Four-Year Outcomes of Faricimab in Diabetic Macular Edema in the RHONE-X Extension Trial: A Podcast

00:00:00: You are listening to an AIDIS Journal podcast.

00:00:05: My name is Viril Shatth, I'm a retina specialist at University Retina and Macula Associates in Chicago Illinois

00:00:13: And i am Stella Bujosewicz ,I m also reacting as Specialist at the university of Milan And we are here today to discuss the long-term outcomes of Farissimab in patients with diabetic macular edema from the Ronix trial and implications for these findings on clinical practice.

00:00:34: This podcast is brought you by Ophthalmology & Therapy.

00:00:39: So, before diving into Ronix can you give us a background about Farisimab and dual pathway inhibition in DME especially on the mechanism of action?

00:00:51: Sure, of course.

00:00:52: Yeah This is kind of the critical part of this because you know Ferisimab for us For those that treat retinal disease was really a new type of treatment for us.

00:01:02: There's dual mechanism of action.

00:01:04: It was first approved by specific antibody for intracular use and so when we were used to using mono-specific antibodies targeted at VEGF A, it changed.

00:01:18: When we say it's bispecific, when you say that its really independently and simultaneously binding both VEGF-A which has been used for many years but also ANGE II.

00:01:30: And so the relevance especially to our conversation today about diabetic macular edema is And so this dual mechanism of action can really enhance the disease control, especially when we compare it to traditional anti-vegF monotherapy.

00:01:49: So for us with these newer treatments our goal is always to achieve better and more sustained disease control in this case by targeting both.

00:02:01: Yes, I agree completely with you and we also have a lot of no-clinical biomarkers that can help us in the monitoring Sure.

00:02:11: So the Roninx study design,

00:02:18: it's really an extension studies to discuss and extensions that you need.

00:02:31: looking at both treatment naive and previously treated patients with diabetic macular edema, those original studies were two-year studies.

00:02:39: And the RoHneX study was an additional two years beyond those.

00:02:43: Those were phase three trials.

00:02:46: What that means is gives us really four years of data on these cohorts of patients.

00:02:53: When we look when this patient started their original Yosemite and Ryan Trials They were randomized into one of three groups.

00:03:27: and we followed them for two years in that first MAB treat-and-extend protocol during the extension.

00:03:34: So, that's kind of how the trial was structured.

00:03:37: And then when you look at what were actually looking?

00:03:39: What is the objective of the extensions?

00:03:41: The primary objective in extension studies like this Is really long term safety intolerability these medications.

00:03:47: These are the patients who will be receiving potentially this first Mab.

00:03:51: four years and so that data is very important to us in terms of how these patients do from a safety intolerability standpoint.

00:03:58: Now, that being said we're also looking at other exploratory objectives—that includes efficacy uh...and also durability which for us and Stella as you know really were looking for treatments that work well- that we can kind of extend in terms.

00:04:12: the durability ...uh..which…which really translates into better outcomes our patient's ah...and …better treatment care for them, especially if they're getting less injections over time.

00:04:24: Really kind of one of the highlights here is that we had a large number of patients in this trial.

00:04:29: so this is the largest extension study and DME to date.

00:04:32: We had over one thousand four hundred patients rollover into the extension which was a ninety-one percent retention rate from the parent studies which really says a lot.

00:04:42: I think about treatment itself protocol on how well it Now just kind of I mentioned that these patients are in.

00:04:50: the extension were transitioned to a treat and extend regimen Just to drill down on that a little bit.

00:04:55: That means that they were able to be extended out up to every sixteen weeks.

00:05:00: So again, that translates too for us.

00:05:02: we want to know how long we can go with durability for these patients, and what kind of percentages were looking at?

00:05:09: What percentage of our patient population are getting out to this more extended treatment intervals.

00:05:14: And so we can certainly talk a little bit about that data.

00:05:17: The other thing I think was interesting is the extension Patients, there was one group in the parent study that received a flibrisis up two milligrams every eight weeks.

