NovaBridge Biosciences ($NBP)

Good morning, and welcome to the NovaBridge Biosciences Business Update Call. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the NovaBridge website following the conclusion of the event. I'd now like to turn the call over to Xi-Yong Fu, Chief Executive Officer at NovaBridge Biosciences. Please go ahead, Xi-Yong Fu.

Thanks, Tara. Good morning, everyone. I'm Xi-Yong Fu, CEO of NovaBridge. Once again, welcome to VIS-101 clinical data and the development plan update. Next slide. In this presentation, we will share forecast about future performances, which are speculative, not guarantees. Actual results may differ materially. And like Tara mentioned, I wanted to reiterate the material presented today will be publicly available on NovaBridge website. Next. So during today's call, we'll first walk you through some high-level information about NovaBridge, our hub-and-spoke business model and the first spoke company, Visara, focus on ophthalmology, obviously. And then I will cover a few more topics, including detail the Phase IIa clinical data of the first pipeline asset of Visara, we call it VIS-101 and we'll also include important perspectives from respect to the KOLs on the call, and I will comment about the next phase clinical development plan as well. Finally, we'll be happy to answer some questions from the audience. Next. So joining me today are Visara management team and the guest experts to walk you through Phase IIa VIS-101 clinical data. It's my pleasure to introduce today's speakers. Dr. Emmett Cunningham, Executive Chairman and Co-Founder of Visara and also Vice Chairman of the Board, NovaBridge. Dr. Cadmus Rich, Chief Medical Officer of Visara; and Dr. Carlos Quezada-Ruiz, Chairman of the SAB of Visara; and last but not the least, Dr. Nikolas London, Managing Partner, President of Retina Consultants San Diego. And we are excited to tell you about NovaBridge, Visara and VIS-101. Next. So let's start with some intro of NovaBridge. Next slide, please. NovaBridge is a global biotech platform with a portfolio of first and best-in-class programs. At this moment, we have 2 lead assets. Let me give you a quick download of who they are. Both demonstrated a compelling clinical proof of concept supporting differentiated positioning. The first one we're talking about today is VIS-101. This is a molecule that's purposely designed and was a differentiated molecular structure targeting VEGF-A and Ang-2, has a favorable safety profile and a rapid durable response supporting a potential best-in-class durability, I'll show you a lot more data in the next hour or so. The other asset we have is in the oncology space, we call it givastomig. It is a Claudin 18.2/4-1BB bispecific antibody, which demonstrated a robust and durable response in patients across broad biomarker expression levels, be it PD-L1 or Claudin 18.2. It is a potential best-in-class molecule that can be bolt-on to the current standard of care for the frontline gastric cancer patients. We are super excited about this molecule, just like we are today for VIS-101s, two, very impressive, very important molecules. We have a healthy balance sheet, talking about our finance as of last SEC filing, we have $228 million in cash, providing operational runway through 2028. And if you look at our upcoming milestones, we expect multiple near-term catalysts from the lead assets VIS-101 and givastomig in those therapeutic areas in the coming months and a period of time near term. It's a very exciting pipeline. Next slide, please. So I wanted to give you a high-level overview of NovaBridge's business model. NovaBridge is a hub-and-spoke gateway connecting innovation from China and other emerging biopharma ecosystems to global patients. We believe the quality and efficiency of a China biotech industry will continue to create significant value going forward. So there are 3 components of our business model. The first thing we do is to leverage our strong access to China biotech ecosystem to identify and license in innovative assets in a capital-efficient way. We prefer clinical stage or clinical ready stage programs in order to reduce our exposure to biology risk. In doing so, we take a therapeutic agnostic approach, really focusing on the overall value and the quality of the assets. Then subsequently, we built an industry-leading development team around this asset in U.S., form a subsidiary or a spoke company. The spoke company will then design, implement clinical trials with a goal to demonstrate clinical POC at which time we expected the asset value to increase significantly, 5x, 10x or even more. When we have achieved the clinical POC in some of those programs comes the step #3, which is the value realization. In this phase, we could pursue an out-licensing deal, a co-development deal or in selected cases where when we feel the circumstances are right, the molecule is right, that the team is great and the therapeutic area is suitable and the commercial opportunity is right, competitive landscape. The subco under those circumstances, then we have the option to let subco be in a vehicle to raise additional fund engage itself in late-stage development in order to capture additional upside. So we have flexibility in this particular business model step. So NovaBridge doing those 3 things really is the only publicly listed company to engage itself in systematically creating value through the bridging of China innovation to global markets, building a differentiated capability based on BD in, BD out capability as well as industry-leading clinical development capabilities. Next slide, please. So what about Visara, what is the relationship between Visara and the NovaBridge? NovaBridge invested $37 million cash October of last year, I highlighted on the left-hand side, the cap table. So NovaBridge currently owns 65% of Visara. AffaMed contributed its right in interest in VIS-101 in exchange for 30% of equity in Visara, the remaining 5% is ESOP. So Visara is the first spoke company in the hub-and-spoke model of NovaBridge. As I mentioned earlier, our business model combines the strength of the molecule with the quality of the management team. So on the right-hand side, I think you will see that the Visara is a wonderful example of that. And the Visara company is led by Co-Founder, Executive Chairman, as I introduced earlier, Dr. Emmett Cunningham, give you a little bit more background about Emmett. Emmett is the world-renowned ophthalmologists, also a former senior managing partner of Blackstone Group with over 25 years of experience as entrepreneur as an investor, as a drug developer, cofounded more than 5 different companies with successful track record exiting IPO or acquisition and published over 450 papers in the field. And notably was also one of the leading scientist behind the Macugen and it is -- which is the first VEGF-A inhibitor for AMD and DME. Cadmus, as I introduced earlier, is our CMO with over 18 years of experience in ophthalmology R&D with companies such as Lassen or Alcon, major players, all major players in the field, great experience working with regulatory agencies, FDA, EMA, MHRA on multiple projects. Dr. Carlos Quezada-Ruiz is the Chairman of our SAB again, with over 25 years of experience in ophthalmology R&D. Most recently, I wanted to highlight that the Carlos was the medical lead for, VABYSMO at Roche, and he played a pivotal role in the global development and approval of VABYSMO [ itself ] which targets the same 2 targets that VIS-101 target and also other drugs like SUSIVMO. And Carlos led the design execution readout filing and launch activity for those products. I cannot think of a better person guide us as SAB chair through the clinical development for VIS-101. So we are extremely happy to have such an experienced management team for Visara. And now to tell you more about Visara and VIS-101, here is Visara Co-Founder and Executive Chairman, Dr. Emmett Cunningham. Emmett?

