[creativ_pullleft colour=”light-gray” colour_custom=”” text=”Episode 075″]
Jeff Heier, MD, is the Director of the Vitreoretinal Service and the Director of Retina Research at Ophthalmic Consultants of Boston (OCB) gives an update from the Angiogenesis conference about the advancing anti-angiopoietin programs.
Jeffrey Heier, MD
Jeffrey S. Heier, MD is the Director of the Vitreoretinal Service at Ophthalmic Consultants of Boston (OCB) and Co-Director of the Vitreoretinal Fellowship at OCB/Tufts School of Medicine. He is one of the leading retinal clinical researchers in the country for new treatments in macular degeneration, diabetic macular edema, venous occlusive disease, vitreoretinal surgical techniques and instrumentation, and diagnostic imaging of the retina.
Tom Salemi: Dr. Jeff Heier, welcome to the Podcast.
Jeff Heier: Thank you, Tom. My pleasure.
TS: I’m happy to have you here because I need your expert opinion as both a Red Sox fan and a physician. Do you –
JH: So there’s absolutely no question we’ll win it all this year.
TS: Mine was more specific. I have no doubt that we’re going to win everything, but do you really believe that Pablo Sandoval has a BMI of 17%?
JH: He is in remarkably outstanding shape and I think all of the photos have been horribly doctored.
TS: I like your style. I like the – I actually read an interview that you gave in 2012 and you said you were sadly a Red Sox follower, and that was like after we won two World Series.
JH: Yeah, it was. Well, it’s pretty amazing to think that out of the last 4 years we’ve won one World Series and come in last three times. A hundred and fifty million, hundred eighty million just doesn’t get you what it used to.
TS: I’m sure there are a lot of tiny violins playing in the Podcast right now.
TS: Well, we’re not here to talk about the Red Sox. I’m sure we could take our entire time doing that. We’re following up on the Angiogenesis meeting in Miami, just getting some of the feedback from folks who attended, but also people who presented. I know you gave a presentation on behalf of Regeneron. It’s a publicly traded company, so we need to be a bit careful as to what you say and such. But can you give our Podcast audience update on the data you presented there?
JH: Sure. So what I spoke on was two combination programs using aflibercept, their anti-VEGF agent, and other agents to attack other targets. And one of those I had previously spoken about was an anti-PDGF, anti-VEGF therapy. And I really didn’t cover that in very much detail other than to say that it’s currently enrolling a large phase 2 study. More up to date or newer area of topic was a combined anti-ANG2, anti-VEGF approach to both neovascular AMD as well as diabetic macular edema. And as we all feel that we have probably come close to maximizing the treatment effect of anti-VEGF therapy, that we’re largely at the top of the dose response curve, certainly with some patients and some disease states there may still be a little area to work there. And durability may be an area to approach. But in terms of overall efficacy, we’ve really done quite well with anti-VEGF therapy. So a lot of groups, Regeneron certainly being one of them, are looking at combination therapies to try to maximize efficacy, durability and safety in the treatment of common retinal diseases like neovascular AMD, diabetic retinopathy, and retinal venous occlusive disease. There’s certainly ground work for that. A lot of our treatments for retinal disease from treatments from oncology diseases. And those processes are ongoing, have been ongoing for years in oncology, where they take certain approaches, combine targets, and try to maximize outcomes based on that. And that’s what we’re looking at right here. The theory behind this is that we know that ocular levels of both ANG2 and VEGF are elevated in diseases like wet AMD and ischemic retinopathies. And they appear to be co-regulated in these disease states, and act together to promote bad things: neovascularization, increases in vascular permeability. It’s unlike the VEGF pathway, and when I say unlike, to most retina specialists, the VEGF pathway is relatively straightforward. You have insults, whether it’s ischemia or trauma or other insults that lead to an increase in VEGF. And that leads to angiogenesis, and it leads to increased vascular permeability. The angiopoietin Tie2 pathway is much more complex, or at least to us at this stage in our understanding, it’s much more complex. So to sort of simplify this, the way we look at it is Tie2 is an endothelial cell specific tyrosine kinase receptor that really binds two ligands. One ANG1, which is expressed in normal tissues and helps maintain vascular integrity, and the other is ANG2. And that’s where we’re focusing on. For all intents and purposes, ANG2 is only expressed under pathological conditions, and is known to be in high levels in the angiogenic vessels. So we believe you get increases in the levels of VEGF from various conditions, as we said. Ultimately, this leads to increased levels of ANG2, which leads to vessel destabilization, angiogenesis, vascular leakage, all the things that we like to block. And Regeneron has done preclinical work, work in animal models which has shown that when you combine an anti-ANG2 drug and that drug is nesvacumab – that’s their name for their drug, their anti-ANG2 – when you combine that with afilbercept, you actually see effects that are greater than either one alone. And so that’s a very positive from the combination therapy. They’ve also shown that when you combine these two agents, you may get increased durability of the anti-permeability effect. So not only do you see what may be a greater effect, but that effect may last longer than just using either agent alone. So they have what I presented was the co-formulated product in a phase 1 study. And the phase 1 study had five cohorts, in essence. The first four cohorts involved increasing amounts of nesvacumab with two milligrams of aflibercept, which is the conventional approved dose of aflibercept. And so it went from .5 mgs to 1 mg to 2 mgs to 6 mgs combined with 2 milligrams of aflibercept. And these were dose escalating cohorts with four patients each. And then cohort 5 was nesvacumab alone, the anti-ANG2 alone in the high dose. And so basically, patients were dosed – they received a dose every 4 weeks for a total of 3 doses, and then they were followed PRN and dosed with aflibercept based on criteria driven certain specifications.
