Anti-VEGF, A Biography: Part 3

This story started in the early days of VEGF's isolation in the 1970s and brought us to the discovery of ranibizumab and bevacizumab in the mid 2000s. The data revealed at the ASRS meeting in 2005 would change retina forever-and usher in a new competitor with a chance to disrupt the landscape yet again.

Don't miss the final episode of this fascinating and important story told by those that lived it. We're bringing back some of the voices you've heard before, and some new ones, too. John D. Pitcher III, MD, invites Bob Avery, MD; David Brown, MD; Jeffrey Heier, MD; Nancy Holekamp, MD; Kirk Packo, MD; Phillip Rosenfeld, MD, PhD; and Bob Vitti, MD, to tell the latest chapter of anti-VEGF's biography.

Nothstein: On this episode of New Retina Radio.

Heier: It is remarkable how quickly bevacizumab was, um, embraced by the retina community, and how quickly it was used for these patients.

Holekamp: What we learned is that we were under treating way back then, and people weren't getting the visual acuity results that they did in the clinical trials.

Vitti: It's a decoy receptor, and that's why we call it a trap.

Packo: This was the only talk I've ever given in my professional career where I got a standing ovation.

Rosenfeld: Claiming that we'd performed these horrendous, heinous, outrageous, dangerous experimentation on patients.

Avery: Really could have ended it right there.

Nothstein: That, and more, coming up.


Nothstein: You're listening to New Retina Radio, from Retina Today, Eyetube, and Bryn Mawr Communications.

Krzywonos: Um, Greg, are we recording?

Greg: Yes.

Krzywonos: Okay, cool. Uh, welcome back, everybody. I’m Scott.

Jaraha: I'm Ranna.

Krzywonos: Here it is, the season one finale of New Retina Radio. We're going to conclude the anti-VEGF biography we've explored in two previous episodes.

Jaraha: Scott and I are going to recap those two installments, and we're going to do so quickly. If you haven't listened to them, stop this episode, download them, and listen to them. There are lots of important details in there.

Krzywonos: Ranna's going to start us off. You ready?

Jaraha: Oh, yes. All right, so in 1971, Judah Folkman discovers angiogenesis, and in 1989, Henzel and Ferrara isolate VEGF.

Krzywonos: Angiogenesis, it was determined, is a key reason that patients are diagnosed with AMD. It was also determined that intravitreal injection of anti-VEGF could halt progression of AMD in some patients.

Jaraha: In 2004, the FDA approved one drug that addressed angiogenesis. That drug, Macugen, was a modest success at best.

Krzywonos: While all of this was going on, Genentech developed an anti-VEGF agent called Lucentis, which would be used to treat wet AMD. Researchers in the study got the impression that the drug worked, and that it worked well.

Jaraha: Phil Rosenfeld, a retina specialist at the Bascom Palmer Eye Institute, was the lead researcher in trials assessing Lucentis. He spent time looking into another method of treating wet AMD: by using intravenous Avastin to treat bilateral disease. Avastin was a cancer drug which was produced by Genentech, the same company producing Lucentis.

Krzywonos: Phil evaluated intravenous Avastin for bilateral AMD in the SANA trial. He tried to expand the study, but he faced some resistance, primarily due to safety concerns.

Jaraha: Meanwhile, Lucentis' pair of phase 3 trials continued to chug along. Phil knew this, because he was the lead researcher on one of those studies.

Krzywonos: And then, aha.

Jaraha: Aha.

Krzywonos: Phil had a eureka moment. What if, he asked, I compound Avastin and inject it into the eye? His calculations showed that he could do this for about $50 a dose.

Jaraha: Phil consulted with the leadership at Bascom Palmer. He got their blessing and started working with a pharmacist there to compound Avastin and soon gathered some patient data.

Krzywonos: All of this was coming to a head in the summer of 2005. The place: Montreal, Canada. The setting: the ASRS Annual Meeting.

Jaraha: Once again, we're turning to John Pitcher III, to tell the story. Here it goes.

Pitcher: Where we last left off, we were discussing the ASRS 2005 meeting in Montreal. You remember some of our story tellers. There's Phil.

