ONLINE EXCLUSIVE
Refractive
November 2026
The FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee met in October to discuss the new drug application that had been submitted by Sydnexis Inc. in the prior year for its low-dose atropine solution indicated for slowing pediatric myopia progression. Despite meeting the primary endpoint in its Phase 3 clinical program—and its approval by regulatory bodies in the U.K. and E.U.—the FDA issued a Complete Response Letter in October 2025, rejecting approval of the atropine sulfate ophthalmic solution, 0.01%, in the U.S.
William Boyd, MD, Deputy Director of the Division of Ophthalmology in the Office of New Drugs, Center for Drug Evaluation and Research (CDER), said the primary objective of the advisory committee meeting on October 30, 2026, was to discuss whether a clinically meaningful benefit has been established for SYD-101, based on the efficacy and safety results derived from its pivotal clinical trial. Furthermore, Dr. Boyd said the committee would also weigh in on the persuasiveness of the findings.
According to information from the company, the NDA for SYD-101 “was supported by the results of the Phase 3 STAR (Study of Atropine for the Reduction of Myopia Progression) trial, the largest global clinical program completed to date in pediatric myopia, which evaluated more than 800 children aged 3–14 at treatment initiation.” The study met its primary efficacy endpoint of proportion of patients with confirmed progression of –0.75 D. It also showed statistical significance for a secondary endpoint of annual progression rate at 12, 24, and 36 months. “Furthermore, in a subgroup of fast progressors [more than –0.5 D/yr] at 36 months, SYD-101 demonstrated statistically significant treatment effects of a reduction in progression of more than 50%,” the company’s press release said.
At the October 2026 meeting, representatives for Sydnexis shared data on their specific product and results from the trial, noting that the FDA provided input into the study design and that the study dose met both primary and key secondary endpoints. Jason Connor, PhD, an independent statistical consultant, addressed some of the statistical aspects of the FDA’s concerns.
“The FDA cites the magnitude of the effect and characterizes the primary statistical result as borderline,” he said. However, he noted that the trial did meet its primary endpoint, whether that was “borderline” or not. He also addressed the FDA’s concern that the results were sensitive to missing data. “Based upon prior pediatric studies, a fair bit of dropout was anticipated in this 3-year trial. The protocol estimated 7% dropout per year for an overall 3-year rate of approximately 20%,” he said. “The observed rates of missing data were very close to those expectations, even despite the fact that the trial was run and enrolled during the COVID pandemic.”
Another concern the FDA expressed, Dr. Connor said, was that the treatment effect declined over time. “The FDA has asserted that the treatment effect erodes based upon the fact that the difference in annual progression rates declined and went to zero in year 3. However, this is exactly what we’d expect for an effective treatment for a progressive disease that slows as people age,” he said.
The company also addressed comments from the FDA regarding axial length and biologic plausibility. Janet Cheetham, PharmD, with Sydnexis, said that “axial length is currently recognized as an important structural measure in pediatric myopia management because it provides a direct assessment of ocular growth, which is associated with long-term risks of myopia-related pathology.” While the Sydnexis study did not specifically show a benefit on axial length, she noted that in 2018 when the study was designed, axial length was not part of routine clinical practice, and axial length was optional in this specific study. Dr. Connor completed the company’s presentation by addressing the FDA’s concern that the NDA relies on an exploratory subgroup analysis to prove efficacy, but he said the company “is not basing the approval solely on the younger patient or fast progressor subgroups, nor does the application rely on any post hoc subgroup analysis to establish efficacy.”
The committee was chaired by pediatric ophthalmologist Michael Repka, MD, of the Johns Hopkins Wilmer Eye Institute. Dr. Repka was lead author of a 2023 National Eye Institute-funded Pediatric Eye Disease Investigator Group trial that found a 0.01% atropine (but with a different formulation from SYD-101) to be no better than placebo in U.S. children.1
The committee addressed several discussion questions, noting lack of robustness of the data as a concern, as well as lack of significant effect on axial length. They also expressed that they think exploratory, pre-planned, stratified, randomized analyses of subgroups could help establish an age range for effective and clinically meaningful treatment. Discussing whether the published literature provides sufficient corroboration to satisfy the substantial evidence standard for approval, Dr. Repka summarized the committee’s perspective as, “the committee is not impressed with the additional evidentiary standard for corroboration,” further clarifying that there is “a signal in the literature but it doesn’t meet this standard.”
