Hi, good afternoon. Welcome to Needham's 23rd Annual Healthcare Conference. I'm Serge Bélanger, one of the senior analysts on the healthcare team at Needham. Happy to have for our next session, Opthea, a clinical-stage ophthalmology company with a late-stage development program in retinal disease. And with us this afternoon, we have Fred Guerard, the company's CEO, as well as Peter Lang, the company's CFO. So I'll hand it over to Fred. He's gonna take us through a presentation of the company, then we'll do Q&A. For those listening online, you do have the option to submit questions, I think via the portal that you're watching the presentation on, or you can just shoot the question to me via email. We'll. I'll be checking those as the presentation proceeds.
With that said, welcome, gentlemen, and I'll hand it over to you to tell us more about Opthea.
Thank you, Serge, and thank you for having us today at your conference. It's very appreciated. We're a public company traded in the U.S. on Nasdaq and in Australia on ASX, and we'll be making forward-looking statements in this presentation. You can find all disclaimers here, as well as on our website. This is an overview of our team. We're very lucky to have a very experienced professional. Peter is with me today. Peter is our CFO, comes from a long career in investment banking, as well as being an operator in an ophthalmology company called Aerie that was acquired by Alcon recently. Our founder, Megan Baldwin, is our Chief Innovation Officer and founder of the company.
As I said before, she's the person that should be thanked for all the science that went into developing sozinibercept, which is our molecule, and she's now helping us bringing the next wave of innovation to the company. Notably as well, we welcomed Dr. Arshad Khanani as our chief medical advisor recently. And Arshad is still practicing medicine most of the time, and dedicating some of his time to Opthea, helping us and advising us on the medical strategy moving forward. We also have an esteemed clinical advisory board with Charles Wykoff, who is the chief investigator of the COAST clinical trial. Tim Jackson is the chief investigator of the ShORe clinical trials.
Both are pivotal trials, phase 3, as well as Jason Slakter, who runs for us the centralized reading center of the pivotal program. We are working on a new approach in wet age-related macular degeneration, and this disease was revolutionized around 20 years ago with the emergence of anti-VEGF therapies, which are incredible molecules and drugs. Multiple of them have been approved. But despite their use, most patients actually do not go back after vision loss because of the disease, do not go back to driving vision levels or cannot resume normal daily activities.
Actually, it's very well published that after a while, normally it's around two years post-diagnosis and initiation of treatment, patients are back to their baseline vision, the baseline vision when they were diagnosed having the disease, despite these amazing molecules being injected in their eyes on a regular basis. All the existing molecules that have been approved by the FDA and abroad actually target a part of the VEGF pathway in the eye, blocking the effect of VEGF-A and B and PLGF on the first and the second type of VEGF receptors, leaving wide open the third VEGF receptor for stimulation by VEGF-C and D.
Our approach is a combination approach where we would add OPT-302 or sozinibercept to existing standard of care and fully block this VEGF pathway. As mentioned before, this disease was revolutionized almost 20 years ago with the approval of Lucentis around the world, and that was the amazing improvement in standard of care compared to existing interventions that were in place before. But since 2006, not much progress has been made on additional efficacy on vision for these patients. New drugs came on board. Some of them can be injected at longer intervals, but none of them are really superior to one another, and therefore, deliver all of the same type of visual outcomes.
What we are trying to do with sozinibercept is actually in combination therapy with or any of these anti-VEGF-A that are currently approved, is to really improve the visual outcomes of the patients. This is a very large market. It was a rare disease 20 years ago because patients were going blind very fast without proper treatment, where now these anti-VEGF-A are maintaining some sort of visual acuity over time, and we estimate the market to be around $14 billion a year for wet AMD only around the world. That's a mix of branded molecules that are being used, as well as emerging biosimilars that become, in many cases, first-line treatments, anti-VEGF-A, and some of them are already approved and launched.... Our first program is in wet AMD.
We do expect these trials. I'm gonna detail more in the presentation to read out by the middle of 2025. We are preparing for a diabetic macular edema program. The idea is to write the protocol, collect the FDA feedback, and be in a position to start our pivotal program whenever we get the top-line data on the wet AMD program. Finally, we are doing feasibility work to have a fixed-dose combination of sozinibercept with an anti-VEGF-A to be selected. Sozinibercept has been extensively studied in multiple trials. On the left-hand side are the completed phase I and II trials.