Rosenfeld: Hi. My name is Philip Rosenfeld. I'm a professor of ophthalmology at the Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine.

Pitcher: There's Kirk.

Packo: Hi. I'm Kirk Pacco, retinal specialist in Chicago. I'm also the professor and chair of the Department of Ophthalmology at Rush University here in Chicago.

Pitcher: And there's Jeff.

Heier: Hi. I'm Jeffrey Heier. I'm the co-president and medical director of Ophthalmic Consultants of Boston, and for the last 18 years or so, I've served as the Director of Retinal Research for Ophthalmic Consultants of Boston.

Pitcher: They were all in Montreal that summer.

Rosenfeld: So, here we are at the ASRS meeting, July, 2005.

Pitcher: The phase 3 MARINA data was about to be released, which would show quantitatively what meeting attendees already knew. The intravitreal Lucentis injections could be used to treat wet AMD. But this wasn't only the Lucentis show. There were some presentations slated on the use of intravitreal Avastin for treating wet AMD, and anecdotal evidence was encouraging, but the scientists in the room wanted to see the data.

Packo: We were anxious to see the real data, because none of us, I think, even at that time, knew just how good the drug was actually working until we saw the graphs.

Pitcher: No one can quite remember the order in which the presentations for Avastin and Lucentis were given. Each person we talked to remembered it differently, but for the sake of sticking to a story, let's say that MARINA was presented first.

Heier: Those of us heavily involved in the ranibizumab trials had just seen it.

Pitcher: That is to say, those researchers who worked in the Lucentis clinical trials were privy to the data first-hand. They knew the drug worked. It was the data's job to quantify how well it worked.

Heier: The data's just overwhelmingly positive. There's absolutely no question, and that was remarkably exciting.

Pitcher: Kirk describes the feeling in the room.

Packo: The wow effect when we saw the graphs was really apparent. Everybody thought, “Oh, my Lord, this medication works fabulously well.”

Pitcher: So, there it is, the MARINA data, confirming for everyone that Lucentis was restoring sight in blind patients, and that it worked remarkably well, certainly better than any option retina specialists ever had before. Then, the Bascom team got to the podium.

Rosenfeld: Ann Fung presents the PRoNTO data.

Pitcher: Which, as you'll recall, assessed the response to Lucentis injections via OCT imaging.

Rosenfeld: Andrew Moshfeghi presents the first three months of the SANA trial, and I present the six months of the SANA trial.

Pitcher: The SANA study is the one we discussed in the previous episode, which assessed intravenous Avastin for bilateral wet AMD.

Rosenfeld: At the end of my presentation, I show an intravitreal injection of Avastin.

Pitcher: What happens next is something pretty special.

Rosenfeld: The excitement in the air was palpable.

Pitcher: Bob Avery, whose voice we have heard before, was in the audience.

Rosenfeld: Bob Avery and Gary Thomas were in the audience, and they provided support, confirmation of the results that we'd been having.

Pitcher: That is, they got up to the mic and started saying, "Yeah, this works. I've tried it."

Rosenfeld: If I had just shown a case report, I don't think it would have gained the traction that it did.

Pitcher: But, Bob helped lend Phil's presentation the credence it needed to quiet the skeptics.

Rosenfeld: Having two respected retina specialists in Bob Avery and Gary Thomas there telling our colleagues that yes, it really does work, and the OCT results were remarkable, I think really pushed the whole Avastin movement forward.

Pitcher: It's actually pretty interesting that it was Bob Avery who got to the mic, because the Avastin revolution could have ended on his watch if not for an odd turn of events. Here's Bob.

Avery: I'll tell you an interesting, an interesting story.

Pitcher: Bob talks about an early patient in whom he planned to give intravitreal Avastin. She had not been previously treated.

Avery: I wrote a pretty comprehensive consent form to try to protect me. It was long. There was no OMIC consent form back then.

Pitcher: The patient was in her 90s.

Avery: After the fluorescein and the visit, she was just too tired to have the Avastin. She didn't want to have it that day, because she was burned out. She was going to come back the next day and have the injection after she read the consent form.

