Anti-VEGF, A Biography: Part 1

Many young retina specialists have always known retina as an anti-VEGF world. But how did this happen? John D. Pitcher III, MD, joins Scott and Ranna in studio to deliver the first part of the tale of anti-VEGF in retina, taking the story back to the 1970s to tell the story of the discovery of VEGF, the creation of pegaptanib, and the struggles that early anti-VEGF encountered in retina. There are a lot of guests for this one, but the major players for this episode are Tony Adamis, MD; Bob Avery, MD; Jeff Heier, MD; and Kirk Packo, MD.

Nothstein:

On this episode of New Retina Radio.

Tony Adamis:

We wanted to do it ourselves if nobody else was going to do it. By that, I mean we were going to develop an anti-VEGF.

Jeff Heier:

You have to remember what treatment was like back in the early 2000s.

Bob Avery:

The theory from the guru of angiogenesis, Judah Folkman, was if we can stop angiogenesis, we may be able to stop the progression of metastatic cancer.

Kirk Packo:

Who in God's name is going to want to inject, stick needles in people's eyes?

Nothstein:

That and more coming up.

New Retina Radio is an independent podcast supported with advertising by Alcon.

Mike Lee:

This is Mike Lee at Horton Plaza Park in San Diego. Here for the Retina Society 2016 meeting. New Retina Radio is brought to you by Alcon Surgical. Stop by our booth at an upcoming meeting to see how Alcon is advancing vetreoretinal surgery.

Nothstein:

You're listening to New Retina Radio from New Retina MD and Bryn Mawr Communications.

Scott Krzywonos:

Greg, are we good?

Nothstein:

Yes.

Scott Krzywonos:

I'm Scott Krzywonos.

Ranna Jaraha:

I'm Ranna Jaraha.

Scott Krzywonos:

This is New Retina Radio. Today, we're doing something new. We're having a guest storyteller shepherd us through a history lesson.

Ranna Jaraha:

So, gather around, everyone.

Scott Krzywonos:

But before we get there, Ranna—and she doesn't know this yet—is going to do a little exercise.

Ranna Jaraha:

Oh, yeah, I didn't know we're doing this.

Scott Krzywonos:

That's right.

Ranna Jaraha:

So, am I?

Scott Krzywonos:

Uh huh, uh huh—and, uhh, listeners we want you to play along, too.

Ranna Jaraha:

Okay then. I guess, get ready everyone.

Scott Krzywonos:

I want you to think back to when you graduated high school. I know it seems like a long time ago, but think about what your senior thesis was on, or what project you turned in that gave you that extra oomph to get over the hill and into a good college. Try to articulate that project as best you can.

Ranna Jaraha:

Oh, okay, I'm trying. I mean, it's a little hazy.

Scott Krzywonos:

You probably have a vague idea of what it was about or who helped you on it, but the operative details of the project are probably lost to time and memory. In fact, there's every possibility that you don't even see that paper or project as all that important. That you think your body of work is more a measure of your academic and professional achievement than a single project.

Ranna Jaraha:

Yeah, I mean, I would like to think so.

Scott Krzywonos:

Sure, and that's part of being human. But also part of being human dictates that we view past events, while important in their moment, as stepping stones rather than as mountains climbed. We tend to understate their importance, even when we know that they are seminal links to our contemporary lives, because we are more focused on the immediate. This is where historians come in. They parse history into nuggets, and they highlight moments that may seem small in hindsight as watershed moments in a narrative. Take the US Civil War, for instance. Speak all you want about the competing forces that drove the South to secede from the Union, but none of that happens—or, at least, none of that happens in the same way—without South Carolina representative Preston Brooks beating Massachusetts Senator Charles Sumner on the floor of the Senate with his cane. That moment, distilled today into little more than anecdote, may have been the catalyst that pushed the fledgling Republican Party into maturation. Resulting in the eventual presidency of Abraham Lincoln. And the rest, they say, is history.

Ranna Jaraha:

Interesting enough—great insights, but Scott, what does this have to do with Retina?