Yes. Thank you, Xi-Yong. Emmett Cunningham here. As Xi-Yong said, compounding Executive Chair of the company. Next slide, please. Today, we're going to hear some pretty exciting results from VIS-101, which was, as you've heard, purpose designed to be best-in-class for retinal vascular disease. The molecule schematized here on the left, you can see is tetravalent. It has 2 anti-VEGF-A binding sites and 2 ANG-2 neutralizing sites with an Fc modification to limit systemic circulation. These attributes, which you'll hear more about in just a second, make it, we believe, best-in-class. You'll also hear today the results of our Phase IIa trial performed in China, which demonstrate that the drug is safe and well tolerated. You'll see that it has a very rapid, robust and durable treatment response. With a mean vision and CST response that are, I believe, at least equal to best-in-class. Notably, the durability, as we saw in this trial showed that up to 2/3 of patients were retreatment free at 4 months with about half retreatment free at 6 months, again, potentially best in class. Next slide. Now Xi-Yong has introduced Carlos Quezada-Ruiz, and so I'll let those words stand for themselves. Carlos will be presenting our clinical data. Dr. Nikolas London was an investigator in the U.S. portion of VIS-101 development and we'll give some perspective from that experience following Carlos' presentation. Dr. London is a world-renowned KOL a retina specialist who practices in San Diego. With that, I'm going to hand this over to Cadmus Rich, my colleague at Visara, to do a brief introduction of the molecule and its properties. Cadmus?

