AAO 2026: Tinlarebant in Stargardt disease: Jacque Duncan, MD, on DRAGON results

Retina specialists who manage ABCA4-related Stargardt disease have had no approved therapy to offer patients, but that could change early next year. The FDA has accepted Belite Bio's new drug application for tinlarebant in Stargardt disease type 1 under priority review, with a Prescription Drug User Fee Act (PDUFA) target action date of February 12, 2027.¹ The application rests on the phase 3 DRAGON trial (NCT05244304), a 24-month, randomized, double-masked, placebo-controlled study of oral tinlarebant 5 mg daily in 104 patients aged 12 to 20 years.² Tinlarebant reduced the lesion growth rate by 35.7% vs placebo (P = .0033), as measured by retinal imaging.³

At the American Academy of Ophthalmology (AAO) 2026 Annual Meeting in New Orleans, Jacque Duncan, MD, chair and distinguished professor in the Department of Ophthalmology at the University of California, San Francisco (UCSF), presented the phase 3 results on behalf of the DRAGON investigators.⁴ In a conversation with Ophthalmology Times, she discussed how tinlarebant targets the disease process, the trial's efficacy and safety findings, the mechanism-related visual adverse effects clinicians should anticipate, and how an oral therapy might work alongside future genetic approaches.

The Q&A

Note: transcript lightly edited for clarity and length.

What drives ABCA4-related Stargardt disease, and how does tinlarebant target it?

Jacque Duncan, MD: [Stargardt disease] is a rare inherited retinal degeneration caused by changes in a gene called ABCA4. Currently, there [are no] FDA-approved treatments for ABCA4-related retinal diseases. [The disease] tends to be a challenging one to treat because the gene is too large to fit into standard viral vectors that we use to deliver genes for gene therapy.

The effect of mutations in the ABCA4 gene is to lose the ability to transport retinoids from the RPE [retinal pigment epithelium] into the photoreceptors, and it leads to increased formation of harmful compounds that lead over time to accumulation of a cytotoxic compound called A2E. This ends up causing the RPE cells and the photoreceptors to not work properly and eventually to die, and causes ultimate vision loss, which is not reversible.

Tinlarebant is a compound that antagonizes—or blocks—a protein called RBP4 [retinol-binding protein 4]. This is [an] important pathway to get retinol into the retinal pigment epithelial cells, and this antagonist—tinlarebant—blocks this binding protein and prevents getting retinol into the eye. So, it ends up reducing the toxic compound buildup and hopefully will preserve vision and prolong survival of photoreceptors.

How was the phase 3 DRAGON trial designed?

Duncan: A multicenter phase 3 trial called DRAGON was conducted in both adolescent and adult patients who had Stargardt disease associated with mutations in the ABCA4 gene.

A total of 104 people were screened. Sixty-nine were randomized 2 to 1 to receive tinlarebant or a placebo and then followed for 24 months. At the end of that time, 62 of the patients in the treatment group completed the study, and 32 in the placebo group completed the study. At the beginning of the trial, the groups were relatively well balanced.

What did DRAGON show on its primary end point and other measures?

Duncan: The outcome measures looked at atrophy of photoreceptors measured by fundus autofluorescence photos. They included both the definitely decreased autofluorescence, which is areas where the cells are completely lost, and the [questionably] decreased, where they're kind of questionably lost and not functioning properly. The study met its primary end point of reduction in the area of definitely decreased autofluorescence by 35.7% by the 25th month.

Patients who were randomly assigned to receive tinlarebant showed a significantly reduced rate of increase in the area of definitely decreased autofluorescence compared with those assigned to the placebo group.

There was similar efficacy in the fellow eye, which is because this is a systemic treatment. Not only did the eye that was chosen to be the study eye benefit; the other eye benefited too.

[Investigators] didn't see much difference in visual acuity in patients, perhaps because visual acuity is an insensitive measure of disease progression in this study population. They did see a significant decrease in the blood levels of RBP4, indicating that there was a biological effect of the compound.

Which serious and ocular adverse events were reported in DRAGON?

Duncan: Importantly for safety, there were 6 serious treatment-emergent adverse events. All of them were nonocular. There was one patient who had an infection of the salivary gland and one pulmonary embolism in those assigned to tinlarebant, and then in the placebo group there was one with an ear infection, urinary retention, pneumothorax, and inguinal hernia, not related to the mechanism of the drug.

Most of the ocular events were very mild. The ones that were more common in the study drug group included delayed dark adaptation, which is a result of having reduced vitamin A compounds delivered to the eye; xanthopsia, which is like yellow vision; difficulty with vision at night; and sensitivity to light. And then there were two severe and no serious treatment-emergent adverse events that led to study drug discontinuation, including difficulty with night vision in two patients that led them to discontinue the study.

