Oculis phase 3 DIAMOND trials miss vision endpoints in diabetic macular edema

Oculis has announced its phase 3 DIAMOND-1 and DIAMOND-2 trials of OCS-01 eye drops in patients with diabetic macular edema (DME) did not improve best corrected visual acuity (BCVA) at 52 weeks. The findings effectively close the regulatory path for OCS-01 eye drops in DME, with the company confirming it does not plan to submit a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for this indication.

The failure of DIAMOND-1 (NCT05066997) and DIAMOND-2 (NCT06172257) represents a significant setback for a drug class that had sought to relieve patients and clinicians from the injection-dependent treatment paradigm that currently defines the standard of care.^1,2 The results underscore a longstanding challenge in DME management: the imperfect coupling between anatomical improvement and functional visual recovery.

Trial design and endpoints

The DIAMOND program consisted of 2 phase 3, double-masked, randomized, multicenter trials evaluating the efficacy and safety of OCS-01 eye drops in patients with DME following 52 weeks of treatment. More than 800 patients were enrolled across both pivotal trials at 119 investigational sites throughout the United States and several other countries.

Patients were randomized 1:1 to receive OCS-01 or vehicle 6 times daily during a 6-week induction phase, followed by three times daily through week 52 for the maintenance phase. The primary endpoint was change in BCVA early treatment diabetic retinopathy study (ETDRS) letter score at week 52 compared with baseline. Secondary endpoints included the percentage of patients with a ≥15-letter gain in BCVA and change in central subfield thickness (CST), both at week 52 compared with baseline.

Key efficacy and safety findings

The primary endpoint of mean change in BCVA from baseline to week 52 was not met in both Phase 3 trials. The key secondary endpoint—the proportion of patients achieving a ≥15-letter gain in BCVA—was also not met in both trials.

Despite the absence of functional benefit, the trials produced a potentially noteworthy anatomical signal. The secondary endpoint of retinal thickness, as measured by optical coherence tomography (OCT), showed a substantial and persistent reduction with OCS-01 versus vehicle at all visits in DIAMOND-2 and at all visits except week 52 in DIAMOND-1.

On safety, OCS-01 was reported to be well tolerated, with no unexpected adverse events and a profile consistent with prior clinical experience. Previously documented adverse effects in earlier OCS-01 studies included intraocular pressure elevation, ocular hypertension, and eye irritation, which are class-typical effects of topical corticosteroids.⁵

Based on these results, Oculis stated it does not plan to pursue an FDA regulatory filing for OCS-01 in DME at this time.

Clinical context: Diabetic macular edema burden and treatment landscape

In type 1 diabetes, approximately 27% of patients develop DME within 9 years; for type 2 diabetes, DME prevalence increases from 3% within 5 years of diagnosis to 28% after 20 years of disease duration.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is currently the standard of care for DME management; however, best-achievable vision outcomes depend on frequent injections and close monitoring, which are difficult to maintain in clinical practice because of the burden this imposes on patients. Due to the short duration of action of anti-VEGF agents and persistent disease activity, treatment usually requires frequent administration over several years to maintain therapeutic effect, placing a high treatment burden on patients and their caregivers.

Real-world data confirm significant response heterogeneity: approximately 65.8% of phakic eyes demonstrate a suboptimal response to anti-VEGF treatment at 6 months in some cohorts, and continuing treatment in these suboptimal responders may impose unnecessary burden without meaningful change in visual acuity. These clinical realities created a compelling rationale for a self-administered, noninvasive alternative—and represented the central premise of OCS-01's development program.

Drug background: OCS-01 and OPTIREACH Technology

Leveraging Oculis' proprietary OPTIREACH technology, OCS-01 is a novel, high-concentration (15 mg/ml) topical formulation of dexamethasone developed to reach the retina via an eye drop—a route of administration for DME differentiated from currently available therapies, which are all invasive, such as ocular implants or intravitreal injections.

The OPTIREACH solubilizing formulation technology addresses the main limitations of conventional eye drops by improving the solubility of lipophilic drugs, increasing residence time on the ocular surface, and enabling drug passage from the eye surface to the posterior segment for back-of-the-eye diseases.

Dexamethasone's anti-inflammatory mechanism—suppression of vascular permeability, downregulation of pro-inflammatory cytokines including VEGF, and stabilization of the blood-retinal barrier—provides a biological rationale for use in DME, a condition in which neuroinflammation and vascular leakage contribute to macular thickening and photoreceptor stress.⁶ Prior approval of intravitreal dexamethasone implant (Ozurdex; AbbVie) for DME demonstrated the efficacy of corticosteroid therapy delivered directly to the posterior segment, supporting the therapeutic hypothesis underlying OCS-01.

