Cases From The Real World: A Long Battle With BRVO-ME

Dr. Modi:  
Good morning. This is CME on ReachMD. I’m Dr. Yasha Modi from NYU Langone, and I'm joined with my good friend and colleague, Dr. Ferhina Ali.  

Dr. Ali:  
Hi, Yasha. Great to see you. 

Dr. Modi:  
Well, thanks so much for being here. We're going to be talking a little bit about retinal vein occlusion.And for the most part, when we start patients who are treatment-naïve, we oftentimes have this really binary, amazing response to treatment, but there are a few cases where it can be very, very difficult to treat patients, and that's what I wanted to share here with you. 

So let's kind of jump into this case.  

This is a 70-year-old man. He presents for a second opinion. He's been treated long-standing for a branch retinal vein occlusion with macular edema, all the way back to 2017. And actually, when he presented, his vision was 20/100, that improved to about 20/50 with his initial treatment. And his treatment history is extensive: 22 bevacizumab injections, 4 ranibizumab injections, he's had 18 aflibercept injections, being unable to extend more than 4 weeks, and triamcinolone, which he can only extend to about 6 weeks, and he's had a total of 4 injections. 

So the referring retina specialist wanted me to see this patient because of the possibility of doing dexamethasone injections. And so at that point, I initiated that  

treatment plan, and we were able to extend to about 10 weeks in duration. And this person had received a total of 13 dexamethasone injections over the course of a couple of years, and was doing reasonably well with maintenance of about 20/60 vision.  

But then I give dexamethasone number 14, and what we see is the patient coming back, and this is that sort of dreaded moment where they come in with endophthalmitis. Remember, the rate of endophthalmitis is probably about 1 in 500 with dexamethasone, as opposed to about 1 in 2,000 with intravitreal injections. So the vision is hand motion, there's a hypopyon in his vitritis, and this is sort of like my worst nightmare. I absolutely hate when this happens, but if you are a retina specialist and you're treating long enough, this is the inevitable outcome for a minority of our patients. 

So this person gets a tap and injection of vancomycin and ceftazidime on 2 separate visits because I was worried about the dexamethasone implant, and the culture grows staph epi, which is overall a very good prognosis for this patient, and then ultimately undergoes a vitrectomy to follow. 

So this is the OCT at the time of endophthalmitis. No macular edema. And this is the patient 3 months later, the vision is improved to about 20/100 but not quite back to that 20/60 vision. And there are some reports in macular degeneration that after endophthalmitis, the treatment burden goes down, so we opted to just pause treatment. So this is now 5 months after vitrectomy, and he said about 3 to 4 weeks ago his vision had worsened. The vision is now 20/200, there's now a recurrence of macular edema, and we end up giving aflibercept 2 mg.  

Then 4 weeks later, there still is a persistence of macular edema. And at this point, we start introducing the concept of faricimab versus dexamethasone, but the patient says, ‘Hey, I really want to just try going back on aflibercept.’ 

Remember, the patient had 18 injections of aflibercept before coming to see me. So we continue this medication. He then comes back 8 weeks later, so he's missed a visit, so we can't truly assess the effect of aflibercept. And at this point, he noticed that his vision is considerably worse, and so we opted to doing a dexamethasone implant. 

Now, this is one of those patients that's really driving the ship, really motivated to say this is the medication that I want. And for the most part, because we're in the absence of meaningful evidence here, so far down the treatment algorithm, I'm obliging by treating this patient with dexamethasone. 

So here we go a little further. I've now recommended faricimab because you can see the dex implant 4 weeks later really hasn't budged the macular edema. And so actually at this point, I do off-label aflibercept 8 mg, because I had a sample in the office. And you can see that 4 weeks after that, there's really no response. So I said at this point, I will give you anything. I will give you faricimab, I will give you bevacizumab, ranibizumab, but he opted for the dexamethasone implant again.  

This is him now 3 weeks later, and what we're starting to see is that really nothing that I'm doing is working. So I told him, I was like, at this point, you have to let me drive the ship a little bit. And I then was finally able to convince him to give him faricimab. And this is what he looks like 4 weeks later.  

Now, interestingly, this was about a few months ago, and I've been able to sort of continue him at just about 4 weeks with faricimab. His vision has not improved back to where it was, it's still about 20/80 to 20/100, but he absolutely cannot extend beyond 4 weeks. So every time he goes to a 5-week extension of faricimab, he has recurrence of his macular edema.  

