 or colitis-associated cancer can be debilitating for patients.

Often chronic inflammation of the intestines is a common part of the colonic neoplastic process, fostering the proliferation, survival and migration of colonic tumor cells.

Currently, the most potent drugs to treat this condition are anti-tumor necrosis factor inhibitor agents (anti-TNF), which exploit the targets involved in the pathophysiology of the inflammatory responses in inflammatory bowel disease (IBD). This class of drugs may also have some anti-colon cancer effects.

However, anti-TNF agents also come with severe side effects, mainly inflammation, and are administered intravenously.

In data presented during the Crohn’s and Colitis Congress 2022 Annual Meeting, presented initial data showing the value in utilizing nanoliposomes loaded with a stable metabolite from 6-Shogaol called M13 to treat ulcerative colitis and colitis-associated cancer.

, Didier Merlin, Institute for Biomedical Sciences, Georgia State University, explained how the nanoliposomes work and what benefit this would have for patients.

Merlin said the orally taken drug delivery system would both be more convenient for patients, but also be able to provide cancer-fighting drugs as well as medication that would reduce the side effects of the drugs.

The nanoliposomes are derived from the lipids of ginger-derived-nanoparticles and loaded with M13, which is an anti-inflammatory drug candidate.

Videos

Anti-TNF agents often cause various side effects, including inflammation. 

Didier Merlin, PhD: Using Nanoliposomes to Treat IBD Inflammation 

Since the start of the COVID-19 pandemic, the amount of blood donors has decreased tremendously. January is National Blood Donor Month, which has coincided with the COVID-19 Omicron surge and the first-ever national blood crisis declaration from the 

Last year, the American Red Cross, who supplies approximately 40% of the nation's blood supply, reported a 34% decline in new blood donors. 

“While some types of medical care can wait, others can’t,” Dr. Pampee Young, chief medical officer of the Red Cross, 

 “Hospitals are still seeing accident victims, cancer patients, those with blood disorders like sickle cell disease, and individuals who are seriously ill who all need blood transfusions to live even as Omicron cases surge across the country."

The shortage has had a tremendous effect on the country's health care system and patients. Valentina Baez-Sosa, MD, Chief Hematology-Oncology Fellow at MedStar Washington Hospital Center, explained the possible implications of the blood crisis in an interview with 

"This is a huge concern," Baez-Sosa said, "and I think I can give you even more numbers because, according to the American Red Cross, we need like 36,000 units of red blood cells, and 7000 units of platelets, and even 10,000 units of plasma. That is the daily requirements."

Among the patient populations at risk is the 

 community. Depending on the type of SCD,  patients may be undergoing frequent blood transfusions as necessary treatment. 

"We also know that blood is used for a number of treatments like cancer, orthopedic surgeries, transplant, but especially patients with blood disorders, like sickle cell," Baez-Sosa explained. "So without the necessary amount of donations, hospitals will be prevented from providing the best care to our patients." 

"And I've seen firsthand, the implications of the blood shortage affecting patient care," she continued, "even in the life threatening situation where patients with sickle cell are highly affected."

The convenience of donating blood may have disappeared as the pandemic spread, and as long as the necessary precautions are taken, it's absolutely possible to donate blood and stay safe during the Omicron surge. 

"So," Baez-Sosa said, "the biggest take home point will be to encourage people to donate and save lives."

While Omicron cases surge, Valentina, Baez-Sosa, MD, speaks on the national blood shortage and the risk it poses to patients with sickle cell disease in particular. 

Valentina Baez-Sosa, MD: The Blood Crisis is a Huge Concern

The latest results from HOPE trial open label extension showed that after 144 weeks, the majority of patients with 

 taking voxelotor (Oxbryta) continued to see the positive results previously revealed in the trial, without any unexpected adverse events.

Maureen Achebe, MD, MPH, Assistant Professor of Medicine, Hematology, Brigham and Women's Hospital, presented the interim analysis of the open label extension of the HOPE trial at the 

2021 American Society of Hematology (ASH) Annual Meeting & Exposition

According to Achebe, there were no severe adverse events but there were some.