Pitcher: And then…

Avery: And, uh, and she went home and died, and, uh, you know, it was crazy, because if we'd done the injection, that would have been it. We never would have, you know, proceeded with what we ended up doing. It was really, really an odd time, because, you know, she didn't die from the drug, because we didn't give it to her, but it was really ... really could have ended it right there.

Pitcher: A sad story for sure, and an important one. This case illustrates just how tenuous all of the Avastin work was. One patient death could have derailed the entire program. Anyway, back to the ASRS meeting in Montreal. Kirk summarized it this way.

Packo: Phil didn't say it in these words, but the perception that I came away with is, is he kind of pointed to the one-year presentations.

Pitcher: That is, the one-year Lucentis data.

Packo: And he says yeah, we, you can do everything you want with that, but you can do it tomorrow, off-label, and it'd be a whole lot cheaper.

Pitcher: Dave Brown was there, too.

Brown: I'm Dr. David Brown. I'm a retina specialist in Houston, Texas and a Clinical Professor of Ophthalmology at Baylor College of Medicine and Houston Methodist Hospital.

Pitcher: He said that despite the good news from Lucentis' year 1 trials, people were especially excited about the Avastin news.

Brown: There was more buzz about Avastin than there was ... it sort of, it sort of eclipsed the buzz that you would have expected to get, uh, from that first presentation.

Packo: Lucentis looks like it's going to be a blockbuster, but it wasn't available yet. Avastin was.

Heier: It is remarkable how quickly bevacizumab was, um, embraced by the retina community and how quickly it was used for these patients.

Pitcher: In fact, the discussion as we know it now—which agent works better in which conditions, etc.—was framed differently.

Packo: Well, there was not much of a fracture at that time, because Lucentis was not FDA approved.

Pitcher: Meaning that retina doctors couldn't get their hands on Lucentis just yet.

Packo: We were excited that that might be a potential, that we could use while waiting for the FDA approval, and at the time you have patients that don't respond well to current treatments.

Pitcher: All that excitement was moored to uncertainty. What exactly Avastin's long-term consequences could be, for example.

Packo: We were all ecstatic that it was such a powerful agent, and we didn't know that much about Avastin at the time.

Pitcher: Still, as you can imagine, something is better than nothing, especially when that something works.

Packo: It was much easier to justify using an off-label agent without a lot of history behind it just on the basis of, you know, your best guess that the science is, is, is, uh, gonna make it safe. It was similar to other agents, and that we seemed to see a penetration effect.

Pitcher: Nancy Holekamp had something to say about this.

Holekamp: Hi. I'm Nancy Holekamp. I'm a retina specialist in St. Louis, Missouri. I'm the Director of Retina Services at the Pepose Vision Institute. I'm also Clinical Professor of Ophthalmology at the Washington University School of Medicine in St. Louis.

Pitcher: She told us what it was like to understand both sides of the story: that Avastin was off-label and untested and available, and Lucentis was soon to be on-label and tested, but unavailable.

Holekamp: We could prevent blindness with Avastin, and so there was no doubt in your mind that you would try and going to Avastin for your patients, but there was also an option for using ranibizumab prior to FDA approval.

Pitcher: You could join a Phase 3b clinical trial.

Holekamp: The SAILOR trial. And it was supposed to look at safety and it required that the physician give the, the patient three loading doses of ranibizumab.

Pitcher: The study protocol is wordy and, for the sake of simplicity, we'll highlight this point. Patients in one cohort were treated according to OCT and visual acuity criteria. Patients in the other cohort were treated at the physician's discretion. In Nancy's estimation, the findings from SAILOR confirm something important, if obvious. That real-world outcomes differ from clinical trial results.

Holekamp: What we learned is that we were under-treating way back then and people weren't getting the visual acuity results that they did in the clinical trials.

Pitcher: Lucentis and Avastin had that in common too.

Holekamp: Whether it's Avastin or ranibizumab or any of the other anti-VEGF agents, you have to dose it frequently enough to get the desired effect.

Pitcher: We could talk all day about the dead zone between Avastin's quote-unquote discovery and Lucentis' market availability, but all of that ended when Lucentis was finally approved. Kirk knew how special the years 2005 and 2006 were.

