Protocol T Year 2: What Doctors Are Saying

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APRIL 2016 = .18; ranibi .18; = P NOW > .10 for pairwisefor .10 > P = .18). = P WATCH IT WATCH = .02; aflibercept vs. ranibizumab, ranibizumab, vs. aflibercept .02; = P bit.ly/eyewire0416 EyewireTV Protocol T Year 2 Update 2 Year T Protocol EyewireTV Focal or grid laser was administered in 41%, 64%, and 52%and 64%, 41%, in administered was laser grid or Focal Overall, 2-year mean visual acuity letter score improvedscore letter acuity visual mean 2-year Overall, zumab, zumab, bevacizumab, vs. zumab ranibizumaband bevacizumab, aflibercept, the in patients of associatedwas treatment aflibercept respectively; groups, treatedpatients of percentage reduced significantly a with ranibi and ranibizumab, and bevacizumab versus laser with laserless significantly with associated was treatment zumab 2). (Table bevacizumab than patients with baseline visual acuity of 20/32 to 20/40, all threeall 20/40, to 20/32 of acuity visual baseline with patients outcomes. acuity visual similar in resulted agents anti-VEGF thein letters 10.0 arm, aflibercept the in letters 12.8 by arm ranibizumab the in letters 12.3 and arm, bevacizumab to20/32 of acuity visual baseline with patients In 1). (Table thein letters 7.8 was years2 at improvement mean 20/40, andgroup, bevacizumab the in letters 6.8 group, aflibercept ( group ranibizumab the in letters 8.6 20/50of acuity visual baseline with patients In comparisons). inletters 18.3 was years 2 at improvement mean 20/320, to andarm, bevacizumab the in letters 13.3 arm, aflibercept the bevaci vs. (aflibercept arm ranibizumab the in letters 16.1 - - - -

2 The 1 RETINA TODAY and EyewireTV sat down with a number ofnumber a with down sat EyewireTV and

In patients with baseline visual acuity of 20/50 or worse,or 20/50 of acuity visual baseline with patients In In Protocol T, researchers randomly assigned 660 patients660 assigned randomly researchers T, Protocol In Retina Today Retina But year 1 was only half of the story. Would the superior the Would story. the of half only was 1 year But for patients with baseline visual acuity of 20/50 or worse. In In worse. or 20/50 of acuity visual baseline with patients for time point of the study was no longer seen at the 2-yearthe at seen longer no was study the of point time observedwas result acuity visual in difference no point; time armstreatment bevacizumab and ranibizumab the between aflibercept treatment at first showed superior visual acuityvisual superior showed first at treatment aflibercept supe the but bevacizumab, with compared improvement 1-yearthe at noted ranibizumab over aflibercept of riority During year 1 of the study, patient visits occurred everyoccurred visits patient study, the of 1 year During months4 every to up extended was interval the and weeks, 4 stable. were thickness macular and acuity visual if thereafter with DME to treatment with 2.0 mg aflibercept, 1.25 mg com mg 1.25 aflibercept, mg 2.0 with treatment to DME with Participantsranibizumab. mg 0.3 or bevacizumab, pounded months.6 beyond persisted DME if therapy laser received STUDY DESIGN AND DATA OUTLINE retina specialists to hear their interpretation of the 2-yearthe of interpretation their hear to specialists retina data. T Protocol effective? Would any of the treatment arms see a declinea see arms treatment the of any Would effective? theat up crop signals safety Would gains? acuity visual in point?time 2-year patients treated with bevacizumab or ranibizumab. or bevacizumab with treated patients years2 after seen be eyes worse-seeing in aflibercept of ity asbe agents anti-VEGF other the of one would or data, of baseline visual acuity of 20/50 or worse as measured on anon measured as worse or 20/50 of acuity visual baseline signifi showed aflibercept with treated those chart, ETDRS withcompared year 1 at gains acuity visual better cantly (Avastin, Genentech), and 0.3 mg ranibizumab (Lucentis, ranibizumab mg 0.3 and Genentech), (Avastin, improvementsvisual impressive provided Genentech) startingwith patients among that, and patients, DME for for treatment of diabetic macular edema (DME). edema macular diabetic of treatment for thatshowed 2015, February in released data, study 1-year bevacizumabmg 1.25 Regeneron), (Eylea, aflibercept mg 2.0 In February, the Diabetic Retinopathy Clinical ResearchClinical Retinopathy Diabetic the February, In ofresults the detailing data released (DRCR.net) Network firstthe trial, T Protocol group’s the of endpoint 2-year the agents anti-VEGF three of evaluation head-to-head-to-head February. How have retina specialists reacted? February. How THE EDITORS OF BY DOCTORS ARE SAYING DOCTORS Two-year end of T trial were released at the the DRCR.net’s Protocol results from PROTOCOL T YEAR 2: WHAT PROTOCOL T YEAR 2: WHAT NEWS FEATURE 12