"The adverse events were pain crisis, which we expect in patients who have sickle cell disease, arthralgias, some abdominal upset, and minor adverse events that were reversible," she said.

The open label extension followed the HOPE trial. HOPE was a randomized control trial that examined the use of voxelotor, a molecule that increases hemoglobin's affinity for oxygen, currently indicated for patients with sickle cell disease and anemia.

"The HOPE trial was, I think, a remarkable study and that we were able to enroll patients onto the study in record time with positive results," Achebe said. "And the open label extension shows us that the improvements in hemoglobin that were achieved in HOPE are durable, and that the side effect profile, even over a longer period of time, has not expanded to include side effects that we didn't see on trial."

Watch the first segment of Dr. Achebe's interview with HCPLive

Maureen Achebe goes into detail about the open label extension of the HOPE trial that evaluated to use of Voxelotor in patients with sickle cell disease and anemia. 

Maureen Achebe, MD, MPH, Shares Extended Durable Data on Voxelotor for SCD

 When I’m talking with patients, I make several points. One of the most important points I tell them is that it takes time for melanocytes to migrate and repigment areas of depigmentation, it doesn’t happen quickly. Melanocytes can come in from the edges, but can also come from the base of black hairs, migrate up the sides of the hair and the outer root sheath, and then fill in the epidermis, and this takes time. I must set expectations with patients and inform them that, with treatment that includes topicals, phototherapy, and oral therapy, they can expect on average a 25% improvement in 3 months, 50% improvement in 6 months, and 75% improvement in 9 months; after that, it often plateaus. I can’t guarantee that they will have 90% or 100% repigmentation, but on average those are the numbers that we see in various studies. Areas like the hands will do less well, and areas like the face will do better, and I let them know that.

I also discuss different aspects of prognosis. For example, if they have areas with white hairs, and I use a dermatoscope to look at the small vellus hairs, if I see that most of their hairs are white, they have a poorer prognosis versus those who have all pigmented hairs. Younger patients tend to have a better prognosis than older patients. If they’ve had vitiligo for less than 2 years, they also have a better prognosis than those who have had it for more than 2 years, especially for 10 years or longer. Areas that are prone to trauma, such as elbows, knees, ankles, wrists, hands, and feet, tend to do worse than areas that are not exposed to trauma. Areas that have less concentration of hair follicles, such as the clavicle, do worse than areas that have a higher concentration of hair follicles, such as the face. These are some of the points that I communicate. I also tell patients that I look for signs of activity. I look at their skin and see if they have confetti-like lesions, or trichrome vitiligo, where the borders of the vitiligo lesions are hypopigmented or blurred. I also look for the Koebner phenomenon. If they have those type of lesions, then I know they have more active disease. I talk to them first about stabilization, then repigmentation, and finally maintenance of therapy. I tell them that we must stop the disease from spreading, and then we must try to repigment the lesions. Once we have repigmented, we must reduce the frequency of phototherapy and the application of topicals, and find what type of maintenance treatment will maintain their disease in that improved state without it returning.

Compliance is extremely important to achieve success in the treatment of vitiligo. When I see patients come back, I try to evaluate several things. I ask them how many treatments they are getting, and if they’re getting phototherapy. Typically I treat 3 times a week, for example, Monday, Wednesday, and Friday, and I ask them if they’re getting 12 treatments per month. I often look at their medical record if they come into my clinic to see how many times they have come in. Patients must try to come in for the majority of their treatments, I would say 75% or more, in order to get good results. I look for compliance from that standpoint. I also look for refills, are they asking for refills of the topicals on a routine basis or are they still on that first tube 6 months later? In which case I know that they’re not using it properly, and I’ll ask them how many times a week they apply it, and how many applications they get in 1 week with their topical. I’ll also ask about the oral therapy, for example, we’ll give dexamethasone mini-pulse therapy for patients with very active vitiligo, and I’ll ask them how they’re doing with that, and whether they’ve had any adverse effects. With the examination of their skin, I’m often able to correlate the improvement with their compliance. Patients who are less compliant will not show improvement percentage wise when it comes to stabilization and repigmentation of their skin.