Thank you, Emmett, and thank you all for attending today. I'm really excited and feel privileged to be able to introduce our lead program, VIS-101 to you today. Next slide. A few words first about the unmet need and the disease that we are treating with VIS-101. Basically, the main retinal vascular diseases, including, as you see here, wet AMD which has over 20 million patients. This is where abnormal blood vessels grow under or within the retina from the choroid and cause damage to the vision. Diabetic macular edema in the middle, which is a manifestation of diabetes and sick blood vessels in the retina leak and cause edema of the central part of the retina, which impacts the vision as well. There are 21 million people with this condition. And then last, retinal vein occlusion, where a blood vessel is occluded and the backup of the blood flow causes edema of the macula, which VEGF therapy can also reduce, you see 16-plus million people afflicted with this condition. So overall, there's more than 57 million people affected globally. And there's a large unmet need to have therapies that could extend the treatment interval to reduce the number of injections needed, which means there will be less disease fluctuation and fewer injections over time. Next slide. This durability is very important, and we know that the market does have a lot of impact with Verbility. You see this here on this slide with the graphic you see on the left. With LUCENTIS was the first drug after Emmett's Macugen, the first anti-VEGF drug, which took market share from Macugen. And that was every 4 weeks, as you could see on the right. And then EYLEA was developed with every 8-week therapy and came in and reduced the growth of LUCENTIS and took over market share. Then VABYSMO and EYLEA were developed recently and have now have a treatment interval of around Q8 to Q16 weeks and have taken over a large amount of the market share. And now we want to introduce you to VIS-101, where we feel we will have Q8 to Q24-week treatment intervals and that we think that this will give us a best-in-class durability as well as a potential in the marketplace. Next slide. So introducing you to the molecule, which Emmett touched on briefly. This is VIS-101, the next-generation bispecific purpose designed to be best-in-class with dual -- well VEGF-A and ANG-2 inhibition. This bispecific tetravalent design increases the number of binding sites and has a higher affinity for both the VEGF-A and ANG-2 receptors. You could see on the molecule on the left, the 2 anti-VEGF sites on the top. These are 2x more inhibitory than faricimab. And you could see on the bottom, the 2-inch 2 receptors on the other side of this traditional antibody molecule the 18 aptamers that are for ANG2 that are 17x the inhibitory activity of the faricimab ANG-2. And we touched on the optimized Fc region for shortened half-life with bypassing the FcRn pathway. So this combination gives us a purpose timed molecule that in both our Phase I study, which we won't cover today, and our Phase IIa study that we will cover today where about half the patients remain treatment-free at 6 months. Next slide. So comparing our drug to the market leader of VABYSMO, how do we compare? You could see on the left, the VABYSMO molecule with one site for anti-VEGF and one site for ANG-2 versus VIS-101 on the right, where we have 2 binding sites for VEGF and 2 binding sites for ANG2 or the [ tetrameric platform ]. And the antibody format is bispecific for VABYSMO and tetravalent bispecific for VIS-101. The molecular weights are similar, but the VIS-101 is slightly larger, which may also confer a slight advantage on the PK profile. The dosing that we compared in this study are similar at 6 milligrams each. Although in our Phase IIb study, we will investigate a 9-milligram dose as well. There are 3 loading doses for VIS-101 versus 4 loading doses for VABYSMO and I think this is partly because of the tetravalent molecule and the better affinity giving us longer inhibitory activity, and I'll show you a model of this in just a moment. You could see the durability of response up to 16 weeks has been investigated for VABYSMO. And then for VIS-101, we have up to 24 weeks of durability. So overall, this is a purpose-built molecule bioengineered for rapid, robust and durable response. Next slide. So I'm going to show you our PK/PD model which helps to demonstrate the advantage of the inhibitory activity with VIS-101 compared to faricimab and this PK/PD model was developed specifically for faricimab. The reference to that model is at bottom of the slide. This model was used to estimate the inhibitory potential for VIS-101 and compare that to faricimab. And this was developed by the engineer who actually built and designed the VIS-101 molecule Jeff Lu in China at AskGene. So this shows both the VEGF-A on the right axis. If you see on the right side on the Y-axis, predictive free VEGF-A levels in the aqueous humor. And then on the left, the ANG-2 levels, and we'll go through this graph together here. So with an injection, the level of both the VEGF and ANG-2 with the inhibitory drug dropped down to 0, and you could see that at the bottom left of the slide. Then as the drugs both due to PK, but also due to the inhibitory activity and affinity of the binding sites and the number of binding sites as the drug starts to leave the eye, you could see that the levels of both of these molecules start to increase in the aqueous humor again. And you could see on the solid lines to the left in red is the faricimab VEGF activity. And then in blue, with a 1-week benefit of longer inhibitory activity is the VIS-101. And then on the dotted lines, with ANG-2, you could see in red, the faricimab ANG-2 inhibitory activity lasting about 16 weeks, which goes along with its testing interval and then for VIS-101, you could see we significantly extend that over 4 more weeks or longer with our dotted blue line here. And this shows that we are able to have longer VEGF and ANG-2 inhibition, which may predict increased VIS-101 durability. And so we feel that this will also be shown to you by Dr. Carlos Quezada-Ruiz on the next part of the presentation where he will show the clinical data that supports this. Next slide. So let me turn it over to Carlos. Thank you for your time and attention.