Packo: That was this fortuitous thing in history here, where you had this one critical year from the presentation of that original 1-year data in Montreal until the ultimate approval of Lucentis, which didn't come until, uh, end of June of 2006.

Krzywonos: Scott and Ranna here to interrupt. There are two important points to this story that we wanted to add and both involve people from inside the Beltway. There was some good news and there was some bad news.

Jaraha: I've got the bad news. Scott's got the good news.

Krzywonos: And that means Ranna goes first.

Jaraha: Thanks.

Krzywonos: Uh-huh.

Jaraha: Alright, so bad news from Washington, D.C. In October of 2005, Phil started working on a head-to-head trial assessing Avastin and Lucentis for wet AMD.

Rosenfeld: I presented a protocol, prospective protocol, to the FDA and it, it was put on hold.

Jaraha: There was a bit of regulatory work he had to submit to the FDA that delayed the trial.

Rosenfeld: The FDA wanted to make sure that Avastin was stable in the syringes; they wanted a full retrospective report of all the patients I had injected; and they wanted a full description of how Avastin would be compounded.

Jaraha: Things were going swimmingly.

Rosenfeld: So, as I was in the process of getting all of that together, we had set up stability studies, um, we were writing retrospective papers on all the patients we had treated, not only with wet AMD, but diabetes and vein occlusion.

Jaraha: And then, a knock at the door from Washington.

Rosenfeld: As we were doing all that, I got a surprise letter from the Federal Office of Human Research Protection.

Jaraha: Turns out that someone wasn't very happy with the work Phil had done.

Rosenfeld: There had been an official complaint written about me and it was a very interesting complaint.

Jaraha: There were enough claims to scuttle the operation into Avastin if not addressed properly.

Rosenfeld: Claiming that we'd performed these horrendous, heinous, outrageous, dangerous experimentation on patients.

Jaraha: Phil said that the letter was serious stuff.

Rosenfeld: It was a 20-page, single-spaced letter with footnotes at the bottom, highly professional with fabricated points.

Jaraha: This put the brakes on everything.

Rosenfeld: And what ensued was an 18-month investigation between Washington and the University of Miami with exchange of information. They actually brought in a special investigator to review everything.

Jaraha: And a year and a half later...

Rosenfeld: There was a meeting at the University of Miami, the head of the Office of Human Research Protection, the lawyers, outside specialists came down and we met with them.

Krzywonos: Sounds like a tense moment.

Jaraha: It must have been.

Rosenfeld: And I walked into the room and I got a standing ovation.

Jaraha: Phil and Bascom were off the hook.

Rosenfeld: I did not perform experimentation. There was no protocol at the time. I used my clinical judgment using off-label drugs in the best interest of my patients. The Belmont Report clearly states that that's appropriate, acceptable, and legal.

Jaraha: In fact, the investigators were impressed with Phil and his crew.

Rosenfeld: They commended me for my actions because I prevented blindness.

Krzywonos: What did the person who started the complaint have to say about this?

Jaraha: No one knows because no one knows who it was.

Rosenfeld: The whistleblower, the origin of the complaint, was redacted from the letter and remains anonymous to this day. They're protected by federal statutes.

Krzywonos: So this all worked out in the end?

Jaraha: Yeah, by, I mean, by the spring of 2007, all was resolved. So the bad news was the study was delayed, not that it was halted. At the time, it underscored the level of scrutiny that Phil and his team would face.

Krzywonos: Hmm. Alright, well, uh, time for the good news.

Jaraha: Yes, please. So what did you find?

Krzywonos: Phil's investigation ends by the spring of 2007, but retina doctors still have some difficulty getting their hands on Avastin. Washington steps in again.

Rosenfeld: The real hero in all of this is Jack Mitchell.

Krzywonos: Turns out that not all heroes wear lab coats. There are two major players in this one, Herb Cole and Jack Mitchell. Herb Cole was the US Senator from Wisconsin, who headed the Senate Special Committee on Aging from 2007 until he retired in 2013. Jack Mitchell is the Chief of Investigations for the Senate Special Committee on Aging.