Dr Amit G. Pandya discusses the role of an HCP in motivating patients and setting their expectations for successfully managing and treating vitiligo.

Role of HCPs in the Management of Vitiligo

Even though vitiligo doesn’t seem to affect internal organs, except the thyroid gland, it can have profound psychological implications. I tell patients that inside they’re normal; they must have their thyroid checked once a year with a TSH [thyrotropin] check, which is important, but otherwise their heart, lungs, kidneys, liver are normal. However, vitiligo can have a profound effect on patients’ psychological well-being. It can affect their careers; many patients don’t want careers in which they’re in the public eye and are giving presentations, because they say that people look at their vitiligo and are not listening to them. It can have a profound social impact in terms of their relationships with friends or intimate relationships. They may be reluctant to form these relationships because of their vitiligo. It can cause various psychological disorders, anxiety, depression, even suicidal ideation in many patients, and body dysmorphic disorder. There are many psychological comorbidities that have been found and published about in patients with vitiligo.

It can have an economic impact as these patients often have a high burden of disease in terms of treatment. They need to go sometimes 3 times a week to the doctor’s office, there are a lot of expenses with that. Purchasing medications for their vitiligo can have an economic burden, and they may be afraid to even seek a job because they’re concerned about the way they look and how people will treat them. There are many psychological implications that patients have with vitiligo, and we as clinicians must keep this in mind when we’re evaluating patients.

An expert dermatologist comments on the real-world impact of vitiligo and how it can affect a patient’s quality of life.

Real-World Impact of Vitiligo

 Ehsan, can you discuss the diabetic retinopathy severity scale [DRSS] score and how these anti-VEGF agents had a surprise benefit? It was initially a secondary end point, but it’s becoming something attractive about anti-VEGF therapy.

 Back to the RISE and RIDE studies, 1 of the secondary end points from those studies is that they saw that patients’ DRSS was improving. There became this metric to look at 2-step progression, to go back in time by 2 steps of severity, so if you’re moderately severe, you go down to moderate and all the way to mild. This was an added benefit that was noted with anti-VEGF treatment in these clinical trials. Similarly, VISTA and VIVID were landmark studies looking at aflibercept, or Eylea, for treatment of DME [diabetic macular edema]. They saw the same thing in both studies: roughly 1 of 3 patients, 33% or so, would experience 2-step improvements. Those observations served as the launching pad to do the PANORAMA study and also Protocol W study through the DRCR [Diabetic Retinopathy Clinical Research Network], which is essentially the same protocol as PANORAMA. In this case, we’re cherry-picking those patients at highest risk for progression to PDR [proliferative diabetic retinopathy], which is that moderately severe to severe group with ETR scores of 47 and 53. We saw in PANORAMA, and again in Protocol W, is that a significantly higher proportion of patients experienced 2-step progression—upward of 60% to 70%, depending on which treatment group you were in, that aflibercept study and PANORAMA.

One way we can reconcile this big difference has to do with what I just said: there was a ceiling effect in place. When you look at the patients enrolled in RISE and RISE or VISTA and VIVID, they may have had mild NPDR [nonproliferative diabetic retinopathy] or moderate NPDR. There’s only so much they can improve. You can’t improve by 2 steps of DRSS, as opposed to these states looking at the treatment of severe NPDR. There’s a lot of potential for improvement, and that’s 1 reason we had such a big disparity in terms of that DRSS improvement. The second reason is that in PANORAMA, all those patients were treatment-naïve. That was a very difficult study to recruit for. Many patients had 20, 25 visits—how long do you want to give monthly injections? it was a difficult and challenging site to recruit for, but all the better for having it been done, because we got some very powerful information, not only from the treatment but also from the observation group.