Thank you very much, Cadmus, and good day to everyone. I'm Carlos Quezada-Ruiz, and I'm a retina specialist, I'm a drug developer, and I'm the Chair of the Scientific Board of Visara. I'm honored to present to you this morning the top line data for the Phase IIa study, and I want to thank the teams of Visara, the investigators, the study staff and the patients who participated in this study. Next. First, I want to take some time to explain the trial design on this slide. This was a multicenter, open-label, randomized, multiple-dose study to evaluate the safety, the tolerability, the pharmacokinetics and the pharmacodynamics of VIS-101, in patients with neovascular AMD, but important to note both in treatment-naive and previously treated patients. The key inclusion criteria included patients with active macular neovascularization secondary to AMD who are between 50 and 80 years of age. The total lesion size of up to 12 disc of areas, a baseline BCVA on ETDRS of the study eye that fell between 19 and 78 letters which represents approximately 20/400 to 20/40 on the Snellen chart where the key ocular inclusion criteria. On the exclusion criteria front, we excluded fibrosis or geographic atrophy that involve the fovea, any history of glaucoma or having received any anti-VEGFs within 60 days prior to screening. The primary endpoints of this Phase IIa study was the incidence and severity of ocular and nonocular adverse events, treatment-emergent adverse events and serious adverse events. The selected secondary endpoints include the mean change from baseline in BCVA, CST and the durability. So a total of 38 patients in China were randomized in a 2:1 ratio to either the 6 or the 3-milligram VIS-101 groups with 25 and 13 patients in each group, respectively. And important to note, the patients were stratified by baseline BCVA at day 0. Patients then received 3 monthly injections, often referred to as loading or initiation doses and starting at week 12 the investigators evaluated for disease activity every 4 weeks and gave rescue treatment based on street and prespecified disease activity criteria that I will explain a little bit later. The duration of the study was 20 weeks post first dose with monthly follow-up visits. And if a patient had not received rescue treatment by that time, then the study would be extended to a maximum of 36 weeks post the first dose or until the disease activity criteria are met and rescue therapies initiated, whichever occurs first. Next. Here, we see the baseline characteristics, and they're generally comparable between the 2 groups. But I want to point to your attention a couple of topics here. BCVA was a few letters better in the 6-milligram group at 54.7 ETDRS letters, which represents approximately 20/80 on the Snellen equivalent and 52.3 ETDRS letters for the 3-milligram group or 20/90 in Snellen equivalent. The central subfield thickness, or CST was in the thick side with about 410 microns at baseline in both groups. As you can see on this table, more previously treated patients were randomized to the VIS-101 6-milligram group. This baseline visual and anatomic values, the existence of a pretreated cohort show here that probably this population represents a sicker patient population than those that were included in more recent trials for neovascular AMD. Next. Here, we see patients treated with VIS-101 at both the 3- and 6-milligram experiencing a rapid and robust BCVA gain during the loading phase. The solid and dotted lines represent the treatment naive and the previously treated groups, respectively. And as mentioned during the trial design slide, starting at week 12, all patients were assessed every month for science of disease activity. And if they met criteria, they receive supplemental treatment and left the study. You can see this part of the study reflected in the table on the bottom, and you can see this attrition by the number of patients per visit as it's declining as patients receive supplemental treatment and then exit the study. Both the 3- and the 6-milligram groups showed very good treatment response and durability. Next. Here to the right of this slide, you can see the BCVA results from the STAIRWAY study, which was the Phase III study of faricimab that was designed to evaluate its durability potential. The STAIRWAY study included monthly 0.5-milligram LUCENTIS arm in addition to the Q12 and Q16-week arms of faricimab, as you can note. The BVA gains by VIS-101 in the treatment-naive and previously treated patients are comparable to those achieved by faricimab and other anti-VEGFs. Important to note, there's only 3 loading doses that were given in the VIS-101 study versus 4 loading doses that were given at the STAIRWAY and the TENAYA and LUCERNE studies for faricimab. Next slide. Now when we look at the treatment-naive population, we see that about 70% of the patients are treatment free at 4 months and about 40% are treatment-free 6 months after the last loading dose. And important to note with a strict prespecified disease activity criteria. Next. Treatment with VIS-101 also resulted in rapid and robust anatomic improvements with a decrease in central subfield thickness by over 100 microns. And this was after the first injection in both the 3 and the 6-milligram arms and across both treatment-naive and previously treated groups. Next. These anatomical results were achieved with about 70% of the patients being treatment-free at the 4-month and about 40% treatment-free at the 6 month after the loading dose. Next. Now this graph shows the durability over time for the 6-milligram arm with approximately half of the 6-milligram patients being treatment-free out to in past 6 months with visual stability as shown in the previous slides. Now here to the right, you can see the disease activity criteria that had a combination of visual, anatomical and clinical criteria to ensure the safety of the patients. You can see that having an increase of 75 microns or more in CST compared to the previous lower CST in the study or having a BCA decrease of 5 letters or more compared to the mean BCVA of the previous 2 scheduled visits or having a loss of 10 letters or more compared to the previous highest BCVA or having new or recurrent fluid due to neovascular AMD activity or the presence of macro hemorrhage that in the criteria of the investigator was due to neovascular AMD activity could trigger a supplemental treatment in these patients. Next. And as always, super important, safety. Throughout the study, VIS-101 at both the 3 and the 6-milligram arms were well tolerated and there was no dose-limiting toxicities. There were 2 patients who had treatment-related adverse events, 1 patient that had 3 episodes of uveitis, those were detected on the slit lamp exam, the patient was asymptomatic and did not affect vision. There was one case of vitreous opacities. There was no cases of ocular hypertensive events. And across all patients dose, there was no patient who lost 10 letters or more during the study. And lastly, there were no cases of occlusive vasculitis or retinitis. Next slide. And with that, I now want to hand over to my dear colleague, Dr. Nikolas London. Thank you.

