AAO 2024: Late-breaking developments in a novel treatment for adolescents with Stargardt disease

At this year's American Academy of Ophthalmology (AAO) meeting, Quan Dong Nguyen, MD, MSc, of the Byers Eye Institute at Stanford University School of Medicine, presented as part of the late-breaking developments broadcast. Ahead of his presentation, "Tinlarebant (LBS-008) for Adolescents with Stargardt Disease," he sat down with David Hutton of Ophthalmology Times to discuss the research findings and their implications.

Editor's note: This transcript has been lightly edited for clarity.

David Hutton: Hi, I'm David Hutton of Ophthalmology Times. The American Academy of Ophthalmology is hosting its annual meeting in Chicago. At the meeting, Dr Quan Dong Nguyen is presenting data on Stargardt. Thanks for joining me today. Can you tell us the key points of this data?

Quan Dong Nguyen, MD, MSc: Thank you, David, for having me involved with your programme. It is certainly my great, great pleasure to share with you the work that our colleagues and I have been doing, looking at a compound called Tinlarebent, which we have been studying for adolescents with Stargardt disease. Certainly. as an answer, one can say that even at this time in the year 2024 we currently do not have any treatment for our patient with Stargardt. And throughout the year, we have very much witnessed the tragedy and the devastation when many of our patients, some of them are really young, are losing their vision to Stargardt disease. Patients affected with Stargardt disease, or STGD1, harbor a genetic mutation in a key protein within the retina, which then interfere with the normal vitamin A processing in the visual cycle, and which result in significantly increased accumulation of cytotoxic byproducts of Vitamin A, so-called bisretinoids, and with subsequent progressive retinal cell death.
Because these retinoids are derived from circulating vitamin A entering the eye, reduction of vitamin A delivery to the eye is therefore expected to reduce the formation and accumulation of bisretinoid, leading to reduced pathology and preservation of vision in patient with Stargardt Tinlarebent, the medicinal product being investigated here is a novel once a day oral tablet, completely non invasive, oral tablet designed to bind to serum retinal binding protein 4, or RBP4, as a means to specifically reduce vitamin A delivery to the eye in order to slow or hurt the accumulation of this bisretinoid that I have mentioned. It is our hope and believe that early intervention directed at retinopathology, which is not mediated by inflammation, would be the best approach to potentially slow disease progression in Stargardt as well in geographic atrophy. And again, David, here, I want to emphasize that we believe that early intervention is best here, because we don't want damage to have occurred and then at that time, we would not be able to replace the dead tissue. So we want to make sure that things are treated and managed at the very early stage.

We know that vitamin A is transported to the eye in a protein complex with RBP4 and transthyretin, or TTR. Unlike other tissue, the eye has a unique requirement for uptake of retinal-bound RBP4 due to abundant oppression of the RBP4 receptor, and this aspect from there. In Stargardt patients, this dysfunction of the APCR protein, which then results in the accumulation...and deposition of these complexes into the retinal pigment epithelium, then result in accumulation of cytotoxic retinoids I have mentioned, and then lead to retinal cell death. From this aspect, how does Tinlarebent work? Tinlarebent, as I mentioned, is a small molecule RBP4 antagonist that can compete with retinoid retinol for the binding of RBP4, and does not allow the binding of TTR to the eye. The Tinlarebent RPB4 complex are then liberated into the circulation and then eliminated to the kidney, due to its small size, and result in a reduced retinol delivery to the eye.

So in our Phase 2 study, we enrolled thirteen subjects that have no definite decrease in auto fluorescence and have questionable decrease in autofluorescence. These subjects were treated with a dose of Tinlarebent, 5mg/day, for the treatment duration of 2 years, and I'm sharing with you the result now, the 2-year outcome of that. The primary measure certainly would be the safety and the tolerability and the optimal dose. But we also look at other measures, just at DDAF, QDAF, visual acuity, OCT and microperimetry as well. And the key inclusion criteria here I alluded to, we aim for young subjects, patients. The criteria of age was 12 to 18 years old, diagnosed with Stargardt with at least one mutation identified in the ABCA4 gene. Definitely, we like to do that to make sure that we have the right patient and the right target. The 5 milligram daily dose: where's that coming from? That is being used because the 5mg daily dose have been known to effective, to be quite effective, in reducing the RBP4 level by a mean of approximately 80% relative to baseline.