Scott Krzywonos:

Well, the story we're going on starts about two years ago. I forget exactly with whom I was talking—that patterned, foggy memory is a staple of this story—but we were gathered around what I'm sure were a few cocktails at the end of a long meeting, and the doctors I was with were talking about the first time the anchor and marina data were shared at a meeting. Anchor and Marina, you'll recall, were the phase three clinical trials assessing the safety and efficacy of Genentech's drug, Ranibizumab, or Lucentis, for wet age-related macular degeneration.

All of the doctors I was speaking with remembered that the presentation was important, but they differed on the details. Some said that they were surprised, others said that they were more interested in hearing about data from an alternative drug, Genetech's Avastin, which was being administered to patients with wet AMD in a different trial. Here's what they can at least agree on.

Kirk Packo:

And I remember being in the room, which was absolutely packed, and it was packed not only with every doctor who registered—I mean, everybody, whether you wanted to go out and enjoy Montreal—but everybody for that session was in the room.

Bob Avery:

It was very interesting. The—there were a lot of analysts in the room, which was unusual for us in ophthalmology at the time. There was a lot of hype about what was coming, and people sort of expected there to be, uhh, a positive result.

Jeff Heier:

Yeah, so—so, Joan Miller presented the Marina data. I presented—I don't remember if it was right before or right after her—I presented the focus data.

Anne Fung:

I remember Joan Miller coming up to deliver it. Umm, she started with the introduction, the study design—all of the typical parts, and then when she showed the slide of the visual QD results of Marina, I think there was an audible gasp in the audience.

Dave Brown:

The reaction was really surprised that anything could work this good. At the very same meeting, though, Phil Rosenfelt's presenting, you know, case reports of Avastin. And so, really, there was more buzz about Avastin.

Scott Krzywonos:

That was, in order: Kirk Packo, Bob Avery, Jeff Heier, Anne Fung, and Dave Brown—all of whom will be joining us on a trip through the biography of anti-VEGF. We've added a few others, too.

Anyway, ask anyone who was there and you'll get different answers on how the room responded. “Quiet,” like Anne Phung said, was a common answer, but so were “raucous,” “surprised,” and “excited.”

New Retina Radio wants to sift through all these stories and come out with something definitive. The answer may very well be that there were competing versions of history, and that's fine. But it's better to record these histories than let them fade to black.

Ranna Jaraha:

Yes, and we'll need a doctor to help guide us. When John Pitcher from Eye Associates of New Mexico said he was interested in telling this story, we jumped at the chance. So, this story comes to us from him. Let's begin.

John Pitcher:

We like to think of the anti-VEGF story as starting in the mid-2000s, or maybe even in the mid-‘90s, but really this story takes us way back—back to 1971.

Scott Krzywonos:

'71. That seems like forever ago.

John Pitcher:

Yeah, in some ways, it's not. I mean, we still hear that year’s hits on the radio… …And it was that year that James Bond was cranking out classic after classic, something that we're still seeing today.

Ranna Jaraha:

Yeah, these all seem like recent developments.

John Pitcher:

Yeah, culture moves slower than science, though. I mean, take angiogenesis, for example. In 1971, this word was just entering the scientific lexicon. With today, retina specialists use this term all the time. And take it from the angle of treatment—I mean, in '71, there wasn't even a treatment for angiogenesis. Today, we think of angiogenesis and three pharmacotherapies come to mind.

Scott Krzywonos:

We've got Lucentis, Avastin, and Eylea.

John Pitcher:

…And Eylea, right, right, you got it. It's easy to forget that these drugs didn't spring up out of nowhere. In fact, they're the products of a bumpy road that involved a number of failures and a lot of bench work that didn't pan out quite as planned.

Scott Krzywonos:

Okay, I got it.

Ranna Jaraha:

Mm-hmm [affirmative], all right.

John Pitcher:

In 1971, you know, the concept of angiogenesis was just in its infancy. Judah Folkman published an article in the New England Journal in 1971, called "Tumor Angiogenesis: Therapeutic Implications".

Scott Krzywonos:

And Judah was an ophthalmologist?