During the open public hearing portion, several physicians and others spoke in favor of approval of SYD-101, emphasizing the need for a low-dose atropine product and concern regarding the broader impact such a denial would have. Panelists had no comments in response to these concerns.
David Hunter, MD, PhD, chair of ophthalmology, Boston Children’s Hospital, professor and vice chair of ophthalmology, Harvard Medical School, and immediate past president of AAPOS, said, “If a sponsor can conduct the trial FDA requested, meet the endpoints FDA specified, and then not obtain approval after the fact, companies and investors will invariably question whether pediatric drug development is a predictable path. This will result in fewer investments, fewer studies, and fewer treatments for children across the healthcare spectrum.”
Cheryl Chapman, OD, commented on the under-representation of optometrists on the panel. As the past president and advisory board member of the American Academy of Orthokeratology and Myopia Control (AAOMC) and a parent of a child with myopia, she said, “Optometrists provide the overwhelming majority of frontline care for children with progressive myopia in the United States. We are the doctors who identify these children, counsel their families, monitor their progression, and make the treatment decisions that will impact their vision for the rest of their lives. I respect the expertise of this committee, but excluding the profession most directly involved in delivering this care represents a significant gap in clinical perspective. Our patients deserve to have their treating clinicians represented at the table, and I sincerely hope that future advisory committees evaluating myopia treatments will include optometric representation.”
“We have a standard of care without a standard product. SYD-101 closes that gap,” said Vance Thompson, MD, founder of Vance Thompson Vision and ASCRS past president, during his public comment. “In pediatric progressive myopia, every diopter a child progresses is permanent. As a lens implant surgeon, I see where it leads. … In this disease, there’s no such thing as a small benefit because damage that never happens is damage a child never has to live with.”
Donny Suh, MD, professor and chief of pediatric ophthalmology and adult strabismus, Gavin Herbert Eye Institute, University of California, Irvine, said myopia is rapidly becoming a global epidemic, and children need a standardized treatment. “Estimates of incidence and prevalence vary, but the trend is unmistakable,” Dr. Suh told EyeWorld in an interview after the FDA’s denial but prior to the committee meeting. Dr. Suh said the strongest case for an FDA-approved low-dose atropine is the shortcomings of what children use today. Current low-dose atropine is compounded, so clinicians cannot confirm that the concentration a child receives matches what was prescribed. “From my experience, there is variability,” Dr. Suh said. Consistent concentration across compounded batches is difficult to guarantee, he added. Supply is also unreliable. Compounding pharmacies frequently close or change ownership, forcing practices to repeatedly find new sources. “This actually takes a lot of time and effort for us to chase things down,” Dr. Suh said. His conclusion is simple: “We would love to have a regular medication that we can use that’s standardized.”
Eric Donnenfeld, MD, ASCRS past president, also shared his thoughts with EyeWorld on this topic in an interview prior to the committee meeting, noting that he thinks that the FDA and Sydnexis need to work together to find a path for quick resolution so doctors can have access to prescribe this medication as soon as possible to their patients in need. “Doctors are not stopping prescribing low-dose atropine because of this non-approval,” he said. “The FDA has merely continued to push tens of thousands of children into non-FDA approved compounded atropine, which is not optimal and could be viewed as directly contrasting with what the FDA’s objective should be.”
Like perspectives expressed in the committee hearing, Dr. Donnenfeld also noted concerns that the non-approval could put future investment into eyecare pharmaceutical development at risk. “If an investor puts millions of dollars toward the development of a new drug, and that drug meets the FDA study endpoints with no discernable safety issues and is then rejected, why would any company ever risk capital on a future drug?” Dr. Donnenfeld said this situation is unfamiliar territory.
“Another thing I think that seems like common sense supporting the approval is atropine is already approved for use in children, for amblyopia and mydriasis, at 100 times the concentration Sydnexis is trying to get approved,” he said. “All we are asking for is access to an FDA-approved version of a drug that we already know works and is safe that we can trust.”
Reference
- Repka MX, et al. Low-dose 0.01% atropine eye drops vs. placebo for myopia control: a randomized clinical trial. JAMA Ophthalmol. 2023;141:756–765.
