Welcome back to H.C. Wainwright's Second Annual BioConnect Investor Conference and Nasdaq. For this session, we are glad to have Mr. Nathan Mata, Chief Scientific Officer of Belite Bio, join us for a fireside chat. Welcome.
Thank you.
We know Belite Bio is developing an orally administered drug candidate called Tinlarebant for the treatment of Stargardt disease-
Mm-hmm.
-and geographic atrophy. Could you talk about the mechanism of action for Tinlarebant?
Right, right. So what's important to understand in order to really understand our mechanism of action, is to understand that in both of these diseases, Stargardt disease, which is a juvenile macular dystrophy, and of course, geographic atrophy, which is an age-related macular dystrophy, they both have in common the accumulation of toxic byproducts of vitamin A in the back of the eye. These byproducts are derived from circulating vitamin A. So our mechanism of action really is to antagonize the protein that delivers vitamin A from the liver to the eye. That protein is called the retinol binding protein 4. So our drug, Tinlarebant, is a retinol binding protein 4 antagonist, that modulates downward the amount of retinol going into the eye as a means of slowing the production of these bisretinoids-
Mm-hmm.
-and slowing disease progression.
I see. And what clinical efficacy and safety has Tinlarebant demonstrated?
Right, so-
in Stargardt disease patients?
Yeah, so we've just finished an open-label Phase II in 13 adolescent Stargardt subjects. This was a 2-year study. Subjects were taking 5 milligrams of tinlarebant orally per day. This reduced the retinol binding protein 4 levels to about 80% below the baseline value.
Mm-hmm.
In those subjects, what we saw something very interesting. These subjects came in with a very early stage of disease, but natural history predicted they would progress rapidly over two years to the more advanced stage-
Mm.
-which is called the atrophic stage.
Mm-hmm
of the disease. So they all came in with these early autofluorescent lesions, and in fact, over two years, five of the subjects, that's 42% of the cohort, never developed atrophic lesions, and their disease was static. So that is really remarkable because you never see a stasis of disease-
Mm-hmm
without intervention. And by the way, there's no currently approved therapy for Stargardt disease.
Mm-hmm.
So that was a very profound finding to see, the slowing of the conversion and the slowing of the growth rate of the atrophy, in addition to knowing that the cohort was predominantly severely affected, their mutations were quite severe, leading to a pathogenic disease. So we know that the absence of no lesions in these subjects was not because of mild or benign mutations.
Got it.
Yeah.
How many Stargardt disease patients are seeking treatment in the U.S., and how are these patients currently managed?
Yeah. First of all, there's no management.
Mm.
So any patient that's diagnosed with Stargardt disease typically sees their ophthalmologist or even optometrist probably once a year, just to basically check and to make sure, you know, they're not going, you know, quickly blind.
Mm-hmm.
But really, what they tell them is: stay out of the bright light.
Mm-hmm.
Cut down on your screen time.
Mm-hmm.
I don't know if people know this, but your iPads and computer screens emit a lot of blue light energy that actually drives the disease process. Of course, they tell them not to consume excess vitamin A.
Mm-hmm.
But that's it.
Okay.
That's really all they can do.
Okay. And, Tinlarebant is currently being evaluated in two pivotal trials in Stargardt disease, correct?
Right.
What is the current status of the pivotal trials?
Right. So the phase III study in Stargardt's has enrolled 104 subjects.
Mm.
That is a two-year study. We're approximately one year in to that two-year study, so we'll have an interim analysis in Q4 of this year-
Mm
... where, all of the subjects will have had their 12-month imaging, analysis.
Mm-hmm.
So we'll be looking to see, you know, what our treatment effect looks like.
Mm-hmm.
We're very optimistic, based upon our phase II data, that we'll see something promising there. In geographic atrophy, we're currently enrolling that study.
Mm-hmm. Yeah.
We're targeting 429 patients for that study.
We can talk about that later.
Sorry?
We can talk about that GA trial later.
Okay.
Let's focus on the Stargardt disease. Is there a second pivotal trial you need to complete?