And the one we are gonna spend most time on today is a phase IIb in wet AMD patients, and I'll come back to this. We have these ongoing trials on the right, as I said, COAST and ShORe. One is using aflibercept as a comparator, or Eylea. The other one is using ranibizumab or Lucentis as a comparator, and I'll come back into the design of these trials a bit later. The phase IIb trial in wet AMD is the one we are detailing today. This is a very traditional dose-ranging phase II trial in wet AMD. Patient treatment-naive patients were enrolled. They had just been diagnosed with wet AMD, had never received any treatment.
The inclusion and exclusion criteria were pretty standard, with the exception of baseline best corrected visual acuity, which I'll come back to a bit later. The patients were randomized into three arms, so all of them were getting standard of care Lucentis injected every 4 weeks for 6 months. It was a 6-month trial. They were randomized to get either sham every 4 weeks for 6 months, or a low dose of sozinibercept every 4 weeks for 6 months, or a high dose, same, every 4 weeks for 6 months. Around 120 patients per arm finished the trial. These are the baseline characteristics, very similar to what is normally observed for these clinical trials in wet AMD. Patients were in their late 70s.
No particular baseline characteristics were exceptional, with the exception of the mean visual acuity at baseline, which was around 50 letters, depending on the arms in this trial. The reason for it was our inclusion criteria. The idea was to pre-select patients that were more visually impaired than in most of the other clinical trials out there, simply to be able to show the additional efficacy of a second drug in these patients. And this- the same spirit was applied in the way the phase III program was designed. We will also have patients with a slightly lower vision than what is normally expected in these clinical trials. That's as per design. The patients were also classified into different lesion types.
That was predefined in the protocol of the phase IIb, simply because it's been known for many years that depending on the lesion types of the patients, you get very different responses to anti-VEGF-A alone. That was very well published 20 years ago. And therefore, the patients were classified in these different lesions, and I'll come back to this a bit later. And finally, CST, which is the measure of the retinal thickness using an OCT device, showed that the patients were wet when they were enrolled. They had never been treated before, so they had fluid in the back of the eye, as you can see here, with an average CST of around 410-420 micrometers.
The primary endpoint was the mean change in best-corrected visual acuity from baseline at week 24 in the all-comer population. So this is the graph with all the patients put together, regardless of their lesion types. And as you can see here, the high dose combination of sozinibercept with ranibizumab delivered a 3.4-letter improvement over ranibizumab and sham. And that was very statistically significant, as you can see. The low dose sozinibercept, the 0.5 milligram, did not deliver on vision an efficacy that was different to ranibizumab alone. So we decided to move forward with the clinical program with a 2 milligram of sozinibercept. So basically, the dose was found during this dose-ranging phase IIb trial.
Quite interestingly, on the predefined lesions that were known to be less responsive to anti-VEGF-A alone, we had actually a better vision improvement. So these, these patient populations are classified as occult and minimally classic lesion patients, and we excluded the RAP lesions, which also are responding pretty well to anti-VEGF-A. So we ended up with, you know, around 88 patients per arm when you take these predefined subpopulations in the phase IIb trial. And on that population, we showed an increased difference between ranibizumab alone and ranibizumab combined with a high dose of sozinibercept, and that difference was 5.7 letters, which is highly clinically significant, as well as statistically significant in that case. This type of patient population represents three-quarters of the wet AMD patients in the clinical practice.
So it's clearly the majority of the population, but for the ones in which we have more chance to see an added benefit of a combination versus monotherapy approach. This is the patient population we are studying as a primary endpoint of our pivotal program. I'm going to skip that one. Of course, beyond best-corrected visual acuity, which is the primary endpoint in our pivotal program as well, we looked at a whole range of anatomical endpoints. And here are just a few examples of what we observed, which is a trend towards a better anatomical control with a combination of sozinibercept 2 mg and ranibizumab compared to ranibizumab alone. Whether it was on central subfield thickness or the presence of subretinal fluid, intraretinal cyst, or—I'm sorry, I'm going the wrong way.
Or the mean change of total lesion area, or the mean change is choroidal neovascularization area. You can see the trend of a better control for the combination as opposed to the monotherapy. So that brings us brings a lot of confidence that actually this anatomical- better anatomical control translate into these vision gains I have just shown before. An interesting subpopulation are the PCV patients. These patients are known to be exceptionally hard to treat. This is a very prevalent form of wet AMD. Actually, so majority of patients in Asia suffer from these lesions, as well as a large number of Caucasian patients.
But you can see here that the standard of care only improved the vision by an average of, by a mean of 6.9 letters in our trial. It was only 20 patients per arm. Yet, we got a p-value on the added benefit of the combination with sozinibercept 2 milligram, and you can see here is the benefit was around 6.7 letters more than Lucentis alone. And these patients are enrolled and included in our phase 3, and this will be an indication we would get if we were to get the wet AMD indication after our pivotal trials readout. On the safety side, this table here includes all injections done all the way to phase 2B.