Dr. Ali:  
So that is a very interesting case and challenging. Quite a variety of treatment options were offered to this patient, a lot of trial and error. And then, of course, the dreaded endophthalmitis, which we know there can be postinflammatory edemaas well as related to that. Sothere's a combination of factors here, but it does seem as though he ultimately responded well to the faricimab. 

And we do know there's a subset of patients that do require q4 week treatment,but as you've mentioned, and as we've seen in him, he really does require combination therapy with the steroids as well. Tell me a little bit about your practice pattern with respect to combination therapy. 

Dr. Modi:  
Yeah, it's a great question. Oftentimes I try to introduce steroids, like I did in this case, with the goal of extending the interval. And so for a long window of time, this person who was getting basically every4-to-6-week injections was able to get out to 10 weeks with dexamethasone monotherapy. 

So we do know that when you give steroids, certainly the anatomic response can be quite profound. But if I can get them onto monotherapy, I prefer that. But I also know that there's a lot of patients who do need sort of this combination therapy. And here what I'm trying to do is just throw everything at this patient. 

Now, the reason why this individual was sort of opposed to faricimab was just because he had a complication with the medication, and he was very, sort of, gun shy to try anything new, to deviate from anything that was familiar to him. Andas a result, it took a little bit of time to kind of get over the PTSD of the endophthalmitis, if you will. And I think he's quite happy now getting faricimab injections. 

Now,obviously endophthalmitis can further reduce your vision, and then persistence of macular edema that's long-standing can reduce your vision, in addition to the untreatable component, which is macular ischemia. And he certainly has some elements of macular ischemia. I have OCTAs that really show that he's got extensive nonperfusion of the superficial capillary plexus as well as the deep capillary plexus, and that extends all the way to the fovea. 

So I think we're kind of at the best that we're going to do, but he certainly notices that it's clearly better when we're giving him these treatments and drying up his macula. 

Dr. Modi:  
For those just tuning in, you're listening to CME on ReachMD. I'm Dr. Yasha Modi, and here with me today is Dr. Ferhina Ali. We're discussing real-world use of second-generation retina treatments in patients with difficult-to-treat retinal vein occlusions.  

Dr. Ali:  
Yeah, and I think it's interesting that you mentioned, certainly a resistance, and fully understandablearound something new, as compared to what he's had before. I do think that as we were studying faricimab in the large registration trials,it is a bispecific molecule. It does target Ang-2 as well as the VEGF-A. And I think for me, I was very, very curious to see how it would respond, how our patients with RVO would respond, which is a very distinctly vascular process.And soI think ultimately ithas been helpful for him, but definitely understand the resistance to that, but offering something a little bit different and more vascular-mediated for him.  

Dr. Modi: 
Oh, yeah. And what's interesting is that Isort of call retinal vein occlusion phase 3 studies, I call it the ugly stepchild study. And the reason being is because, companies invest so much in AMD and DME, and they create these beautifully designed studies that not only get FDA registration, but also inform decision-making. Like, for instance, YOSEMITE, RHINE, TENAYA, LUCERNE. And specifically YOSEMITE, RHINE where we had a really interesting sort of treat and extend. It sort of challenged the idea of going up to every 4-week extension intervals. It showed us the true durability of faricimab.  

But when you look at BALATON and COMINO, which were the registration studies for faricimab, these are patients who got monthly injections of faricimab out to 6 months, and/or aflibercept monthly out to 6 months. And so essentially the primary endpoint being 24 weeks. And what this is just trying to show is noninferiority to aflibercept. 

Now, after this window, there was a treat and extend, so it will be really interesting to see the 2-year results as to what is the durability of this medication. But very early on, even just repeating the FA at 24 weeks, what we can see is that the same analysis that they did for YOSEMITE and RHINE where you're looking at macular leakage, there was some incremental benefit in reducing leakage in the macula with faricimab relative to that of aflibercept 2 mg. 

So again, a true noninferiority study. Very, very little phase 3 evidence to sort of support the implicit superiority, if you will, of one medication over the other. But I think that's really where real-world studies are going to come into play.For instance, if patients are getting treated with aflibercept, what is the extension interval that we would get with faricimab or aflibercept 8 mg? And I know that,Ferhina, you've been really involved in some of the real-world studies in DME. What are your thoughts on real-world studies withfaricimab as well as aflibercept 8 mg? 

Dr. Ali:  
Sure. Sodefinitely the first steps have beenlooking at the DME populations and the neovascular AMD. Of course, based on the indication, that is what is first available to us in the real world. That's how we've used it, and we've been able to track treatment patterns, and we've been able to look at proxies for durability, both for AMD and DME. The data is forthcoming for RVO, following that indication for faricimab. 