To that end, our field is all about durability. Is there a permanent benefit or treatment effect from this 2-step progression? In other words, if we stop, do we lose it all? Was it all for nothing? Will it quickly regress back to where it was? We’re seeing mixed studies and mixed results from our peer literature. Some people have hypothesized and decided to study fluorescein angiograms. Are we seeing reperfusion of tissue from earlier treatment, anti-VEGF, and is that sustainable over a longer period of time? When I get to a point in a patient’s treatment course—every 3, 4, 6 months, and their DME has regressed, they want to give a trial coming off therapy—we must be very careful that we’re monitoring that their diabetic retinopathy doesn’t start to progress. I’m reminded of Charlie Wyckoff, who did an open-label extension study of VISTA with aflibercept that looked beyond the 3-year study period and at patients who were getting whatever treatment their clinician decided they should and fewer injections. At that point, there were 60 patients who I studied, but 10% progressed from NPDR to PDR [proliferative diabetic retinopathy]. I tell these patients that we’ll know each other for life in a lot of instances.

 In that study, they didn’t require many injections. They were randomized to either acute QA or Q16 at the loading dose. We know that if individuals don’t have diabetic macular edema, the number of injections they will require will not just save vision—there were people in that study who did not have diabetic edema; their vision improved. There’s something going on that we still don’t know, but there was a visual improvement. There was an OCT [optical coherence tomography], a drying effect, although you couldn’t clinically see any swelling. If you look at the composite of sight-threatening problems, it was 42% compared with 10%. That’s a drastic improvement in someone’s vision that could have potentially been lost vision and that you ordinarily wouldn’t have retained. The study was hard to recruit for. It’s the same reason why people are nervous about treating individuals without sight-threatening problems. To this day, I don’t think it’s caught on as much as it should have, because it’s hard to talk to someone about putting a needle in the eye that’s 20/20.

If we want to try to save an organ, with the eye we still have to find the right people to move the needle. It’s not an emergent thing you must do, but we need to start having the discussion, especially if it’s your patient—you saw the person 5 years ago, when they had moderate disease, and now they’re starting to get severe NPDR. You can see that progression. That may be the perfect person to have that discussion with. It’s difficult when a patient comes in for the first time and they’re healthy and vibrant, playing basketball, running. They didn’t know they had diabetes. They have a severe disease, but they’re not bothered by it. That’s a very hard person to have that discussion with. This is where our optometric colleagues can help us out, by facilitating those questions to the health care professionals to talk about multisystem organs. Once they have kidney, foot, eye, and heart problems, you start to build up a story. This patient’s journey over time is not going to be very good. You have to look at a patient as a composite. Let them know that the same thing going on in your heart, toes, and kidneys and is going on in your eyes, and if we don’t get this under control in the next 3 to 5 years, you can have severe blindness.

Thanks to all of you for this rich and informative discussion, and thank you for watching this 

. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming 

 and other great content right in your in-box.

Retina specialists review clinical trial data on the impact of anti-VEGF agents on diabetic retinopathy severity scores.

Anti-VEGF Agents and Diabetic Retinopathy Severity Score

 It’s important for our audience to understand that when we initiate treatment, it will likely be monthly because we want to give everyone the best chance to end up on that curve. That curve is improvement in vision. It happens early, and we want everyone to maximally be there. Monthly injections are difficult because of the treatment burden once we’ve established that someone is responding. Joe, are you using therapy when necessary? Are you using a treat-and-extend? Do you observe and reinstitute therapy if there’s a relapse? What are you doing after that initiation? Because these patients have diabetes and are at risk for DME [diabetic macular edema], what do you do for their maintenance phase?

 [First I make sure] they’re stable, meaning the OCT [optical coherence tomography] is the best I can get. Let’s take an eye that’s completely dry, with no fluid in the retina. I don’t have to do all the loading doses. In clinical trials we have the set criteria where we do 5 loading doses depending on the drugs. If they’re dry after 2 successive injections, I typically extend them out. Each time they’re dry, I’d go out by 2 weeks longer. Typically I would go out to about 12 weeks before I skipped an injection. This was about a year of therapy, a year and a half of therapy, depending on how many injections they had.