There is.
Okay.
There is. So, we're focused on getting our approval as quickly-
Mm-hmm
... as possible. In the U.S., we've spoken with the FDA, and typically, they wanna see two studies-
Okay
... in this type of-
Yeah
... in this type of indication. However, they've given us a little bit of wiggle room because they've said: "We'll take it under review." So when we get to the end of the phase III, two-year trial-
Okay
... we'll submit that data to the FDA, and we'll see if we can get a conditional approval. However, on the other hand, Japan has already-
Mm
... committed to us that they would accept a single, study for, approval study for approval-
Mm
... as long as we include Japanese subjects, of course.
Mm-hmm.
And so we're starting a phase II/ III-
Okay
... that will involve Japan, U.K., and U.S.
Mm-hmm.
That will enroll 60 subjects.
Okay.
We've already started recruiting that study.
Okay.
Yeah.
Can you talk about your expectation for the data readout? Do you expect them to produce similar efficacy as observed in the phase II trial?
Yeah, and the reason is, is because in our phase II trial, we compared our efficacy to natural history-
Mm-hmm
... of the disease in patients that have the same baseline characteristics as our phase II subjects. If you look at all the published literature in this group of subjects, the growth rate is consistent. Across all studies, the growth rate is consistent. I can't believe that our phase III placebo group would have a different growth rate than what's been published in Natural History Studies.
Okay.
Based purely upon that, I expect we'll see a pretty substantial treatment effect.
Okay, got it. So, who are the main competitors in the Stargardt disease space? Is there any other drug that has a mechanism of action similar to Tinlarebant?
There was one. There was a company called Stargazer-
Mm-hmm
... that had a direct competitor. They had an RBP4 antagonist, but it was a very weak antagonist, and in their phase I clinical study, they realized they couldn't get to the level of RBP4 reduction-
Mm
... that they needed.
Mm-hmm.
That company doesn't exist anymore.
Mm.
They went away. The next closest competitor also has an oral therapeutic.
Mm-hmm.
That company is called Alkeus.
Mm-hmm.
The MOA is very different because what this is, is a synthetic vitamin A that doesn't convert to these byproducts-
Mm-hmm
... these toxic byproducts, as readily as native vitamin A.
Mm-hmm.
The idea here is that you would essentially replace all of your endogenous vitamin A with this synthetic vitamin A.
Mm.
In fact, you have to create a state of hypervitaminosis A in order to achieve this effect.
Mm-hmm.
But, you know, preclinical data show it works. They did get clinical breakthrough therapy, showing a slowing of lesion growth. So there could be something to that, but again, it's very difficult to understand what this company is doing because it's hard to follow.
Okay
... and they're a private company.
Okay... So I guess, the main competitive advantage of Tinlarebant compared to all other candidates being investigated for Stargardt disease include oral administration, right?
And early intervention.
Early intervention. Okay, I see.
Yeah.
So, can we talk about the commercial? I mean, is the company doing any commercial preparation for Stargardt disease?
Not at this time. It's very difficult because it's very likely that the first approval will be in Japan-
Mm-hmm. Mm-hmm.
and that will change our commercialization strategy
Mm.
-significantly.
Mm.
It's a sort of, "Let's wait and see thing.
Yeah.
I predict that will happen, and then we'll have to bring people in to tell us-
I see.
how we commercialize in, in Japan.
Okay.
That's not something that we're familiar with.
I recall the company recently reported some new data from the phase 2 trial at the ARVO conference.
Yeah.
Are the new data important for us to interpret clinical observations?
Yes, they are, in fact, because what we saw previously, just looking at a visual acuity-
Mm.
Was a stabilization of visual acuity. We never really looked at what subjects' visual acuity looked like prior to coming into the study.
Mm.
So we were able to get their retrospective data for all subjects.
Mm.
What we found is, in the cohort, 6 of the subjects, so 6, 6 of 13 subjects, had significant-
Mm
-visual acuity loss prior to coming in. 10 letters per eye, so bilateral loss of 10 letters, for the previous 2-3 years-
Mm
before coming into the trial.
