Welcome to H.C. Wainwright's annual Ophthalmology Virtual Conference. My name is Eduardo Martinez. I'm a biotechnology equity researcher at H.C. Wainwright, and it's my pleasure to introduce Dr. Hendrik Scholl, Chief Medical Officer at Belite Bio. Dr. Scholl, please take it away.
Thank you very much. I'm happy to present on early intervention with an oral treatment for macular degeneration. This is our forward-looking statement. We have an experienced leadership team at Belite Bio that includes our Chairman, Founder, and COO, Dr. Tom Lin, who is a neurologist by training, has more than testimony.
Welcome to H.C. Wainwright's annual Ophthalmology Virtual Conference. My name is Eduardo Martinez. I'm a biotechnology equity researcher at H.C. Wainwright, and it's my pleasure to introduce Dr. Hendrik Scholl, Chief Medical Officer at Belite Bio. Dr. Scholl, please take it away.
Thank you very much. I'm happy to present on early intervention with an oral treatment for macular degeneration. This is our forward-looking statement. We have an experienced leadership team at Belite Bio that includes our Chairman, Founder, and COO, Dr. Tom Lin, who is a neurologist by training, has more than 10 years of experience in executive management in biotech, and was involved in over 10 new drug developments in multiple therapeutic areas that include ophthalmology. A little bit about myself. I have 25 years of experience in treating retinal diseases. I was trained in Germany and the United Kingdom. I joined a large department in Germany as a vitreoretinal surgeon and led the research at the department before, after a worldwide surge, I was recruited to Johns Hopkins University and led at the Wilmer Institute of Retinal Dystrophies.
At the time, together with the Foundation Fighting Blindness, we implemented the largest natural history study for Stargardt disease. I will get to the disease in a moment. That was a worldwide natural history study that allowed us to establish outcome measures for this rare but still relatively prevalent disease. I participated in over 10 clinical studies, both in Stargardt disease and AMD, and published, meanwhile, almost 300 peer-reviewed papers in the field. In 2016, I returned back to Europe, led the department in Basel, and a year ago, that speaks for my enthusiasm for Tinlarebant, I joined Belite Bio as Chief Medical Officer. We have a very experienced Chief Science Officer, Dr. Nathan
Mata, who has more than 15 years of expertise in ophthalmic drug development across numerous indications, but very specifically, he led the clinical development efforts for the first retinol binding protein antagonist, RBP antagonist, in advanced dry AMD and the first visual cycle modulator in dry AMD in Stargardt disease. He's really a pioneer in the field and introduced the first ABCA4 Stargardt knockout mouse model in the field. Our Chief Financial Officer, with more than 30 years of experience in the capital market, closed more than $32 billion transactions. This is Hao-Yuan Chuang. This slide shows our pipeline that includes Tinlarebant. You see it on the upper left for two indications, Stargardt disease, where we run currently two phase 3 clinical trials. We completed a phase 2 clinical trial that was a 24-month clinical trial, open label, that showed to slow lesion growth.
Currently, we are running a global registration trial named DRAGON, which is ongoing but will be completed in September. It enrolled 104 adolescent subjects between 12 and 20 years old. We are running a phase 1/phase 2/3 clinical trial in Japan, the U.S., and the United Kingdom, which is the second registration trial. There's a second indication, which is very important, obviously, geographic atrophy secondary to age-related macular degeneration. Indeed, we run the PHOENIX trial, which is a phase 3 two-year randomized placebo-controlled interventional trial that is ongoing. We completed enrollment a couple of weeks ago, and that was announced in a press release. Tinlarebant is a novel once-daily oral tablet designed to bind serum retinol binding protein 4, or briefly RBP4, as a means to specifically reduce retinol or vitamin A delivery to the eye.
