Why Didn't Low Dose Atropine Get FDA Approval? A Review of the STAR Study Data
FDA approval low dose atropine 16:28Have you heard about eye drops that slow down prescription worsening in children with myopia (or nearsightedness)? That's low dose atropine, and doctors have increasingly been offering this option to patients since the publication of the landmark LAMP and LAMP 2 Trials showed positive effects for dosages between 0.01% and 0.05% atropine used nightly. The reason that atropine drop use for slowing childhood prescription changes hasn't fully entered the main stream? Only 1% atropine is available at traditional pharmacies - a concentration so high that it would dilate the pupil for a week or more and cause considerable blurry vision, making it impractical for routine use for myopia management. Parents and doctors are left with having to use compounding pharmacies to create the lower doses of atropine needed for myopia management, and a designation of "off label" treatment which also gives many parents concerns. The idea of an FDA approved low dose atropine formulation for myopia management has thus been a big excitement for doctors in the myopia management community - making it easier for parents to access the drop, and allaying any fears about treatments that are off label. Sydnexis currently has approved low dose atropine available in Japan under the brand name Ryjusea and Europe under the brand name Ryjunea, and was slated for an FDA decision date on approval on October 23, 2025. The decision took many in the community by surprise: no FDA approval, and instead a request for more data.
What did the FDA see (or not see) that caused them to pause low dose atropine approval? Let's dive into the details behind the Phase 3 STAR Study that was used for FDA submission:
STAR Study Set Up:
This STAR study is the largest low dose atropine study published to date, with 847 children between the ages if 3 to 14 enrolled. Study participants had between -0.50D to -6.00D of myopia at the time of enrollment, and countries of enrollment included the USA, Austria, and Slovakia. Participants were split 282 with vehicle (placebo), 282 with 0.01% atropine, and 283 with 0.03% atropine used nightly and followed every 6 months for 36 months. At that time all drops were stopped and a 12 month follow-up was performed to assess any rebound effect. Cycloplegic refraction was used to determine prescription at each follow-up visit. Primary study endpoint was defined as -0.75D or less of myopia progression by 36 months of treatment.
STAR Study Results
Patient receiving placebo drops by 36 months had myopic spherical progression rate of -0.38D/year on average. Treatment groups with 0.01% and 0.03% had no statistically significant difference in their effect: 0.01% atropine group had an average -0.30D/year progression and 0.03% atropine group had a -0.32/D year progression. If you broke out "fast progressing" myopic patients (those changing at a rate of greater than -0.50D/year prior to enrolling in the study), the effect was slightly bigger, with a -0.41/D year average progression with vehicle, and -0.30D/year progression with 0.01% atropine and -0.32/D year progression with 0.03% atropine.
Looking at this data alone, there was a 21% spherical equivalent myopia management effect with 0.01% atropine, and for fast progressors a 27% myopia management effect with 0.01% atropine for spherical equivalent.
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| Link to Full Study PDF |
The most effective myopia management effect was seen in a subgroup of fast progressors with prescriptions between -0.50 and -3.00D at enrollment: there was a 56.8% myopia management effect with 0.01% atropine with this one specific subgroup at 36 months. Interestingly, those taking 0.03% atropine in this subgroup only had a 22.1% myopia management effect. Fast progressors with higher baseline prescriptions >-3.00 to -6.00D at enrollment only had a 19.5% myopia management effect with 0.01% atropine and a 25.3% effect with 0.03% atropine.
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| Link to Full Study PDF |
There was no reporting on axial length elongation with the published study data.
No adverse events were reported with atropine use during the clinical trials.
Conclusion: The study authors concluded that for children aged 3-14 there was statistically significant benefit to slow myopia progression with 0.01% atropine, with the greatest benefit observed when treatment was initiated early in their myopic progression. See the subgroup of patients between -0.50 and -3.00 with significantly stronger effect than those with prescriptions >-3.00 to -6.00D of myopia.
The FDA's Conclusion: In their Complete Response Letter to Sydnexis' application for approval of SYD-101 (0.01% atropine) based on the STAR Study, the FDA acknowledged the primary endpoint goal was met of statistically significant reduction in myopic progression of -0.75D or better over 3 years. But the letter requested more data was needed to support the effectiveness of low dose atropine.