Great, Carlos. That was an amazing overview. This is an exciting molecule and as a clinician, I'm very excited to see these early results, very hopeful that they are replicated. I think if they're replicated in late phase clinical trials, we're going to have a real great blockbuster on our hands. We can go to the next slide. So we've seen this slide before. This is comparing VIS-101 to currently available best-in-class VABYSMO, faricimab. And you can see some of the key differences that have been reviewed. But just to review, we've got about double the anti-VEGF inhibition and about 17x the anti-ANG-2 inhibition. For faricimab, there are 4 fixed loading doses compared to 3 exploding doses, and we see a post-dosing loading dose durability in faricimab up to 16 weeks with up to 24 weeks or longer with -- appears a single dose of VIS-101 similar BCVA gain and a really strong safety signal. This all clinicians are concerned about inflammation. This one case of mild easily controlled uveitis to me as a clinician is not overly concerning. So for me, from a clinical perspective, when faricimab came on to the market, it was fairly slow at the beginning to adopt because we were not at all comfortable with the ANG-2 component. We weren't convinced. We have subsequently become convinced and you can see the overwhelming increase in the market share that shows that on a previous slide. I kind of think of VABYSMO as a speeding train. We are aggressively adopting it. And VIS-101 is not trying to change the direction of that train or compete with that train. It's really grabbing onto that momentum with an improved product. So personally, I can't wait to see my patients benefit from a medication like this. Next slide.