This approach is intended to slow or halt the formation of toxic retinal derived byproducts that are generated in the visual cycle. I will explain the visual cycle in a moment, and they're implicated in the progression of Stargardt disease and geographic atrophy. Belite Bio believes that early intervention directed at emerging retinal pathology, which is not mediated by inflammation, would be the best approach to potentially slow disease progression in Stargardt disease and GA. The market opportunity is significant. This is a completely unmet medical need for Stargardt disease. There's no FDA-approved treatment for Stargardt. There's no treatment worldwide for Stargardt, and there are no FDA-approved orally administered treatments for GA in the United States and overall in the world. Other than the two injectables in the United States, there's no treatment for GA currently.
We received breakthrough therapy, fast track, and rare pediatric disease designation in the United States, and orphan drug designation in the U.S., the European Union, and Japan, and pioneer drug designation in Japan for Stargardt disease. Belite Bio has 14 active patent families, mostly composition of matter. It will last until at least 2040 without patent term extension. A little bit about Tinlarebant. Before I explain, I explain the visual cycle, and this is indeed one of the best understood biochemical processes in the human body. The visual cycle means the regeneration of the visual pigment. We see the visual pigment on top, rhodopsin. If there wasn't the visual cycle, if there wasn't the regeneration of the visual pigment in our eye, we would only see once at birth, and then it would be dark. This pigment needs to be regenerated, and it needs vitamin A in order to be regenerated.
We see the cascade of enzymes that are involved, such as RPE65, for example, or LRAT. We see on the lower right how vitamin A or all-trans retinol enters the eye, specifically the retinal pigment epithelium, namely through the RBP4 receptor. It's only the eye that expresses the RBP4 receptor, and this allows the retinal pigment epithelium to suck in vitamin A. No other organ in the human body is dependent on that, which also means that targeting RBP4 is eye-specific. By targeting RBP4 that is bound to TTR and all-trans retinol, we can reduce the level of vitamin A that would enter the eye. That will be explained in another slide. If ABCA4 is mutated, we see it on the upper right, and this is quite a frequent disease.
It belongs to the rare diseases because the threshold is under one in 2,000 individuals, but it's the second most prevalent autosomal recessively inherited disease in medicine after cystic fibrosis, with a prevalence of about one in 7,000. If that molecule is dysfunctional, there's a buildup of all-trans retinol, which is very toxic and also very reactive, and it will build bis-retinoids. One of the most well-known is A2E, and A2E is known to be very toxic. This is the pathophysiology in Stargardt disease. In age-related macular degeneration, it is very similar. We see pathology between the photoreceptors and the retinal pigment epithelium, and we see pathology underneath the RPE between RPE and Bruch's membrane. We know that that pathology leads to also dysfunction of the visual cycle and buildup of toxic bis-retinoids in the retinal pigment epithelium. The two diseases are very similar.
We see an example of a late-onset Stargardt case on the upper right and a case of geographic atrophy on the lower right. Stargardt and GA share a similar pathophysiology characterized by excessive accumulation of cytotoxic bis-retinoids, retinal cell death, and subsequently loss of vision. Vision loss occurs slowly despite peripheral expansion of that retina until the disease reaches the center of the eye, specifically the macula. Slowing or halting the spread of that retina is the intended effect of the Tinlarebant treatment. Introduction to Tinlarebant. This is a novel once-a-day oral tablet designed to bind to serum retinol binding protein 4 or RBP4 as a means to specifically reduce retinal delivery to the eye in order to slow or halt the accumulation of cytotoxic bis-retinoids.
Belite Bio believes that intervention directed at emerging retinal pathology, which is not primarily mediated by complement activation or inflammation, would be the best approach to potentially slow disease progression in Stargardt and geographic atrophy. How does Tinlarebant act? Here we see Tinlarebant binding to RBP4 underneath the retinal pigment epithelium and in the peripheral bloodstream. That complex is small and will be eliminated through the kidney. As a net result, we see that less RBP4 is available to bind to all-trans retinol and TTR. Therefore, all-trans retinol delivery to the retinal pigment epithelium is reduced, and as a result, we see less buildup of toxic bis-retinoids in the photoreceptors and the RPE, and we see less accumulation of all-trans retinol in the photoreceptors. After extensive preclinical research, including rescue of photoreceptor degeneration in the double knockout mouse model, RDH8 and ABCA4, the compound went into human clinical development.
