Clearside Biomedical, Inc. released new findings from its phase 2b ODYSSEY clinical trial evaluating the use of CLS-AX (axitinib injectable suspension) for patients diagnosed with neovascular age-related macular degeneration (wet or nAMD).
The results were presented during the 2025 Angiogenesis, Exudation, and Degeneration meeting over the weekend.
First thing’s first: CLS-AX.
CLS-AX is currently under clinical development and investigation as a longer-acting therapy for retinal disease treatment (specifically: wet AMD).
What it is: A highly potent tyrosine kinase inhibitor (TKI) that originated as an oral tablet formulation widely used for the treatment of advanced renal cell carcinoma.
- About TKIs: These are known to block chemical messengers (enzymes referred to as tyrosine kinases, which send growth signals in cells) to prevent cell growth and division.
And what’s the intent?
Pan-VEGF inhibition—achieved by targeting vascular endothelial growth factor (VEGF) to directly block the three VEGF receptors (-1, -2, and -3) with a high specificity.
What this means for wet AMD: The company has stated that “this broad VEGF blockade may have efficacy advantages over existing retinal therapies” by:
- Acting at a different level of angiogenesis cascade
- Potentially benefiting patients who have “sub-optimally” responded to “narrowly-focused” anti-VEGF therapies currently on the market
Sounds promising … so how is this TKI delivered?
This is where Clearside’s proprietary and patent-protected technology comes into play: the suprachoroidal space (SCS) Microinjector.
- Quick SCS refresh: This is the space between the sclera and choroid encompassing the circumference of the eye’s posterior segment
Why target the SCS: As previous research has pointed out: “The SCS is an attractive site for drug delivery because it targets the choroid, retinal pigment epithelium and retina with high bioavailability, while maintaining low levels elsewhere in the eye.”
Got it. Next: Explain what this microinjector is.
The SCS Microinjector is an injection platform (microneedle device, really) that enables back-of-the-eye (retina) access to deliver drugs into the SCS—ideally resulting in targeted delivery and a reduction or even elimination of potential toxic effects.
What it encompasses:
- A syringe
- Custom-designed hub
- Two 30-gauge hollow microneedles (for suprachoroidal administration)
A regulatory note: While the SCS Microinjector has not yet received independent FDA approval, it is used with Clearside’s XIPERE (triamcinolone acetonide injectable suspension), which is currently the first and only FDA-approved therapy for suprachoroidal use (to treat uveitis macular edema).
- Check out how this process works (visually speaking)
Alrighty, now talk about this Odyssey trial.
This was a randomized, double-masked, parallel-group, active-controlled, multicenter phase 2b trial (NCT05891548).
Its purpose: To evaluate the use of CLS-AX 1.0 mg when administered via the SCS Microinjector with a flexible dosing regimen in wet AMD patients previously treated with intravitreal (IVT) anti-VEGF therapy.
- The setup:
- Participants: 60 patients (aged 51-96; mean age of 78) diagnosed with wet AMD within 36 months of Visit 1
- The design: Participants randomized 2:1 between the CLS-AX 1.0 mg (and aflibercept 2 mg arms.
- Group 1 (n = 40): CLS-AX 10 mg/mL (1.0 mg in 0.1 mL) administered via suprachoroidal injection on Day 1 (loading dose) and then every 12 to 24 weeks
- CLS-AX was dosed at least every 24 weeks unless disease activity assessment indicated the need for supplemental treatment.
- Subsequently, CLS-AX was administered 12 weeks after the last dose; however, if less than 12 weeks, aflibercept may be given.
- Group 2 (n = 20): Aflibercept (2 mg in 0.05 mL) administered via intravitreal injection on a fixed-dose regimen once every 8 weeks (Q8W)
- Group 1 (n = 40): CLS-AX 10 mg/mL (1.0 mg in 0.1 mL) administered via suprachoroidal injection on Day 1 (loading dose) and then every 12 to 24 weeks
- The study duration: 36 weeks
- The outcome measures:
- Primary: mean change in best-corrected visual acuity (BCVA) from baseline to Week 36
- Secondary: Other changes in ocular anatomy and visual function; a need for supplemental treatment; treatment burden through Week 36 (see here for complete list)
About these findings … what did the company originally report?
As we reported in October 2024, the study met both its primary and secondary endpoints, with CLS-AX demonstrating a “well-tolerated” safety profile.
As for CLS-AX-treated patients not requiring any additional treatment:
- 100% lasted up to 12 weeks
- 67% lasted up to 24 weeks
Plus: Injection frequency among these patients was reduced by 84%.
- See here for more details.
And what is this new data regarding?
In a nutshell: The most recent results encompassed analyses from two sub-groups of the phase 2b study that served as “key clinical insights” in determining the design of Clearside’s anticipated phase 3 non-inferiority clinical trials on CLS-AX.
Break these analyses down by group.
First sub-group: Supports enrolling treatment-naïve wet AMD patients.
- The analysis: Stabilization observed in both BCVA and central subfield thickness (CST) among CLS-AX patients re-dosed at Week 24 with no need for aflibercept or prior re-dosing
- The data: 67% of CLS-AX-treated patients did not require re-dosing at 6 months or aflibercept rescue
- For phase 3 study plans: By targeting the more general wet AMD population in the planned phase 3 trial, there may be an even greater percentage of participants who can reach 6 months without the need for any intervention.
Second sub-group: Supports excluding participants prior to randomization in the phase 3 trial “who demonstrated significant non-disease-related changes in VA.”
- The analysis: Removed visit data from patients with a >10 letter change in BCVA without a corresponding 50 µm change in CST from the previous visit
- Specifically: This demonstrated “compelling BCVA results and provided evidence that excluding this group of potential participants may reduce BCVA variability unrelated to wet AMD.”
- For phase 3 study plans: This may better ensure that the CLS-AX phase 3 data reflects real-world treatment practices
Interesting … where can I see more from this new data report?
Presented by Roger Goldberg, MD, MBA, of Bay Area Retinal Associates Medical Group, the presentation—titled Phase 2b CLS-AX ODYSSEY Trial Results—can be viewed here.
And when can we anticipate these phase 3 plans to kick off?
Based on that presentation, the company intends to initiate two phase 3 studies by the second half (H2) of 2025.
In the meantime, Clearside is expected to meet with the FDA for an end-of-phase 2 meeting before the end of Q1 2025.