00:05:25: Well even those patients were transitioned over to the fursimab treat and extend.

00:05:29: so that's kind of very valuable data for us.

00:05:31: right we often Switch treatments on our patient.

00:05:35: And this core particular We get to see what happens to patients when they're on a Fliber set For Two years?

00:05:41: Then They switch to fursumab for two Years.

00:05:43: and So That Data is Very interesting as well.

00:05:46: And the treatment and extent algorithm that we used in this extension very much mirror what we did in the parent studies, in the Yosemite and Ryan trials.

00:05:56: Very nice.

00:05:59: I would like to add something that was also interesting is the patients, even those who were on a fever set and then switched to Pharissimab in the Ronix trial did not need to be reloaded with Pharisimab but immediately went on treated extent.

00:06:17: And this gives us lots of valuable data which can be used for clinical practice.

00:06:22: So now what does long term safety and tolerability data from Ronix show?

00:06:28: Yeah, and that's a great question.

00:06:30: That's really the primary objective of this long-term extension And what we saw was that safety was consistent with the initial Yosemite and Ryan trials over these additional two years.

00:06:44: So what does that mean?

00:06:45: We looked specifically, especially you know Stella we're looking at things like intraocular inflammation and again this was well balanced across the treatment groups.

00:06:54: We saw low IOI rates between one point one in four percent across the group's uh-and these were mostly mild and moderate cases resolved by end of study.

00:07:04: And I think really important to highlight is there are no reports of retinal vasculitis or retinal occlusive vasculitus And in a very low discontinuation rate, only about one point five percent of patients discontinued treatment due to adverse events.

00:07:17: Again this is important for us because you know this compliance and the ability.

00:07:27: Yeah, I agree with you completely and as the physician we all want first of all to have a safe drug And then the effective drugs.

00:07:35: so having this long-term data on The safety is something that gives us the confidence.

00:07:42: I would say do use it Patients in every day clinical practice both in late patients and also in switched patient that we switch from other drugs.

00:07:53: So can you tell us more about the sustained efficacy and switch improvement observed in Ronick's trial?

00:08:01: Yeah, absolutely.

00:08:02: When I think about advocacy... ...I think of three distinct categories— vision, anatomy… …and durability.

00:08:12: All those things are things that we really looked at closely not only in the parent study but also this extension especially.

00:08:19: so Let's take visual acuity as the first pillar of this.

00:08:23: When we look at BCVA and adjusted mean BCVA, across all groups, so we're talking about two lines of vision improved in these DME patients.

00:08:39: Now that's important but also we want to match that up with anatomy right?

00:08:43: Does that make sense?

00:08:44: and are we seeing that on our clinical findings?

00:08:47: uh... And indeed that is true right!

00:08:48: So we see sustained central subfield thickness or CST That we measure in our OCT scans With reductions between a hundred ninety-eight microns to two hundred five microns um.. Across this group.

00:09:01: And I think the other thing we look at in terms of anatomy is not just CST reduction, but we also want to see what percentage of our patients had their DME resolved essentially.

00:09:10: Absence of DME?

00:09:12: We can say so.

00:09:13: over ninety percent of the patient's achieved a CST of less than three hundred and twenty five microns by the end of study In other words achieving kind that dry macula.

00:09:25: Now, in terms of the response we see that patients starting for SMAB and parent trials reached that protocol-defined absence of DME.

00:09:34: In other words less than CST at three hundred twenty five microns faster with fewer injections then those patients who were in a flibrecept group.

00:09:44: There's lots ways to look at this but one way is looking at it as ninety percentile.

00:09:49: so how do you get ninety percent of patient CST?

00:09:53: When we look at how quickly we got there, the ferricimab patients reached that point—that dry-point—twelve to fifteen months faster than the efflibricept group.

00:10:05: This is important for us right?

00:10:06: Stella when we treat our patients who are trying not only get them seeing better and not just getting drier but also wanting it as fast as possible.

