Hey, we're ready to get started. Good afternoon, and welcome, everyone. Thank you for joining me today for another Virtual Investor Closing Bell segment. My name is Janine Thomas. I am CEO of JTC Team, and I will be the moderator for today's event. The Closing Bell series starts at market close, and allows companies to share an overview of their story and connect with investors. So for this session, I am very pleased to be joined by Russell Trenary. He is Former Chief Executive Officer of Outlook Therapeutics. Welcome, Russell.
Thanks for having us, Janine.
Oh, so happy to have you on our platform. Can't wait to dive right in. What we're going to do is start with a corporate overview from Russell, followed by the questions from myself and the audience. Before we get started, I want to remind our audience that Outlook Therapeutics is publicly listed on Nasdaq and trades under the ticker OTLK. So Russell, we're ready to get started. I'm going to turn it to you for an overview of Outlook Therapeutics.
Great. Thank you, Janine. And so even this cover slide, this first slide in our deck, is meaningful to us, because it talks about our desire to enhance the standard of care within the realm of bevacizumab for treating retina diseases, and I hope by the time we get through this presentation, it will be obvious why we feel like that is a possibility. Next slide, please. So for all you speed readers, I'm sure you're familiar with our disclaimer slide. We will be making forward-looking statements here. Next slide, please. So the opportunity that we have right now is quite palpable.
We believe we have the opportunity to enhance the standard of care, because bevacizumab today is a molecule that's been in use fairly safely for about 20 years, but it's been used off-label, and we're going to explain some of the nuances of the molecule that is in use today, and the molecule that we're aiming to get approval for, in the United States. While we strive for that approval in the United States, it's worth noting we were just granted the first European Union and U.K. authorization for bevacizumab in ophthalmology. It was in wet AMD. That is our first indication. That is about two-thirds to 70% or so of the anti-VEGF space in retina.
There are additional opportunities to expand into diabetic macular edema and branch retinal vein occlusion, which are two other somewhat similar conditions in retina that are also treated with anti-VEGFs, like our ONS-5010 bevacizumab candidate. This is a big, big space. It's about $16-plus billion, with most of it being in the United States and in Europe. I mentioned the approval that we already have in Europe, and, you know, inclusive of the UK. But in the United States, the biggest market, we have just completed enrollment in what we believe is the final clinical trial that is required for us in order to resubmit our BLA to FDA.
We just finished enrollment, or just announced that the first week of September, and so we will be announcing top-line results in the fourth quarter of this year. It's a non-inferiority trial, and I'll get into those details in a little bit, but in the fourth quarter, we will announce efficacy results. Next slide, please. As I mentioned, big space here. It's about $8-$9 billion in the United States, about $3-$4 billion in Europe. But I want to focus your attention on that third column over there that talks about physician interest. I mentioned at the onset that bevacizumab has been used off-label for about 20 years.
So it does beg the question, if it's been used off-label for 20 years, do people really care whether it comes with a regulatory approval or not? And we did some work with Guidehouse and did a deep dive and some market research and with physicians in both the U.K., the E.U., and the United States, and what we found was 82%-85% of the doctors were interested or highly interested in a regulatory-approved version of bevacizumab. So intuitively, they knew there's a real no-kidding difference between that preparation that can get an approval in ophthalmology and that preparation which was originally designed for oncology. Next slide, please. So the situation right now is it's kind of a two-segment market.
If you look at the number of injections, for example, I'm going to just focus this on the United States, since this is where most of our audience is here today. But in the US, there are seven-plus million injections of anti-VEGFs to treat these retina conditions. About half of those are for the brands that are already approved, the very high-priced brands that are approved in the United States. The other half are for off-label Avastin, a cheap version of bevacizumab that's able to get the patients started. But what we have found is, although two-thirds of the doctors indicate that they start their patients on off-label bevacizumab, they switch them to a branded ophthalmic-approved version about 40% of the time or more... nobody starts with a brand and switches 40%. Those switch rates are in the single digits. So there's something going on.