John Pitcher:

No, not exactly, he was a clinician with an interest in cancer. And he was something of a prodigy. According to his biography on the Harvard Med School website, Judah was still in high school when he developed a profusion system in his basement that kept a rat heart beating days after surgical removal.

Scott Krzywonos:

Sounds like standard, teenage boy stuff. I had a lab in my basement with dead rats and beating hearts, et cetera.

John Pitcher:

Yeah, I’m sure—I'm so sure—And when he was 15, he was admitted into Ohio State University, and at 19, he entered Harvard Med School. And he worked on a team with Robert Gross to help implant the first pacemaker.

Scott Krzywonos:

Wow, wow.

John Pitcher:

Yeah, he conducted medical research in the Navy during the middle of his residency at Mass General, and then went back to Mass General to complete his residency. And along the way he compiled a number of medical achievements, including inventing Norplant, for birth control. And at the age of 35, he became the head honcho at Boston Pediatric Hospital.

Ranna Jaraha:

35? Wow, that's awfully young.

John Pitcher:

Yeah, it's crazy.

Ranna Jaraha:

What year was that?

John Pitcher:

Uh, this was '67.

Scott Krzywonos:

Okay, so that's like 4 years or so before he publishes this tumor paper.

John Pitcher:

Yeah, yeah, yeah, I'm getting there.

Scott Krzywonos:

Okay. All right, so tell us more.

John Pitcher:

Right, so Judah Folkman is just an exhaustive researcher, and by '71, he articulates the concept of what he calls "tumor angiogenesis." And it might seem like old hat now, but in '71, this was a big deal. Let's meet Bob.

Bob Avery:

Hi, I'm Bob Avery, I'm a retina specialist at California Retina Consultants in Santa Barbara.

John Pitcher:

Bob summarized the prevailing theory at the time regarding tumors and angiogenesis.

Bob Avery:

The theory from the guru of angiogenesis, Judah Folkman, was if we can stop the angiogenesis, we may be able to stop the progression of metastatic cancer. You know, preventing small metastases from having a blood supply to allow them to grow to a size to be a problem.

John Pitcher:

But how was angiogenesis occurring? Judah Folkman theorized that the tumors release some sort of growth factor that allowed new blood vessels to form, thus feeding the tumor and allowing or proliferation.

Scott Krzywonos:

And this growth factor was VEGF, right?

John Pitcher:

Well, at first, no one was quite sure. Even Judah, himself, wasn't sure what the growth factor was—and that Harvard Med School biography I mentioned earlier said that it wasn't until '84 that basic fibroblast growth factor was discovered. Around the same time, researchers who published in the journal Science explained that tumors in small mammals expressed the same thing—something that they called vascular permeability factor.

Bob Avery:

And it turned out, when it was later cloned, it was one and the same.

Scott Krzywonos:

When what was cloned?

John Pitcher:

VEGF. Basically, it turned out that the vascular permeability factor and vascular endothelial growth factor, or VEGF, were the same thing.

Scott Krzywonos:

Oh, okay. So, it was two groups of researchers, really, that were studying the same molecule, but they thought that they were different molecules.

John Pitcher:

Yep, exactly. And Napoleone Ferrara and William Hensoldt, two scientists at Genentech, published in a journal called Biochemical and Biophysical Research Communications in '89 that they'd purified a growth factor they identified in bovine pituitary follicular cells. They profiled the growth factors characteristics and here I'm actually quoting from the abstract, "On the basis of it's apparent target cell selectivity, we propose to name this vascular endothelial growth factor, or VEGF".

Scott Krzywonos:

VEGF. A star is born.

John Pitcher:

Yep, just like that, a star is born. The name that would be the source of much frustration over the coming decades as scientists try to figure out how to combat the effects of over-expression of VEGF in the eye. Later scientists would discover different types of VEGF: VEGF-A, VEGF-B, C, and D. But VEGF-A is the big deal in ophthalmology. And there are various isoforms of the protein, but we'll get into that later.

Scott Krzywonos:

Okay, got it. So, the isoforms part is on hold. Umm, can Rana and I run through everything that you've just uploaded here? Because it's quite a bit.

