All right, good morning and welcome again to the 37th Annual Piper Sandler Healthcare Conference. This is David Amsellem from the Piper Biopharma Research Team, and we're delighted to have Outlook Therapeutics with us as our next company, Fireside. We have Bob Jahr, CEO, with us. Thanks so much for joining us. You have a PDUFA coming up, so an exciting time. Let's just jump right in. Like I said, you have a PDUFA on your ophthalmic form of bevacizumab. It has been a long road with the FDA, but let's just start with your complete response letter that you got this summer, maybe provide some background on that, and then the outcome of your recent Type A meeting with the agency and then your subsequent resubmission. I think that context would be helpful for everyone listening in and in the audience.
Sure, thank you, and thanks for having me here today. In late August, we received a Complete Response Letter, and we had a phone call with the FDA where they actually encouraged us to request a Type A meeting, and we actually also did an informal call with them prior to the Type A meeting. The context of the CRL, what they indicated, was that the NORSE EIGHT trial missed its endpoint and therefore did not provide the confirmatory evidence for NORSE TWO for the approval. I think it's also important we did want to make sure that we clarify that we didn't have any manufacturing, any CMC tech-related CRL. We went into that Type A meeting very much wanting to focus in on the issues that the FDA raised about the NORSE EIGHT trial. During the process, we had conversations with them.
We wanted to understand what is the meaningfulness of that eight-week endpoint, which is a we agreed to that under an SPA. At week eight, it demonstrated we missed the non-inferiority endpoint P- value against ranibizumab, which was different than what we saw in the NORSE TWO. We wanted to have some context with the FDA in terms of what is that meaning of that endpoint. We had KOLs also to discuss it with them in terms of 12-week is much more of a clinically relevant timing when decision-making is actually made depending upon how to dose extend or treat treatment. The week eight was a bioequivalence endpoint if you were studying two biosimilars for a biosimilar, which obviously bevacizumab and ranibizumab are not equivalent for biosimilars. We missed the endpoint, but we talked about what was the relevance and the clinical relevance of that endpoint.
More importantly, the other evidence in the NORSE EIGHT trial, such as the 4 and the 12-week, as well as the retinal thickness data, which clearly lined up and from our perspective demonstrated confirmatory evidence that NORSE TWO was not a fluke, which is the bar that we wanted to make sure that we hit. We also confirmed with the FDA sort of we were not seeking to make any comparatory claims against ranibizumab with a non-inferiority. We were not trying to leverage what the NORSE TWO data said that superior or non-inferior. Also, we were able to discuss sort of our dosing and that our requested dosing for the FDA would be the same that we did in NORSE TWO and NORSE EIGHT, which is monthly.
Yeah, okay. That's helpful context. One question I had is we've seen when you think about wet AMD, you think about 12-week endpoints and longer-term endpoints. Why was there an eight-week endpoint in this study?
The eight-week was the agreed-upon endpoint for the SPA because it is the steepest part of the curve from a bioequivalence perspective. That was what was sort of agreed to with the FDA when that was there when we signed up for the SPA for the trial for NORSE EIGHT. The other endpoints were also secondary endpoints. They were not exploratory, but that was the primary endpoint of the trial. It was really just primarily because it helped from their perspective. It was an endpoint that showed bioequivalence, and that is the one they wanted to work on. We wanted a 12-week endpoint, but what we ultimately signed the SPA for was the eight-week endpoint.
Got it. There is NORSE TWO, which we touched on, but there is also NORSE EIGHT, which was a successful study. Just before we get into the outcomes of NORSE EIGHT, just give us some background on that study and the rationale behind that study.
The NORSE EIGHT was an adequately well-controlled trial. That is the one that we missed the eight-week endpoint. We failed on that one endpoint, but really NORSE TWO was a one-year trial right ahead. We demonstrated non-inferiority, actually superiority against ranibizumab. The evidence for the confirmatory trial, that is how we agreed upon when the FDA said you have to do two adequately well-controlled trials. That was the trial design that we agreed to because first it would be just over 12 weeks. It was a shorter trial in total duration. We were blinded. It was a blinded study, but also we wanted to make sure that we hit the bar of what was the definition with the FDA of an adequately well-controlled.
Got it. Yeah, okay. Just digging more into the data. Visual acuity for ophthalmic bevacizumab actually was numerically quite close to that of ranibizumab at 12 weeks. There is that. How should we think about the meaning of that and how the FDA views that? Also, retinal thickness changes in the two arms were also quite similar. As I'm kind of thinking about your clinical program, I'm looking at a study. I realize that they missed the eight-week endpoint, but I'm kind of looking at a clinical program where you kind of checked a number of key boxes, right? Just help us contextualize that.