We have some early data for the real world with aflibercept 8 mg. Of course, the introduction into our clinical practice, not off-label butsort of commercially available a bit later than faricimab. So I think we're really seeing validation for sure of safety and efficacy because real-world shows us that doctors are using things that they feel confident in using and are getting good results. So that is somewhat of a proxy for that.

But we're also seeing validation of some of that durability data that we've seen in the clinical trials in terms of fewer number of injections. And we can only surmise,we can'tvalidate for sure what's happening in the real world, but that doctors are using these injections with less frequency, suggesting they're getting outcomes that they're happy with, allowing for that interval extension. 

So definitely, there will be more data forthcoming for the RVO indication for faricimab. And once that is approved for aflibercept 8 mg, we'll be looking at that as well with the IRIS registry and Vestrum? 

Dr. Modi: 
Yeah, absolutely. And so let's talk a little bit about Vestrum, because thereare some really cool data. Actually, I had the opportunity to work on this project with Mike Ip and a whole team of great sort of researchers, and what we had looked at was sort of the correlation between injection frequency, both in retinal vein occlusion, both BRVO and CRVO, with long-term follow-up up to about 5 years.Andthe nice part about the Vestrumdatabase is the numbers are huge compared to what we can otherwise get just by institutional evaluations. 

Dr. Ali:
Especially at 5 years.   

Dr. Modi:  
Exactly. Right?  

Dr. Ali: 
That’s quite an impressive number, yeah. 

Dr. Modi: 
Yeah. Socertainly, there is attrition, right? And we know that patients are going to be lost to follow-up either because they're doing really welland they don't need treatment, they're doing quite poorly and the treatments are not responsive, or just because life happens and we end up losing those patients. 

But here you can see, out to 5 years, patients are still hanging outinthe thousands of patients. And what we see is that in the first year, on average, patients received the most number of injections, somewhere around 7 injections, and that teeters off to about 4 in year 2.But interestingly, years 3 to 5, it doesn't drop to zero.  

And I love this slide because it really tells you that a lot of times we're dealing with a chronic disease. Now, we normally say you have this blockage, maybe we'll treat you intensively for a window of time, and then we could potentially stop you. And there's a bit of a dearth of information on how to stop these patients and when are they likely to recur. And I think you're going to talk about that a little bit later.  

But what we sort of see is that yes, initially you get this really incredible visual acuity gain, even in the real world, up to about 2 lines of vision. And that actually can be relatively well preserved in BRVO. But in CRVO, what we start to see is, as we get out to 5 years, there is a slow decline in the vision as we get out to 5 years. And those who maintain their vision are those who tend to get more intensive injections. 

So when you're looking at these curves, when you look at the blue line relative to the red line, the differentiator is those who've had a high number of injections versus a low number of injections. And a high number of injections as a population tend to do better than those who receive a low number of injections. 

So all of these are things that we kind of already know. Ferhina, when you saw this, what were your thoughts? 

Dr. Ali:  
Yeah. So I think the real-world data through and through has supported the more number of injections you get, the better you do. But as you mentioned, I think with thissubset of patients with RVO, there is a slight nuance to the discussion on the initial treatment that maybe we'll get to stop. 

And I think I like offering that because –  

Dr. Modi:  
Yeah, absolutely.  

Dr. Ali: 
Yeah, I mean, I like offering it. I hope it's true for sure, and we'll talk about it a little bit with a different case. But I think this highlights well that it maybe is less true than we want it to be. And I think that in terms of outcomes, patients still will do better if they get more treatments. 

Aswith your patient, our patients have their own preferences for what they want and how they want their time to be spent, and what sort of treatments they get.So we can show them lots of real-world data that say the more you get, the better you do. But it may not always be the case that they are on board.  

Dr. Modi:  
Ferhina, those are all excellent points. In short, we really always want to use the best drying agent available to us. And what we've learned even from SCORE2, that may be bevacizumab, that may be aflibercept 2 mg. But there are certainly going to be cases where what we've learned about these second-generation agents, extrapolating from AMD, extrapolating from DME, is that these may offer patients excellent drying, maybe superior drying, with a longer duration between visits. And that's going to be hugely impactful to patients.But what we really need is robust real-world data to kind of inform our treatment decisions. How much additional time can we buy for our patients on average?

So that'sall the time we have for today. Thank you to the audience for joining us, and thank you,Ferhina, for joining me today. 

Dr. Ali:  
Thank you, Yasha.