Okay. I think we're going to hand over to Carlos at this point -- I'm sorry, to Cadmus at this point to take us through the next steps.

Thanks, Emmett. I appreciate that. Let's go to the next slide. So just to reiterate what you heard today. VIS-101 is a purpose design, best-in-class molecule for retinal vascular diseases. Our early data here is a Phase IIa and wet AMD. The drug was safe and well tolerated. There was rapid, robust and durable treatment responses both for BCVA and CST and we did not really show retinal drying, but also retinal drying, potentially, this is a best-in-class durability with up to 24 weeks or longer, shown now in our early Phase I study that Nick was an investigator in and this Phase IIa study. And our next steps you see are to begin our Phase IIb study in China, which will be initiated in the second half of this year. And then we're looking forward to beginning our global Phase III program which will begin in 2027. So thank you all for your attention, and I'm going to turn it back over -- if you go to the next slide, turn it over to Emmett for the Q&A.

Thank you, Cadmus. I think at this point, we're going to try Hollywood Square type interaction just to keep it more lively and organic. You'll get to see all of our faces. Tara, can you have it such that we can see the Hollywood Square block template as well?

Yes. We'll just ask everyone to turn their cameras on that is participating into the Q&A.

Great. Now you have several world experts regarding VEGF-A and VEGF-A and ANG-2 inhibition. I'm going to take the questions in sort of shuttle them off to others. But I would just say to my colleagues, if you feel as though you'd like to add to a comment, please just speak up and let us know. First question, Tara.

[Operator Instructions]. So our first question comes from Christopher Liu at Lucid Capital Markets.

I just wanted to ask what the key differences are between the study you had here and maybe something like faricimab. Also, what are your plans or preliminary ideas for the global Phase III design in terms of where patients might be coming from and anything else that might be important.

Yes. So there are a couple of questions there, Christopher. Thank you for those. The first is, what is the difference between faricimab. And as you know, there are more than one faricimab study. They were the Phase II, the Phase IIIs. What we've done in this presentation is compared directly to the STAIRWAY of Phase II study. And the key difference was that faricimab was entirely treatment-naive where we had a mix, 2:1 mix of naive to pretreated patients. We also think our patients were somewhat slightly more severe in that they had lower vision at entry and a little bit more fluid. Another key difference was we had 3 loading doses versus there are 4. So those, to my mind are the key differences. But, Cadmus, do you want to add to that before we go to the Phase III plan?

Yes. I think those were the key differences, Emmett. We showed a comparable vision response to the STAIRWAY study with those advantages you listed.

Right. So the Phase III plan, the traditional Phase III plan would be 2 Phase III trials globally, each comparing to a standard of care and recognized by the agency, and that is typically monthly LUCENTIS, ranibizumab or every other month, EYLEA or aflibercept. And that is the base case plan for us now to have 2 Phase III global studies. It is interesting, as I'm sure everyone has seen that the agency has said they're moving toward a 1 Phase III paradigm. And we will have that discussion with them. We will, by that time, have a large randomized Phase IIb study done in China. We know from other companies doing studies globally, including in China, that the patients respond identically and so we expect that to be a recognized trial. And so that could be 2 trials. And in the worst-case scenario, we could have 1 trial that would be centered in Asia and a second center outside of Asia, which could meet the 2 trial rule. So all that is sort of on the table and we plan to have those discussions with the agency moving forward. Cadmus, you're leading that effort, anything to add there?