Mm.
Once they got into the trial, they were stabilized, so they lost 2 letters per year instead of 10.
Mm.
So that's phenomenal, and we're wondering: why is that? Again, we looked at the genotypes. It couldn't be explained by genotypes because they had very severe-
Yeah
Genetic mutations. But what we did find, actually, was that when we looked at macular lesion involvement, we actually saw a slowing of lesion growth into the macula. And of course, the macula is your vision center, so it makes sense that you would stabilize or even improve vision if you slowed lesion growth into the macula.
Okay.
Yeah.
Okay. But, was there also a improvement in terms of reading algorithm?
Right. So that's the, that's what I'm talking about.
Mm.
That's the imaging grading algorithm.
Okay. Yeah.
So that's what we've developed with our reading center, is a new methodology for actually grading the images.
Mm-hmm.
Right now, what everyone is using is an analysis that requires reader, you know, the human eye-
Yeah
to grade the images. And because of that, there could be subjective reader bias, and not all readers read the same image in the same way. So there's a lot of errors prone into that, into that methodology.
Mm.
This new methodology that we're using, I told you, for this macular analysis-
Mm
-basically relies on AI.
Right.
So it's a mathematically generated algorithm that looks for lesions in the back of the eye at a very, very sensitive density.
Mm.
And so it can pick up these lesions that the human eye cannot pick up, and with that analysis, we saw some very interesting data in terms of this slowing of lesion growth into the macula.
Got it. Got it.
Yeah.
Switching to GA-
Yeah
... as you just mentioned, so, another pivotal trial is being conducted right now.
Yeah.
Can you talk a little bit more about why, if Tinlarebant works for Stargardt disease patients, it should also work for GA patients?
Yeah. The short answer is that because in GA patients, they have the same toxic byproducts-
Mm
that Stargardt patients have. And that's been demonstrated both clinically and, and in, models, and of course, in post-mortem tissue with patients, you can actually see these compounds. So those compounds are there, and if they're causing pathology in Stargardts, I'm confident they'll be causing pathology in geographic atrophy.
Okay. There are already two approved GA drugs on the market today.
Yeah.
Do you believe Tinlarebant needs to outperform those drugs to be successful in the GA space?
That's a really good question-
Mm
because the reason I like approval. And those, those two drugs are the Apellis drug, Syfovre, and the one from Iveric, Izervay. The reason I think that's really important, because the first time in history, the FDA has told the world, or certainly the US, what they're looking for in terms of a treatment effect.
Mm-hmm.
That treatment effect is anywhere between, let's say, 15%-25%-
Yeah
is what they're looking at.
Mm-hmm.
If you have a drug for GA, and you can achieve that treatment effect with a clean safety profile.
Mm
You've already got a competitive drug.
Mm-hmm.
Now, the advantage we have is that we're oral.
Mm-hmm.
So if we get that same level of efficacy with safety-
Mm-hmm
with an oral therapeutic
Mm
we're gonna pull a lot of market share away from
Mm
from those two drugs.
Mm.
The other important aspect to remember is that those drugs, those intravitreal injections, those are anti-inflammatory agents, and the disease doesn't really trigger inflammation-
Mm
until very late in the disease course.
Mm.
Our patients have very early-stage disease. There's no inflammation.
Mm.
So those drugs would not be expected to be effective in our pa...
Mm
-patient population, whereas ours would be effective across all,
Right
... the whole spectrum of disease. Yeah.
The enrollment criteria for your GA phase III trial is different from the enrollment criteria for those two drugs?
Very different.
Mm.
If you look at our lesion size criteria, we're gonna get patients in with-- Our lesion size is between 1-10 millimeters.
Mm-hmm.
So our mean is probably gonna fall about five.
Mm.
Their mean was upwards of 10-
Mm-hmm
or 12 mm². So they're dealing with very large lesions. Again, they want that because-
Yes
those lesions have inflammation, and if you quell that inflammation-
Mm
you can slow the lesion growth, and that's exactly what they showed.
I see.
