Alternative Therapies - Nancy Melberg Holekamp
There have been other therapies for choroidal neovascularization, so whathappened to those or what are we going to see in the future. Yes there arealternatives for treating our patients with exudative age-related maculardegeneration. You might remember the old days when all we had was laser andwe had no other choice, but we actually have some choices and we're going totalk about those choices in the next twenty minutes or so and we'll round up theusual suspects.
Verteporfin, pegaptanib and triamcinolone, we've used all of these things forexudative AMD in the past. Glaringly absent from here is bevacizumab, which iscertainly a choice for all of us, but I'm actually not going to talk aboutbevacizumab. Larry has touched on it and it really could be a discussion untoitself and I'm not going to talk about triamcinolone, and I'm not going to talk abouttriamcinolone or bevacizumab because again we want our discussions couchedin evidence-based medicine and we don't really have good level one evidence forthose two agents in exudative AMD and you'll see that we're going to talk mostlyabout the clinical trial results in verteporfin and pegaptanib and see where theymeasure up against ranibizumab.
And we're going to do it by looking at lesion types and so what are our choicesas we take care of a patient with predominantly classic choroidalneovascularization?
And we do have level one evidence, we have one-year TAP results and VISIONTrial results and we're going to compare these based on the various studyoutcomes which include loss of <15 letters which is about 3 lines, loss of <30letters which is about 6 lines, gain of > 15 letters, which is that three-line visualgain that we are all keying in on now, and then mean change of vision frombaseline.
So, we'll look at loss of <15 letters and we'll look at the TAP Study forpredominantly classic lesions and you might recall this is how verteporfin gotFDA approval. It seemed to be beneficial compared to placebo for predominantlyclassic membranes, but you'll also see that the mean change in vision is netnegative, and Larry reviewed that, and if we look at pegaptanib for predominantlyclassic lesions, again, there was treatment benefit compared to sham, but themean change in vision is still a net negative.
Well, if we want to see how that measures up to ranibizumab, we look at theANCHOR clinical trial, which again looked at predominantly classic lesions, andthis bar right here of the result for photodynamic therapy at 64%, that's a
repeatable reproducible number for losing <15 letters at baseline. It tends to be inthe mid-60's.
But for the clinically available dose of ranibizumab, that's 96%. In a head to headcomparison of ranibizumab to photodynamic therapy, it really blowsphotodynamic therapy out of the water.
If you look at a secondary endpoint, which is significant visual gain > 15 letters,again we look at PDT. This is a reproducible number. 5.6% was the percentagein the ANCHOR Trial but in the TAP Study this number was 5.7%. It's unlikelyyou're going to get significant visual gain with photodynamic therapy asmonotherapy.
The clinically available dose of ranibizumab was 40%, which is just astounding.
If we look at other visual outcomes such as losing > 6 lines of vision, which isabout 30 letters, we see that you could still have severe vision loss withphotodynamic therapy but not really in the clinically available dose ofranibizumab.
So, what this leaves us with is an algorithm for treatment of predominantly classiclesions and if you look at the level one evidence, if ranibizumab is available, youshould recommend it as first line therapy, the evidence is really that strong.
However, if ranibizumab is not available, what do you do? Well, I would probablyrecommend that you consider extrapolating the results of ranibizumab tobevacizumab, although the precise risks and benefits are unknown, it's probablysuperior to verteporfin and pegaptanib, and you could of course considermonotherapy PDT and you could consider pegaptanib, but you'd likely be givingyour patient an inferior treatment.
So that was predominantly classic lesions. Let's say we're taking care of apatient with a minimally classic choroidal neovascular membrane.
Again, we have good evidence from large clinical trials. We have the one-yearTAP results, the one-year VIM results and we have the VISION Trial results, andwe're going to look at these same study outcomes.
In the TAP Study for minimally classic choroidal neovascularization, there reallywasn't much treatment benefit, and again the mean change from baseline wasquite abysmal.