We also learned that RBP4 level returned to about 87% of the baseline value at the end of the study, like that. So we know that we can reduce the level we need, and then when we start using that, it's back to the normal level of that aspect. So in this study, over the 24 months, we have seen the change in QDAF and DDAF lesion size. We see that the transition from QDAF to DDAF lesions and growth of incident lesions was examined. In five of the twelve subjects, there was no incidence of lesion growth. In seven of the twelve subjects, we see no expansion of the autofluorescin...there. What about visual acuity? Visual acuity was stabilised during the study with a mean loss of five letters in the cohort over 24 months. Many of our subjects who entered the programme have shown significant bilateral vision loss prior to enrollment. For example, in a subgroup of six subjects, they have shown a mean of a ten-letter loss per year prior to enrollment. Following 24 month treatment in the programme, the mean visual acuity loss in this group was just three letters a year. So they went from ten letters per year loss, prior to enrollment, to, on the mean, just three letters per year. So quite a improvement in terms of the vision loss. And so, in addition, we also obviously want to make sure that this drug is well-tolerated. So we looked over the 24 month result, and we noticed some adverse events occur.

For example, there were sentopsia and chromatopsia, but that the degree was very mild. The subject described to us that they experienced some of the symptoms, but they very quickly, easily adapted to it. So that goes along also with delayed adaptation and night vision impairment, they are all considered mild. And the thing that quite encouraged us was that, among the thirteen subjects who will enroll in the programme, none of them dropped out due to any type of adverse event. So yes, they recognise that there's some mild level of...tension adverse events...but that will very quickly resolve and everyone stayed in the programme. And we learned that Tinlarebent continues to be safe and well tolerated. And that is, it can produce a mean 80% reduction of RBP4 from that aspect. So we're very pleased with that. So in summary, David, we are very encouraged because, as we say at the moment, there is no treatment for Stargardt disease, neither for the adolescent or for adult. There was absolutely no treatment across the globe. There are several trials in the past looking for gene therapy for Stargardt disease, but all of them have failed. So at the moment, [in] 2024, we have no treatment. We were encouraged to, when we see a Stargardt a result in here, when we saw that, in this case, 5mg daily of Tinlarebent produced a mean 80% reduction of the plasma of RBP4 retinol, which was very reversible during the drug cessation. So it does what it does during the part we need. But then when we stop the drug, it's back to normal, so no long term or permanent damage. That visual acuity was stabilised in subjects in our study, and definitely did not show the type of visual loss before that. When we look at the lesions and the various type of measurement, grading it, we also note that the growth had halted from month 16 to month 24. So clearly, there's a benefit of the subject being treated, because the growth that we've seen before has slowed down and basically stopped from month 16 to month 24, and no systemic, drug-related adverse events have been led to discontinuation of patients. So we're quite excited about this. And certainly, we have done this study with significant help from our colleague from Australia and from Taiwan, two of the major countries that have contributed subjects and patient to this programme.

David Hutton: What's the next step for this research?

Quan Dong Nguyen, MD, MSc: That's the certainly another point that I'm quite excited to share. So since we finished the Phase 2 study, which I just shared with some results, we have started and already completed the enrollment for the Phase 3 study of Tinlarebent in adolescents with Stargardt disease. It is called the DRAGON study, and is an international study involving different continents and different countries. And we have finished enrollment for it already. We have passed the 1-year mark. And so we are waiting to evaluate the result at the primary endpoint, at the 2-year mark there.

Hopefully, if that turned out to be what we have seen in this Phase 2 study, we are hopeful that Tinlarebent will have the potential to become the first treatment for patients, in particular for adolescents with Stargardt, because currently there's no treatment options. And suddenly those adolescents are the ones that we really hope that we can save the retina before getting too damaged. And then, in addition, David, to the programme in Stargardt, we have already launched a multicenter international study programme to look at the role of Tinlarebent in patients with geographic atrophy, another disease process that can lead to accumulation of the unwanted product in there. And we're hoping that would also show positive [results].

So the Phase 3 study of Tinlarebent in geographic atrophy, which is called PHOENIX, is currently occurring throughout the globe. The United States certainly one of the major countries, but we also have colleagues from Europe as well from other parts of the world, participating in that programme. We're looking forward to perhaps another potential treatment for patients with geographic atrophy, along with the Stargardt disease that we just mentioned.