What did DRAGON show on tinlarebant's overall tolerability?

Duncan: Overall, there were treatment-emergent adverse events in over 80% of the tinlarebant group and over 75% of the placebo group, so they were common.

The most common of them in the tinlarebant group were things that seem not necessarily related to the mechanism of the drug. Nasopharyngitis occurred in 35% in both groups. Headache occurred more commonly in the tinlarebant group. Acne occurred more commonly in the tinlarebant group. Influenza happened in 14.5% of the tinlarebant group and 0% of the placebo group. I don't know if that's related to the drug compound or simply a coincidence, but it certainly is an observation. Upper abdominal pain occurred more commonly in the tinlarebant group. Upper respiratory tract infection happened more commonly in the placebo group, at 17% vs 7% in the tinlarebant group. Cough was similar, at 7% of the tinlarebant group and 5.7% of the placebo group. Pyrexia happened less commonly in the tinlarebant group, but it occurred in both groups, at 5.8% vs 8.6% [with] placebo. Diarrhea happened more commonly in the placebo group, at 8.6% compared with 4.3% with tinlarebant. And abnormal urinary analysis was 8.7% with tinlarebant and 0% with placebo.

A wide range of different effects happened, and certainly these are all things that may or may not have happened whether or not the person was on the compound. There were zero treatment-emergent adverse events that led to study drug discontinuation or study discontinuation or death.

How should clinicians weigh tinlarebant's visual adverse effects against its potential benefit?

Duncan: I would suggest that certainly there were ocular side effects [and] adverse events that were reported more commonly in the tinlarebant group and related to the mechanism of action, including delayed dark adaptation, difficulty with vision at night, and chromatopsia. These are all side effects that have been observed in other studies evaluating treatments that might modify the visual cycle, so they are not surprising. Many patients who have been in other studies and exposed to these kinds of medications feel like the side effects are real but within the range of things that would be acceptable if it would allow them to retain their vision longer.

I'm hopeful that, even though these are visual side effects that are related to the compound and not surprising, if the compounds prevent vision loss, people will be willing to accept these reductions in vision at night and delayed dark adaptation. Certainly, these are things that bother patients already, and the effect of having further difficulty with vision at night is not to be minimized. But I think if people can retain better vision longer, this is certainly something worth considering.

The other nice thing about this compound is that, because it's oral, it works on both eyes, and you can stop it. It's not an irreversible treatment like gene therapy might be, or cell-based therapies that are hard to turn off once they are administered.

How would a first FDA-approved Stargardt therapy change treatment decisions?

Duncan: I am very excited about the opportunity to have, for the first time, an FDA-approved oral systemic compound to treat patients, including adolescent patients, with ABCA4-related Stargardt disease.

I think there are really no good treatments for them right now. They continue to lose vision, and if there were an oral compound that was relatively well tolerated that would reduce the rate of vision loss by 36%, I would prescribe these compounds for patients as soon as they were approved.

How might tinlarebant fit alongside gene therapy for Stargardt disease?

Duncan: Kind of like many complicated diseases, if you can approach treatment from multiple avenues, that would be better. I envision that in a perfect world, one would address the genetic mutation, but I think you would also want to try to protect as many cells as possible during the course of the disease.

So, you might want to do both: one, reduce the amount of vitamin A coming to the eye, and two, correct the genetic defect if you could, so you could reduce the burden on the cells that have been treated. I think it wouldn't necessarily have to be either/or. If there were more than one different mechanism that we could use to target in this disease, I think we would want to use everything available to us to try to help patients.

Many ophthalmologists see Stargardt disease only occasionally. What is the current standard of care for patients with STGD1, and why has it been so difficult to develop a treatment?

Duncan: Standard care for patients with ABCA4-related retinal degeneration includes referring patients for low vision consultation, advising patients to avoid supplemental vitamin A and to wear sunglasses and a hat to avoid excessive exposure to sunlight. Clinical trials are challenging in patients with rare inherited retinal degenerations like ABCA4-related retinal degeneration since few patients that have been characterized genetically and clinically are able to be enrolled in trials, and centers with the expertise to identify and characterize patients are limited. A large natural history study of 259 patients with at least 1 variant in ABCA4 and Stargardt disease called ProgStar followed patients over 24 months to identify outcome measures to follow over time. Although visual acuity changed very little over time in ProgStar, the study demonstrated a strong correlation between visual function and definitely decreased autofluorescence.^5-7

Tinlarebant is an oral RBP4 antagonist. In practical terms, how is lowering RBP4 expected to slow Stargardt disease, and why did DRAGON enroll adolescents rather than adults?