Yes, I think that's exactly right. I think we're looking forward going to FDA, NMPA and to MHRA and EMA to get the advice and align the global program.

One thing that makes me comfortable as a clinician with the clinical trial design is the retreatment criteria. They're fairly -- they're good for patients, right? They're or statements. So they either have a decrease in vision or an increase in anatomic parameters to be retreated, instead of an ANG treatment, which is what the trials require. So I think that's great. It makes me very comfortable.

I agree, Nick. I think that part of the similarities, I guess, with the -- or differences with the faricimab trials, as Emmett and Cadmus highlighted are on the BCVA, the CSC and the inclusion criteria, the size of deletion was also smaller in those studies. And the or as part of that disease activity criteria is definitely a difference when it comes to being strict for extension of the patients.

Next question, Tara?

Our next question comes from Andres Maldonado at H.C. Wainwright.

Congrats on progress. I guess 2 for me. First, from a vascular biology perspective, I guess, how much of the clinical signal observed in the current data set, would you attribute to VEGF suppression versus ANG-2 pathway modulation. And I guess, how should we be thinking about that from an elevated biomarker changes such as Tie2 activation or maybe other vascular stabilization markers to dissect those contributions?

Yes, Andres. I'll try to answer that question. If you look back historically at ANG-2 inhibition at Aerpio, which is a company from, I think, more than a decade ago, they had a small molecule, which was a direct Tie2 activator. It had a very modest effect. And that -- I think they studied mostly diabetic retinopathy, DE. But they did have an effect. It was a drug effect. We all believe there was a drug effect less than I believe what we're seeing with the add-on of faricimab. There, however, when you look at faricimab, you see some of the trials had some vision separation, some -- clearly, there appear to be an enhanced durability but better than, I would say, the Aerpio drug. And so the point I'm trying to make is that as we get a better inhibitor of ANG-2 and we go from, say, what Aerpio had to faricimab to now what we believe we have, we believe we can see better performance. I would suspect mostly on the durability side, although there may be numerical add-on, if you will, to both Vision and CST. Implicit in your question was, what can we expect from a Tie2 activator of the type that others are developing. I'm not sure. We've only seen a handful of patients treated with the Tie2 activator. I have no reason to believe that it should differentiate from a strong ANG-2 inhibitor, but we will see as the studies read out over time. Carlos, should you have anything to add to that?

Thanks, Emmett. Yes, I agree with you. I think where we're seeing really the benefit of the ANG-2 inhibition, which is the most meaningful to our patients is actually on the durability side, which is, again, as noted by the ASRS PAT survey, the biggest unmet need for patients with wet AMD. And I think when you look at AKB-9778, I believe, was the name of that Aerpio asset. There's definitely signals of activity. And we look at the nesvacumab program as well both in the ONYX and the RUBY trial, there's definitely a signal towards better anatomical benefits, which actually do translate to extended durability as well. And this is where I think it's the biggest value proposition that VIS-101 actually brings to our patients. One thing that we have not seen so far has been -- and again, bearing in mind the small numbers and the fact that this is a Phase IIa study. But getting half of the patients to 6-month dosing with a biologic is something that we have never seen. And this is with sustained BCVA and anatomical stability as well. So that, I think, is very powerful.

Just to add on to that, Carlos, before we go to the next question. What excites me most about the possibility here is it we believe and the biology would support that ANG-2 inhibition Tie2 activation is vasorestorative. And so you might be in a situation where as you extend the half-life, especially of the ANG-2 inhibition and we have pretty long-lasting ANG-2 inhibition, you get this virtuous cycle, so to speak, where you can lower the VEGF-A levels and start to heal the vasculature and that may be underlying this amazing durability that we've been seeing in this trial. Next question, Tara.

Our next question comes from Kumar Raja at Brookline.

