Welcome to the H.C. Wainwright 28th Annual Global Investment Conference. My name is Yi Chen. I am a research analyst at H.C. Wainwright. Today, we have Dr. Hendrik Scholl, Chief Medical Officer of Belite Bio, and Mr. Hao-Yuan Chuang, Chief Financial Officer of Belite Bio. Join us for a fireside chat. Thank you. I will start with the first question. The NDA for Stargardt disease, currently under FDA review, is a PDUFA date in February next year. What evidence beyond DRAGON trial's primary endpoint provides the most important independent confirmation?
We submitted a very comprehensive package to the FDA being confirmatory evidence. There is guidance of the FDA what confirmatory evidence actually means. Most importantly, it is natural history evidence. We have access to the largest natural history data set that is available worldwide, the so-called ProgStar study, that I had the honor to lead myself a couple of years ago, which has comprehensive data on natural history progression of patients with Stargardt disease that are, and that is also very important, very similar in disease stage compared to the patients we enrolled in the DRAGON trial. We can and did complement our placebo group with a very large cohort out of ProgStar, and this helped to create substantial confirmation of what we found in the DRAGON trial.
Beyond the guidance of the FDA, and that is specific for an oral treatment or a systemic treatment, is that we have data from the fellow eye.
As you know, in paired organ clinical trials, regulators would like to see one study organ, namely the study eye. If you have eye-specific treatments, such as injectables or surgery, what have you, that is where you study your treatment effect. But we have the opportunity, and we did in DRAGON, to study the fellow eye also. Which was very nice and obviously confirmatory is that we found almost the same effect size in the fellow eye, namely 33%. Even the fellow eye data reached a statistical significance threshold.
That is very encouraging. One more question on the efficacy. Tinlarebant had a 35.7% reduction in DDAF lesion growth in the DRAGON trial. Can physician translate anatomical effect into tangible patient benefit?
The answer is a simple yes. Because in the retina space, we have seen a transition starting two and a half decades ago with the emergence of high-resolution imaging in clinical care that nowadays in retina clinic, you still look at your patients obviously, but you look at images. You look at retinal photography, you look at autofluorescence, you look at OCT images. You make conclusions on efficacy of your therapy, on safety, on any intervention, pretty much based almost exclusively nowadays on retinal imaging. Healthcare providers in the retina space are very much used to look at high-resolution images, and they understand, FDA understands, that if you preserve photoreceptors, that is a good thing. If you lose photoreceptors, it is a bad thing. The immediate relationship between imaging and we call it structure, and visual acuity, we call that visual function.
There are other visual function measures such as visual field measures, specifically from microperimetry, can be complex. Visual acuity, as an example, depends mainly on the fovea and nothing else. Visual field depends on all photoreceptors that are being imaged. But clinicians have a very good understanding what it would mean for a given patient if you have loss of photoreceptors in a given area and how much loss of photoreceptors there is.
Got it. Looking at the placebo group in the DRAGON trial, the DDAF growth rate was 0.59 mm² per year, which is below 0.74 mm² per year observed in ProgStar. What explains that difference, and how confident are you that DRAGON trial's treatment effect will generalize to the broader Stargardt population?
Yeah, so this is an excellent question. You could say bad luck for Belite Bio that in the trial, the placebo group progressed somewhat slower than what was found in the natural history study in ProgStar. Still, we had a very strong treatment effect and still a very low P value. I think that rather validates the finding in the DRAGON trial. When it comes to an explanation, this is maybe counterintuitive, but it is confirmed by what was found in ProgStar. We can be very specific. I can refer the interested audience to table number two in ProgStar report number 17.
This is the 24 months data out of ProgStar. What was found is that the DDAF progression rate, meaning how fast lesions of almost complete atrophy of the outer retina progressed in the natural history study, was not different amongst subjects younger than 18, between 18 and 50, and if at all, slightly higher or slightly faster in subjects that were older than 50. Meaning that DDAF progression rate is relatively homogeneously distributed amongst all the ages. That is important when it comes to generalizability. This is also your question, right? The generalizability of the data to the total population out there. Given the ProgStar data and the relatively homogeneous progression rate amongst all age groups, we feel that the findings of DRAGON can be generalized to all patients affected by Stargardt disease.
Thank you. Were there any clinically identifiable populations in which the treatment effect was most prominent or attenuated?