Duncan: The visual cycle requires retinol to interact with rhodopsin to produce vision. Retinol is transported from the bloodstream to the retinal pigment epithelium, or RPE, by the RBP4-TTR protein complex, where it is taken up by an RBP4 receptor. Inside the RPE, retinol is converted to 11-cis-retinal, a visual chromophore that is shuttled to photoreceptors to enable light sensitivity and retinal function in the form of rhodopsin. Following light detection, the ABCA4 protein clears retinal byproducts from the photoreceptors, completing the cycle, but when ABCA4 isn't working properly, toxic byproducts accumulate and damage the RPE cells and photoreceptors, leading to vision loss. Tinlarebant is an RBP4 antagonist designed to disrupt the transport of retinol into the eye to reduce accumulation of the toxic byproducts. DRAGON enrolled adolescents because most adults have more advanced vision loss than adolescents and earlier treatment permits greater likelihood of identifying a treatment effect.⁸

DRAGON's main finding was slower growth of atrophic lesions on fundus autofluorescence compared with placebo, while visual acuity changed little in either arm. Why is lesion growth the right endpoint for this disease, and how should clinicians explain the absence of a visual acuity difference to patients and families?

Duncan: Definitely decreased autofluorescence (DDAF) is an accepted imaging endpoint used to quantify and track the progressive loss of RPE in STGD1. The ProgStar study, studying the natural history of STGD1, validated DDAF as an approvable primary endpoint by demonstrating that these areas of atrophy grow predictably over time. Measuring lesion growth via FAF is an established method that has been used in the approval of other FDA-approved therapies for retinal disease.^5,6,9

Visual acuity is an insensitive measure of disease progression in most clinical trials and changes over time in a non-linear manner (ref PMID: 41773771).

Drugs that limit vitamin A delivery to the retina have been associated with visual side effects such as delayed dark adaptation and changes in color vision. What did DRAGON show on safety and tolerability over 24 months, and what monitoring would you recommend if tinlarebant is approved?

Duncan: The majority of ocular adverse events observed in the DRAGON trial were mild and included xanthopsia, delayed dark adaptation, and night vision impairment, which are consistent with tinlarebant's mechanism of action, and most resolved while the patients continued the study. Four events led to study drug discontinuation and 2 of led to study discontinuation, including delayed dark adaptation and night vision impairment.

The FDA's PDUFA date for tinlarebant is February 12, 2027. If it is approved, which patients would you consider candidates, and how might it change diagnosis, genetic testing, and referral for STGD1?

Duncan: Given the safety and efficacy results of the DRAGON study if tinlarebant is approved I would consider candidates to be eligible for treatment based on the recommendations provided on the FDA approved label. FDA approval might increase awareness and interest by patients and providers to pursue genetic testing and characterization if patients have central vision loss to determine if they would benefit from treatment with tinlarebant.

What questions does DRAGON leave open, such as durability, use in adults or adolescents, or combination with gene-based therapies, and what research would you like to see next?

Duncan: Longer follow up would be expected to produce significant differences in visual function, measured as microperimetry or visual acuity, than were observed in the 25 month DRAGON study. Future studies should also investigate whether patients with ABCA4-related retinal degeneration who have not yet developed definitely decreased autofluorescence show improved visual function if they are treated with tinlarebant or if the side effects of xanthopsia, delayed dark adaptation and night vision impairment outweigh benefits to patients with earlier or later stages of disease than were studied in DRAGON.

References

1. Belite Bio announces US Food and Drug Administration acceptance and priority review of new drug application for tinlarebant for the treatment of Stargardt disease type 1. News release. Belite Bio. August 11, 2026. Accessed October 9, 2026. https://investors.belitebio.com/node/9321/pdf

2. Bernstein PS, Michaelides M, Sui RF, et al. Results of the phase 3 DRAGON trial of tinlarebant (LBS-008) for Stargardt disease (STGD1). Presentation slides. Belite Bio. Accessed October 9, 2026. https://investors.belitebio.com/static-files/55440621-72d4-44c5-9719-7f53a28e8591

3. Duncan J. Phase 3 DRAGON trial of tinlarebant (LBS-008) for Stargardt disease (STGD1). Presented at: American Academy of Ophthalmology 2026 Annual Meeting; October 11, 2026; New Orleans, LA.

4. Phase 3, randomized, placebo-controlled study of tinlarebant to explore safety and efficacy in adolescent Stargardt disease (DRAGON). ClinicalTrials.gov identifier: NCT05244304. Accessed October 9, 2026. https://clinicaltrials.gov/study/NCT05244304

5. Strauss RW, et al. Ophthalmology. 2016 Apr;123(4):817-28.

6. Strauss RW, et al. Am J Ophthalmol. 2023;250:157-170.

7. Kong X, et al. JAMA Ophthalmol. 2018;136(8):920-928.

8. Polasek TM, et al. Clin Pharmacol Drug Dev. 2026;15(1):e70009.

9. Lad EM, et al. Annu Rev Vis Sci. 2024;10(1):455-476.