Belite Bio conducted a phase 2 clinical trial that is shown here that enrolled 13 subjects in Australia and Taiwan. This was an open-label two-year interventional trial that primarily measured safety and tolerability, but also the development and growth if there was any lesion of DDAF, QDAF, and DAF. I will explain that in a moment. Best corrected visual acuity, spectral domain OCT, and microperimetry. The key inclusion criteria were adolescent patients between 12 and 18 years old diagnosed with Stargardt disease carrying at least one mutation in the ABCA4 gene. From the study, we have a PKPD profile of Tinlarebant. We see the pharmacokinetic profile in blue.
We see that with onset of therapy of 5 mg per day, we see that the level of Tinlarebant in the systemic bloodstream increases and stays at that level over the duration of the trial and obviously goes down after cessation of the treatment. We see a perfect mirroring as the pharmacodynamic effect, namely our biomarker RBP4, that goes down underneath a target threshold that was defined in an interventional trial in age-related macular degeneration where efficacy to slow lesions over time was shown to happen if the threshold of 70% was reached. With a 5 mg dose, it was shown that RBP4 levels would be reduced at approximately 80% relative to baseline, and the RBP4 levels returned to 87% of the baseline value at the end of the study. The recovery of RBP4 concentration correlated very well with a decreased Tinlarebant exposure. What about endpoints in such clinical trials?
It was the PROXA study that in about 2013 that I implemented at the Wilmer Institute with support of the Foundation Fighting Blindness that led to the development and validation of the first endpoint for Stargardt disease, namely DDAF. We see an example on the lower left. We see the optic nerve head that is black, and by that definition is black because there are no fluorophores in the optic nerve head. In the center of the macula, we see this lesion that is surrounded by increased fundus autofluorescence, which actually shows the cause of the problem, but we also see the consequence of accumulation of bis-retinoids, namely loss of retinal pigment epithelium that first becomes thick. We see these areas of QDF, questionably decreased autofluorescence that are not as dark as the optic nerve head.
To the left of QDF, we see this area of DDAF, definitely decreased autofluorescence, very black, blackness level of at least 90% compared to the optic nerve head. We can measure that DDAF area over time, and we see the progression within two years. When we go to the right panel, we see that the DDAF lesion has increased, and the QDF lesion has changed its border. Some of QDF developed into a DDAF. You can also calculate the sum of the two, namely decreased autofluorescence, DAF, and that is our secondary endpoint in our registration trial.
The PROXA study group has shown that these DDAF progression rates can be measured over time reliably, and it was shown that in an all-comers cohort of 291 patients worldwide, the progression rate was pretty much exactly 0.7 sq mm per year, which is compared to geographic atrophy a bit less than half what we observe in geographic atrophy. In the phase two 24-month interventional trial, seven out of 12 subjects developed DDAF lesions. It is important to note that five of the 12 subjects never developed DDAF lesions, which speaks in favor of Tinlarebant being able to prevent the onset of such lesions over time. Those patients that developed these lesions, for those patients, the lesion size was measured by a central reading center, and we see the progression plotted in red in the left figure.
We see the correlating figure on the right, and it was pretty much exactly 0.5 sq mm to two years in the interventional trial with Tinlarebant treatment. That could be compared with the natural history, namely from the PROX A study. In order to compare apples to apples, we extracted an adolescent patient cohort out of PROX A, namely those subjects that were aged between 12 and 18 years out of the PROX A study that resulted in a dataset of 51 patients aged 18 and younger. Those patients progressed at a progression rate of pretty much exactly 1 sq mm per two years, and the difference between the two was highly statistically significant. With that data, we went into a registration trial called DRAGON.