The Reaction
Industry articles have characterized the FDA's decision as "baffling," and "puzzling", and personally I'll be the first to admit that I was surprised by this outcome after spending years practicing with the knowledge of the LAMP 2 study data. But when I saw the actual published study (released after the FDA's decision), the data is definitely not as strong as anything seen in previous atropine studies and warrants some questions on why this study failed to show a more robust myopia management effect. Let's compare the LAMP 2 study and the STAR study to illustrate this point:
Study Participants: LAMP 2: 474 children, STAR: 874 children (the largest atropine study to date!)
Location of Study: LAMP 2: China, STAR: USA, Austria, Slovakia (the most ethnically diverse atropine study to date!)
*Is there a difference in the response to low dose atropine among patients of different ethnicities? Even in the STAR study, if participants of Asian ethnicity were sub-grouped, 0.03% atropine had a more effective myopia management effect, compared to White/Hispanic/African American ethnicities which showed no statistically significant benefit with the higher atropine concentration.
Myopia Management Effect:
LAMP 2: 22% spherical equivalent myopia management effect with 0.01% atropine compared to placebo at the end of 1 year, 44% effect with 0.025% atropine, and 70% effect with 0.05% atropine. In the LAMP 2 study placebo users were switched to treatment groups after that 1 year time frame so there is not longer data for comparison.
STAR: 21% spherical equivalent myopia management effect with 0.01% atropine over 3 years, 16% effect with 0.03% atropine over 3 years.
*Why didn't the STAR study similarly find that a higher concentration of atropine provided a more robust effect? Does it hark back to ethnicity impacting the benefit of low dose atropine? Or is this the result of a larger and longer study just showing less impressive results?
In the LAMP 2 study, axial length progression was also measured, showing a 18.7% myopia management effect in reduction in axial length elongation with 0.01% atropine after 1 year, 32.6% effect with 0.025% atropine, and 54% effect with 0.05% atropine. In the STAR study no axial length progression data was provided. Did the FDA take issue with the lack of inclusion of axial length study data being presented?
My Opinion:
While I agree that the STAR study showed statistically significant myopia management effect, the results of this study felt surprisingly underwhelming. I was expecting a much more robust myopia management response based on the LAMP 2 study data, and was very surprised by the lack of improvement seen with the higher 0.03% atropine data compared to 0.01% atropine data in myopia management. We also expect a dose dependent response to atropine based on previous studies like LAMP 2, and the fact that this was not seen in the STAR study causes some pause. Is the difference in data purely based on a difference in ethnic makeup of the study? And if so, does this mean that United States doctors should expect less effective myopia management results when prescribing low dose atropine to their patients of a more diverse ethnic makeup?
One of the big things that held SYD101 approval back in my opinion was timing. If there was no other myopia management option available, then even a modest 21% myopia management effect would be better than nothing. But the FDA had just one month prior to this decision authorized Essilor Stellest lenses for myopia management with a reported 71% reduction in myopia progression and 53% reduction in axial elongation at 2 years, and MiSight contact lenses are already FDA approved since 2019 with a 59% myopia progression effect and 52% axial elongation reduction effect at 3 years. Both of these treatments show significantly more effective study data. I can picture someone at the FDA asking "why would a doctor prescribe low dose atropine when they have glasses and contact lens options available already, on-label, with significantly more robust data to support their effectiveness?"
Is there a place for FDA approval of atropine - yes, absolutely in my opinion. Studies have shown that using low dose atropine with myopia management glasses can be an effective combination treatment, and also in combination with MiSight contact lenses in fast progressors. Having an FDA approved version of atropine would help minimize risks of inaccurate dosage concentrations that have been reported with doctors using compounding pharmacies. We need standardization of low dose atropine in myopia management. But the FDA request for more study data does seem warranted as we look at some discrepancies in findings between what is considered the landmark atropine study (LAMP 2) used by doctors and what was reported in the STAR study. And I imagine some axial length elongation reporting was probably requested for the next submission as well.
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