Sydnexis, Inc. has received a company response letter (CRL) from the FDA for SYD-101 (low-dose atropine sulfate ophthalmic solution), an eye drop indicated to decrease pediatric myopia progression.
Take note: This news was announced one day after the federal agency’s Prescription Drug User Fee Act (PDUFA) target action date of Oct. 23.
First, refresh me on what a CRL means.
Essentially, the FDA sends a CRL to inform a company that its drug application—a new drug application (NDA) or a Biological License Application (BLA)— is unable to be approved in its current form.
Included in this letter: The agency will offer specific details on the deficiencies found in the application—such as safety, efficacy, or manufacturing issues—as well as suggested steps to correct them.
Gotcha. And this definitely wasn’t the result Sydnexis was looking for, was it?
Indeed not. SYD-101 had (and still has, to be fair) the potential to become the first and only pharmaceutical treatment option approved for progressive myopia for patients aged 3 to 14.
Now tell me more about SYD-101.
Engineered specifically for pediatric patients with "growing eyes,” SYD-101 is formulated with a low-dose (0.01%) atropine formulation.
As Sydnexis has noted, the drop is designed to “optimize tolerability, stability, and clinical performance” via several mechanisms:
- Enhanced ocular tissue permeability (as demonstrated in preclinical animal studies)
- Stable shelf-life for up to 3 years at room temperature
- Near-neutral pH (potentially supporting its favorable ocular safety and comfort profile)
We’ll go more into these later, though.
And why use low-dose atropine over a high-dose version?
We’ve already explained this (see here)—or rather, Sydnexis addressed the decision behind it.
- As for the logic in favor of using low-dose atropine, click here for the pros and cons of it (plus the clinical research behind it).
Hold up: Doesn’t low-dose atropine come with more potential adverse effects?
When it’s available as a compounded formulation—such as through compound pharmacies that, take note, aren’t required to follow any federal guidelines for testing the drop’s safety and efficacy —yes.
Check out those adverse events (AEs), which include degradation after just one month of storage at room temperature.
So how does SYD-101 avoid this risk?
Via its specifically engineered formulation, which features a “unique stabilizing excipient” to prevent rapid atropine degradation occurring in most drops made in water-based solutions.
To be more exact: The SYD-101 formulation encompasses a highly stable form of atropine at a physiologically neutral pH that provides such benefits as improved penetration and comfort.”
- The drop’s shelf life: 3 years (a record).
And how did it perform in clinical trials?
Promising—or so we thought. Three-year clinical findings from the phase 3 Study of Atropine for the Reduction of Myopia Progression (STAR) study (NCT03918915) were included in its NDA submission to the FDA.
What to know about it: The trial evaluated SYD-101 in two doses (0.01% and 0.03%) versus a placebo dose for:
- Its effect in slowing pediatric myopia progression
- Its risk for associated comorbidities
See here for those study details.
… and those results?
Positive findings were reported, with the study meeting both its primary and secondary endpoints:
- Primary: Proportion of patients with confirmed myopic progression of -0.75D
- Secondary: annual progression rate met statistical significance at 12, 24, and 36 months
The company also noted that: “In a subgroup of fast progressors (more than -0.5D/yr) at 36 months, SYD-101 demonstrated statistically significant treatment effects of a reduction in progression of more than 50%.
This all sounds positive … so why did the FDA reject SYD-101?
While the agency reportedly acknowledged that the study’s primary endpoint was met, it emphasized that “the data do not support the effectiveness of low-dose atropine in children with myopia.”
- Specifically: “No deficiencies were noted related to safety or product quality.”
That’s the reason behind the rejection?
Yup. As for Sydnexis: CEO Perry Sternberg shared that the company is both "surprised and disappointed” by the agency’s decision.
Did he say what their plan is moving forward?
Not specifically, no. Just that the company will work with the FDA to address the items outlined in the CRL and determine “the best path toward approval.”
- Sternberg also added that the company remains “confident in our data” as well as the potential of SYD-101 to “fill a critical innovation gap and treat the most common eye disease in children.”
So they can resubmit the NDA?
Absolutely—providing the company resolves the FDA’s issues with the NDA before resubmitting an updated application, that is.
To be clear, though: No timeframe was offered.
So you know what that means… stay tuned!