Yeah.
Do you think there could be synergy produced by, you know, using Tinlarebant and those two drugs in combination?
Absolutely.
Mm.
And so that's why people ask me, they say: "Well, you know, do you see them as being competitive?" I'm like: "Well, I don't think so," because, you know, as I said before, we're targeting two different patient populations. So I envision a scenario, potentially, where, you know, you're using an intravitreal injection as a patient because you have very advanced disease. But again, you're going to get these injections in your eye every other month or every third month for maybe 1-2 years. At some point, you need to go on a little bit of a hiatus, whether it's because of increased ocular pressure, or there is some side effects. By the way, these intravitreal injections do cause Wet AMD.
Mm.
There's a lot of reasons to have to go onto a drug hiatus. It would be very nice for those patients to take an oral once a day as a maintenance therapy to sort of keep the disease and keep the progression, sort of stabilized or at least lower than it would be otherwise. So I can see these two drugs working synergistically.
Mm-hmm.
Intravitreal injections for the very, devastated, you know, advanced disease patients.
Right, right.
Then once they get a little bit sort of calmed down, then you give them the oral therapeutic-
Mm
and this sort of a maintenance therapy for them.
Got it. Got it.... So, when do you expect the GA phase III trial to complete enrollment and then report data?
Right. So the GA phase III enrollment is ongoing.
Mm-hmm.
It should be completed right around, we're predicting, about end of Q1.
Mm-hmm
-of 2025. So one year from that point, Q1 of 2026, we'll have the one-year interim.
Mm-hmm.
And then a year after that, Q1 of 2027, will be the readout for the top line two-year-
Mm-hmm
phase III data for GA.
Got it. Got it. And, I think you just talked about by approving those two drugs, FDA set up an expectation-
Yeah
of the, slow down the lesion growth, right? So, is lesion growth the only thing, the only endpoint that FDA pays attention to?
No. In fact, they would prefer visual acuity.
Mm-hmm.
But the fact is that when you look at the progression of disease, whether it's Stargardt's-
Mm
... or geographic atrophy, you have a massive spreading of dead retina
Mm
Atrophy in the lesion, without really affecting visual acuity until very late in the disease course.
Mm.
So you could lose 90% of your retina-
Mm
and preserve this little island that you can still see with, but you're going to have terrible peripheral vision. Your retina is gone. So the agencies realize there's a poor correlation between the expansion of lesion growth.
Mm-hmm
-and reduction of visual acuity. So they're using the anatomical endpoint, the lesion growth, as a sort of a surrogate to protect against-
Mm-hmm
impending visual acuity loss.
Mm-hmm.
But trust me, if you go in with a drug in a 1- or 2-year study-
Mm
and you show you're not slowing lesion growth, but you're improving vision.
Right
-that's going to be a winner.
Okay.
But again, it has to be three lines.
Mm.
So that's the other problem, is that because vision loss is so slow, in Stargardt disease, in GA, relative to the expansion-
Mm
of lesions, in a two-year study, it will be very difficult to create a delta of three lines.
Mm
-which is 15 letters on a visual acuity chart.
Mm.
You have to have that difference between your placebo and treatment in order to be what the agency would consider clinically meaningful-
Okay
treatment effect. So that's why most people who are doing Stargardt studies, we typically do either 1- or 2-year studies. You rarely see a 3- or 4-year study. But that's what it would require in order to have a visual acuity-
Mm
as a primary.
Mm-hmm.
Probably a 4-5-year study, because then you could have this longer runway-
Mm
to see drops in
Mm
in visual acuity in your placebo in comparison to your treatment arm.
I see. I see.
Yeah.
I mean, would you expect Tinlarebant to have similar efficacy in GA patients as it does in Stargardt disease patients?
I would.
Mm-hmm.
I would, and it's because if you start at the same point of the disease, that is the early-stage disease, where these lesions are really starting to grow and blossom, and we know that a lot of that is predicated on these biochemical toxins that are driving the disease. It's going to be the same as in GA as in Stargardt. So if we slow it down in one, we'll definitely slow it down the other. The only thing I would say is that with respect to AEs, I don't know if you're going to go there-
Mm-hmm.