John Pitcher:

Yeah, yeah, totally, go for it.

Scott Krzywonos:

Okay, Rana, you start.

Ranna Jaraha:

I'm ready. Okay. All right. So, Judah Folkman, this amazing clinician scientist with a passion for it seems like everything, is a big wig at Boston Pediatric Hospital.

John Pitcher:

Yep, he was the surgeon-in-chief by 35.

Ranna Jaraha:

Right, amazing.

Scott Krzywonos:

Okay, so then Judah publishes a paper based on his observations about tumors, and he says that tumors must release something that allows them to create new blood vessels and therefore grow, and he calls this blood vessel growth angiogenesis.

John Pitcher:

Yep, exactly.

Scott Krzywonos:

Okay, but no one has a name for this thing, for this growth factor, and no one's even identified it yet. There are scientists racing to identify it and purify it, and there are two groups that end up studying the same protein at the same time.

John Pitcher:

Mm-hmm [affirmative], correct.

Ranna Jaraha:

Okay, and then it was by the late 1980's, right? One group called it vascular permeability factor, and the other group, led by Genentech scientists Napoleone Ferrera and William Hensoldt, call it vascular endothelial growth factor, or VEGF. Oh, and then the scientific community seems to settle on VEGF as the name.

John Pitcher:

Yep, perfect.

Scott Krzywonos:

Okay, so we've got all that down, but how do we make the jump to retina?

John Pitcher:

Yeah, well that's where the story gets super interesting, because more retina doctors and researchers started to get involved. Let's talk to one of the researchers in Judah's lab, Tony Adamis.

Tony Adamis:

This is Tony Adamis, I'm senior vice president at Genentech, in charge of ophthalmology, immunology, infectious disease, and metabolism clinical research.

John Pitcher:

Tony worked with Judah, and he was one of the people who helped make the jump from cancer to eye disease.

Tony Adamis:

I was in Judah Folkman's laboratory at Harvard, where he studied blood vessel growth but primarily in the context of cancer. His thinking was always, beginning in early 70s, that if you block angiogenesis, that's a new way, a novel way, to treat solid tumor growth. But my being an ophthalmologist, I also knew that blood vessels were important in eye disease.

Scott Krzywonos:

Were they looking at AMD in particular?

John Pitcher:

Well, for that, we need a little history lesson on AMD. Tony can explain more.

Tony Adamis:

It was called AMD in the '90s. Prior to that it was called—somewhat politically-incorrectly—“senile macular degeneration.” Papers started appearing in the '60s and '70s in greater volume. Originally, it was just histopathological analysis, a lot of these coming from Rick Green's lab.

John Pitcher:

That is William Richard Green, MD, from Wilmer Eye Institute at Hopkins in Baltimore.

Tony Adamis:

So, people were talking—in the '90s, it was called age-related macular degeneration, a consensus had formed around that, that term for the disease.

Scott Krzywonos:

What was even known about AMD at the time?

John Pitcher:

Well, the basics were pinned down, for sure.

Tony Adamis:

People realized that it was an androgenic disease. Blood vessels were part of the pathology. How much blood vessels were driving the vision loss wasn't entirely clear, but we knew that there was a lot of edema and fluid leakage as a function of the blood vessels being there.

John Pitcher:

The jump, then, wasn't too far when trying to decide how to treat the disease.

Tony Adamis:

Conceptually, anti-angiogenesis made sense.

John Pitcher:

So, we've got new blood vessel formation in tumors via VEGF, and we've got blood vessel formation in the back of the eye in AMD, and, like Tony just said, anti-angiogenesis seems to be the next logical step.

Ranna Jaraha:

But then, if this next stop is so obvious, someone else has to be looking at it, right?

John Pitcher:

Yeah, for sure—and, uhh, let's get back to Bob Avery.