Yeah. I mean, we believe all the data points clearly, LYTENAVA works and it's very effective. It's been approved in Europe. The visual acuity scores are very standard in terms of how many letter improvements do you want per line. When you stack it up, if you look at us compared to other anti-VEGF approved ones, the mean and median of the approvals, or excuse me, the improvement in letters, are highly aligned across all the approved anti-VEGF. What that demonstrates is we are demonstrating a class effect, but also very much a consistent clinical improvement within that class, right? It's not standing off on its own. I think the other part is retinal thickness. From a perspective of the physician, that is the one area that they'll look at in the eye.
That is demonstrating the anti-VEGF is getting rid of that retinal thickness, which is the fluid which causes the impaired vision. Now, it's not specifically correlated, an improvement in retinal thickness, how much will that improve the number of lines that you will read? However, that's what our physicians will use as a clear indicator of the effectiveness of the drug. As you mentioned, the retinal thickness in the NORSE EIGHT was identical against ranibizumab and the bevacizumab arms.
Yep. Can we talk to safety and tolerability across the NORSE program?
Very good safety and tolerability, very consistent. That's one of the things, particularly the predictability and the safety. If you look at some of the challenges with compounded bevacizumab, it's the inconsistency of what you're getting in each syringe. We've heard from the physicians where we've commercialized so far in Germany and the U.K., that is one area that they really are comfortable with us is because it's this consistent product, the same quality of the product each and every injection that they're going to get. We've seen consistent safety and tolerability across the NORSE program.
Just before we go into the commercial landscape in the U.S. and the role of compounded bevacizumab, and there's a lot of history there, which we definitely want to cover, but maybe just to tie a bow around the regulatory piece, is it fair to say that the agency was just looking in the CRL and then the Type A meeting shortly thereafter, the agency was really looking for more context around the totality of the data here? I mean, is that the way to characterize it? Because it was really a quick turnaround. I mean, you had the CRL, you had the Type A meeting kind of in rapid succession, and then you filed, and then you get a class 1 review, and you have a PDUFA before the end of the year.
You do not usually see that kind of rapid turnaround after a Complete Response Letter when the agency cites a missed endpoint. Is that a good way to think about it?
Yeah. I don't want to speak on behalf of what they were thinking or predict that, but I would definitely say we really, when we got the CRL, we spoke to the FDA directly. We had that informal meeting. We really wanted to listen to understand what was their perspective. First, could we align that the NORSE EIGHT was an adequately well-controlled trial? We understood they had the missed endpoint. They wanted to have a conversation about that and really contextualize what it was in addition to that in the NORSE EIGHT trial that we felt was confirmatory for an approval. Yeah, I think you've characterized it pretty well in terms of we sat down and we listened to them.
We knew that they didn't in the CRL, in the first CRL that we got, they specifically said, "You need to do another adequately well-controlled trial." That was spelled out in the CRL letter. We weren't required in the CRL to do another trial. Obviously we could have if we wanted to. I think that's another important part. In addition to, we didn't have anything, as I mentioned, related to CMC or manufacturing. The issues were quite well defined and they were very specific. I think that helped us be able to move very quickly in terms of responding to them.
Okay. That's helpful. Let's move on to the commercial landscape in the U.S. Compounded bevacizumab for wet AMD has been used for a long time, really as long as ranibizumab has been available. We're talking what, two decades?
Almost 20 years, yeah.
Right. Just help us understand how you think about the U.S. opportunity for your ophthalmic form of bevacizumab and help give us some background and context on off-label compounded usage of the molecule for wet AMD. I know there's a long history here, but I think that context would be helpful.
Yeah. There's roughly just under 3 million injections of compounded anti-VEGF treatment roughly in a year. Okay. I would say for most people, not all patients, but almost 50% of patients, it's usually get compounded bevacizumab as a first-line option. It's been around there, as you said. Doctors are highly comfortable with it. Also, it's been something that they've been able to take and inject right there at that day in the office and start the patient on the treatment. Over the course of the last couple of years, obviously there's been some new advancements and improvements with Vabysmo and Eylea HD and then Pavblu. The market has shifted with the longer-acting ones to a certain degree, but most or the majority will still start with the bevacizumab. That's really where our specific market is. We're not a biosimilar. We have our own NDA.
We'll have our own BLA and we'll have our own ASP and reimbursement codes. I think it's really important to be very clear that that's where we want to look at is that bevacizumab market. Also coming in and saying that we're the first and only FDA-approved bevacizumab for the treatment of wet AMD. Our advisors and the KOLs, they've been very anxious in wanting this for approval for a few years, as you can imagine, as we've worked through the CRLs. We know that there's a broad community out there that are anticipating this. There have been challenges to get compounded bevacizumab in its quality and in its quantity uniformly across the different retina specialists.