00:10:14: Fluid in the anatomy of retinal fluid or subretinal fluid built up into these retinas is pathologic.

00:10:21: so what eliminate that pathology?

00:10:24: as quickly as possible.

00:10:26: And indeed, we see that here with Frisimab achieving that ninetieth percentile twelve to fifteen months faster than the afflictive group.

00:10:35: The other I think key finding and i kind of alluded to this earlier is what happens to patients who switch from a flipper sept to frissimab.

00:10:45: We saw at end in parent study those patient's were on a flippercept for two years.

00:10:52: Eighty-two percent of them had an absence of DME.

00:10:55: In other words, eighty two percent of those patients by the end of this second year were fluid free.

00:11:00: now The question is well what happens to those patients when they switch to ferricimab?

00:11:06: Eighty two percent's pretty good But can we do better when we switched that?

00:11:09: and indeed We do see that right.

00:11:11: so when we switch these patients to ferrissimab Have them on a treat and extend protocol for SMAP, then look two years later at the end of the actual extension trial.

00:11:21: We see that ninety-five point four percent of those patients have an absence of DME.

00:11:26: in other words you kind of alluded to this earlier which is This is relevant to us in the real world because again when we use these medications oftentimes We're not using them and treatment naive patients.

00:11:37: We're using them in patients that have been treated And then possibly treated for many years, so The question is when we switch these patients that still have fluid Despite two years of every eight-week treatment what happens?

00:11:50: Is we see further stabilization Of their anatomy right?

00:11:54: so further drying upon this switch?

00:11:57: So this to me suggests the first amount has a substantial drying effect when you switch from something that is a monotherapeutic agent to a dual inhibition agent.

00:12:08: And then so, I think... You put all of this together visual acuity anatomy-the speed of drying some of the durability signals we're getting..you mentioned other biomarkers in retina and there's treating two pathways or addressing.

00:12:27: this dual pathway provides some additional value than the traditional monotherapy, especially in these patients that remain you know with fluid and unstable anatomy let's call it despite kind of heavy treatment.

00:12:41: And so I think one of the conclusions i make from this trial is we can achieve control anatomically speaking earlier then maintain over a long period.

00:12:54: I

00:12:56: completely agree with you, Veral.

00:12:57: And we all know how, for example, interacting on fluid is a bad prognostic biomarker!

00:13:04: for the visual acuity and especially if you think on a long run.

00:13:08: So, If we have patients who maintain some fluid in retina over longer like two years of follow-up definitely that's not good for them In terms functional outcomes Especially when dealing with chronic diseases such as DME.

00:13:26: so having drug can give us faster drying effect and can reduce better the intra-retinal fluid, especially if something definitely I would say good for our patients.

00:13:41: In addition it has been shown by different research groups also, that more severe edema in the sense of more fluid in retina is usually associated with more disorganization of inner retinal layers or more grills.

00:13:58: More severity and disorganisation on the outer retinal layer changes to the photoreceptors.

00:14:07: That's all we know about prognostic markers.

00:14:14: So, I can't agree more with you than already said about that.

00:14:19: And moving then to what reduction in treatment burden was observed?

00:14:25: Yeah, no great question.

00:14:26: So you know I mentioned visual acuity and mention anatomy But I said that third pillar for me is durability right?

00:14:31: And so Durability for us.

00:14:33: we're looking.

00:14:34: You know historically We used to treat patients every month with these treatments which has a heavy burden Right.

00:14:39: and one of the reasons were looking at durability Is because it's easier for our patience.

00:14:43: It eases the burden on our clinics and its really quite critical in terms Of long-term compliance.

00:14:48: i believe when we look At These Patients That Were In The Extension we see that the overall injection frequency is about, the median was seven to eight injections over-the two year extension.

00:15:01: And there's a median of only three injections in the final year of this study and so it translates into three injections or visits for one patient who once came in twelve times a year potentially right?