Bob Avery:

Well, I first got interested in VEGF back in the early '90s, when Lloyd Aiello and I started a trial. We were both at Hopkins at the time, I was chief resident, and we were taking samples of patients undergoing surgery—or even taking samples in the clinic through an IRB that I wrote at Hopkins there to measure this new growth factor, VEGF, to see if it was correlating with the severity of proliferative diseases. And we ended up publishing that work in the New England Journal in '94, around the time Tony Day was publishing a similar, smaller, study—again, showing the key role of VEGF in many retinal diseases.

John Pitcher:

Tony was at Harvard.

Tony Adamis:

In the '90's, my lab had been doing research on the role of VEGF in the eye, and, uhh, the research told us that VEGF was a very important molecule and it was work we were doing in collaboration with Napoleone Ferrara at Genentech, but I was an academic at the time, at Harvard.

John Pitcher:

Tony, like Bob Avery and Lloyd Aiello, was working on understanding VEGF in the eye and where it came from.

Tony Adamis:

What my lab did is—working with Napoleone Ferrara in the early '90s and mid-90s—is we determined that VEGF was made in the retina; it was up-regulated in conditions, disease conditions, and then, most importantly, by blocking VEGF using antibodies, early antibodies that Napoleone had made, we were able to show that we could block androgenesis and vessel leak in the eye. So, it was a collection of those data that sent us on a search for a VEGF inhibitor that we could use in the eye.

John Pitcher:

Finally, the path to success was coming into focus.

Tony Adamis:

So, by the mid-90s, it had become pretty clear to us that blocking VEGF could potentially be an important therapy for treating angiogenic diseases in the eye—things like diabetic retinopathy and macular degeneration.

John Pitcher:

And it's important to understand what the AMD treatment landscape was like at the time.

Scott Krzywonos:

Was there even anything to do for these patients?

John Pitcher:

Well, sorta, kinda—I mean, not really much by today's standards. And it was far from ideal, let's put it that way.

Scott Krzywonos:

Uhh, what—what was it?

John Pitcher:

Well, I'm going to tell you. After the break.

Ranna Jaraha:

All right.

Scott Krzywonos:

Okay.

[…]

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Nothstein:

New Retina Radio is an independent podcast supported with advertising by Alcon.

Mike Lee:

This is Mike Lee here at the bowling tournament during the final night of the Retina Fellows Forum here in Chicago. New Retina Radio is brought to you by Alcon. Stop by our booth at an upcoming meeting to see how Alcon is taking surgical retina into the future. All right, let's get back to the program.

Scott Krzywonos:

Before the break, John Pitcher shared with us a little bit about how VEGF was discovered, and he told us about how researchers were making the jump from oncology to ophthalmology. Let's get back to the story.

John Pitcher:

Okay, so in order to appreciate how big of a jump anti-VEGF therapy could be, and was, we need to understand what it was like to treat AMD patients in the days before anti-VEGF was ready for prime time. Here's Jeff Heier.

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.

John Pitcher:

Jeff is a good person to contextualize the early days of AMD treatments.

Jeff Heier:

You have to remember what treatment was like back in the early 2000s. We had photocoagulation—in essence, we were wiping out parts of the retina to try to preserve vision.

John Pitcher:

Photocoagulation wasn't a great therapy option, and the payoff was not immediate.

Jeff Heier:

You weren't preserving vision necessarily then or even a year from when you were treating, but this was a benefit that they would hopefully be able to enjoy 2 to 3 years later.

John Pitcher:

Photocoagulation, also called thermal laser, worked for some patients.

Jeff Heier:

There were even studies done with subfoveal CNV, where they would thermally laser the center of the macula, destroy the fovea, um, and the rational was that, years down the line, you would have scotoma control; that patients would have a larger visual field if they were lasered than if the natural history of the disease was allowed to progress. So, really, that was the only treatment option at the time—was thermal laser.

John Pitcher:

Then, along came some good news.

Jeff Heier:

The approval of photodynamic therapy with verteporfin, which was a treatment that was the first approved therapy for neovascular AMD.

John Pitcher:

This photodynamic therapy was preferred to photocoagulation, in part, because it was less destructive. Here's how it worked.

Jeff Heier:

Patients would get a dye infusion of verteporfin.

John Pitcher:

Also called “visudyne.”