If we look at the VIM Study, we actually got some positive results in the VIMStudy where 72% of eyes lost less than 15 letters and there seemed to be asignificant treatment benefit in the VIM Trial with standard fluence.
If we look at pegaptanib, we see in eyes with recent disease progression therealso appeared to be a treatment benefit. But in both of the VIM Trial and thepegaptanib VISION trials, there was still a net loss of vision at one year.
If we are now taking care of a patient with occult but no classic choroidalneovascularization, we have clinical trial results from the VIP Trial and theVISION Trials. If we look at those, in VIP we see that there again was very littletreatment benefit for these occult membranes in the VIP Study and that the meanchange in vision was still a net negative.
And if we look at the VISION Trials, we see that there was some treatmentbenefit, but again, still mean change in vision from baseline was a net negative.
If we compare these clinical trial results to what we know from the MARINA Trial,which included minimally classic or occult with no classic choroidalneovascularization, we see that, that the results of treatment benefit are reallyoutstanding with the clinically available dose of ranibizumab. Ninety-five percentof patients lost <15 letters of vision from baseline. I mean that was anoutstanding result from this clinical trial.
If we look at a secondary endpoint, which is the number of patients showingsignificant visual improvement, that's about 33%, almost 34%.
So if we're look at an algorithm for the treatment of minimally classic or occult noclassic choroidal neovascular membranes and we're looking at the best evidencewe have, if ranibizumab is available, you should recommend it as first linetherapy based on level one evidence, and if ranibizumab is not available, wellagain,
I'd probably considering extrapolating the results of ranibizumab to bevacizumabbecause it is likely that bevacizumab for minimally classic and occult membranesis superior to pegaptanib and verteporfin. There may be one exception in thatPDT seemed to be more beneficial for small lesions <4 disc areas in size, but ifyou were to consider pegaptanib, you'd likely be recommending inferiortreatment.
So, here we are, we are retina specialists and we still have the PDT laser in ouroffice, we still have personnel who know how to give intravenous chemotherapyfor age-related macular degeneration, what's the role of PDT in the era of anti-VEGF therapy.
Well, these are the things you can consider. You could consider PDT whenranibizumab and bevacizumab are not available, and this is true for other parts ofthe world where they haven't, regulatory agencies haven't approved them yet. You could use PDT for patients who cannot tolerate intraocular injections, and inthe past several years I've had only one such patient. It's amazing how acceptingpatients are of intraocular injections by and large. You could consider PDT forpatients who cannot return monthly and you could consider it for patients whomight have a theoretical risk of intraocular injections that might be higher than theaverage eye, although I haven't really run into this yet in my own practice. Andthen finally, and although this is a vanishingly small number of patients, youprobably all remember the days when we did one or two PDT's and people had agreat result. You could consider PDT in those eyes thinking that it would limit thenumber of visits or the number of treatments.
What else could you consider? Well, you could consider PDT when there is asmall classic lesion seen outside the fovea. Again, we all have experience withPDT and we remember those small lesions that did well with just one or twotreatments. I could minimize the need for frequent injections. It could make lesssevere the destructive effect of PDT because it's outside of the fovea, and if theCNV were to recur and enlarge it might do so less quickly under the fovea. Butyou have to remember that verteporfin and photodynamic therapy was notapproved by Medicare for anything but subfoveal choroidal neovascularization. Itmay not be covered by insurance.
And then finally, we all have PDT lasers in our office, we're all used to giving thischemotherapy. We're not hearing a lot about combination therapy with anti-VEGF injections, and that's because of the potential benefits.
If monotherapy is good, maybe dual therapy or triple therapy is even better. Maybe there is a potential for even better visual acuity outcomes. There is also achance to hypothesize about the safety or the benefits of fewer injections. There's going to be less ocular risk, there's going to be less systemic risk.