00:15:16: So thats meaningful impact on these patients without sacrificing efficacy.

00:15:22: So in terms of dosing intervals, how does that look?

00:15:25: We see that eighty percent of these patients are an extended dosing by the end-of-extension study.

00:15:31: That means twelve weeks or longer.

00:15:33: so eighty per cent of this patient's achieved at twelve weeks for a longer extended dosage.

00:15:38: and then we also if you look even further down to the sixteen week interval group ,we see over sixty per cent other patients achieve maximum sixteen week interval extension .So again now four months or three times a year to maintain that treatment.

00:15:55: So I think that's meaningful, right?

00:15:57: We have for the last twenty years been doing these trials on these DME patients and looking at different protocols monthly every eight weeks PRN.

00:16:06: but i think here we really find middle ground where we can treat patients less often without sacrificing vision or anatomy, whatever it is that we think is important for our patients in the long run.

00:16:21: And I think this level of durability allows us to follow these patients less closely but close enough so they're able check-in with them and also treat them in a sixteen week interval fashion.

00:16:37: We have shifted our way of managing patients with DME from the fixed monthly injections to then PRN and finally, but also giving them enough number of injections to allow the best possible outcomes both structural and functional.

00:17:08: And this also give us the possibility now with a treated extent to let's say increase our capacity, to receive more patients and treat more patients by treating them less after the first two years.

00:17:24: So having like three injections in a year is something that I would say feasible.

00:17:30: so are seen by us and they feel that they're followed by the specialist.

00:17:37: This is, I would say a enough number with this dual pattern inhibition drugs that allow the macular to be dry over time.

00:17:48: Vera what were some of the limitations on study?

00:17:51: Sure yeah i think large studies like these will always have some limitation.

00:17:56: but we talked about the initial parent's study was randomized was open label, and so non-comparator controlled trial which is always you know potentially there's always this selection bias that can occur.

00:18:10: That being said I think the fact that ninety one percent of these patients over fourteen hundred patients rolled over into the extension helps mitigate this.

00:18:18: we were collecting data only during the treat and extend phase.

00:18:22: when a patient came in we collected the data unlike the parent trial where they came more often than your collecting data even if the patient wasn't getting treated.

00:18:30: So what happens in the extension is you have less overall data points, which limits kind of the availability.

00:18:37: So one of the other limitations in this trial and extension was that, the efficacy analysis only included the observed patients.

00:18:46: We know sometimes it can overestimate outcomes if patients that discontinued the trials had poorer outcomes.

00:18:52: we know in case at a point five percent discontinue due to adverse events but overall low discontinuation rate so helps mitigate as well.

00:19:03: Viral, let's now touch upon the clinical relevance of these results.

00:19:07: What do you think are most important practical and clinical relevance for our practice?

00:19:14: You talked a little bit about how our landscape has changed not only in how we approach patients.

00:19:20: We used to be very aggressive with treatment because But now we're learning and studies like this help us learn even more in terms of long-term approach to these patients, because you know, how do we approach these patients?

00:19:43: How quickly are we gonna see drying.

00:19:45: What does that translate to in terms of long-term outcomes for these patients?

00:19:50: because it helps us educate our patients as well.

00:19:52: right when we talk about kind of...how we position these treatments for our patients and help give them an outlook what to expect.

00:20:00: I think what really does help us achieve drier retinas, which is addressing this vascular leakage and stability.

00:20:12: And kind of inflammatory component to things versus what we've done for many years was the single pathway approach.

00:20:19: so I think that's why it's valuable And we learn about safety, right?

00:20:26: So how safe are these treatments?

00:20:27: patients often ask us when they're in our clinics.

00:20:30: Doctor How many of these injections can I get and how long Can We Get Treated For?

00:20:34: studies like this give Us confidence that we can treat These Patients consistently and chronically Because their diseases Are chronic Right.

00:20:42: so we need to be able To manage them but also Be Able to confidently Tell Them That We can do that safely.