The safety profile is very similar between OPT-302 or sozinibercept at any dose or at 2 milligrams compared to the anti-VEGF-A control arms we've studied in this program. There is really not much difference between the combination versus monotherapy on any of safety parameters. And this is true also for inflammation. When you look deeper in inflammation, it's very similar across the board. The phase 3 program is really built on the success of the phase 2B and enriched by this hierarchical primary analysis that will be first done on this high-responding occult and minimally classic RAP-absent patient population. So that's the first analysis that will be done. And of course, after we will look at the all-comer patient population in the trial.
We are enrolling all types of patients except RAP patients that are excluded from the trial. We have two designs, two very robust pivotal trials studying sozinibercept in combination with, for one trial, Eylea, the other one is Lucentis. And assuming we are successful in both trials, we expect our label to be quite broad and not necessarily specify which anti-VEGF-A we can be combined with, but be quite open and specify combination with any anti-VEGF-A. So this is a summary of the pivotal program. We expect a complete enrollment by the second quarter of this year, so this quarter, and top-line data, as I said before, by middle of next year, middle of 2025. Both trials are multicenter, double-masked, randomized 1-to-1-to-1, sham-controlled on treatment-naïve wet AMD patients.
So very similar patient population to our phase 2B trial. The big difference is the size. These trials are close to 1,000 patients each, and patients are randomized either. They all get standard of care, and they get either 2 milligrams of sozinibercept every 4 weeks or every 8 weeks or a sham. The comparators, as I said before, are either Eylea, given as per label every 4 weeks - every 8 weeks, sorry, after the loading phase, or Lucentis, given every 4 weeks during the trial. And these trials are very well powered. We are powered at 90% to detect the difference between the control and the combination arms. So this is a schematic of the design. The first trial, COAST, is fully enrolled. We communicated that in February of this year.
Patients get aflibercept as a standard of care, as per label, so 3 loading doses every 4 weeks, and then a maintenance phase of aflibercept given every 8 weeks for 2 years. And patients are either getting a sham every 4 weeks, or they get sozinibercept every 8 weeks with a sham injection in between, or they get sozinibercept every 4 weeks. And the ShORe trial is very similar in design, but using Lucentis as a comparator. That's the one we expect to fully enroll in this quarter, and patients get Lucentis every 4 weeks for 2 years, and they are randomized either to get sham every 4 weeks after the loading phase, or sozinibercept every 4 weeks, or sozinibercept every 8 weeks with a sham injection in between.
The primary endpoint is a mean change of BCV versus baseline as at week 52, but the trials are 2 years, and we are gonna collect the safety information of the second year and submit that in our BLA application. So we're very busy fully enrolling the ShORe trial, which will happen very soon. We communicated last week that we were already 96% enrolled, so we're nearing the end there. We are also manufacturing the molecule at scale at commercial scale, which is required for the BLA filing and the launch, so that work is ongoing now. We are preparing for the BLA submission.
We're already putting modules together, as well as increasing the team size, to make sure we have the right medical expertise in place, as well as market access, and of course, the commercial expertise to prepare for the launch. So with that, I would like to thank you for your time and open the floor for discussion and question.
Great. Well, thank you for the overview. I guess I have a couple questions. First, in terms of the overall market, if you just look at the occult and minimally classic lesions, what do they represent in terms of percentage of the overall wet AMD pie?
Yeah. So if you go back to our phase two, phase two data, if you add these two categories, it's around 85%-
Okay
... of the patient population. Now, you need to subtract the RAP lesions which overlap these other lesions. So we estimate that to be around 75% of the patient population.
Got it. And is it typical for retinal surgeons or retinal physicians to type the, you know, the kind of lesions before they initiate treatment? Is that something that's often done, or since it represents a majority of the wet AMD cases, not, it's not really established?
So it's not necessarily required today because all anti- there is only one treatment, which is anti-VEGF-A, and everyone gets the same treatment. So this, this typing, this phenotyping of the, of the patients has never been really compulsory. It's not included in any label of any product currently. We also don't expect that necessarily to be in our label, too. So it may not be needed to initiate the treatment. It's just a way for us to enrich the trial and maximize the probability of success of the clinical trial. But in real practice, it hasn't been required since anti-VEGF-A was well launched. Now, it's easy to do. It's not something technical, but it has not been required to prescribe anti-VEGF-A so far.
And are these the type of lesions that are more refractory to anti-VEGF-A, or?