There was an interim analysis, and I will speak about that interim analysis that was conducted in February this year by an independent data safety monitoring board. The DRAGON trial is a registration trial that enrolled 104 subjects, which is into the global trial, has a randomization ratio of two to one, so twice as many patients receive Tinlarebant. One third receives placebo. It is double masked. It's a two-year intervention trial with the primary endpoint of slowing atrophic lesions, specifically DDAF lesions, and other measures include QDF lesions, best-corrected visual acuity, spectral domain OCT measures, and microperimetry. The key inclusion criteria, this was an adolescent patient cohort aged between 12 and 20 years old, diagnosed with Stargardt disease and carrying at least one mutation identified in the ABCA4 gene.
We see to the left the demographics that are typical for such an adolescent patient cohort, and on the right, we see further demographic characteristics slightly dominated by a male population over 60% and about 40% Caucasians and a bit more than 50% Asians in the DRAGON clinical trial. As mentioned, the DSMB, an independent DSMB, conducted an interim analysis in February this year. They concluded that no modification of the study is required. They recommended to continue the study without sample size increase. They concluded that Tinlarebant at the 5 mg per day dose continues to be safe and well tolerated in this adolescent Stargardt patient cohort. At the time of the interim analysis, the overall withdrawal rate was less than 10%, and the withdrawal rate due to ocular adverse events was less than 4%.
Visual acuity was stabilized in the majority of subjects with a mean change from baseline of less than three letters under both standard and low luminance throughout the two-year study. There was an additional comment by the DSMB, namely it is recommended to submit the data for further regulatory review for drug approval. We took this mandate and presented the data to various regulatory agencies, for example, an in-person presentation in Tokyo to the PMDA in April and a submission for a breakthrough designation through the FDA. We received breakthrough designation based on the data that was submitted that the DSMB actually looked at in February in May this year. What about safety? Tinlarebant continues to be safe and well tolerated in this adolescent patient cohort.
We see the adverse events listed in this table, Xanthopsia, which means transient yellowish of the visual scene, and delayed dark adaptation, which means that patients need a bit more time to reach their final threshold of being fully sensitive under low light conditions, are the most common drug-related ophthalmic adverse events. The majority of Xanthopsia, delayed dark adaptation, and night vision impairment were mild. Some resolved while on treatment. Headache is the most common treatment-related nonocular AE, and there were no severe or serious treatment-related AEs reported. There were no clinically significant findings in relation to vital signs, physical exams, cardiac health, or organ functions. This slide shows the visual acuity data. This is blended data of the study and fellow eye of the total population of these 104 subjects.
We would not expect a major visual acuity decline in this Stargardt cohort, as was shown in the PROX A study, but it's still reassuring that on average, not a single letter on an EDDRS chart was lost over the duration of two years in the DRAGON trial. Last but not least, Tinlarebant is being developed for geographic atrophy, which is the most common cause of blindness in the Western industrialized countries. We see the clinical trial design for geographic atrophy. We have an established efficacy endpoint, namely the reduction in atrophic lesion growth, very similar to DDAF in Stargardt disease, and this is accepted by the FDA as a primary and an approval endpoint for Stargardt and geographic atrophy secondary to AMD. We believe that early intervention is important to target patients with small lesions to potentially slow the disease at an early stage.
It is an oral once-a-day treatment. It's identical for both GA and Stargardt, namely the 5 mg dose per day, which is well suited for a long-term treatment for chronic diseases, and it has a broad potential. The primary focus right now on GA is simply because there is an approval endpoint, but it has the potential to treat earlier stages such as intermediate AMD. We see the clinical trial design to the right. We targeted an enrollment of 500 subjects, and we reached that target a couple of weeks ago, and that was announced by a press release ahead of time, by the way. This is again a double-blind placebo-controlled clinical trial with a two-to-one randomization of twice as many patients receiving the treatment and one third receiving placebo. Like the DRAGON trial, two-year duration.
Primary measures are very similar to the DRAGON trial, namely slowing of atrophic lesions, and other measures include best-corrected visual acuity, spectral domain OCT-derived outcome measures, and microperimetry. We anticipate that there will also be an interim analysis for the PHOENIX trial. With that, I thank you very much for your attention.