noon. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I am one of the senior biotech analysts here at the bank. It's my pleasure to have our next presenting company, Belite Bio, on stage with us. We have several members from the management team. Speaking for the team today will be Tom Lin, who is Chief Executive Officer, as well as Nathan Mata, who is Chief Scientific Officer. Gentlemen, thank you for making the trip to Las Vegas. Tom especially, I think you had a long flight over, so really appreciate you visiting us.
Oh, it's happy to be here. Oh.
Our pleasure to be here. Thanks for the opportunity.
For those who may not be as familiar with Belite , I thought maybe it would be good to give a two-minute overview of the company, the platform, and then we can go into your lead program in Stargardt.
Okay, this is Sure. You're good at presenting.
You want an overview of the program in Stargardt disease?
Just an overview of the company itself.
Yeah, you better go overview of the company, yeah.
All right. We are ophthalmology or retinal focused company. The company spun out from Lin BioScience. It's a publicly listed company in Taiwan, that's a company that has to do more on the oncology programs. Because this is a unique drug, and uniqueness in the sense that there's nothing out there. It is a very severe med need. The drug has shown very strong potentials early on. We spun the company out in 2018, We listed the company in 2022. The clinical programs has been pretty smooth. We've shown very strong data. Yeah, we are very excited. We see a lot of potential in the company.
Okay. Maybe can you just give us an overview of Stargardt itself? You know, what are the symptoms of the disease? What's the prevalence? We could talk about what doctors are currently prescribing for patients if any of that.
I can do it, yeah. I can take off from there. The disease is a monogenic disease, so it's genetically inherited in an autosomal recessive manner, which means one of each parent contributes a mutant allele, if you will, and that would confer Stargardt disease upon the child. The prevalence is roughly about one in 6,000, so roughly about 53,000 in the U.S. Of course, this is a devastating disease, especially in childhood, because these kids from a very early age have visual acuity loss, and this compromises their social functions, education functions, learning, et cetera. This is one of the reasons that we focused on the adolescent Stargardt patient populations, because there's clearly an unmet need in the entire disease. It affects adults as well.
In children, there's a much more dire need, because from a socioeconomic standpoint, these children will suffer tremendously without treatment. We've obviously have a treatment, a oral once-a-day tablet. Very easy, you know, to administer. No treatment burden whatsoever, that has been shown to reduce lesion growth in these patients by as much as 36% over a two-year period. That's never been seen before, in a clinical study of Stargardt disease or geographic atrophy for that matter. We're very pleased and very hopeful for an approval within the next 6 months or so.
I maybe wanted to stay on what you mentioned for a minute about unmet need.
Other companies have tried to look at Stargardt, but it's been complicated. Why do you think that is?
Yeah. I was involved with one of those companies, a company called, formerly called Acucela, now called Kubota Vision. They also had an oral once-a-day tablet that was directed at a different sort of target than what we're looking at. They were really focused on the visual cycle per se. This drug was a very potent drug, an inhibitor of a key enzyme in the visual cycle, which although it did reduce the accumulation of toxins that are implicated in disease progression, it also had a very negative effect in terms of ocular adverse events. Ultimately that treatment never really worked. They ran a pretty large Stargardt trial in both, well, largely adults, but it was 194 patients, I believe, phase III trial. It did not succeed.
There was that one. Then of course, there have been other attempts at Stargardt disease in phase II trials.
got off the ground.
Yeah
pinnacle of the clinical trial development in Stargardt disease with our drug tinlarebant.
Yeah. Maybe Nathan, can you just remind everyone what the study design was for your DRAGON study?
Right. Our phase III pivotal trial design was 104 subjects. We enrolled globally, all over the world. It was a two-year study where subjects took a 5 mg tablet of our drug tinlarebant once daily, over a period of 24 years. They came in for regular assessments where we measured their lesion growth as well as visual function and safety parameters, et cetera. Of course, we had a placebo group. The study was randomized in a 2-to-1 manner favoring tinlarebant. There was roughly 65 patients in the tinlarebant treatment arm, and the remainder in the placebo arm. That was really the trial design. We did have an interim analysis when all patients had reached their 12-month time point. That triggered an unmasked look at the data by our DSMB.