It is an excellent question. We did comprehensive sensitivity analysis. As an example, we looked at the treatment effect size in the different races in DRAGON trial. Populations of East Asian descent, European descent, African descent. We looked into the different geographies where we conducted the trial, U.S., U.K., Europe, China, Taiwan, and Australia. We looked into sex effects, males versus females. We looked into age effects, younger patients between 12 and 20 years old that we treated in the trial up to 20 years. Long story short, we did not find any specific effect, meaning stronger or less strong treatment effect in any of those analysis. Which is, I feel, positive because that allows, again, to answer the question before about generalizability of the DRAGON trial results.
Given that we found no specific treatment effect, for example, in younger patients or older patients, allows to generalize to essentially all patients affected by Stargardt disease regardless of race, geography, sex, or age.
Got it. Belite Bio presented the Months 25 qAF analysis results, which show stable to slightly reduced levels with Tinlarebant versus roughly 20% growth with placebo. How does that result connect mechanistically with the DDAF benefit? Could qAF help physicians monitor treatment response?
Yeah. Thank you for this question, and there's a lot of excitement about this quantitative autofluorescence. I have to dampen the enthusiasm insofar that quantitative autofluorescence, although it sounds fantastic, and it is in a sense, but it's definitely not a standard clinical care tool. Quantitative autofluorescence is a very complex tool where you, in order to measure it, you have to bleach all photoreceptors. You have to expose subjects to a very bright light in order to really almost abolish light perception, to bleach the photoreceptors, and then measure the autofluorescence signal that comes from the retina. Mechanistically, it's a very strong confirmation about what Tinlarebant does, meaning this objective measure of bisretinoid accumulation in the retina shows that if you give Tinlarebant, there is no further accumulation over the two years under treatment. In the placebo group, as you just pointed out, plus 20%.
It's not clinically meaningful. That doesn't mean anything for a given patient that his or her quantitative autofluorescence signal has increased by 20% or even decreased by 2%, taking Tinlarebant over the two-year study. There's excitement about this finding because it confirms clinically the mechanism of action of Tinlarebant. I have to say, in terms of efficacy, for example, what does it mean for patients and how does it correlate to DDAF? There's no immediate connection, and it's by itself not clinically meaningful, but it underscores how Tinlarebant works. It makes the clinical trial finding, namely that DDAF progression rate will slow down more intuitive.
Got it. Thank you. In the DRAGON trial, BCVA was essentially unchanged in both groups over 2 years, which is expected from Stargardt disease's natural history. What endpoint do you believe will ultimately provide the strongest bridge between slower atrophy and preserved vision?
Yeah. What counts for patients is the ability of any treatment to stabilize vision, or at least to slow down progressive loss of vision. Vision has several dimensions. Visual acuity is one of them. Visual field loss is another one. Color vision is a third one. The relationship between what was measured in the primary endpoint and what is eventually noticeable by the patient is very important. It is just that, and you referred to natural history data, the progression in Stargardt disease is relatively slow, meaning that there is no opportunity really within one year or two to measure a significant decline and correlate that with any imaging measure. We need to look into larger and longer observations in Stargardt disease, as an example, the retrospective and prospective ProgStar study.
By doing so, we find a correlation between visual acuity and DDAF size as an example. What it means is that in the future, patients have to be followed for a longer period of time in order to allow this visual acuity and visual field benefit to emerge. But within a trial period of one or two years, it is impossible to show that correlation. That, by the way, if I may add this comment, is the reason that the FDA not only allows but even has supported imaging marker as approvable and primary endpoints in clinical trials because they allow a precise and objective measurement in a relatively short period of time, as opposed to visual function measures.
Thank you for the clarification. How should physicians identify the optimal time to begin the treatment? For a genetically diagnosed patient without measurable DDAF, what clinical or imaging evidence would support initiating therapy?
Yeah. It's a very important question. I would like to refer the interested audience to our Commercial Day that we held about 10 days ago or almost two weeks ago now, where we discussed it together with key opinion leaders, including Professor Paul Bernstein from University of Utah in Salt Lake City and Professor Michel Michaelides from the Moorfields Eye Hospital in London. Both confirmed the broad applicability of the treatment for all disease stages of Stargardt disease. That is important, right? The clinical trial DRAGON needed to study an endpoint that is measurable. Meaning it needed to be there at baseline and needed still to be measurable at the end of the trial.