That's right. So, predominantly classic lesions, which in our trials were around 12% of the patients, are very responsive to anti-VEGF-A. Minimally classic, a bit less, and occult are the least responsive. So there is this gradient of response that which very well documented. When Lucentis was launched, 20 years ago, or close to 20 years ago now, the pivotal program was done with two different patient population. One was in the ANCHOR trial, was done on predominantly classic lesion patients, and the MARINA trial was done on minimally classic and occult patient. And the outcomes were slightly different because clearly, the predominantly classic patients responded better to anti-VEGF-A. So that difference has been known for a very long time. It's not something we invented.
Okay. And as you think about the readout in mid 2025, maybe if you could just talk about what you would consider success?
Well, so success is a p-value. So,
Right
... that's what we need. You know, to get approved, we need p-value, good safety, obviously, and of course, the idea we look at the totality of data, including anatomical parameters, as you would expect. But what we need is a p-value. And then, of course, there is a range of potential outcomes, you know, from the 5.7 letter we demonstrated in phase 2B, down to maybe a few less letters because of the increase in sample size or simply differences we may have in the patient population. So depending on where we land on that spectrum of clinically significant outcomes, clearly, that will determine how big the drug becomes commercially.
The closer to five letters, obviously, the better, because five letters is considered to be—it's one line of the vision chart, and it's considered to be extremely clinically significant. But we could land a bit under five letters and still be very useful for a large number of patients. So it will very much depend on what the totality of the data would show, but technically, we need a p-value. That's-
Got it.
Yeah.
Thinking ahead here, I know from the FDA standpoint for clinical trials, they want you to evaluate against the label dosing regimen of Eylea and Lucentis. However, in the real world, I think there's a lot of treat and extend. So how would, like it's OPT-302, 'cause I can't pronounce the full generic name here, but how would it be used in the real world?
So sozinibercept. Yes. So indeed, for regulatory purposes, at least during the efficacy phase, the FDA imposes a fixed dose regimen for the comparator, at least. And that's the way we are developing the drug. In practice, we know that the treatments are individualized based on patient needs. So it's very hard to tell how this is gonna be used. But in the trial, we inject the patients when they are in a visit, when they get both drugs at the same time, they're injected at the same time. So there is no mandated delay between the two injections. We are monitoring the intraocular pressure increase in case that happens.
But we know injecting 100 microliters, which is what we inject, 50 microliters of the anti-VEGF-A, 50 microliters of sozinibercept—it's been demonstrated by other companies that this level, this volume of injection is actually safe. So in clinical practice, we think that depends a lot on the pivotal program data, of course, or outcomes. But we think what's gonna happen is people are gonna come to the clinic at a certain frequency, where they come to get their anti-VEGF VEGF-A injection, and they will be getting on top of their first injection, an injection with sozinibercept at the same time. Of course, it could change depending on the outcome of the pivotal program, but as of today, that's the thinking in terms of how it will be used in clinical practice.
Okay. Fred, you've been in the retinal disease space for a long time. I think the last 6 months at Opthea. Maybe if you can just highlight what you think is still kind of misunderstood or underappreciated by investors when it comes to OPT-302 and Opthea.
Well, so I've known the company for much longer than six months because I've known the company and the founder of the company, Megan, for probably seven or eight years now. I was always very interested by the biology, and always found it was tried by other companies, as you know, to add a drug on top of an anti-VEGF-A, and it's never been successful. No one has been able to do better than basically Lucentis since Lucentis has been launched on vision. But I always found interesting the idea of blocking more the pathway we know works, which is the VEGF pathway. So I thought this approach was actually very likely to work already seven, eight years ago. But of course, the data, the phase II data came in, in 2019.
And demonstrated with good P values, despite the small number of patients, that actually, that was the case. It was, it was actually working. So, I find that approach incredibly promising. And there is a medical need. When patients are asked what they care about in their wet AMD treatment, the number one answer is always vision. It's not a place where patients want to compromise. We value our vision, we value our sensory organs a lot, whether it's, you know, sight or hearing or... When you lose them, it's when you lose them, that you realize how much important they are, and no one wants to go visually impaired. So I think this is why I was very excited about the company. Yeah.
Good. All right, well, I think we're gonna wrap it up here. I wanna thank you both for spending time with us this afternoon, giving us a great overview of Opthea. I think this is exciting times for a biopharma company at this stage of development, getting fully enrolled in a year or so away from a phase 3 readout. I think it's a good place to be. So thanks again.
Thank you, Brian.
We appreciate your time.
Thank you for having us.