The DSMB looked at that data, and they made a very sort of unorthodox comment that we should submit the data for further regulatory review. At that point, no one on the Belite Bio side knew what the data looked like. Only the DSMB was unmasked to that. Because they made that strong comment, we went to the FDA and asked, "How can we share this data with you and potentially apply for a Breakthrough Therapy status?" They gave us a path, a roadmap to do that wherein we would unmask just a couple of members on the management team, and that would be our CEO, Tom Lin here, and our CMO, Hendrik Scholl.
They would look at the data, and they would prepare a dossier to submit an application for Breakthrough Status. We got that Breakthrough Status. You know, we're off to the races now.
Okay. In the discussions that you've had, with FDA. Have the people that have been involved in the discussions remained the same?
Yeah
There's been turnover at the agency. There was turnover this week, in fact.
Right.
Can you talk to us about, I guess, based on the most recent change, do you expect any impact? For the day-to-day interactions that you've had over the last couple of years, have they been the same people just for consistency purposes?
It has. Initially, and probably for the last 35 years, the Director of the Division of Ophthalmology was Dr. Wiley Chambers, and he had a very principled and dogmatic approach to all clinical trials, which may have been a little bit restrictive. There's one thing that did change is the incoming Director, William Boyd, it seems to be a little bit more lenient, a little bit more willing to work with sponsors. Not that Wiley didn't work with sponsors. He did. I think with William Boyd coming in, he's given us sort of a more open window, especially in orphan diseases like Stargardt disease, to apply for single study approval. You talk about the Commissioner Makary retiring under pressure, I'm sure.
I don't think the commissioner status really changes what we're doing on a day-to-day at Belite Bio. We were happy when Makary announced that they would be moving away from a requirement for a two study—
Right
—design of, for approval, and they would use a single study with confirmatory evidence, and that's exactly the path that we're taking. In fact, that's what William Boyd supported as well, that we should apply for the NDA with this phase III data and the confirmatory evidence.
Okay.
Yeah.
Yeah, that was gonna be my next question in that that editorial in New England Journal that appeared from Doctors Makary and Prasad. They're both gone from the agency.
What do you think the commitment the agency still has to wanting to pursue, where possible, a one study requirement? Seems like based on what you said, you don't think anything's changed.
I don't think so. Tom, do you have anything to add to that?
I think the path that one single study that understanding what the FDA was prior to that editorial already.
Of course, the editorial came out that—
Okay
—basically generalized the whole FDA approval landscape.
Okay.
For us, it was always a clear path that we worked with the FDA very early on. We had Rare Pediatric Disease designation very on. We had that access to FDA guidance, and then we got a lot of hand-holding by the FDA. It was always communicated, and our clinical trial design was always to satisfy the FDA's requirements.
Okay.
It has been a pretty smooth path, and I think the data speaks for itself.
Yeah
That's number one, and of course, satisfying FDA requirements with that data, helps a lot.
Yeah. Of course, this is a rare disease.
Yes
Rare diseases often, people are able to get approved—
Yeah, so.
—on one study.
Not just rare disease, but there's nothing out there to treat—
Yeah
—the disease.
Right.
Yeah.
Right. Okay. Where are you in the U.S. application process?
Yeah. We've begun our rolling submission. We did have a pre-NDA meeting with the FDA to align on the scheduling for a submission of those modules. We began our module submission on April 21st. We expect to end that sometime early or mid-June. 60 days later, the division will opine on the appropriateness of the application, and then six months after that, we'll get the final decision on approval.
Okay
you know, a, Priority Review status.
Why is this a rolling submission?
Some of our modules, and specifically the non-clinical module and some of our administrative stuff, was sort of lagging behind where we wanted it to be.
Yeah.
We had to time that.
Okay
those data would become available, information would become available at the right time.
Okay.
Yeah.
As far as EU, or is that the same requirement that FDA has asked for in terms of information that needs to be in a package?