It could be most cost-effective even with the increased cost of PDT because ofthe reduced number of injections. And finally, it could be more user-friendly forboth the physician and the patient who aren't making these monthly trips.
So the next series of slides I'm going to take you through an interestingcautionary tale about early clinical trial results in combination therapy. And this isa Phase IB clinical trial combining pegaptanib and photodynamic therapy. Thiswas established for purposes of defining safety of combination therapy, andPhase IB clinical trials tend to be small. This trial only had 18 patients, they allreceived pegaptanib injections and this should say Q 6 weeks for 90 days, andthere were two treatment groups. There were 8 patients who got pegaptanib only
and there were 10 who got combination therapy with pegaptanib and PDT…andagain, the purpose was again to establish safety and after three months theysaid, there appear to be no safety issues. But then they looked at their visualoutcomes and they said well 90% of eyes in both groups lost <3 lines of visionand as it turned out, the combination group may actually be better at giving afinal higher visual acuity and these were their results. If you got pegaptanib aloneyou had a 25% chance of gaining > 3 lines of vision, but if you got pegaptanibwith PDT you had a 60% chance of being in this group that experiencedsignificant visual improvement, but the catch here is that the numbers are small. There were only 8 patients in one group and 10 patients in the other group, andso even though this looks like a huge difference, it was not statistically significantgiven the small numbers. So the clinical trial investigators actually went to thepatients in this combination group and they said, well, we've got to show youthese case examples and that's what I'm going to show you now, the treatmentsequence of case #1. In case #1 there was combination therapy at baseline, andthen there was maintenance therapy with pegaptanib through 9 injections.
And if we look at this case, clearly there was subfoveal exudative age-relatedmacular degeneration with late leakage and vision was poor, 20/160 abouthalfway through the treatment at week 30 there is decreased leakage, vision isbetter and when we get to week 54 there was a 7 line gain at one year and therewas no leakage and you would look at this case and you would say, aha, that'show to give combination therapy. You have to give PDT and pegaptanib atbaseline and then just continue with pegaptanib maintenance.
But then you have Case #2, um, PDT was actually given twice, at week 1 andweek 11, and then maintenance therapy was carried out, and if we look at thiscase we see that clearly there is subfoveal exudative AMD, there is late leakage,vision is poor at 20/320 then we get to about week 30, vision is improved, there isless leakage we get to week 54, things are looking really good and in fact, wehave follow-up on this case through two years it was an 8-line gain at two yearsand still no leakage and you would look at case 2 and you'd say, aha, that's howcombination therapy should be given. Two treatments with PDT at baseline andthen continue with pegaptanib.
I have one other case to show you. In this case the combination therapy wasn'tgiven until week 11 and then maintenance pegaptanib was given through week20, uh, through week 54 and the photodynamic therapy wasn't performed at firstbecause there was hemorrhage and when the hemorrhage cleared thephotodynamic therapy was given and then this eye did very well coming up to20/50 and there was a 5-line gain at one year with no leakage, and you'd look atthis and you'd say, aha, that's when you should give your combination therapy, atweek 11.
Well, it's important to remember that this series was an open-label, non-randomized small Phase IV clinical trial. The physician was knowingly treatingthe classic leakage with photodynamic therapy. The question to ask is, whathappens when the combination therapy is randomized and double-masked.
Well, they did this, and this is an incredibly interesting slide. This is one of thebest slides in this slide deck. They started a randomized clinical trial ofpegaptanib and PDT and everybody was going to get pegaptanib every 6 weeksand they were going to get verteporfin in this group and a sham PDT treatment inthis group and they were going to look at the rate of responders after 54 weeks.
But this is the key. The investigators discontinued this clinical trial when the firstevaluation of the data did not support Phase I experience, and this is quitecommon throughout medicine, where larger clinical trials do not support thefindings of smaller pilot studies, or Phase I clinical trials. And this is anotherexample, we're not going to see this in print. This clinical trial was discontinuedand we're not going to read that combination therapy didn't work.