You touched about the 9-milligram dose a little bit in the prepared remarks. What kind of data do we have with that dose? And what are the expectation in terms of duration of response with that dose. And in terms of the next steps, is the strategy to find a partner and what needs to be done before you can start the next slide.

Yes. Kumar, there are a couple of questions there. So the 9-milligram dose was not studied extensively in trials to date. And so we plan in our China Phase IIb study to directly compare 9 milligrams to 6 milligrams and safety, efficacy and durability. So we'll pick our dose at that point. As you know, generally in the field, people like to dose as much as they can, recognizing that every increased mold, if you will, will lead to some enhanced durability. And we will do the same. Cadmus, you want to add on to that?

Yes. No, I'm excited about the 9-milligram dose. I think that to your point, it may increase the durability. We have in the Phase IIb study, a very good plan to assess that dose against the 6-milligram and then be able to pick the dose for the Phase III program.

Yes. I just want to add on your point, maybe it was made indirectly. The structure of this molecule, well, it's novel and that it's tetravalent, it's novel and that the binders are, I think, sort of best-in-class, the inhibitory function of them. It's in all other respects, a pretty traditional antibody onto which we've linked these 218 versus the FcN and so we expect -- it can be made. We know that it can be manufactured easily, and we expect that it can be given at very high concentrations. And so that's why we're going to explore the 9 milligrams, which would be the highest concentration. To your second question about partnership, that's -- we're open to all sorts of discussions. We're -- as everyone knows, we've kicked off our crossover round now. That obviously crosses over to another round later, let us say within 6 to 18 months, and we think between the crossover round now and that future round will have more than enough to do the global development of this molecule. So we don't need a partnership, but we would always entertain one for the right partner. Next question, Tara.

Yes. I believe we have another question from Andres at H.C. Wainwright.

Sneaking me back on to the queue. Just curious if you could talk a little bit more about how heterogeneous was the patient population in terms of prior anti-VEGF exposure. And more importantly, how does this durability or visual acuity outcomes differ in the treatment naive versus previously treated patients? And how should we be thinking about that in later line trials if that kind of signal further separates or kind of comes together there?

Yes. All good questions, Andres. The Phase IIa from China was 2:1 randomization so treatment naive to treatment experience, and that's about what we saw. So let me just understand your second question, other than the mix of 2:1.

Correct. It's just trying to parse kind of some heavy expectations in the real world versus clinical settings. So if you can give us some historical perspective on prior anti-VEGF exposure kind of differences in that efficacy signal from the clinical study to the real-world set and kind of just setting expectations for the delta there.

Yes. I think obviously, if someone has received some VEGF-A inhibition and gotten some therapeutic benefit from that then there's less of a gain you would -- one would expect going from some treatment to, let's say, best-in-class treatment. So that's exactly what we think we saw. In the naive patients, we had 10 letters and greater improvement, whereas in the experience patients we had. I don't want to misquote the exact number, but it was 6, 7 letters, something like that, still impressive given that these patients have already received treatment. To your -- to the point of what we can expect going forward, it's pretty clear that the agency has -- does not want treatment-experienced patients in trials moving forward. They would much prefer treatment naive and that's what we will do. The reason there is that they have a very good understanding of what the noninferiority margin should be for treatment-naive patients. But for treatment experience, they don't quite know how to interpret that. So they've come down pretty clearly in recent interactions to say that they want treatment naive moving forward. Moving into the -- beyond that, let's say, post approval, I think we would expect to be an agent that could be used in virtually any patient, but we would expect many patients who have a suboptimal response to existing standard of care to be at least tried with new agents, whether it's ours or others.

Great. Thank you for the questions, Andres. So that concludes our Q&A session for today. I'll turn it back to you, Emmett, for some quick closing remarks.

Well, I'd just like to thank everyone for sitting through our first presentation of this exciting Phase IIa data. We are available. You can reach us if you have additional questions, and we'd be happy to chat. As I said, we're in the midst of a crossover financing and we'd welcome any or all of you to reach out directly. Thank you.

Thank you, Emmett. Thank you, everyone.

Thank you, everybody.