COVID-19 has taught me several things. I was surprised how many people did better than I thought they would—this is more in my AMD [age-related macular degeneration] population, but it was also true for some of my DME population. Some of these people I had been treating for many years. They’ve had recurrent fluid multiple times or recurrent blood vessels, etc, but some of these people held up. Now I have those people out 14, 16 weeks, and some of our newer trials are also going to 16 weeks. Whether those biologics are stronger, we don’t know, but we’re looking at that now. Early studies were never powered to go beyond 12 weeks, and now we’re doing that.

I’m pushing my patients more than they can, and I’m trying to customize their therapy. I personalize their therapy to what’s going on in their life, and I’m using everything I have to decrease their drug burden by maximizing everything else. It’s a treat and extend, and you’d be amazed once you get someone stable. After year 2 or 3, and this is reproduced in our studies, people who have been stable don’t require as many injections. It’s important that you still monitor these patients. As long as the patient is about equity, where they were and where they’re going, they’re more likely to keep their appointments.

In medicine at some point, we must make the eye a higher priority. Once we start moving the chain and make it a priority, where we can see eyes earlier, those patients are more likely to come in for therapy. I keep them on a maintenance therapy because people on maintenance therapy tend to keep their appointments, engage, and often do better. There is a pro to continue them on a dosing of every 3, 4, 6 months because they’re less likely to get in trouble and less likely to have a progression in their disease itself, not just in DME.

 Joe, you mentioned something very important, and that’s dosing patients, perhaps those who don’t have active DME but have varying degrees of nonproliferative diabetic retinopathy, such as moderately severe or severe. Regular injections as far as every 16 weeks could keep people from progressing and getting sight-threatening complications.

Ted, we’re talking about the PANORAMA study, and I’m wondering if you could give us an overview and the recommendations that come from it for patients with nonproliferative diabetic retinopathy?

This was an interesting study, and it led to the use of aflibercept molecule to treat diabetic retinopathy in the absence of DME. It showed that a significant portion of patients had a reduction in the severity of diabetic retinopathy. It paved the way to using this therapy for patients with diabetes, which is another problem in that it presents many patients who might need intravitreal therapy and will need our services. There are resource constraints with the number of patients we’re seeing.

However, there are benefits to a treatment using anti-VEGF therapy in patients with diabetic retinopathy. It prevents progression to more advanced stages, and it reduces the risk of having vitreous hemorrhage or needing vitreous surgery, such as vitrectomy and laser. You have the added benefit of prophylactic treatment—more or less of having diabetic macular edema—which was the primary cause of vision loss in these patients. For many reasons, the treatment of diabetic retinopathy is beneficial to our patients.

Key opinion leaders describe maintenance treatments for diabetic macular edema and provide an overview of the PANORAMA study.

Maintenance Treatment for Diabetic Macular Edema

, Edward Ivy, MD, MPH, Vice Chief Medical Officer, 

Sickle Cell Disease Association of America (SCDAA)

, addressed the important elements currently at work in the field of 

 from the blood shortage the nation's facing, to future treatments for the disease. 

Ivy has a comprehensive perspective on the topic. In addition to being an MD and obtaining a Master of Public Health, Ivy is an individual living with sickle cell disease. 

He has first hand knowledge of how difficult it can be to get quality care as a patient. 

"We can do better, we can treat diseases better in the United States," Ivy said. "But I think it's going to take a concerted effort of groups like the Sickle Cell Disease Association, working with the researchers, working with the federal government, and working with states and other entities to figure out--what are those strategies that allow us to more effectively get the therapies that are sitting there and available to the patients that need them?"

Prior to 2019, hydroxyurea was one of the only drugs approved for treating sickle cell disease. Since then Novartis has released crizanlizumab (Adakveo) to treat pain, and Global Blood Therapeutics (GBT) introduced 

, which can reduce the sickling that occurs as a result of the disease. 