TS: Are they administered any differently?
JH: No, intravitreal. So it’s a single intravitreal injection. Again, a 50 microliter injection, no different than the standard aflibercept injection.
TS: I see.
JH: The study was 10 AMD patients and 10 DME patients, and what we presented was the safety data, which looked very good, and which was typical of really an anti-VEGF study or an intravitreal injection study. There were no specific safety signals. There was one MI in a patient who already had a vascular history, a diabetic patient, and this wasn’t felt to be drug related. And really, probably the most interesting component of this was as we got to the higher cohorts, the cohort 3 and cohort 4, a number of patients did not require a rescue treatment or another aflibercept injection, despite being 24 weeks out at that point. So everybody was treated at day zero, week four, and week eight. Then they were followed monthly from beginning at week 12 to week 24, and a number of the patients, more than half of the patients in cohort 3 and cohort 4 did not require an aflibercept injection by the week 24. Now this is very early. This is a phase 1 study. It’s really geared to help us understand the safety of the combination therapy, get some insight potentially into durability and efficacy. But remember, from an efficacy standpoint, every one of these patients was already getting 2 milligrams of aflibercept, which is an outstanding treatment already for wet AMD and diabetic macular edema. So we already saw strong anti-VEGF effects. The interesting thing was to look at the durability and see if you get some insight into that. And really, the take home from this was that the combination therapy was well tolerated, patients did well – or actually, let me take that back. The combination therapy was well tolerated. There were no safety signals. The duration of effect may be extended at higher doses, and this would be consistent with the preclinical findings. But certainly, what we saw from this was that the efficacy and safety certainly merit continuing on to phase 2 studies for both AMD and DME.
TS: So what would – and I know we’re very early in the clinical studies, but if we were to follow this path and we get some of these products on the market, what would the treatment world look like if there are multiple VEGF and PDGF and ANG2 inhibitors? I mean does it change how you would treat patients, how you practice medicine?
JH: So it’s a great question, and it’s really too early to understand what the impact of these agents would be. There are so many questions that are yet to be answered. So is this – would you require these agents early on, but not throughout the course of treatment? So for instance, with an anti-PDGF, which we believe may also inhibit scarring, or may sensitize eyes or lesions to the anti-VEGF effect, do you need that throughout the course of therapy? With the anit-ANG2, same thing. If it increases the durability, does this mean you would need the combo throughout the course of treatment, whether that’s 6 months or 6 years? Or do you just need it periodically, or just at the beginning? And these are all questions that we just really have no idea about. I think right now we’re really just trying to understand the benefits of the different targets, and I think as we go forward, we’ll strive to work out how the treatment paradigms will evolve.
TS: Are those questions that doctors answer themselves on an individual basis? They know what works, they’ve seen –
JH: Oh, I think these are questions that we can’t answer yet in a study basis. I mean right now we’re just trying to demonstrate the safety and increased benefits of combo therapy. But I think once you demonstrate that, then you have to work out, well, in which scenarios how are they used. Is it – do you always use combo therapy? Are there some periods where you want breaks from combo therapy? I just think there’s far too many questions to understand – not only not to know the answers, I don’t even think we know all the questions yet.
TS: Fascinating. There’s obviously a number of these programs. Assuming that – let’s not assume that they all work out, but let’s assume there’s multiple products on the market at some point in a set number of years. Are these competing products or are they likely part of any physician’s toolkit? You’d use this one for certain circumstances, and that one for other circumstances?
JH: It’s a good question. I truly don’t know the answer to that yet. I mean right now we have three anti-VEGF agents and each of those agents is being used in a fair amount, and there are different ways that people use the different agents. So would that play out into combination therapies, both as a combination therapy or as separate agents used in combination? Those questions just aren’t known at this stage.
