Phase 1b LOTUS Trial of EB-105 Targets IL-6R in Diabetic Macular Edema
Overview
The phase 1b LOTUS trial evaluated EB-105, a novel pentavalent trispecific antibody targeting VEGF-A, VEGF-B, PIGF, ANG-2, and IL-6R, in patients with diabetic macular edema (DME). The study demonstrated safety, tolerability, and promising efficacy signals including improved visual acuity and reduced retinal thickness after a single injection.
Background
Diabetic macular edema (DME) is a leading cause of vision loss in diabetic patients, driven by vascular permeability and inflammation. Current treatments primarily target VEGF pathways, but durability and efficacy remain challenges. Faricimab introduced dual targeting of VEGF and ANG-2 pathways, improving outcomes. EB-105 is designed to expand therapeutic mechanisms by additionally inhibiting IL-6R, an inflammatory cytokine implicated in retinal edema, potentially enhancing treatment response.
Data Highlights
| Parameter | Baseline Mean | Post-Treatment Change |
|---|---|---|
| Best-Corrected Visual Acuity (BCVA) | 20/60 | +7 letters mean gain (up to +21 letters in some patients) |
| Central Subfield Thickness (CST) | 492 μm | ~100 μm reduction |
| Number of Patients | 13 (mean age 61 years) | |
| Dose Levels | 1.6 mg, 4 mg, 8 mg single ascending doses | |
| Prior Anti-VEGF Injections | Mean 4.3 injections (2 treatment-naive patients) | |
Key Findings
- EB-105 was safe and well tolerated with no dose-limiting toxicities, serious adverse events, ocular inflammation, or drug-related adverse events.
- All 13 patients completed the 3-month study; only one patient in the low-dose group required rescue treatment at month 2.
- Mean BCVA improved by 7 letters after a single injection, with some patients gaining up to 21 letters.
- Central subfield thickness decreased by approximately 100 μm, indicating reduced retinal edema.
- A slight dose-response relationship was observed despite the small sample size, supporting dose escalation in future studies.
- No detectable systemic levels of EB-105 were found, suggesting limited systemic exposure.
Clinical Implications
EB-105’s multi-targeted approach including IL-6R inhibition represents a promising new mechanism for treating DME, potentially improving efficacy and durability beyond current anti-VEGF therapies. The favorable safety profile and early efficacy signals support further investigation in larger, longer-duration trials. Clinicians should anticipate upcoming phase 1-2 studies evaluating multiple doses and extended follow-up to better define its clinical role.
Conclusion
The phase 1b LOTUS trial of EB-105 demonstrates encouraging safety and efficacy in DME, validating IL-6R as a novel therapeutic target. Continued development may expand treatment options for patients with retinal edema.
References
- Sheth et al. 2024 -- Phase 1b LOTUS Trial Targets IL-6R for DME
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