00:20:48: So that's kind of the way I look at this information and how we use this information in our day-to-day approach to patients.

00:20:57: Yeah, I agree with you And I for example when i treat a patient With DMV with Farisimab either treat them as first line treatment or I try to switch early in the course of other drugs if patients do not respond.

00:21:13: Usually, what we do is three monthly loading doses and then feel absolutely confident to extend by four weeks after the three-monthly injection.

00:21:26: Then you see the patient's eight weeks after that and either treat the patients if they had still some fluid to twelve weeks and treat the patient, so usually we extend by four weeks.

00:21:40: And up until now we have more than two years of follow-up on these patients at experience in our clinical practice where patients.

00:22:00: we really feel very confident in using this drug based on both the safety and efficacy data.

00:22:07: I'll just add, i think you're absolutely right.

00:22:09: One of the things that came out of this trial for me and many my colleagues is we are much more comfortable extending by four-week intervals prior to this protocol in general... We were doing a lot shorter extensions one weeks two weeks because it was all new to us Right?

00:22:25: And so now trials like these give us confidence that our DME patients.

00:22:29: extending up by four intervals Is safe and very effective especially as with a loading dose, you can kind of quickly extend them out.

00:22:38: Again that has a meaningful impact on the patient's life.

00:22:41: and you mentioned going beyond sixteen weeks.

00:22:43: yeah I think we are now getting to the point where we're starting feel more comfortable extending beyond sixteen Lots of real-world evidence.

00:23:00: that's building up because more and more are using FirstMab in the real world, collecting data.

00:23:05: So I think this picture is evolving pretty quickly as well.

00:23:10: What do you think was the most impactful take aways from Ronick trial?

00:23:14: And implications for clinical practice?

00:23:17: Did you notice any change about quality or life of patients given there were less injections over time... ...and also burden on your clinical practice?

00:23:27: Well, I'll take the quality of life comment you made.

00:23:30: Absolutely patients towards the end of this trial were very happy and in fact they were sad when the trial was ending because they thought that it's going to be at the end but we're able continue their treatment on.

00:23:42: But It just shows your kind of...you know..their impression about the treatment.

00:23:47: They felt like they are doing well That this treatment is helping them.

00:23:50: They weren't having an incredible burden as we've seen so absolutely had a positive impact.

00:23:57: And the key there is without sacrificing the outcomes, right?

00:24:01: So in the past if we treated patients less often We often saw that came as at a price and the price was vision.

00:24:09: That was not sustained anatomy.

00:24:10: That was NOT sustained.

00:24:12: so we're seeing it.

00:24:12: a trial like this that that Is NOT THE CASE THAT WE DON'T HAVE TO MAKE THAT SACRIFICE AND WE CAN Maintain that Vision & Anatomy.

00:24:19: and then The last thing I'll say safety Right very important for us just as Important today As efficacy You know, again very comfortable treating these patients and confident that the safety is there as well.

00:24:34: I agree with you completely And also I add That the burden for the patient has definitely decreased.

00:24:41: The burden of us clinicians remains high because we treat more patients But that's our clinical practice.

00:24:47: at least We can treat more patience and we can treat them better.

00:24:51: So i think thats really important.

00:24:54: With this I thank you so much.

00:24:57: I think we had a very nice discussion.

00:25:00: We could do it much, much longer because there are so many things that can be said and definitely continue to use the Farisimab in DME with great confidence!

00:25:11: Thank you.

00:25:12: Stella this has been an amazing conversation.

00:25:15: for anyone who wants further details or really want's to dig into more of these They can go to our published paper in ophthalmology titled, Four-Year Outcomes of Frisimab and Diabetic Macular Edema Results from the Rhonex Extension Trial.

00:25:30: Or if you're short on time we have an infographic that we just published in Ophthalmologin Therapy which is very informative and hits all the highlights.

00:25:39: so I want thank again for having me and this discussion with today.

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