Why are people starting their patients on off-label? Most people would say because it's cheap. But why don't they finish them? And it's due to either a lack of potency, safety concerns, or quality and supply issues, according to the research that we've done and the conversations that we've had with ophthalmologists. So we expect to be able to bring a new level of quality to bevacizumab. That's our goal, and I think our clinical data will bear out that we have the opportunity to do that. Now, by virtue of getting an approval in Europe, it's worth noting that gives us ten years of market exclusivity in Europe, and if we're successful getting FDA approval in the United States, that will give us twelve years of regulatory exclusivity in the United States. Next slide, please.
So here's where we start to peel the onion on what's the difference between the bevacizumab that they've seen before versus the requirements that we have in order to get approval in ophthalmology. So the first bevacizumab that's been used was originally developed to treat oncology, and it was developed to go into a drip IV. Well, if you're going into a drip IV, do you really care about the number of particulates that are in that preparation? It's just being delivered systemically. It's not going directly into the eye. So the requirements for that oncologic version of off-label Avastin, for example, for lack of particulates. Let me just give you these numbers, 'cause it'll be meaningful even to a lay audience. You're allowed to have up to six thousand particulates per milliliter of particulates that are greater than 10 microns in size for the oncologic version.
It's just a regulatory requirement. Six thousand. We have to have fewer than 50, and so on and so forth. If you look at bacterial endotoxin requirements, if you look at the stability data that we have to show, if you look at pH levels that are peculiar to the eye, these are requirements to get approval in ophthalmology. If you look at potency and osmolarity specifications, how that drug is suspended in the product, ophthalmology has specific requirements that are different than oncology. And so today's preparation of off-label Avastin that was delivered for oncology, that then has to go through the repackaging process, that has an untoward effect on the protein drug concentration. The repackaged off-label bevacizumab just has requirements that could not meet the requirements that we have to live up to, to get approval in ophthalmology.
So in socializing this information with ophthalmologists, with retina specialists, they get it. Once they understand what the real differences are between an ophthalmology approval and an oncology approval, I think it gets to a point where it raises to a level where it matters to them. Next slide, please. Now, I mentioned the repackaging process, and what happens? So when compounders get hold of off-label Avastin, what they'll do or when they get hold of Avastin for oncology, it comes in a very large vial. They will then take thirty or forty or fifty aliquots out of that vial and put it into small volume syringes or vials to be used specifically for ophthalmology. That's a lot of rehandling of that molecule that's occurring, and what happens when that occurs?
One study in New York by a group of ophthalmologists showed that in 81% of the samples that they looked at, there was a statistically significant less amount of drug protein concentration in repackaged Avastin than there was even in Avastin. The doctor's left with a preparation that doesn't meet ophthalmic specifications to begin with, and then it gets repackaged, which lowers the amount of drug. Remember we said earlier that 40% of the time or more, patients are started on off-label Avastin, but then they're switched? If there's not enough drug in the preparation, that could explain a lot of the reason that switching is going on. Next slide, please. We did already receive the first ophthalmic approval for the European Union, as well as the U.K.
We're doing the market access work that's required, the health technology assessment work that's required in both the UK and in Germany right now. Those are the first two lead markets that either we or a partner that we like to work with will ultimately be launching in. And then once those two markets are addressed initially, which tend to be higher-priced markets, and establish a good reference pricing level for the other countries, then over time, we'll start to feather out into those additional countries. At least that's the plan. Next slide, please. To help support that effort in Europe, and the group that will also support the effort of the launch, if we launch directly into the United States, is Cencora. They're formerly AmerisourceBergen. They're a Fortune 10 company.