Jeff Heier:

This is a dye that sensitized abnormal blood vessels, such as corneal vascular membrances, to a subthreshold, or cold laser, and that therapy would shut down the neovascular complex.

John Pitcher:

There definitely were some down sides, though.

Jeff Heier:

Unfortunately, it also often led to scarring in the eyes. There was a relatively high recurrence rate. There were some homeruns, some patients did very well, but on average, patients still lost vision with this therapy.

Scott Krzywonos:

All right, so, just to make sure I have it straight: photodynamic therapy was better than photocoagulation, which was better than nothing, but none of these options were that great.

John Pitcher:

Yep, exactly, and there still wasn't a pharmacotherapy option.

Ranna Jaraha:

And, hey, which is the entire reason why we're here.

John Pitcher:

Exactly. The entire reason why we're here.

Ranna Jaraha:

So, when does it pick up?

John Pitcher:

Good question. Jeff?

Jeff Heier:

Around that time, again the early 2000's, Eyetech and their drug, pegaptanib, was coming onto the scene and many clinical sites were heavily involved in those studies.

Scott Krzywonos:

Wait, what's Eyetech?

Ranna Jaraha:

And what's pegaptanib?

Scott Krzywonos:

Yeah, what's pegaptanib?

John Pitcher:

Okay, so this might be a good place to slow down for a sec. Pegaptanib is Macugen, and Eyetech was a little company started by Tony Adamis.

Scott Krzywonos:

And Eyetech invented Macugen, then?

John Pitcher:

Mm, not quite.

Jeff Heier:

Lot of people started Eyetech in April of 2000.

John Pitcher:

They were?

Jeff Heier:

Dave Guyer, Sam Patel, John McLaughlin, Marty Glick.

John Pitcher:

And Tony Adamis, of course. That makes five. Tony and his team knew that treating angiogenesis must be the key to treating eye disease, and they already knew, thanks to earlier research, that treatment had to be oriented towards neutralizing VEGF. Before there was Eyetech, entrepreneur that he was, Tony decided to approach companies to see who would be interested in a project of this scale and focus.

Tony Adamis:

Dave Guyer and I, in particular, went around to companies who were potentially interested in working on VEGF, including Genentech. We had talked to Rich Enron, as well as a small startup in Colorado called NeXstar.

Ranna Jaraha:

Any luck?

John Pitcher:

Nada.

Tony Adamis:

Long story short, we couldn't get traction, meaning that we couldn't convince a company to work on any VEGF for the eye.

John Pitcher:

So, they created the company themselves.

Tony Adamis:

Eyetech was started, in part, out of frustration because we wanted to do it ourselves if nobody else was going to do it. By that I mean, we were going to develop an anti-VEGF.

John Pitcher:

There was already anti-VEGF that had been created. Remember NeXstar?

Scott Krzywonos:

That was one of the companies that Tony and Dave Guyer had approached earlier?

John Pitcher:

Right, right, yeah. NeXstar was founded by Larry Gold.

Scott Krzywonos:

G-o-l-d.

John Pitcher:

Larry Gold played a big part in the creation of the very first ocular anti-VEGF.

Tony Adamis:

Larry was a person who discovered aptamers and how to make them using a process called selex.

John Pitcher:

Aptamers were a new molecule at the time.

Tony Adamis:

So, it was a new class of molecules. They're basically nucleic acids that have a 3-D confirmation that will bind a molecule of interest, in this case VEGF, very specifically and with high affinity.

John Pitcher:

NeXstar had engineered something special.

Tony Adamis:

NeXstar had an aptamer for VEGF that blocked VEGF that became Macugen.

John Pitcher:

A little bit was known about Macugen.

Tony Adamis:

There had already been a small, phase 1, partly-done, at NeXstar. Dave and I were lead consultants for that.

John Pitcher:

Because Dave and Tony were already familiar with the molecule, they decided to strike a deal for Macugen.

Tony Adamis:

So, in 2000, what we did is we actually bought Macugen, so we took it away from NeXstar, brought it in to Eyetech, and that's when we started our full-blown clinical development program with Macugen.