Maybe kind of opining here, but given all of the challenges with compounded drugs in general, and this is an intravitreal injection, it's almost shocking that we've gotten almost two decades with just accepting usage of compounded bevacizumab for intravitreal use. That's more of a comment than a question, but love to get your thoughts on that.
I think it's important because there hasn't been an FDA approval and you also haven't had the benefit of the MedWatch program or any reported IOIs or anything like that in a standardized format, right? Because they haven't needed to report that. Everything we hear anecdotally is it does happen out there. I think that's one element that's really important is we are coming in with a high-quality product manufactured and has passed the inspections that are required to commercialize both in Europe and in the U.S. That's something that no other compounded bevacizumab has had to do. Right there, that's a differentiator for us in terms of that. More importantly, you get the confidence of knowing what bevacizumab can do. Plus, we have a very safe and potent product that we've seen consistently throughout the development program.
You talk about the roughly 3 million injections. What portion specifically of the overall injection volume base is that right now? If you had to sort of take a look at a pie of bevacizumab and ranibizumab and then aflibercept, how would you slice and dice that right now at present?
Ranibizumab has historically had lower market share. Obviously, aflibercept and Eylea has a large market share. Vabysmo is growing. Bevacizumab, I would say, last tracked with claims is around 44% of the claims of all those injections for anti-VEGF.
Okay. Wanted to get your thoughts on Eylea HD and Vabysmo. You alluded to the market shifting, but you also now have the emergence of Pavblu. That's been a pretty successful launch on the part of Amgen. How do you see Vabysmo, Eylea HD, Pavblu? How do you see these newer entrants, I should say, impacting usage of compounded, sorry, not compounded, just any bevacizumab product over time? In other words, do you still see a shrinking market or because of affordability issues, it's really going to be a pretty stable presence as a frontline option?
Yeah. I think it'll still stay a frontline option. It'll be more competitive, of course. There's more treatment options. Also, you have the affordability with the impact that the Good Days Foundation had in this last year. You have aflibercept biosimilars entering the market, which will put some downward pressure on their pricing. Also, how payers will address the affordability and provide access. Oftentimes, trying with something that's more shorter-acting than before deciding to go to a longer-acting one is the way some physicians practice. I think really it will come down to that affordability and that access piece.
Okay. Let's talk about U.S. pricing. I mean, at the risk of putting the cart before the horse here, obviously, you want to get approval first and that's the top priority. Pricing, obviously important. We talk about affordability. How are you thinking about pricing of your product? Just talk about at present where pricing is for compounded forms of bevacizumab and also talk to pricing of the branded products and even Pavblu.
Yeah. I mean, the newer agents tend to be on the far right side of the spectrum in terms of pricing, and then you see the biosimilars coming in to the left, right? And then compounded beva is to the left of that, right? What's unique for us, and we haven't made any public statements yet about where our pricing is, but I feel very comfortable that we have a good pricing corridor that's publicly announced with Germany and the U.K. that we can operate in. We do have to go back and reassess sort of the changes in affordability, particularly with managed Medicare and Medicare Advantage plans to make sure that we can provide something that is affordable for that. I think the other part too is discipline and management that goes to an ASP.
I think that's what some of the other ones that have done very well in launches have done, and that's what we'll want to do. I think you have a range, near or long-acting agents on the far right, compounded bevacizumab on the far left, biosimilars somewhere there. I think we tend to see ourselves, and if you look at the other markets we're in, we tend to be maybe right at or around biosimilar pricing. I would expect unless we look at the market dynamics in the U.S., but I would anticipate we'll probably be somewhere around there too.
Okay. Over time though, and you mentioned additional aflibercept biosimilar launches over the next few years. I mean, right now Amgen is the only one, but there will be others. Ostensibly, there will be some pricing pressure in the category. I guess my question is longer term, do you look at pricing dynamics as sort of just a continual pressure point, or do you see some room for pricing stability even with a greater presence of aflibercept biosimilars?
For us, because we'll be the first and only, if we're fortunate enough for an approval on compounded bevacizumab, we aren't going to be tied to a biosimilar or biosimilar pricing or reimbursement. It does take a little bit of discipline for that. I do think predictability, particularly when you're in the buy and bill space, that's really what the offices want is they want a horizon of predictability in terms of acquisition, affordability, and reimbursement. That does require, I would say, some discipline so you can provide that horizon. You don't see what has happened with previous biosimilar launches where they've gotten upside down in terms of reimbursement and they've had to go from the market to get their ASP reset. I think it's a dynamic.