RETINA TODAY responders in a particular cohort responders in a particular cohort least 10 letters. The proportion of age of patients who gained at the data by noting the percent responders.” Dr. Zarbin discussed to look at the proportion of visual outcome, so it’s important given study achieve the average a minority of patients in any parse data. He said that “only unique ways that researchers can a DME patient. which anti-VEGF would best suit treatment burden when choosing cialist would have to consider the possibility that a retina spe he said. Such a finding rules out with one agent versus another,” burden of treatment isn’t less among the treatment arms. “The was not significantly different the median number of injections the 2-year trial data showed that at the Rutgers New Jersey Medical School, pointed out that chair of the Institute of Ophthalmology and Visual Science PHYSICIAN REACTION Ranibizumab Ranibizumab Bevacizumab Aflibercept Agent Anti-VEGF TABLE 2.LASERAND SAFETYDATAFROMTHEPROTOCOLTSTUDY, 2-YEARDATA Dr. Zarbin also pointed to the Dr. Zarbin also pointed to the In an interview with

APRIL 2016 0.3 mg 1.25 mg 2 mg Dose Retina Today 6 6 5 During Year2 Median Injections - - , Marco Zarbin, MD, PhD, , Marco Zarbin, MD, PhD, Ranibizumab Bevacizumab Aflibercept Agent Anti-VEGF ENROLLED INPROTOCOLT,2-YEARDATA TABLE 1.VISUALACUITYIMPROVEMENTINPATIENTS Abbreviation: VA, visual acuity 0.3 mg 1.25 mg 2 mg Dose global P 15 16 15 Total, Years1and2 Median Injection value P =.08 15-letter gain in vision from baseline, there is no significant 15-letter gain in vision from baseline, there is no significant meaningful response to the treatment, he said. indicates the likelihood of the patient having a clinically “If you look at the percent of patients achieving a 10- or “If you look at the percent of patients achieving a 10- or 12.3 letters 10 letters 12.8 letters at 2years Letters Gained Overall bevacizumab: ranibizumab vs ranibizumab: aflibercept vs bevacizumab: aflibercept vs global confounders, adjusted forpotential global P 12% 8% 5% With APTCEvents Percentage ofPatients values P P =.09 =.047; P 8.6 letters 6.8 letters 7.8 letters Baseline VA 20/32 to20/40 Patients With at Year2in Letters Gained interactions P .10 for all all for >.10 values P

P P =.047 =.20 =.34

P 16.1 letters 13.3 letters 18.1 letters Baseline VA With 20/50to 20/320 Year 2inPatients Letters Gained at bevacizumab: aflibercept vs bevacizumab: ranibizumab vs ranibizumab: aflibercept vs bevacizumab: aflibercept vs P 52% 64% 41% Laser Therapy Patients Receiving Percentage of ranibizumab: bevacizumab vs ranibizumab: aflibercept vs values values P