Pretty much. There's pretty good alignment across regulatory agencies about what they're looking for. In terms of the submission timelines, we're still working on that. We are working with various regulatory agencies almost in parallel.
That we can facilitate a rapid launch across multiple territories.
Okay. What is the prevalence of Stargardt outside the U.S., and how easy are these patients to find?
Yeah, two good questions. Outside of the U.S., the prevalence is pretty much the same. You know, like in Europe, for instance, Asia, there's some pockets where it's even higher prevalence.
How easy are they to find—
Yeah
—these patients?
That's really a better question for the CMO. These patients are pretty focused because even though it's an orphan disease, there are patient advocacy groups that are sort of holding these patients in sort of a registry. I'm sure they are just all waiting for a therapy. Of course, when I go to conferences and we talk about the data, there's patients in the audience that are asking about when is the drug gonna be available. I think they're gonna come out of the woodwork once the approval is announced. You know, I don't think they'll be coming to us.
Yeah.
I think we won't have to go out and search for them.
Okay.
Yeah.
Okay. Tom?
Yeah. Stargardt's is, it's a inherited disease that quite a lot of patients experience symptoms of declining.
visual acuity. They may go a long route, but majority of these patients have family members that also have the disease.
If one patients ends up at a retinal specialist or IRD specialist, and then they have a clinical and genetic diagnosis, and then basically the whole family gets go through the whole same process. I would say it's pretty centered around teaching hospitals—
Okay
—outside of U.S—
Right.
—where there's probably less retinal specialists, but there's even probably less IRD specialists, but they manage majority of the Stargardt patients.
Okay. Got it. Now, as we think about pricing range, what would be a good comparison?
Wow.
Well, it's probably still, you know, early to come up with a price range. I think we talk about that a good reference will be, you know, the rare disease price in the U.S., which is somewhere about $350,000 a year. We do think that we probably will do better than that, maybe up to somewhere like $500,000 without, you know, much medical exceptions. It's not like you cannot price it higher, but if you do, you do expect probably some medical exception coming.
Okay.
You try to find a good balance between that.
Okay. What type of commercial footprint do you think you'll need? Let's start with the U.S.
Probably, we plan for maybe a diagnostic plus the sales team, somewhere like 30 people at launch, potentially get that, you know, grow to probably double the size maybe after two years of the launch. Like, you know, Tom said, it's more likely the patient will come to us. It's more about reminding the patient and the physician that, yes, there's now a treatment available. Go get your testing done so you can get the coverage.
Okay. For those that are not here, this is Hao-Yuan Chuang answering the question, CFO of the company. As we think about the competitive landscape in Stargardt, how are you thinking about the evolution of this over the next five to seven years?
Yeah, that's a great question. I mean, you know, there are competitors, but we don't believe that there's a competitor that's within, let's say, five years of being competitive on the market with us.
Yeah.
There's other oral therapeutics that are sort of chasing us. I think one of the problem for those companies like that have oral therapeutics will be, you know, when they're running clinical trials in the face of a launched drug, how well will they be able to recruit that trial? They'll suffer there. Of course, there are more novel therapies. There's RNAi, which is looking at two different approaches. One is gonna knock out the RBP4 protein.
Yeah
which by the way, is the protein that we target, because this is the protein that takes vitamin A from the liver to the eye, and in the diseased eye, vitamin A turns as, into nasty toxins called bisretinoids, and that's what we're trying to stop. There are companies sort of directing RNAi approaches and RBP4 knockout to do the same thing. With respect to RNAi that's directed at the gene, I think that's gonna be more personalized medicine because, very few people know this, but there's over 2,000 mutations associated with Stargardt disease. In the— you know, without replacing the entire gene, you have to go after those certain mutations in the gene construct, that will be personalized medicine because there's—
Yeah.
—so many of them. I see a longer road for gene therapies and RNAi approaches. The small molecules are the other ones that will have a tough time recruiting if there's a launched drug at the time that they are recruiting for trials. Again, on the five-year time horizon, I don't think that there's anyone that's gonna be really competitive on the market with us. Yeah.