From the buy and bill space, we can look and there are good analogs, obviously with oncology biosimilars to see how have they managed their price increases and their reimbursement over time. There are good analogs out there to do exactly what you just said, provide that sort of stability in there. When new entrants come in, it always makes things can move from stability-wise, but I think it is something that definitely it is in the best interest for payers, for providers, and for patients to provide some sort of level of stability so they are not worried about can they afford it, do they need to start making changes in their treatment choices from one quarter to the next.
Yeah. I would imagine starting at the left side of that continuum that we talked about, it probably puts you in a good spot even as more and more aflibercept entrants come into the market. Okay. Commercial infrastructure in the U.S. Just talk to what you're going to need to build here, how many boots on the ground, MSLs, and just overall launch and commercialization spend.
Yeah. We haven't predicted any public numbers on that yet, but I mean, obviously, particularly going up to the CRL in August, we were pretty well prepared. I think first and foremost, boots on the ground and MSLs. Fortunately, bevacizumab and this MOA is pretty well understood. We will get a lot of questions on off-label and you want to deploy their MSLs. I think also the market access, field reimbursement management is critical because these offices really are reliant on the ability to order and get reimbursed. When I think about the overall combination of that, we've given ranges of somewhere between 30 and 50 from a commercial team. Now, how much of that we build internally versus do we partner with an outside partner for field reimbursement and MSLs?
I don't think it's not there's also been quite a bit of consolidation in the retina space, RCA and Cencora. That also puts decision-making and control kind of in more centralized areas there that for us require you don't need as many boots on the ground if we were launching a first-time MOA that they hadn't heard about before, right? We're taking that into consideration for how we build the go-to-market model. Also, the benefit for what we can do because we're not explaining a brand new MOA, we can use that resource in more innovative ways to make sure that we are addressing affordability and market access and things like that.
Got it. One question that I wanted, I think it's important to touch on is once there is an approved ophthalmic form of bevacizumab, how do you think about the cadence of movement away from compounded forms? I'm assuming they're not just going to go away, but having an approved product is certainly, I think, more optimal than an unapproved product. How do you think about that, your ability to capture as much of that current base of bevacizumab business that's out there?
You know, part of us, what we're doing right now is refreshing that work because obviously we did it prior to 2023 and the market's changed. I feel based on what the providers and their office managers are telling us, we will be able to capture some of that market. I mean, but you have to have the infrastructure and the confidence, like for example, coding and billing and reimbursement. You want to have all that confidence for that to be able to be set up. There will be some, obviously we're in wet AMD and there's other utilizations for compounded bevacizumab that we will not have the indication for out of the gate. I think it's important that the patients and physicians still have that choice. We have seen some consolidation or some compounders in the last two years have actually pulled out of the market.
There have also been recalls with some prefilled syringes. Depending upon, and also too, there's such institutional risk where some people, the informed consent, where some institutions or practices will say, "We're just going to move away from that." How fast that happens, first of all, nothing should happen upon our approval because we'd still have to get it into the market, into the channel. It'll be interesting to watch that. Obviously, with all compounding, there have been other assets that have launched and GLP-1s that we can see how compounders have behaved and performed when things came into the market so we can look at.
Okay. In the 90 seconds or so we have left, I wanted to touch on Europe. The product's available in the U.K. and Germany. Just talk about the progress of the rollout in those countries.
Sure. Obviously, we got approved in late December 2024, almost a year ago in the U.K. We started commercializing late summer, so late June, early July, so mid-summer with our first patients on in both. Germany is a very large bevacizumab market, but they also have some internal and inherent obstacles into entry. I am very pleased to say we have about 77% of market access with Signalens. We have good access and we are currently negotiating in the analog process there for pricing. We have activated some hospitals. Each week we are activating more accounts. I will say it is going probably a little slower, but part of that also is we moved into the market very quickly. We continue to see momentum growing in terms of getting through all the testing and approval that we need to do.
U.K., I'll say there we're in the U.K., in Scotland, in Wales. Again, we've had very good early utilization. They were not as big a bevacizumab market, so we're dealing with a smaller entry point. Again, it was announced today that we made it onto a tender. We're competing very effectively in there. I think it's just going to take a little bit more time. I wouldn't say it's behind any other product launch in those countries, just in terms of navigating the hurdles that can come up when launching in Europe.
Just a couple of quick ones. My understanding is Germany is a bigger bevacizumab market.
More bevacizumab was used in Germany. Germany represented almost 50% of the bevacizumab market for all of Europe.
Oh, wow. Okay. What about other country launches?
Austria, we're looking at it in the beginning of the year, and the Netherlands and Scotland will be the next waves that we're looking at, and then we'll assess the reimbursement pricing in the remaining countries.
All right. Terrific. I am showing out of time. Thanks, Bob, and thanks to everyone in the audience.
Thank you.