They are the kings of cold chain distribution and third-party logistics services and distribution masters in this space. They carry the lion's share of the anti-VEGF volume through their channel, and so we've signed an exclusive arrangement with Cencora to not only be our 3PL provider, but also provide services for us, like pharmacovigilance, patient hub services, payer connectivity, all the technical front and back office stuff, including some of the regulatory services in Europe that are required to successfully launch a product, so it won't just be a small, early-stage company called Outlook that's involved in launching this product. We'll be standing shoulder to shoulder with Cencora in that effort. Next slide, please, so the work that we're doing in Europe, like that we're doing in the United States with Cencora, is gonna be key.
As I think, as most people know, going in and establishing infrastructure in Europe all by yourself is expensive, it's time-consuming. So by having Cencora as a partner with us, that's gonna be what would help us to get the work done in Germany and the UK initially. And again, we've always said that we're open to the things that need to be done to maximize shareholder value, and one of those in Europe would include attracting a partner to help us distribute this product. So we will always entertain those conversations, but in the meantime, we will stay focused on Germany and UK to get those markets ready for us or for somebody else. Next slide, please. So what's left for us with the FDA? Next slide.
We've already performed three human clinical trials, NORSE 1, 2, and 3 that were part of our original BLA submission. We did receive a CRL in August 29, 2023, and in that CRL, the FDA alluded to the fact that they'd like to see an additional level of clinical evidence. So we met with them afterwards to find out what exactly did they have in mind. And one of the things that we discussed with them in that Type A meeting, October 2023, was that it looked like they wanted to see an additional three-month non-inferiority trial that would include an eight-week efficacy endpoint. So we took that advice. We put together a protocol, submitted that back to FDA in another Type A meeting, along with our statistical analysis plan.
Got agreement of what that SAP and what the clinical protocol would look like, and then resubmitted it back to FDA with an additional question, which was: "Will successful non-inferiority data from this trial satisfy your need for additional clinical data?" And the answer came back yes, from that SPA agreement. Next slide, please. To peel that onion just a little bit more, this study design mirrors the first three months of our already successful NORSE-2 trial. It was actually a one-year study. But in both that trial, NORSE-2, and in NORSE-8, we dosed ONS-5010, our bevacizumab candidate, or ranibizumab at day zero, day thirty, or day sixty. And in NORSE-8, we're gonna look at the efficacy data at eight weeks, and we have to show a non-inferiority margin of three and a half letters.
We're enrolling four hundred treatment-naive, wet AMD subjects across 61 sites. As I mentioned earlier, we've already enrolled this cohort. Then, we announced that in the first week of September. Next slide, please. What we learned in NORSE-2 during that first eight-week period of time, which again, the first three doses of NORSE-2 mirror the entirety of NORSE-8 that we just finished enrolling. What we showed was that there was about a one-letter difference between the two arms, well within the three-and-a-half letter non-inferiority margin. Happened to be in our favor, but statistically, that's the same number. Y'all have been to the eye doctor before, and if you test your own eyes, you do it twice in a row, if you can be a letter off, that's kind of deemed as the same vision.
In fact, with FDA, if you're within three and a half letters, that vision is statistically the same. So because we've already demonstrated this margin by a large margin in NORSE-2, we expect to see that in NORSE-8 as well. Next slide, please. So what we've accomplished this year, we had a lot of things on our checklist. In the United States, we wanted to get an FDA approval on the SPA. We got that in January. We wanted to commence the study. We did in January. We wanted to be able to engage in Type C and Type D meetings with FDA on our CMC subjects in quarter two and quarter three. We've completed those. We wanted to finish full enrollment within the third quarter of this year. We did that.
Now we just need to announce top-line data in Q4, resubmit our BLA in Q1 of next year, and then that would hopefully lead to a positive FDA decision in the second half of next year. We also had a good start in Europe, where we started the year with a positive CHMP opinion, submission of our UK MAA. We were granted EU marketing authorization in Q2 of this year, and got UK marketing authorization in Q3, and now we're engaged in the hard work of doing the market access activities and continuing partnering discussions. All the goals we've set for ourselves in Europe and the UK this year, we've met. Next slide, please. Bottom line is...