So, I know you're sitting in the audience and you're saying, gee they used thewrong agent, of course it wasn't going to work. They used pegaptanib, why didn'tthey use something that really works, and of course we have data because of theFOCUS Trial, which was a Phase I, Phase II clinical trial that looked atranibizumab and compared it to, well actually it was verteporfin and compared itto verteporfin-ranibizumab combination therapy. And for being a Phase I, PhaseII clinical trial, these are pretty good numbers, 81 patients in each group and theylooked as a primary endpoint the percentage of patients with <3 lines of visionloss and these are the results and the PDT only group, again, this is areproducible, repeatable finding that about 68% of patients could lose <15 letters,but in the PDT plus ranibizumab group, that result was 91% and you have to askyour question. Was it the addition of ranibizumab to PDT or was it ranibizumabalone, and though we're not supposed to make comparisons across clinical trialsbecause they were non-concurrent, they might not have had the exactly sameinclusion criteria, but the FOCUS Study results were pretty much likeranibizumab alone, where 96% of patients had significant, uh, loss <15 letters ofvision.
So we can look at the FOCUS Trial again, we can look at another one of thevisual acuity endpoints of subjects gaining > 15 letters, that's that five, that's that3-line improvement in vision and we see that for photodynamic therapy, againthis is a reproducible number, it's very low around 5%. For PDT plus ranibizumabcombination therapy it was 24%, and again we're not supposed to do this, we'renot supposed to compare across clinical trials but in the ANCHOR trial withranibizumab alone, that result was 40% and both of these trials were looking atpredominantly classic choroidal neovascularization.
So, I'll end by saying that that combination therapy is exciting. I'm excited to seethe clinical trials that are going to be well done and compare combination therapyto monotherapy with ranibizumab because I do like the prospect of better visualacuity outcomes. I do like the prospect of the potential advantages of fewerinjections, and again, it's less ocular risk, its less systemic risk, it could be morecost effective, it could be more user-friendly.
I think that there are great potential advantages to combination therapy. Soagain, if we want to review the alternative therapies in the era of ranibizumab, inconclusion I would say that you could consider photodynamic therapy asmonotherapy when ranibizumab and also bevacizumab are not available, if youhave predominantly classic and smaller minimally classic or occult with no classiclesions with presumed recent disease progression.
When ranibizumab and bevacizumab are available you could consider PDT in alimited number of situations, such as when patients can't tolerate intraocularinjections, they can't make the monthly visits, they might have an increased riskof these injections, um, in patients who did well with PDT, but again as we saidthis is a vanishingly small number since we are not doing PDT monotherapy verymuch anymore, or for an extrafoveal lesion though you may run into someinsurance issues.
Um, if you're looking at combination therapy of ranibizumab or bevacizumab, forme the bottom line is vision. If I were a patient, I would want the best chance atfinal visual outcome and that would be the bottom line for me. But, it's interestingto think that if combination therapy can at least match that visual acuity outcomeand do it with fewer injections in a safer overall profile, it's really quite exciting tothink about, but we have to remind ourselves that there still really is no good levelone data yet.
So at that, maybe some questions, uh….so, Nancy, have you let's say in the lastsix months of clinical practice given a combination of something in addition toranibizumab or bevacizumab?
NANCY MELBERG: No, I don't give combination therapy myself. Um, and I don'tdo it for a lot of reasons. One has to do with the distinction between clinicalpractice and research. In clinical practice you have an ethical obligation to do thevery best thing for your patient and in clinical research you're designing a trial toanswer a specific question. And so if I were going to give a treatment to mypatient I would have to have good evidence that I was doing the best thing forthem. That evidence hasn't really reached a point where I'm comfortable givingcombination therapy. I will tell you that in our office we do have an ongoing IRBapproved protocol for combination therapy that my partners are using, but there
the patient is told that they are part of a clinical trial and that they are randomizedto either monotherapy or a combination therapy.
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