TS: Is it difficult to get patients to participate in a trial like this one?
JH: Not really. I think that we’re – so let’s take the anti-PDGF story, for instance. There, we’re offering patients the opportunity to be in a study where there’s some data which has shown that the combination of an anti-VEGF and an anti-PDGF agent may offer benefits above and beyond the anti-VEGF agent alone. And so in a study where you’re already essentially guaranteeing patients the standard of care, and you have a fair number of studies to date talking about safety of the combination therapy, with a potential for increased efficacy, I find that a lot of patients are very interested in participating in the studies.
TS: That makes sense. What if one of these products is approved and there’s something out there that they can use without participating in a trial? Do you think that would complicate things for patient recruitment?
JH: It certainly could. It certainly – before we had an approved anti-VEGF agent, the patients who needed either anti-VEGF therapy for wet AMD or DME or RVO, the only way they could get it was a clinical trial. And it was very easy to enroll patients at that time. Now we have great treatments, and so for a lot of patients, just the ease of just getting the treatment, staying closer to home rather than going to a study center – for instance, for us our study center is – most patients who are in studies are in downtown Boston, which means you have to travel to downtown Boston, take care of parking and traffic. And even though a lot of that may be taken care of by the study, that may be a lot more work than just staying out in a satellite ten minutes from their home without traffic. Still, patients are – you know, some patients are very hesitant to participate in clinical trials. Other patients are highly motivated to participate in clinical trials. They know that we’ve worked really hard to establish a very strong clinical trial program, and that we are highly selective in selecting studies that we believe have the potential to benefit patients. And many of them have a great interest in participating.
TS: It’s an interesting point. Is there a type of person who is more likely to participate in a clinical trial? A growth mindset person, optimist?
JH: Absolutely. Without a doubt. So there are some patients who you mention clinical trials, and the first thing that comes out of their mouth is “guinea pig.” And right away, you know that’s not somebody who would be a good clinical trial patient. And we, because of our reputation as a clinical trial site, we see patients from all over the region, if not all over the world, who are interested in participating in trials. So we’re very careful when we discuss them to in no way oversell the program. And so we talk to them about the risks and benefits of it. We talk to them about the time commitment that clinical trials will mandate. But find that there are certainly a number of patients who are excited to participate in clinical trials. They may have done it in other areas of medicine. They’re very much aware of our clinical trial reputation. And so they’re very excited to do it. And those patients who we have in studies for 2 to 3 to 4 years, they almost become like family members of our clinic. And our study team is very dedicated to the studies and the patients. The patients who are in our studies understand that they take priority over the study. Our primary interest is in their safety and their efficacy. And so we focus very much on them. We want the study to be done meticulously, but we never lose sight of the fact that it’s the patients who we’re there for. And I think that translates into our clinical study team and how the trials are run. And we have a very high retention rate. We have patients who’ve had family members in clinical trials.
JH: We’re heavily involved in the very early anti-VEGF studies, so we have patients who were getting treated years before these drugs were available. So I think patients are very much aware of that. And the patients who are interested are interested for the right reasons. And the ones who are not, we will actually discourage patients. If there are patients who are clear are very nervous about being in a clinical trial, have any concerns, we will actually say we do not feel that a clinical trial may be the best thing for you. We’ve got these other options that we can treat you, or let’s say dry AMD studies with geographic atrophy. There is no treatment option there. But we’ll still say if somebody seems overly anxious about participation, we’ll actually discourage them from participating.
TS: And the good news, though, is your endpoints are measurable. It’s not based upon a person’s – the way they feel. I would think the things like –
JH: Correct, correct.
TS: – pain wise it’s a lot more complicated because you’re already biasing the results by getting people who are optimistic and hopeful into a trial.
JH: That’s one of the really nice things about retinal disease is the endpoints are measurable. So placebo effect is always an issue with clinical trials, but for instance when you’re treating diabetics or vein occlusion patients or wet AMD, the endpoints are reproducible and measurable. And so it doesn’t really matter what they think. We’ve got objective endpoints that we look at and can really tell what’s going on. Similarly, with geographic atrophy for dry AMD, we’re measuring progression of geographic atrophy over time. And so while patients may think they’re getting better or think they’re getting worse, we’ve got objective endpoints to really dictate that.
TS: Fascinating. Well, it’s an area that I don’t give a lot of thought to, but it really is a whole industry, obviously unto itself. But also you have to – I suppose the more you do, the more clinical trials you participate in, the better you’re at sort of managing the patients coming in and out of your practice.
JH: Exactly right.
TS: OK. Well, I know you’re in Florida. I hope you can catch some spring training in while you’re down there.
JH: That’d be great.
TS: Thanks for taking the time today.
JH: You bet, Tom. Take care.