Our goal is to achieve the first authorized ophthalmic formulation of bevacizumab approval with FDA, like we already have in the EU and U.K. We will engage in discussions with potential licensing partners for Europe. Our goal is to enhance the standard of care, and to enhance shareholder value however we can. One of the things we think we can do to do that is to announce top-line data in the fourth quarter of this year, which we are still planning on doing, and then ultimately focus on what it will take to successfully launch this product in the U.S. and throughout the European countries in 2025. Thank you.
Great presentation, Russell. Appreciate you walking us through the Outlook Therapeutics story. Lots of progress. I know our audience has questions for you today, so we are going to turn to our Q&A. A reminder for our audience, if you have a question, click the Q&A button at the bottom of your screen, type in your questions. I know Russell has been looking forward to taking them, so we will get to as many as time allows. We have some that have been submitted already here. All right. Our first question, Russell, is, can you walk through the rollout for your EU commercialization?
So if we end up launching directly next year, again, it will start with the UK and Germany, because, again, whether it's potential partners we're talking to or the other folks that are in our organization and elsewhere who have experience in this area, we all know that it's important to establish the highest level of reference pricing for Europe that you can, and to launch initially in those countries, and those just happen to in the anti-VEGF space be the UK and Germany. So that's where we're gonna focus initially. And those HTA, those health technology assessment dossiers are extensive. It takes a long time to walk the governments through what the value of your technology looks like compared to the competition that's out there. Europe, unlike the United States, isn't just looking for an approval.
They're looking for an approval that comes with economic value. And so we believe we've got the opportunity to do that. So we're gonna start with the UK and Germany, and then if we end up engaging with other partners to roll this launch out, we'll be in discussions with them to determine when the next wave of countries, when it comes, and which ones they are.
Okay, our next question: How should we think about what a transaction would look like with a potential partner ex-US?
Every deal is different, but I think that the standard over there have been deals where some sort of a profit-sharing arrangement is agreed to between the two parties, and in our particular case, it would probably also come with some joint commercialization committees between our company and theirs, so that we're able to harvest everybody's best thinking in terms of everything from product positioning to launch sequencing, as well as pricing.
Okay. What is your IP in the U.S., and what will prevent others from reformulating bevacizumab?
Yeah, so this is not an IP deal. The IP for bevacizumab was originally associated with Avastin. Those oncology products were launched in the early 2000s, and so the IP have expired in those areas. What we're if you'll recall the beginning of the presentation, it's regulatory or market exclusivity that you're granted with approval of these biologics. It's not unique to us. Everybody gets that. If you're the first molecule of your kind to get approval in your indications, in this case, the ophthalmic indications, then in Europe, you're granted up to ten years of market exclusivity, and in the United States, it's 12 years of regulatory exclusivity.
The reason you probably have not heard of this before is because most companies have patent portfolios that may be equal to or in excess of the amount of time associated with the market and regulatory exclusivity, but it's something that comes with every biologics approval.
Okay. Our next data: Are the data from NORSE the only thing pending for your BLA resubmission?
It's a great question. So the CRL that we had that we received from FDA on August 29 of last year, although the core part of the CRL included executing NORSE-8, there were also a handful of questions associated with our chemistry manufacturing and controls area. So while we were in our first Type A meeting with FDA, they suggested, "Listen, don't wait to resubmit your BLA before talking to us again. Come in, and let us know how you're doing as you're going through the CRL item. Don't be strangers. Come on in and set up meetings, and talk to us about it." So we did. So we set up a series of Type C and Type D meetings with FDA, and we went through every single-...
CRL item that was associated with CMC to show FDA what we were doing, how we were answering the question, the data that were associated with that, and ask them if there was anything else that they needed. So from our standpoint, we feel like we've had some great relationship-building moments with them, and feel like that in those meetings, we had agreement that we were headed in the right direction in answering all of those questions.
Great. We do have a few financial questions that have come in. And for those of you that have asked that, we are going to respond post the webinar, and you'll get a response. Everyone actually will get a response to your questions if we're not able to get to them. So the next question is: how long does the FDA have this time around to respond to the resubmission?