Ivy spoke about new therapies that are in the pipeline. Specifically, he focused on several different strategies that are being examined in 

"Now, as I've mentioned previously though, bone marrow transplant has been a therapy that has been used since the 1990s, but it has those limitations around on finding matching donors," Ivy explained. "

, the idea is to use the individual's own bone marrow, 

 to the bone marrow, and then give that back to the patient so that they can be cured of sickle cell disease."

It's not a lack of treatment options that poses a threat to the quality of care for these patients, but accessibility. Ivy mentioned the importance of training medical professionals and students on how to treat sickle cell disease and implement the treatment approaches that are known to be successful.

 patients with sickle cell disease already struggle with when seeking treatment, the current blood shortage--deemed a "blood crisis" this month by the 

--could have negative implications for the population. 

"With the blood shortage that's happening nationally, unfortunately, that will impact sickle cell patients because it will reduce their ability, of course, to get access to the blood they need for their therapies," Ivy said. 

However, he also emphasized the great progress that's been made with models of care, which can begin promoting better access to care.

"How do we create the entire spectrum of care for individual patients so that they can be managed whether they have a chronic disease, whether they had their primary health that needs to be managed," Ivy asked, "we're right now in a situation of COVID, so managing that."

"So, we need to look at a map of the medical neighborhood model that helps us to look at treating the whole patient," he explained. "And I'm happy to say that there has been a lot of progress made at the national level, in sickle cell in particular, to develop models that allow hematologists to more effectively connect to primary care providers and get that information."

As the year begins, Edward Ivy addresses what's currently happening in the field of sickle cell disease from the impact of the blood shortage to exciting new therapies.

Edward Ivy, MD, MPH: A Comprehensive Perspective on Sickle Cell Disease

It should be noted that all of these drugs are given as injections in the eye. Lloyd, for our primary care partners, can you describe what a process is to give an injection in the eye to a patient and how well tolerated it is?

: Roger brought up pegaptanib [Macugen] a little while ago. One of the interesting things about this drug is, this is the first drug we had as an injectable for the eye. We weren’t used to doing high-volume intravitreal injections in the office. There were limited indications for intravitreal injections, let’s say in 2003, 2004. Once these drugs hit the market and we were able to see how effective they were in the treatment of age-related macular degeneration [AMD] and other conditions, we had to completely change the way our practices operated. We went from seeing half the number of patients we’re seeing now to developing incredible efficiencies to deliver these drugs to 40, 50, 60 patients a day, just injection patients alone in the practice, which can be staggering numbers. We all have a different way of doing this to some degree, of delivering high-volume efficient intravitreal injections in our offices, but there are a few common threads.

There are a few things that we have to do in order to do this safely and effectively. We’ve got to deliver these drugs in an aseptic fashion, so the drug has to be sterile. That was more of an issue prior to the advent of prefilled syringes. We now have prefilled syringes for the approved agents, and that’s helped not only with efficiency but with the ability to ensure sterility of the drug as it goes in the eye. It’s important that we sterilize as best as possible the ocular surface, and we do that with betadine, we apply a betadine solution. Most people apply it to the surrounding skin, and then a less concentrated betadine solution into the conjunctival fornices. That’s a critical step because we’ve got to get as much of the bacteria off of the ocular surface as possible because if a patient gets an infection, it typically occurs with the needle introducing bacteria into the eye.

There’s a number of other things that some physicians use, for example, a lid speculum. Some physicians hold the eyelids open, some use sterile gloves, some use nonsterile gloves, and some use no gloves at all. There’s variability there as well, and then the choice of anesthesia. The majority of physicians today use a topical anesthetic that is applied to the eye via a drop, but there are other ways to apply anesthesia as well. The critical components of delivering these safely and effectively is a sterile drug, and an aseptic technique with betadine to the surface of the eye. If you do that, then we’re able to do this efficiently and safely for dozens of patients every day for each physician.

: Roger from a patient’s perspective, how do they do getting shots in the eye?