John Pitcher:

They shepherded Macugen from that phase 1 trial.

Tony Adamis:

We finished that and went on all the way through phase 3.

John Pitcher:

Submitted the data to the FDA.

Tony Adamis:

And ultimately got Macugen approved in 2004, uh, as the first anti-VEGF and first drug, frankly, for macular degeneration, wet variety.

John Pitcher:

And approval is good, of course, but there's always bumps in the road when you're presenting a new drug with a delivery route which, at the time, was brand new: intravitreal injection. Kirk Packo has some thoughts on that.

Kirk Packo:

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

John Pitcher:

Intravitreal injections weren't all the rage they are now at the start of the 21st century.

Kirk Packo:

Now, we do it second nature and look at how commonplace that's become—and the young people training think, "Oh, intravitreal injections have always been with us," but they weren't. And in 2000, we thought, "Well, this is crazy, maybe the drug works, but this will never catch on."

John Pitcher:

In short—

Kirk Packo:

Who in God's name is going to want to inject, stick needles in people's eyes? And would patients go for that?

John Pitcher:

Well, somebody was. Tony explained that this route, while unusual, wasn't unheard of. There was already some clinical experiences associated with intravitreal injections that showed that it was safe.

Tony Adamis:

Glancyclovera was identified as an antiviral that would treat a complication of HIV, which is CMV retinitis.

John Pitcher:

The high frequency with which these injections were used meant that these eyes were going to face high treatment volumes.

Tony Adamis:

Doctors at that time were injecting glancyclovera into the eye weekly, for up to a year. And those initial investigators showed the world, basically, that you can inject drugs into the eye on a very frequent basis, and the eye would tolerate it well. The infection rate was low and, um, that in the case of CMV retinitis, you could actually effectively treat the disease.

John Pitcher:

And the bottom line was: intravitreal injections worked.

Tony Adamis:

Intravitreal glancyclovera was—no pun intended—was an eye-opener for us. It said that this was a root of delivery that is potentially useful.

John Pitcher:

As far as this whole story of anti-VEGF is concerned, Macugen helped show that long term intravitreal injections were a viable route of drug administration. All anti-VEGFs owe Macugen a debt of gratitude for that; however, in the grand scheme of things, Macugen didn't work out so well for treating wet AMD. And it largely had to do with the design of the drug.

Tony Adamis:

The best way to term it is it's a partial-VEGF inhibitor.

John Pitcher:

It was designed to block a few isoforms of VEGF-A.

Tony Adamis:

When we say VEGF-A, we're actually talking about four different, uh, forms of VEGF-A that are differing amino acid lengths.

John Pitcher:

These isoforms of VEGF-A are named according to the length of their amino acid chains.

Tony Adamis:

There's VEGF 121, 165, 189, and 205. And, uh, and three of those are made in the eye.

John Pitcher:

VEGF-205 isn't made in the eye, so we don't have to worry about that one. And, in the end, Macugen blocked some VEGF-A isoforms.

Tony Adamis:

Macugen blocked 165 and 189; did not block 121. So, it would block some of the VEGF made in the eye, not all of it.

John Pitcher:

Because it only blocked two of the three VEGF-A isoforms in the eye, Macugen didn't deliver the high level of efficacy that future drugs would provide.

Tony Adamis:

Turns out, it's very important to block all of VEGF-A, including VEGF-121, because that leads to better efficacy.

John Pitcher:

But that's not to say Macugen wasn't a big deal.

Tony Adamis:

People were very excited to have a new therapeutic, uh, modality to treat patients with, and, at the time that the Macugen data came out, it was shortly after photodynamic therapy and visudyne was approved, which also had an effect on CMV. So, people were happy to have another therapeutic option because both Macugen and, um, photodynamic therapy slowed the rate of decline.

John Pitcher:

Problem was, though, that patients weren't improving in visual acuity.

Tony Adamis:

You did not see a lot of patients improving vision.

John Pitcher:

Still, back in 2005, Macugen was the only girl at the dance.