It's a great question. So this is a major amendment to an already submitted BLA, so that puts them on a 180-day clock. They need to get a decision back to the sponsor within 180 days of the time the resubmission of the major amendment occurs.
Would it make sense to complete NORSE-8 and secure a global commercialization partner?
So our focus is around maximizing shareholder value, so we would look at any opportunity to do that. And if there was something that we believed would benefit our shareholders more from a partnering standpoint than us doing things by ourselves, then, of course, we would look at that. This company is not being run at the pleasure of the management. Management serves at the pleasure of the board, and the board serves the best ambitions of the shareholders. So maximizing shareholder value is, well, how we'll look at every single deal.
Great. Our next question: How are doctors able to use bevacizumab off-label if there are approved branded products, and why would they switch to yours once approved?
So doctors can use anything off-label that they wanted to. The FDA regulates, you know, drug companies, biologics companies. You know, they've got a lot, but they don't regulate doctors. They don't regulate the practice of medicine. So doctors can use any product that they want off-label, should they choose to. Why have they so far? Because there's been a very cheap version of an anti-VEGF that allows the doctor to diagnose the patient and treat them on the exact same day. Typically, what happens, or let's put it this way, not atypically, will patients be switched from those off-label therapies to a more potent on-label therapy once the patient is able to get approved from their insurance companies for those more expensive treatments. So what would make us attractive?
One, if we can bring a differentiated product that has better quality than off-label bevacizumab. Two, if we can show the payers that what they're paying now for off-label bevacizumab patients that then get switched to a higher priced candidate, if we can show payers you're gonna be better off if the patients start and stay on our therapy, according to the price that we're going to price it at, then we can show payers that we can save the system money, we can deliver better quality to the doctor, and hopefully a better outcome to the patient.
Great. Great, our next question: you keep saying you would entertain partners in Europe. Are you in current conversations?
Yeah, we would never be in a position to confirm or deny any conversations that we're in with any outside partners, but I do think it's fair for our shareholders to know that we're not closed-minded about having those conversations.
Okay, great. Next question: How long after receiving an approval from FDA will you be ready to launch and start selling?
So that will always depend on partnering options that we have and/or funding that leads up to that. But we have inventory available today. And if we receive approval in the second half of next year, we will still have inventory on the shelf to support that launch. So it's really the time and money associated with putting a sales force on the ground along with your MSL group and of course, having some corporate sales functionality as well, to be able to move some bulk orders. So I think given the fact that that moment in time is in the second half of next year, we'll just so a lot to happen between now and then. We'll just leave it at that for now.
Excellent. Okay. Our next question, I know you covered this, but, I saw that some people did join late, so, and I think it's an important question, for those that may not have heard it. So when would you resubmit to U.S. FDA?
We plan to resubmit our BLA in the first quarter of next year, after having revealed the top-line results of the fourth quarter of this year.
... Okay, our next question, if data from NORSE-8 meets the primary endpoint, how confident are you in receiving a successful outcome from your BLA resubmission?
I think everybody, every company, you know, expresses confidence. Of course, you're dealing with the FDA. But I think the nice thing for us is severalfold. First of all, the NORSE-8 study protocol, the NORSE-8 statistical analysis plan, are both the subject of a SPA agreement with FDA. So we have agreed with FDA on both those, both of those aspects in advance of engaging in the trial. In addition, we did ask the additional question, "Will successful data from this trial satisfy your need for additional clinical data that you mentioned in your CRL?" They said, "Yes." So I think that provides an additional level of security that's not necessarily available to every company and every study.
In addition to that, I think it's important to understand that the CRL that we received last year, it's called a complete response letter. What that means is, those are all the questions that the FDA had regarding our BLA, so successfully answering those should portend a good possibility of an approval. So we feel like the SPA approval from our NORSE-8 study, and the fact that the CRL, there are four corners to that letter, and we've gone in and met with FDA on all the aspects in there.