: The scariest time is the time between when a patient is told they need a shot in the eye, and when they get their first injection because it goes back to that childhood taunt about, “stick a needle in your eye.” It sounds scary, but then they get that first injection, and they realize they don’t feel it. The typical response I get is, “Wait doctor, did you do it yet?” I always take that as a compliment when they don’t know that they were given an injection. Then they realize, “I didn’t need to be so worried about that.” I want to emphasize for the audience here, to the extent that you know patients who either might need to get an injection or you’re sending, where you say, “Geez, you’ve got wet AMD.” Or maybe it’s an optometrist who’s listening now and they’ve diagnosed it, reassure your patients that, “You might need treatment. You might need an injection in the eye, but don’t be scared it doesn’t hurt, and they’re remarkably well-tolerated.”

: It’s important to realize that when we talk about giving a shot in the eye, we’re talking about giving it through the white part of the eye off to the side. Patients are not having to sit there and stare at a needle as it gets closer and closer to their eye, as you might see in an episode of 

I want to thank everyone for watching this 

 and other great content right in your inbox.

Lloyd Clark, MD, and Roger A. Goldberg, MD, MBA, share the process for giving injections in the eye for patients who have wet AMD.

Using Intravitreal Injections for the Treatment of Wet AMD

Presently, there are 4 main anti-VEGF therapies utilized here in the United States. We’re going to start with them in the order in which we started to use them. It was back in 2004 and 2005 that we began to use off-label bevacizumab, or Avastin as it’s known, in the eye. Dante, your group in California did a lot to innovate with this being used in an off-label fashion. Tell us about how you all helped the development of this.

: Phil Rosenfeld, MD, PhD, had given a talk where he was using IV [intravitreal injection] bevacizumab because bevacizumab was a cancer drug. If you look at a lot of the agents that were used, they were initially used for cancer therapy because Judah Folkman, MD, came up with the idea that you could restrict cancer growth by getting rid of the vascularization in the tumor. So we used this agent that was being used for cancer therapy, and they showed a response in patients given IV, but there were a lot of complications, things like hypertension and potential strokes. Phil had done 1 or 2 patients, he had done an intravitreal injection, and I thought it was brave, but it was remarkable. One of my partners, Bob Avery, MD, came back and said, “We should start doing this.” We were thinking about doing IV therapy, so we just started using it in our patients. It was one of those treatments where the effect was so large that you almost don’t need a clinical trial to know that it’s working. You need a trial to make sure it’s safe in the long run and such.

This drug was a one that the company didn’t want marketed for this use because it was being used off label, and it was very inexpensive compared to the ones that they were developing. But it quickly took hold like wildfire, not only around the United States, but around the world, with no marketing dollars spent trying to get this drug in use. It was used worldwide, that was the large effect of it. It was one of those things in my career that, we had been through PDT [photodynamic therapy], and we did submacular surgery, and some of the things Roger talked about, for example, laser. It was unsatisfying for the patients and for the doctors. When you gave this patient an injection, they came back a month later and they said, “I’m seeing a whole lot better doctor.” You looked at the pictures and they were much better. It was a big effect, and it’s continued to be so.

: Absolutely. And as Dante pointed out we’re still using bevacizumab to this day. It’s an affordable option for our patients. Next up in 2006, ranibizumab was approved for the treatment of exudative age-related macular degeneration. Lloyd, talk to us a about the effect of ranibizumab and the place it’s found in your armamentarium.

: Ranibizumab was the first FDA-approved drug for use in the eye for wet macular degeneration. It was the first anti-VEGF agent that was specifically studied in the eye for treatment of these common retinal diseases, including age-related macular degeneration. It shares many similarities with bevacizumab, but it has a higher affinity to the target protein than bevacizumab, and it’s also significantly less stable in the serum. It has a serum half-life of around 5 hours compared to almost 3 weeks with bevacizumab. That makes it a drug that’s ideally suited for use in the eye. It has a higher affinity, so that it sticks tightly to the target protein, but once it’s expelled from the eye, it’s rapidly metabolized in the systemic circulation. What it was designed to do was have a stronger effect inside the eye than bevacizumab but have a limitation in systemic cardiovascular events, as Dante discussed.