I'd just like to add that I think the DRAGON study demonstrated 36% efficacy. That's a pretty high bar, especially for a neurodegenerative disease. Coming from a neurodegenerative background, I was quite surprised at 36%.
That tinlarebant achieved is actually a very high bar. If you look at others like Apellis and all that, they were like hovering around about 15%.
In geographic atrophy, yeah.
Yeah.
In geographic atrophy. Yeah.
36% is very high. For competitors coming into the space to aim for that 36%, they'll probably be looking at patient numbers on their clinical side of over 1,000 if you do the statistics.
Right
That number and the power calculations on the sample size. They have to do this on the background of tinlarebant getting approved and being the standard of care. I think competitive landscape for next five years at least, seems less likely, I think.
Okay.
Yeah.
Based on the DRAGON data so far, can you share with us feedback that physicians have given you?
Well, I can tell you as an oral once a day treatment, physicians are wildly excited about this.
Yeah.
I mean, even though most ophthalmologists are I think at their heart engineers and they like to inject things and cut things. To have a treatment for an unmet need, especially in adolescent patients, really gives them something to promote to patients, right? Because patients go in, and let's say they get diagnosed with the disease, which is a devastating diagnosis, there's nothing for them to do. There's no follow-up. There's nothing that they can do to slow the disease except maybe avoid bright sunlight, wear sunglasses, that type of thing. For a physician now to be able to say, "Hey, I've got something. Guess what? It's a pill.
It's a once a day pill, and the safety profile looks great, and the treatment efficacy looks great. Yeah, I mean, everywhere I go, when I talk about our treatment and I talk about the DRAGON study, I get nothing but positive reviews from PIs and ophthalmologists that are anxious to see this drug on the market.
Would you say that physician awareness is. We'll get to you in, right after this, Tom.
Yeah.
Would you say that physician awareness is high about this drug?
It is now because, you know, now that we're hitting the circuit more with our actual data. Before this, we had open label phase II data where we saw positive treatment trends. Because we had no placebo group, we couldn't say anything definitive about the true treatment effect. Now with a two-year phase III study, 104 subjects, 36% treatment over two years, there's something to sort of hang the information on. Physicians are, and ophthalmologists are becoming aware of that. Yeah, they're reaching out and talking to us and even asking for compassionate use before, you know, we launch, which we can't do. It's very clear that the drumbeat is getting louder and the message is becoming more resonant with these specialists.
Tom?
Yeah. When we started the phase III or even during the phase II, our KOLs or our principal investigators, they were actually hoping that tinlarebant, if they could show, if it can show a 15%, maybe even a 10%, they think that's already clinically meaningful.
Right.
Of course, based on panels and all that, we thought that 20% would be approvable, and then with that, we're aiming for all 20% is probably where we want to be. Of course, retinal specialist certainly think that's definitely a meaningful treatment. When we saw that the final data be 36%, nearly double that of the 20% that we expected, everyone was ecstatic about, you know, seeing their numbers.
How big of an opportunity dollar-wise do you think the U.S. market is?
How?
Well, you know, they have given, like, a guidance on the price.
Yeah
You know that, you know, 53,000 patient in the U.S., assuming maybe, you know, one-third of the patient on the drug, which we think is very reasonable and maybe conservative already.
Yeah.
You're talking about potentially if it, the price we say $400,000-$500,000, that's potentially $7 billion—
Right
—peak sales. It's very large.
How easy is it to find these Stargardt patients? Could you locate them within a short amount of time, just to get a sense of how long it would take for you to get to peak penetration?
Yeah. I'll start it. Maybe Nathan can add to it as well. I think right now there are probably 10,000 patient that's probably actively managed by retinal specialists.
For sure. Yeah.
About 10,000 patients. I'll say a third of them are early adopters where the physicians are very keen on—
Yeah.
—putting their patients onto the study. Of course, there's probably another third of retinal specialists that's probably not well informed or not updated with the new information that the treatment is just around the corner. That's why we wanna do all this reach out and letting the retinal specialists know that, you know, there's a treatment out there.
Right
Of course, with the patient advocacy group and all that, they're always updating their knowledge of what's coming out, what treatments are out there—
Yeah.