So if at the end of the day, upon review of our amendment, of our major amendment to the BLA, they agree with the answers that we've given on these, on the CRL items, on the CMC items that were in the CRL, you know, we think that this, that puts us in a strong position.
Okay. Time for just about one more, and then I want to get to your closing remarks for us. Final question. Currently, many doctors, payers will turn to compounded bevacizumab as a first-line treatment for wet AMD, due to its low price. Assuming Lytenava successfully commercialize and compounded bevacizumab is no longer an option, what makes Outlook Management confident that Lytenava ophthalmic bevacizumab will continue to maintain share in light of similarly priced anti-VEGF alternatives, some of which are potentially more advanced, example, biosimilar Eylea?
So you have made an assumption that we're similarly priced, and yet we have not named our price yet. I think what's important to understand about our pricing strategy is we've gone and done real data polls on patients who were started on off-label bevacizumab, and we've looked at the average cost per injection per patient over a three-year period of time, including the price of the product that those patients were switched to, and we've seen why so many of them are switched. The off-label bevacizumab that is repackaged by compounders doesn't meet ophthalmic requirements, and untoward things happen to the molecule during the repackaging process. So something's happening post-operatively, post-injection-wise, that's causing those doctors to switch those patients. They must not be doing as well as the doctors think they could, so they switch them. Well, that adds a lot of cost.
So if we can show payers that the price that they would pay for our biologic, if they start and stay on our product, like they start and stay on the other approved products, if we can show them that it's less than the other approved brands, and even less than the price of starting and switching a patient on off-label bevacizumab, we think that puts us in a position to be able to tell the payers, and the doctors, and the patients, "There's real value here." We've shown we're non-inferior, if we end up demonstrating that, to ranibizumab, which has also been shown to be non-inferior to Eylea, et cetera. We've got a price point that is less than the average that's being paid now, when you take switching cost into account. We think that's a cost-benefit conversation we'd love having with the payers.
Great. Okay, just a final comment, Russell. So you've shared a great presentation. Lots of exciting things happening with Outlook Therapeutics, and certainly in the next several months, it's going to be an important time for the company. Can you share with our audience why you think it makes sense for investors to consider Outlook Therapeutics as an investment opportunity right now?
We think our ability to maximize shareholder value is partially tied to the structure of this industry. Right now, this industry is two segments. One segment is represented by a whole host of brands that have done a great job of treating patients, and will continue to do a great job, we believe. They represent about 50% of the injections. The other 50%, or 3.5 million injections, are represented by off-label oncologic repackaged bevacizumab. Sometimes people get confused and say, "Why do you think you're better than Lucentis or Eylea?" Nobody's trying to claim that. Our clinical studies won't show that. Our clinical study, we hope to show non-inferiority to Lucentis. We're trying to be better than the off-label repackaged oncologic bevacizumab.
That's our job, and if we can do that, if we can give every mom and dad a chance to receive a treatment from an on-label anti-VEGF that meets all ophthalmic requirements, and has been shown to be non-inferior in this most recent study, hopefully, once we name those top-line data, then we think that enhances the standard of care for retina anti-VEGF.
Excellent, Russell. Appreciate your time today. Certainly a lot for investors to follow, definitely in the near term, so we wish you all the best. Can't wait to have you back on. This does conclude our Virtual Investor Closing Bell segment for today, featuring Outlook Therapeutics. I'd like to extend a huge thank you to Russell Trenary for joining us. I'd also like to thank our audience for your participation and great questions as always. As a reminder, Outlook Therapeutics trades on Nasdaq under the ticker OTLK. And if you like what you saw today, I encourage you to visit outlooktherapeutics.com for more information on the company, to sign up to follow the company, to receive their alerts, as well as follow their social channels to stay current on the latest information.
You can also visit virtualinvestorco.com for a replay of today's event, as well as our latest segments and event calendar. Thanks again, Russ. Thank you to our audience, and I wish everyone a great evening.
Thanks very much.