But I will just volunteer it.
Yeah.
I think that the GA patients will not tolerate the ocular AEs as well as our Stargardt kids.
Mm-hmm.
So we have these adolescent kids in the 2-year study. We didn't lose one subject to an AE.
Mm-hmm.
Now, in our phase III study, as I said, we're almost one year into dosing. We've lost five out of 104.
Mm-hmm.
That's less than 5%-
Mm-hmm
due to AE. So that dropout is significantly lower than what I observed with a different drug, but had the same MOA-
Mm
called fenretinide, in GA patients.
Okay.
And again, it's because GA patients have much more severe disease. Even though the lesions are small, it's sort of widespread everywhere.
Mm-hmm.
These patients are older, right?
Mm-hmm.
So their retina is not as responsive. It's going to be much more susceptible to drops in vitamin A content-
Right
-which is what we're doing.
Got it.
Yeah.
Speaking of intellectual property, is Tinlarebant protected by any issued patents?
Oh, yes.
Mm.
A number.
Mm.
We have 14, 14 patent families.
Mm.
I think eight of those are composition of matter, covering approximately 425 compounds, Tinlarebant and related, and related compounds. We have formulation patents and other methods of use patents. We have patent protection to 2040-
Mm
without patent term extension. With patent term extension, we could get conceivably up to 2045.
Okay.
We have a pretty good portfolio, IP portfolio, with a pretty nice runway.
Got it.
Yeah.
Could you give us a brief review of the upcoming catalysts within the next 12-18 months?
Right. So the first one is going to be this interim in Stargardt's-
Mm
-which is coming up in Q4 of this year.
Mm.
So probably November, maybe even-
Mm
December-ish, we'll have the readout there. The study will be masked to the sponsor, the results, but we have a DSMB that will independently unmask, look at the data, and report back to us, you know, what the data are looking like.
Okay.
We'll have a signal then. The next one would probably be just a closing enrollment of both the Phase II/III in this Japanese study.
Mm
I spoke with, as well as the Phase III in geographic atrophy. And then, of course, the interim analyses, one year from this time.
Okay.
So-
Okay
... a number of them coming up. I, I predict from 2025 through 2027, we're going to have a lot of things cropping up-
Okay
Because we have so many studies going on.
Okay. Great.
Yeah.
Yeah. And, does the company have sufficient capital to fund operations for the next two years?
Right. We're very fortunate.
Mm-hmm
We did a really good IPO. We have a lot of investor interest.
Mm.
We just recently raised another $25 million. So we've got roughly about 3.5 years-
Okay
-of runway. So that gets us through the phase III Stargardt, the phase II/III Stargardt in Japan, the first GA study. We won't have enough to do the second GA study.
Okay.
I expect that with positive phase III data in Stargardt's-
Mm
We won't have any trouble raising additional capital to
Okay
do that secondary study, because we will have to do that second study.
Okay. Got it.
Yeah.
Lastly, what do you think is the key takeaway message for investors today?
You know, I think for the first time ever-
Mm
If you know, investors are looking at the competitive landscape, as I say, talk about our differentiators. You have an oral therapeutic with early intervention that is showing a robust safety and efficacy profile-
Mm
Granted in an open label study.
Mm.
But when you look at the MOA and you look at the data itself, especially with stabilization of visual acuity, this is something that's never been seen before in Stargardt. So quite honestly, this is sort of, for me, it's a momentous time because I've been in the field for about 22 years, and this is the closest we've gotten to something that's this effective and this safe-
Yeah
—for Stargardt disease. And I think the same could be said for GA, but we haven't gotten any data with Tinlarebant—
Yeah
in GA, but I expect we'll see something similar.
Okay, great.
Yeah.
Best wishes to you and Belite Bio.
Thank you so much, Yi.
Yep. Thank you for joining us.
Thank you. Yeah.
Thank you.
Appreciate it.
Thank you.
Thank you. Thank you, all.