—and all that. I think the patients are not hard to find. They are there already. It is a severe disease. There's a lot of awareness in the IRD space. Especially if you have young adults or kids that's going blind and all that. They will want to get a treatment very desperately.
Okay.
Yeah.
Given the drug is coming, I think the willingness for getting the testing—
Yeah.
—is going to be much, much higher—
Right.
—as well.
Okay. Maybe let's talk about manufacturing. Where is the drug manufactured, and how ready will you be to meet demand as soon as you launch?
Well, the manufacturing is in China with WuXi. Probably the one of the best CDMO there. The drug itself is small molecule drug, is easy to manufacture and delivery.
Yeah.
The, you know, stability data is long. Any kind of supply would be easy for us to manage.
Okay. How should we be thinking about gross margin for the product?
Well, that's a good questions. You know, we probably would not be able to, in a position to know that very well yet. We do see that this could be potentially a much lower kind of a, you know, discount rate —
Yeah
—given, you know, there's no other treatment there so
Right
—gross net probably will be pretty high.
Okay.
Yeah.
Okay. Looks like you have a clean runway as the launch approaches, it looks like doctors are largely aware of the product, it looks like, you know, demand should be high. If you think about, you know, the speed with which you can get penetration, is there a reason to think why it shouldn't be steep?
Shouldn't be—
Steep uptake.
Steep uptake. I think we're expecting a steep uptake.
Yeah.
If there's any other reasons I can't think of. If there's any setbacks, that there's probably gonna be side effects to the drug which we're not seeing.
Yeah.
I don't see if there's any setbacks. Can you think of any?
Nothing I can think of.
Okay.
I think our safety profile is actually very clean.
Yeah.
The drug is very well-tolerated. The overall dropout rate in the study was less than 10% over two years. That was remarkable. I've been on a lot of clinical trials in ophthalmology. I've never seen dropout rates that low.
Yeah.
I think it's a very well-tolerated drug, and we're happy to see the data.
Okay.
Yeah.
We're looking forward to seeing that launch coming up. I did wanna spend some time talking about geographic atrophy, which is your next area of focus. Maybe just give us a background about how you decided that that should be your next indication.
That's a really good question, the story goes back many years. I don't wanna bore the audience with the history of it. Many years ago, when I was the CSO of a different company, this idea of reducing vitamin A delivery to the eye as a means of slowing lesion progression actually began in geographic atrophy.
with a phase II study that enrolled 246 patients that had GA. At that time, I used a surrogate drug, an anti-cancer drug known as fenretinide, which had a side effect of reducing Retinol binding protein 4 in blood, and this had always been my approach. We developed that in the Stargardt disease animal model and shown that efficacy in the model, and so we wanted to transfer that to the clinic. We used this anti-cancer drug. At the end of this two-year study in these 246 patients, we found that patients that achieved at least a 70% reduction of this Retinol binding protein 4 had a statistically significant slowing of lesion growth.
That was sort of the proof of concept that showed that, you know, you could use a systemic treatment to reduce retinal delivery to the eye as a means of slowing lesion growth. The pathophysiology with respect to lesion growth in GA is very similar to that in Stargardts. We basically transferred that whole therapeutic approach to Stargardt disease. At the time I did this study in GA, there was very little known about the natural history of Stargardt disease. There was no regulatory path toward approval, so that's why I looked at GA rather than Stargardts as a proof of concept. So that really gives us the impetus to do the trial. Now that DRAGON is done, and we see now that we were shooting for that 70%. We got to 80%.
It was a 80% reduction of Retinol binding protein 4 across the two-year study. As Tom noted, we have this 36% treatment effect. I think it validates the therapeutic approach, and it gives us even more confidence that this is gonna be effective again in GA so that's—
Right.
—why we came back to GA, to basically go back in with a better drug. fenretinide was a terrible drug. As an anti-cancer drug and a retinoid, it had a lot of side effects that were untoward. Now we got a drug that's not a retinoid. It's a small molecule that's very safe. The treatment effect is immediately reversible over about a month if you wanna come off the drug. Superior drug, great bioavailability, great potency, and now we're going back into GA to see if we can get that same type of treatment effect in the population.