According to Phil, in 2007, retina specialists were having trouble getting their hands on Avastin. The details are many and have myriad complexities common of most policy debates. Those are something to discuss in a different podcast episode. But the crux of it was this, there was some degree of confusion as to whether the FDA was comfortable with allowing compounded intraocular Avastin to be used for wet AMD. Enter the US Senate.

Rosenfeld: There was an investigation that was started by Jack Mitchell in the Special Committee of Aging under Senator Cole.

Krzywonos: Anti-VEGF was such an important part of the lives of so many senior citizens, the very citizens that the Senate Special Committee was supposed to have an interest in, that the gears started turning on this quite quickly. Jack's work was swift.

Rosenfeld: He unambiguously demonstrated that there was absolutely no FDA pressure to withhold the use of Avastin from intraocular use.

Krzywonos: So at least they had Washington's endorsement to use Avastin, but the agents of changed were present in more than just Senate chambers. A number of societies mobilized to make sure retina doctors had access to the drug. Kirk Packo made the argument for having expanded access to Avastin at the AAO annual meeting in the fall of 2007, capturing the zeitgeist like few could.

Packo: I've been happy to participate in meetings now for over 30 years and I've given a few, uh, talks in my time and a, more than a few PowerPoint presentations.

Krzywonos: His talk was well received.

Packo: This was the only talk I've ever given in my professional career where I got a standing ovation. It's extraordinary to see 5000 people leap to their feet applauding wildly at the end of my presentation.

Krzywonos: The crowd was passionate about ensuring that they had access to Avastin.

Packo: The community was obviously very concerned about access to a drug that they already had, you know, a year's experience in seeing just how fabulous it was working.

Krzywonos: The conversation kept going.

Packo: The discussion went on and, and the, the, there was a panel discussion that followed the two presentations.

Krzywonos: Outcry about access as captured in Kirk's presentation combined with the investigation by Jack Mitchell on behalf of Senator Cole's committee saw access restored shortly after the AAO 2007 meeting.

Packo: Christmastime of, of 2007.

Krzywonos: Phil said that the doctors and organizations all had to band together to get this job done.

Rosenfeld: And along with our leaders, Kirk Packo, the American Academy of Ophthalmology, our specialty societies, ASRS, Retinal Society, Macula Society. We were able to push back and make Avastin available to retina specialists.

Krzywonos: Phil emphasized the role of the subcommittee's investigator.

Rosenfeld: I have to single out Jack Mitchell as being the pivotal player in all of this that made it all possible.

Jaraha: Okay, that was some good news. Washington worked!

Krzywonos: As it so often does.

Jaraha: Okay, so we're done here right?

Krzywonos: I think so.

Jaraha: Back to John Pitcher.

Pitcher: Once Avastin and Lucentis are swimming in the vitreous of patients with wet AMD, everything is going just hunky-dory for the retina world. Or at least it's going better than it had in decades. Or arguably since the sub-specialty's inception. But of course, there's still another player to arrive on the market: Eylea. More on that after this.


Krzywonos: When we last left, John Pitcher III was guiding us through the history of anti-VEGF. At this point in the story, Lucentis is approved by the FDA, Avastin is being compounded across the country, and wet AMD is being treated everywhere. Back to John.

Pitcher: Practicing retina had changed significantly following the approval of Lucentis for wet AMD treatment. Retina specialists whose training had been surgically focused were now charged with administering vast amounts of medication and the resulting disruption to the industry was significant. Not to say that such a disruption was a bad thing. Quite the opposite actually. Patients who were previously untreated or under-treated were now receiving treatment that improved their lives significantly. With the influx of patients came a new problem: treatment burden. Anti-VEGF injections were delivered once a month and some patients were unable to stay compliant with the treatment regimen. In all of this, a new player was entering the wet AMD landscape: aflibercept. For the sake of time, we'll spare you the details. Suffice it to say that aflibercept completed phase 1 and 2 clinical trials and phase 3 was on the horizon. Today, we know aflibercept as Eylea. At the time, it went by another name.

Vitti: VEGF-Trap.

