and con-
`ducted at centers in Europe.
`The study evaluated the effect of ranibizumab on retinal
`edema and visual acuity in 151 patients with DME with
`center involvement. Patients with central macular thick-
`ness of 300 µm or greater were randomly assigned to
`receive sham injection or one of two doses of ranibizumab
`— 0.3 mg or 0.5 mg — in three monthly intravitreal injec-
`tions followed by treatment as required for 9 months. The
`primary endpoint in the 1-year study was visual function
`at 6 months. The study design allowed escape to photoco-
`agulation if necessary, and also allowed the investigator to
`double the dose (from 0.3 mg to 0.6 mg or from 0.5 mg to
`1.0 mg, depending on which arm the patient was in) after
`1 month if resolution of edema was incomplete.
`The RESOLVE trial is now concluded, and final data
`should be available soon. In an interim analysis of
`6-month data in 42 patients,14 an improvement in visual
`acuity and a decrease in central macular thickness was
`observed in patients treated with ranibizumab.
`Mean central macular thickness increased in
`17 patients receiving sham injection and decreased in
`25 patients receiving either dose of ranibizumab. In
`accord with the study design and treatment criteria, the
`dose was doubled in 12 of the 14 patients receiving
`0.3 mg and in four of the 11 patients receiving 0.5 mg.
`Visual acuity decreased at 6 months in the patients receiv-
`ing sham injections and increased in both treatment groups.
`While these preliminary results were promising, few
`patients in this interim analysis experienced complete
`resolution of DME. With this in mind, a phase 3 trial of
`ranibizumab for DME, which recently began enrolling
`patients, has been designed to include a laser photocoag-
`ulation group and further explore the effect of
`ranibizumab on visual function and macular thickness.
`
`PHA SE 3 TRIAL DE SIGN
`The phase 3 trial, called RESTORE (A Randomized,
`Double-Masked, Multicenter, Laser-Controlled Phase 3
`Study Assessing the Efficacy and Safety of Ranibizumab
`
`[Intravitreal Injections] as Adjunctive and Mono-Therapy
`in Patients With Visual Impairment Due to Diabetic
`Macular Edema),15 will enroll 315 patients with either
`type 1 or type 2 diabetes.
`This multicenter international trial, sponsored by
`Novartis, is designed to confirm the efficacy and safety of
`ranibizumab 0.5 mg as adjunctive therapy added to laser
`photocoagulation and/or as monotherapy in patients
`with visual impairment due to DME.
`Patients in the RESTORE trial will be randomly
`assigned to one of three arms: laser photocoagulation
`plus ranibizumab 0.5 mg, laser plus sham injection, and
`sham laser plus ranibizumab injection. They will receive
`monthly treatments for 12 months.
`Notably, the primary endpoint of the RESTORE trial is
`symptomatic or functional rather than anatomic change.
`The primary endpoint will be mean change in best cor-
`rected visual acuity from baseline over 12 months.
`Secondary endpoints will include central retinal thick-
`ness, patient-reported outcomes and other measures.
`Treatment begins with a loading phase, with three con-
`secutive monthly injections of ranibizumab or sham. This
`is followed by a maintenance phase, in which monthly
`injections continue unless stable vision is reached. Stable
`vision is defined as either (1) no further improvement in
`BCVA is attributed to treatment with intravitreal injec-
`tion at the last two consecutive visits in the opinion of
`the investigator, or (2) BCVA of greater than 84 letters
`(the approximate equivalent of Snellen 20/20) is
`observed at the two last consecutive visits. If BCVA
`decreases due to DME progression in the investigator’s
`opinion, treatment is reinitiated with more than two
`monthly injections until stable vision is reached again.
`
`CONCLUSIONS
`A strong rationale exists for the further study of
`ranibizumab as a treatment for DME. The aim of treat-
`ment of ocular neovascular diseases with ranibizumab is
`to reduce hyperpermeability of retinal vessels and inhibit
`neovascularization. Preliminary results from early
`exploratory clinical trials are encouraging and will clarify
`the future role of ranibizumab therapy across the spec-
`trum of retinal vascular diseases.16,17
`Treatment of DME with ranibizumab has shown prom-
`ising results in investigator-initiated phase 1 and 2 clinical
`trials in the United States.18 In the READ (Ranibizumab
`for Edema of the Macula in Diabetes) phase 2 study, the
`vision of ranibizumab-treated patients improved to a
`mean 20/63 at 6 months, while acuity remained essen-
`tially unchanged at 20/80 in both laser and combination
`treatment groups.
`The study design for the RESTORE trial, using
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`SEPTEMBER/OCTOBER 2008 I RETINA TODAY I 55
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`COVER STORY
`
`ranibizumab as an adjunct to laser photocoagulation in
`the treatment of DME, is a rational concept worthy of
`evaluation. Laser photocoagulation remains the gold
`standard of treatment for DME. In our participation in
`phase 2 RESOLVE study, many patients treated with
`ranibizumab experienced improvement in edema, but
`few experienced complete resolution. With ranibizumab
`as an adjuvant to laser photocoagulation, the chance of
`resolving edema and improving visual acuity promises to
`be much greater. ■
`
`Pascale G. Massin, MD, PhD, is in the Department of
`Ophthalmology of the Hôpital Lariboisière, Paris, France.
`Dr. Massin states that she is a paid consultant for Novartis
`and principal investigator in the RESOLVE and RESTORE
`studies. She may be reached at +33 1 49 95 64 88; fax: +33
`1 49 95 64 83; or e-mail: p.massin@lrb.aphp.fr.
`
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`Mylan v. Regeneron, IPR2021-00881
`Page 3
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