P P P P

= P

= =

=.01 =.04

<.01 .18

.18 .02

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N Engl J APRIL 2016 n . Dr. Brown agreed, and noted that the risk of APTC eventsAPTC riskof the that noted and agreed, Brown Dr. on colleagues his as dismissive as not was Khurana Dr. 2year T Protocol the although that, noted Khurana Dr. TProtocol data, the treats industry how of Regardless Dr. Brown noted that such APTC events were not seen inseen not were events APTC such that noted Brown Dr. couldtrial the for criteria entry the that said Zarbin Dr. . 2015;372(13):1193-1203. delivered good news for patients and doctors: it showed thatdelivered good news for patients and doctors: effective,are DME treat to usedagents anti-VEGF three all ofmenu a have to continue will doctors retina that meaning treatment. DME initiating when options 1. Wells JA, Glassman AR, Ayala A, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from the comparative effectiveness randomized clinical trial [published online ahead of print February 27, 2016]. Ophthalmology 2. Wells JA, Glassman AR, Ayala A, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. Med identify the magnitude of risk of APTC events is not presentnot is events APTC riskof of magnitude the identify theseof incidence expected the given size this of study a in said. he patients,” diabetic comparable in events of population a in blindness of risk the by outweighed was ortime the of 99% are, patients think “I patients. diabetic there though even shots,’ the want I ‘Hey, say, to going more, said.he event,” APTC an of risk theoretical a is data “[The anomaly. an as data safety the of question the we think I “However, said. he concern,” for cause give do] prac into it put to information more and data more need which influence to going is that how on perspective tical choose.” we treatment OUTSIDE CONSIDERATIONS pickus helping in information valuable “very provide data patients, DME for agent” anti-VEGF appropriate most the becan data the how regarding concern of areas are there playersother by used are this like data “Sometimes used. tocompanies, insurance as such field, care health the in “Isaid. Khurana Dr. using,” be should doctors what mandate alluse to choice the have doctors that important is it think population.” patient our for agents three ranibizumab should have the best safety profile because it because profile safety best the have should ranibizumab “It remarked. he faster,” circulation systemic the from clears issuescardiac some in imbalance an to due been have could say.”to hard it’s “but said, Brown Dr. baseline,” at ocu for agents anti-VEGF assessed that scope similar of trials rememberto important is it that said he and indications, lar forrisk at already is study DME a in population the that he patients,” sicker much have trials “These issues. safety events adverse show to likely more much are they “and said, strokes.”and attacks heart as such events,adverse of rate the on influence important an have withpatients which in T, Protocol as such trials in that and seeto unsurprising is it enrolled, were stroke of history a trialthe said, Zarbin Dr. Further, events. APTC of rates high agent’s anti-VEGF an detect to powered not simply was accuratelyto ability “The occurrence. event APTC on effect - - - - - = .34) or the ranibi the or .34) = P = .20). The study authorsstudy The .20). = P that, although the gap between aflibercept andaflibercept between gap the although that, = .047), but the difference was not significant between significant not was difference the but .047), = P Dr. Brown found the safety results surprising after consid after surprising results safety the found Brown Dr. Dr. Zarbin said that, in general, retina doctors should con should doctors retina general, in that, said Zarbin Dr. The researchers found that APTC events occurred at a ratea at occurred events APTC that found researchers The The surprises Dr. Khurana mentioned may include include may mentioned Khurana Dr. surprisesThe Surprises aside, Dr. Khurana praised the study because itbecause study the praised Khurana Dr. aside, Surprises The results at year 2 “were a little bit surprising becausesurprising bit little a “were 2 year at results The Dr. Brown also pointed to the fact that gains for afliberceptfor gains that fact the to pointed also Brown Dr. David Brown, MD, of Retina Consultants Houston, toldHouston, Consultants Retina of MD, Brown, David ering the pharmacokinetics of the three drugs. “If anything,“If drugs. three the of pharmacokinetics the ering states that a class effect of the drug is a risk of stroke, heartstroke, of risk a is drug the of effect class a that states death.” vascular and attack, of systemic safety risk for patients, and the reason I feelI reason the and patients, for risk safety systemic of said.he drugs,” the of effect class a is it because is way that clearlyvery it drug, each for label the at look you if fact, “In warranted continued evaluation in future trials. future in evaluation continued warranted have“I agents. anti-VEGF administering when safety sider degreesome pose do drugs these that concern a had always noted that similar APTC events data had not been demon been not had data events APTC similar that noted andtrials, clinical reported previously in consistently strated arm ranibizumab the in events APTC of rate higher the that arms ( arms ( arms bevacizumab and aflibercept the ( arms bevacizumab and zumab of 5% in the aflibercept arm, 8% in the bevacizumab arm, andarm, bevacizumab the in 8% arm, aflibercept the in 5% of differ significant a was There arm. ranibizumab the in 13% ranibizumaband aflibercept the between measure thisin ence Collaboration (APTC) events found in the ranibizumab ranibizumab the in found events (APTC) Collaboration 2. year in arm SAFETY Trialists’ Anti-Platelet of number higher significantly the does give us a lot of guidance, in the sense that this is theis this that sense the in guidance, of lot a us give does agents anti-VEGF three all compared really that study first said. he treatment,” DME for provided data that retina specialists can use when choosingwhen use can specialists retina that data provided studythe believe “I treatment. DME for agent anti-VEGF an they were not consistent with the year 1 data,” Rahuldata,” 1 year the with consistent not were they Vitreous Retina California Northern of MD, Khurana, EyewireTV.told Associates, at year 1 were sustained through year 2, which dispels thedispels which 2, year through sustained were 1 year at unluckywas reason, whatever for “ranibizumab, that notion 1. year at expected” than better performed aflibercept and patient’s standpoint, the quicker you get to your best vision,best your to get you quicker the standpoint, patient’s said. he life,” of quality your for is it better the ranibizumab was closed by year 2, retina specialists should specialists retina 2, year by closed was ranibizumab afliberceptof superiority showed that data the ignore not a“From 1. year at bevacizumab and ranibizumab over continued to require some injections in year 2.” year in injections some require to continued Today Retina “I think that means there is no clinically important differenceimportant clinically no is there means that think “I by drugs different three the among outcome visual the in cohorteach in patients the of 80% approximately and 2, year difference among the three drugs by year 2,” Dr. Zarbin said. Zarbin Dr. 2,” year by drugs three the among difference