Pitcher: That's Bob Vitti.

Vitti: I'm Bob Vitti and I'm the Therapeutic Area Head for Clinical Sciences, uh, in Ophthalmology here at Regeneron.

Pitcher: Eylea's original name isn't just an interesting footnote in history. It's a window into how the molecule's designers viewed its role in the biologic process.

Vitti: Aflibercept is a decoy receptor of the VEGF family of isoforms, particularly VEGF-A, and it's comprised of elements of VEGF receptor 1 and VEGF receptor 2 and that's attached to a constant region of an immunoglobulin.

Pitcher: A bit sciency, perhaps, but it means this.

Vitti: It has a very, very interesting profile, in, in the sense that it has a very high affinity for native VEGF.

Pitcher: Aflibercept was a VEGF binding machine.

Vitti: One aflibercept molecule binds to one VEGF molecule on a one-to-one basis.

Pitcher: Sort of tricks the VEGF molecule into binding.

Vitti: It's a decoy receptor, that's why we call it a trap.

Pitcher: Hence, VEGF-Trap. Dave Brown put it this way ...

Brown: The differences between Eylea and Lucentis and Avastin is that Eylea has tighter binding affinity.

Pitcher: Meaning ...

Brown: More of it is stuck more of the time to a VEGF molecule than Lucentis.

Pitcher: Now it's worth pointing out that the notion that Eylea has a higher binding affinity has been confirmed in some research, but has been denied by other research. Anyway, Eylea binds to more than just VEGF-A.

Brown: It binds something called placental growth factor, uh, it binds some VEGF-B and so it blocks multiple things that may be important. We honestly don't know what's the most important component.

Pitcher: Binding to more VEGF doesn't necessarily mean greater safety or efficacy. And to prove its safety and efficacy, Eylea still had to complete Phase 3 to get to market and actually compete with Lucentis, which was king of the jungle at this point. There was a pair of Phase 3 clinical trials already underway.

Heier: VIEW 1, VIEW 2.

Pitcher: Jeff said that the marketplace into which Eylea would enter, should it get approved by the FDA, was different than the marketplace that Lucentis had entered. Lucentis treated wet AMD, but there was one big problem.

Heier: Treatment burden.

Pitcher: Dosing frequency was a big concern at this point.

Heier: Many patients require frequent therapy, maybe monthly, pretty close to that. Maybe some patients go 6 weeks, 8 weeks, but it's pretty clear we've gotta treat patients regularly.

Pitcher: Genentech knew this was the case, too. Remember the SAILOR trial? The trial which followed ANCHOR and MARINA?

Heier: I had over 100 patients in SAILOR.

Pitcher: SAILOR played with the idea of dosing patients less frequently.

Heier: SAILOR gave us some leeway in terms of how we were monitoring patients and how frequently we were treating patients.

Pitcher: Jeff felt that, as someone who had seen hundreds of patients in various clinical trials, his professional judgment might play a role when it came to dosing.

Heier: I felt that I could probably manage these patients better than the guidelines from the randomized controlled trials, so I tried to follow them in a manner I thought was appropriate.

Pitcher: But ...

Heier: I was very surprised at the end of a year to look at my data and see that my outcomes were nowhere near as, as, um, dramatic, or as beneficial, or as efficacious as the randomized controlled trials.

Pitcher: Patients did not see the same increases with therapy that differed from the recommended dosing regimen.

Heier: On average, my patients gained a single letter instead of the 6 to 10 letters in the studies.

Pitcher: It was obvious to the retina community what this meant.

Heier: It was clear to me from that, as to many others, that PRN therapy or, or when we broke away from regular therapy and/or regular monitoring that we weren't gonna get the same outcome.

Pitcher: But there was a glimmer of hope in the early Eylea studies.

Heier: The early phase studies suggested that there may be an advantage in durability.

Pitcher: So, Bob Vitti said, the Phase 3 trials were designed with this in mind.

Vitti: The most fundamental trial design issue was already made by the time the trials were, uh, discussed with FDA. And that was the inclusion of a group in the Eylea family of groups that tested a q8, or an every 8 week interval injection after, uh, 3 monthly initial injections.