There was a full, robust, 3-phase clinical research development program that Genentech underwent with ranibizumab. It showed about a 10- to 12-letter improvement of vision in patients with wet macular degeneration compared to the current standard of care. The overall delta between this drug and the standard of care was approximately 4 lines of vision. As Dante described with bevacizumab, even though we were masked in these clinical trials, and we weren’t allowed to know what they were getting, it was clear early on in the first few months that these patients were receiving something that was completely different. These trials were remarkably positive in terms of favoring ranibizumab as a superior drug in wet macular degeneration, and ultimately it was approved in 2006. It became the gold standard for treating wet macular degeneration, both in the clinic as well as a gold standard comparator for the clinical trials that would follow the approval of ranibizumab.

: Roger, a decade ago we had approval of a third agent, aflibercept, for the treatment of exudative age-related macular degeneration. Talk to us about aflibercept and how it's different from ranibizumab or bevacizumab.

: Aflibercept, the brand name is Eylea, it’s made by Regeneron. Back then Regeneron was a relative start-up biotech. It’d been around for a long time, but it never had a big commercial success. We now know Regeneron as one of the major biopharmaceutical companies that have been very involved with the COVID-19 treatments with an antibody treatment, and they have multiple other drugs. Eylea is what put them on the map with aflibercept. Aflibercept is what’s called a fusion protein, and it’s more akin to a full-length antibody in terms of its size. They call it a VEGF trap because it binds soluble VEGF, and it has a tight binding affinity and soaks up all the free VEGF that’s there. Based on some work that they did early in the clinical development pathway, it seemed to have a longer half-life in terms of its potential for efficacy. When aflibercept was developed, by 2011 when it got FDA approved, it wasn’t ethical anymore to have a sham or a PDT [photodynamic therapy] control. It was a controlled trial against ranibizumab, which is what we said was the gold standard. They were able to show that patients who were treated every other month after a series of loading doses did equivalently as well as patients treated monthly with ranibizumab. It offered the prospect of longer time in between treatments when it came to market.

: Last, we had approval about 2 years ago of a medication called brolucizumab. Dante, talk to us about the type of molecule that brolucizumab is, how it may have some differences from the drugs we’ve talked about previously.

: It’s another molecule design, a very small peptide molecule. You could have a large concentration molar equivalent of the drug, it had a very high binding affinity. We thought one of the ways to extend the durability of a drug is to put more of it in there. That was part of it with brolucizumab, and the high binding affinity. This drug came out, and was looked at in clinical trials, and it was compared with the standards of care at the time and shown to be equivalent and perhaps having a longer durability. We were excited about the drug, and we started using it, a number of our patients were part of the clinical trials. We were enthusiastic about the possibility in patients who didn’t seem to dry up completely with the other agents, that this would be a better drying agent. In some cases, anecdotally it seemed to be that way.

It turns out, unfortunately, there were some increased risks of complications, intraocular inflammation, and rare occlusive arterial occlusions that occurred in these patients that are inflammatory related. These caused very abrupt and severe loss of vision. These are rare events, but in the environment where you have other agents that are working close to the same efficacy and durability, it was hard for a doctor to choose this type of agent. For the most part we, at least in my practice, don't use brolucizumab much. We still have some patients who were placed on it and seem to be doing pretty well. If you don’t overuse it or use it on a less frequent basis, the risks are less. That’s the latest one that got FDA approval, but the use of it has been less.

: It had a lot of excitement when it first launched, and we were all disappointed to see some of these as you mentioned very unusual events, and not a class effect. We don’t see these vascular occlusions with other drugs in these classes. It gave us a lot of pause before we jumped in wholeheartedly. It has caused a big pause among our community in utilizing this.

A panel of eye care specialists review the 4 currently available anti-VEGF agents available for the treatment of wet AMD.