We did that to collect data that eventually are generalizable to all patients out there, including patients that are very early on in the disease and have not yet developed any lesion, but also to patients that are beyond the threshold that we set in the DRAGON trial as the largest lesion that was measurable. Also visual acuity, such as 20/200, which was the upper threshold in the DRAGON trial. That was also underscored by Professor Michaelides in our Commercial Day, that patients that are beyond 20/200 visual acuity would still benefit from the drug.
Thank you. For an early-stage patient who still functions well, the trade-off could be immediate color vision or dark adaptation symptoms in exchange for a structural benefit that becomes apparent over years. How should clinicians frame the benefit-risk discussion, and which patient characteristics are most likely to influence the decision?
Yeah. Very important that this refers to safety and the safety we observed in the DRAGON trial. I can just express my opinion, but in my opinion, the safety and tolerability of Tinlarebant was excellent in the DRAGON trial. This is reflected by the very low dropout rate over the two-year study, where only four patients dropped out of the 104 that were studied in the DRAGON trial. The two, and we should call that on-target side effects of Tinlarebant, are actually very mild. One is delayed dark adaptation. When you think about it, Tinlarebant affects the influx of vitamin A into photoreceptors, meaning that it simply needs a bit more time when you transition from light to dark, and I mean very dark, to fully adapt to a very dark environment. It simply takes a bit longer. Is that manageable?
In my opinion, it is absolutely manageable, but you should educate your patient that that is something they could observe. The other on-target effect was, I would call it discoloration of the visual scene. There are some fancy Greek names like xanthopsia for yellowish tint or cyanopsia for bluish tint. But what it means is it is not a color vision deficiency. It is the adaptation from now from going to dark to light, where a subject would experience a discoloration of the visual scene, meaning a tinting of the visual scene for seconds or minutes during this light adaptation process, which is very fast. Again, this may be surprising for somebody who experience it for the first time, but it is a very benign side effect, and it is easily manageable.
Thank you. RBP4 returns towards baseline after treatment stops, right? How quickly might biologic protection be lost following missed doses or interruptions, and what level of adherence do you believe is required to preserve the efficacy observed in the DRAGON trial?
Yeah. This is also important when it comes to retention to the treatment. Retention in the DRAGON trial was excellent. Compliance rate far above 90% in the DRAGON trial. Patients understand they have to take the drug in order to benefit from the treatment effect. The half-life can be as long as four days, meaning if you actually miss a dose, it is not so bad, right? You simply resume the next day. You do not have to take two pills the next day. You simply resume if you miss a dose or two. That is not so important. But of course, if you miss the dose for many days or for weeks or months, then there would be a drop in efficacy over time. That means patients need to encourage to take that one pill a day in order to fully benefit from the treatment effect.
Thank you. In the U.S., how many patients have been clinically diagnosed with STGD1 and confirmed with genetic testing, thus making them ready to treat upon commercial launch of Tinlarebant?
Yeah, as we disclosed this on the Commercial Day, we believe there is about 20,000 patients already clinically diagnosed with Stargardt disease, and about half of them already have a genetic testing confirmed.
Thank you. What do you expect the reimbursement pathway to look like immediately after FDA approval?
Well, first of all, you do need to give the payers some time to confirm or finalize that policy. We have done several rounds of payer research, and we have to say that the payers are very, very supportive. They are well aware of this disease. It is strong mainly without any treatment. I think they are very supportive and we talk about rare disease pricing, and they seem to be supportive on that as well. We think we should be okay on the payer side.
Do you expect payer to impose any restrictions?
Well, I think that to be honest, we do not know at the moment. It may very likely depend on the FDA's final label.
Which we cannot comment at the point. But so far, based on the conversation, we know the payer is supportive to cover this.
As long as the price is within their expectation, I do not think there is going to be too much of a medical exception being imposed.
Thank you. Does Belite Bio currently have sufficient capital to support commercialization as well as the ongoing clinical development?
Yeah, I would say so, because we expect as we guide the market for three years of operating cost is probably about total $450 million for this year and the next two years, which will get us to the commercial launch. And our existing cash and cash equivalent, U.S. Treasury bill in total is $780 million by the end of last quarter. So I think we're fine on that.
Okay, great. Any questions from the audience? No question. Okay, thank you very much.
Thank you very much.
Thank you very much for having us.