Pitcher: Time for the results.

Heier: VIEW 1 and VIEW 2 were presented by myself and Dr. Ursula Schmidt-Erfurth and we presented those at the Angiogenesis Conference in Miami.

Pitcher: It should be noted that the reaction to VIEW 1 and VIEW 2 was not the same reaction as to ANCHOR and MARINA.

Heier: It wasn't the excitement that had been seen in 2005 when, when literally that was the introduction of a whole new treatment paradigm.

Pitcher: Still, retina specialists were happy, and the reactions to the studies were positive.

Vitti: Very favorable, very well-received. Um, you know, whenever those, the retinologist could get another, uh, very potent, you know, arrow in their quiver, so to speak, uh, to, to treat patient, uh, disease, the, they're extremely thankful.

Pitcher: The hypothesis that Eylea could result in less dosing, but greater efficacy was a major story in the VIEW trials. The VIEW 1 study abstract said that treating every 2 months offered, and I quote, "the potential to reduce the risk for monthly intravitreal injections and the burden of monthly monitoring. “

Which brings us to a crux in the contemporary retina debate. When it comes to anti-VEGF treatments for AMD, what is the best way to balance cost and efficacy with treatment frequency? In other words, how do we define treatment burden? And how do we make sure it is as low as possible while still maximizing the likelihood of success?

This debate still occurs on the podium and the story is not over. Multiple companies are exploring options that could further reduce treatment burden and potentially improve outcomes. Also, these drugs are not perfect. Here's Kirk.

Packo: As we've seen more, uh, of the drugs used over years now, all of the drugs, uh, start to lose their effectiveness and the, the vision starts to decline after 5 years and 6 years. So, um, they're not as absolutely spectacular as we thought. Really, really good, I mean, and we're saving a lot of vision with it, but, but they're dropping. So, we still need more answers to this.

Pitcher: So, there's room for improvement, but these drugs are a start, a really good start.

Packo: The history's not over yet. There's gonna be new things that are coming out and how are we adapting to this.

Pitcher: He says, the impetus for change will come from young retina doctors.

Packo: The young people who are living through this and don't know any, uh, other way of doing it, eh, by and large I think it'll be easier to accept some of the things that, that some of the older folks like myself are resisting here.

Pitcher: Phil points out that working with the industry was key in the past and will likely be key again.

Rosenfeld: In looking over the history of Avastin, you might think of it as a confrontation between clinicians and the pharmaceutical industry. But I have to emphasize that none of this would have been possible without the drugs that were developed by the pharmaceutical industry. What we did was repurpose the end product, bevacizumab. But they're the ones that created the drug.

Pitcher: So, listen up, young retina docs (and I'm including myself in this announcement): It's time to take what you've learned in this history of anti-VEGF, apply those lessons to developing the next paradigm shift in retina. These developments did not spontaneously generate. They were the result of inspiration, critical thinking and decades of work. We've done it before and we'll do it again.

This is the end of our tale, at least for the moment. For now, though, I want to thank you for listening and leave you with this final thought from Phil.

Rosenfeld: Looking back on the development of Avastin, it seems so obvious now. But it wasn't so obvious at the time. It's, it's those stages of, of, of discovery where in hindsight it seems obvious, but at the time was met with great skepticism, antagonism by some people and what started off as an off-the-wall idea slowly gained acceptance to the point that people give themselves a dope slap and say, "Of course! I shoulda thought about this!"

Pitcher: Hopefully, I'll have a lot to report back in a decade and we can continue this story with Part 4.

Now, go be curious, fellow scientists and happy researching.

Krzywonos: Alright, that's a wrap on the first season of New Retina Radio.

Jaraha: Believe it or not. Okay, a big thank you goes out to all our contributors this episode. And a special thanks to John Pitcher, III for helping us navigate the ins and outs of this story.

Krzywonos: And the most very special thank you to you, our listeners, for supporting us in our foray into podcasting.

I'm Scott Krzywonos.

Jaraha: I'm Ranna Jaraha.

Krzywonos: See ya next time.

Jaraha: Bye.