Tony Adamis:

In 2005, when the drug was launched, it was, for that period of time, the biggest launch in ophthalmology. More people were using it more quickly than any other drug in this the history of ophthalmology.

Scott Krzywonos:

How expensive are we talking here, and how often is the drug administered?

John Pitcher:

So, it was administered every six weeks, and no, it wasn't cheap.

Tony Adamis:

It was launched at $995, which at the time was more expensive than visudyne and was viewed as an expensive drug.

John Pitcher:

Things were going so well that they decided to initiate other trials.

Tony Adamis:

We did the first phase 2 trials in both DME and RBO, and there, the efficacy was better than what we had seen in wet AMD, leading me to believe that VEGF-121 didn't play such a big role in those diseases.

John Pitcher:

Unlike in wet AMD trials, patients were actually improving with Macugen treatment.

Tony Adamis:

We clearly saw visual acuity gains. The average patient gained vision with Macugen in both RVO and DME, and so there were plans for us to go forward in those indications as well.

Scott Krzywonos:

And how did those plans go?

John Pitcher:

Well, they never went anywhere.

Ranna Jaraha:

Really? Why?

John Pitcher:

Business happened.

Tony Adamis:

We thought there was a way forward, but then Eyetech got acquired, and so those plans—at least, our plans—were put on hold.

John Pitcher:

Also, Lucentis happened.

Scott Krzywonos:

Meaning?

John Pitcher:

That is a story for another time.

Ranna Jaraha:

Oh, man.

Scott Krzywonos:

Okay, well, leave us hanging.

John Pitcher:

I don't want to, but I’ve got to bring you back for the next episode.

Scott Krzywonos:

Okay, cool—

Ranna Jaraha:

Fair enough.

Scott Krzywonos:

—which will be in a couple of months. So, we'll meet back then, and we'll hear the rest of the story.

Ranna Jaraha:

Yep.

John Pitcher:

All right. Sounds good.

Ranna Jaraha:

All right.

John Pitcher:

See you guys soon.

Ranna Jaraha:

Bye.

Scott Krzywonos:

See you.

John Pitcher:

Bye.

Scott Krzywonos:

Okay, we're back in the New Retina Radio studio. Thank you for joining us on this first episode in our series on the history—or the biography, if you will—of anti-VEGF. You all know what's coming up next: Lucentis and Avastin.

Ranna Jaraha:

Mmhmm, and very special thanks to John Pitcher in Albuquerque, who made this whole thing possible.

Scott Krzywonos:

And to WHYY, the station in Philadelphia where Rana and I recorded, and to KANW in Albuquerque where John was.

Ranna Jaraha:

Finally, to our contributors. We'll hear a lot more from them as the story progresses. They were Tony Adamis, Bob Avery, Dave Brown, Anne Fung, Jeff Heier, and Kirk Packo.

Scott Krzywonos:

I'm Scott Krzywonos.

Ranna Jaraha:

I'm Ranna Jaraha.

Scott Krzywonos:

See you next time.

Ranna Jaraha:

Bye.

Voicemail:

Press "2" to play new messages.

John Pitcher:

Hey, this is Pitcher, and I'm in a cab on my way to JFK airport. I'm going to read the credits for New Retina Radio.

New Retina Radio is a production of Bryn Mawr Communications and New Retina MD. The show is produced by Scott Krzywonos, with help from Ranna Jaraha. The show was recorded, mixed, and edited by Greg Mostein. Our staff includes Dave Lavine, Megan Vicer, Elisa DeMato, Laura Dyce, Julie Kasab, Kira Mazurik, Meredith Pollack, and MJ Stewart. Our publisher is Janet Burke. For advertising questions, contact us at NewRetinaRadio@bmctoday.com.

Goodbye!

Voicemail:

End of messages.

Scott Krzywonos:

Hey, it’s Scott. I'm atop the Space Needle in Seattle. New Retina Radio is brought to you by the New Retina MD app. Search "New Retina MD" in the app store, download the app, select the issue you want to read, and, after that, you've got Retina on the go. Inside the app, you'll find exclusive content, including videos, interactive features, and social media access. Enjoy.