Yeah. mechanistically, do you expect it to show a visual acuity benefit?
No, we don't. You know, people always talk about visual function benefits. In a two-year study, it's just very difficult to do in patients where visual acuity loss is exceedingly slow particularly in Stargardt's. Very —maybe one to two letters per year. The bar for the FDA in terms of clinical meaningful data is 15 letter, a 15-letter difference between your placebo and your active. In two years, patients just don't lose that much vision. Other sponsors are going after, for instance, time to event horizons, like time to lose 10 letters time to lose 15. We did that differently because we know that a lot of regulatory agencies now are agreeing to look at lesion growth—
Yeah.
—which is because eventually lesion growth, which is dead photoreceptors, is gonna affect your vision. Most regulatory agencies understand that, and it's a more quantifiable, reproducible metric for measuring treatment efficacy versus BCVA. We, you know, we're sticking with that. I think eventually over time, you know, if you show a trajectory of slowing of growth over time, that's gonna keep happening as you take the treatment. Eventually, three years, four years, five years down the road, you will have an effect on slowing visual acuity loss.
Is it your view that Well, there's two drugs that are currently on the market for GA. Both of those are injectables.
Is it your view that simply replicating the type of efficacy they've shown would be the desired outcome given that you're an oral, and so you wouldn't have the side effect profile of those drugs?
Yeah, absolutely. They do have terrible side effects. I'll let the audience look for themselves. Yeah, if we achieve the similar level of efficacy, which is 14%-18%.
slowing of growth, and we have an oral drug once a day with a very clean, safety profile, I think that those injectables are in trouble.
Okay.
Because there's a really high treatment burden for patients receiving those drugs. I think once they find out there's an oral that achieves the same treatment effect, why would you wanna go to the doctor every month, every other month to get a needle in the eye when you could just wake up every morning and take a pill like a vitamin supplement or something like that?
Yeah. Let me talk to you about that for one minute because I think there might be some people that are wondering, "Well, why would you If it's a disease of the eye, why wouldn't you want concentrated drug delivery into the eye? Why would an oral, which is a systemic therapy, be more ideal?
That was intended. That's intended in the therapeutic approach. Again, we just referenced Stargardt disease. The underlying cause of Stargardt disease is toxic byproducts of vitamin A building up in the eye.
As I mentioned earlier, vitamin A going into the eye, the diseased eye, is not processed the same way as in a healthy eye, and it produces all these byproducts. The best way to do that really is to slow the delivery of that vitamin to the eye in a very controlled—
Sure.
—and methodical manner so that you can balance risk-benefit, and that's what we're doing with tinlarebant. I think this is the way to go. The drug is reversible so that the tinlarebant itself really doesn't accumulate in the body. It grabs Retinol binding protein 4 and causes it to be eliminated in urine, and this is sort of the treatment effect. We think it's very clean, very well-tolerated, very reversible, if patients need to come off, and just has so many benefits versus needle in the eye.
Okay.
You don't need to have the drug inside the eye. I think this therapeutic approach demonstrates something people never thought of before.
Yeah.
Just like you sort of think, Well, it has to go into the eye if you're gonna—
Right
—or change the eye." We're showing that's not necessarily the case.
Okay. When is the next data readout for GA?
We're aiming for end of the year for the interim.
What would that be? Like how many patients?
That would probably be all, right?
Yes.
Oh
We enrolled 530 patients with geographic atrophy.
You'll have how many, Hao-Yuan Chuang ?
It'll be $530 up to the 12-month mark.
We haven't confirmed the study design.
Okay.
Yeah.
You know, you have to do the assumptions calculation. You propose to the FDA, you talk with them. We'll make that, you know, information available once we confirm the design.
Yeah.
Okay.
Roughly halfway.
Okay. Perfect. Okay. With that, we are out of time. Thank you so much—
Thank you so much.
—for the last half hour—
Thank you.
—to sit with us. Thanks everyone for listening.
Yep. Thank you all.