A peer-reviewed Phase 2 study of OCS-01 in DME published in 2022 reported that the agent was significantly more effective than vehicle in reducing central macular thickness; visual improvement was greater in eyes with lower baseline visual acuity in that cohort.⁷ Additionally, Stage 1 of the DIAMOND program met its primary objective of validating the loading and maintenance dosing regimen with robust statistical significance—a 7.2-letter improvement in BCVA and a 63.6 µm reduction in CST at 6 weeks after initiating topical treatment were reported by an investigator at that time. These earlier positive signals informed the decision to advance to the full Phase 3 program.

OCS-01 also generated a separate positive dataset in the Phase 3 OPTIMIZE trial, where it met both primary endpoints for treatment of inflammation and pain following cataract surgery.⁸

Expert and interpretive framing

The anatomical-functional dissociation observed in DIAMOND is not without precedent in the DME literature and warrants careful consideration rather than dismissal. A systematic review examining the relationship between central macular thickness measured by OCT and visual acuity in DME patients receiving anti-VEGF treatment found no statistically significant association between change in logMAR visual acuity and change in central macular thickness across 41 eligible studies evaluating 2,667 eyes, suggesting that further exploration of additional anatomic factors contributing to visual outcomes is needed.

This body of evidence implies that a reduction in macular fluid volume alone may be insufficient to restore visual function, particularly in eyes with chronic macular edema where photoreceptor or ganglion cell layer damage may have already occurred—damage that persists irrespective of fluid resolution. The significance of the OCT signal in DIAMOND therefore remains unclear without data on baseline photoreceptor integrity, duration of edema, and patterns of individual patient response.

References

1. Oculis Holding AG. Oculis Announces Topline Results from DIAMOND Phase 3 Trials with OCS-01 in Diabetic Macular Edema. GlobeNewswire. May 29, 2026. https://www.globenewswire.com/news-release/2026/05/29/3303787/0/en/Oculis-Announces-Topline-Results-from-DIAMOND-Phase-3-Trials-with-OCS-01-in-Diabetic-Macular-Edema.html

2. Nakao S, Kusuhara S, Murakami T. Anti-VEGF therapy for the long-term management of diabetic macular edema: a treat-to-target strategy based on macular morphology. Graefes Arch Clin Exp Ophthalmol. 2024;262(12):3749-3759. doi:10.1007/s00417-024-06558-y. https://pubmed.ncbi.nlm.nih.gov/38995350/

3. ClinicalTrials.gov. A Pivotal Safety and Efficacy Study of OCS-01 Eye Drops in Participants With Diabetic Macular Edema (DIAMOND-1). NCT05066997. https://clinicaltrials.gov/study/NCT05066997

4. ClinicalTrials.gov. A Pivotal Safety and Efficacy Study of OCS-01 Eye Drops in Participants With Diabetic Macular Edema (DIAMOND-2). NCT06172257. https://clinicaltrials.gov/study/NCT06172257

5. Diamond Trial. What to Expect: Potential Side Effects. Accessed June 2, 2026. https://diamondtrial.com/what-to-expect/

6. Plackett B. Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options. J Ophthalmol. 2021;2021:8847406. doi:10.1155/2021/8847406. https://pmc.ncbi.nlm.nih.gov/articles/PMC8145407/

7. Khanani AM, Kozak I, Tadayoni R, et al. Topical treatment of diabetic macular edema using dexamethasone ophthalmic suspension: A randomized, double-masked, vehicle-controlled study. Acta Ophthalmol. 2022. doi:10.1111/aos.15195. https://pubmed.ncbi.nlm.nih.gov/35848336/

8. Hutton D. First investigational eye drop for front and back of the eye met both primary endpoints in Phase 3 OPTIMIZE trial. Ophthalmology Times. August 8, 2023. https://www.ophthalmologytimes.com/view/first-investigational-eye-drop-for-front-and-back-of-the-eye-met-both-primary-endpoints-in-phase-3-optimize-trial

9. Oculis Holding AG. Oculis Announces Positive Top Line Results from Phase 3 Trial of OCS-01 Drops for Diabetic Macular Edema [Stage 1]. Ophthalmology Times. 2023. https://www.ophthalmologytimes.com/view/oculis-announces-positive-top-line-results-from-phase-3-trial-of-ocs-01-drops-for-diabetic-macular-edema

10. Gao B, Bhosle D, Bhosle V, Gao R, Bhosle M. Diabetic Macular Edema Management: A Review of Anti-Vascular Endothelial Growth Factor (VEGF) Therapies. J Clin Med. 2024;13(2):416. doi:10.3390/jcm13020416. https://pmc.ncbi.nlm.nih.gov/articles/PMC10804209/

11. Romao EB, Ferreira C, Rodrigues IA, et al. Suboptimal outcomes and treatment burden of anti-vascular endothelial growth factor treatment for diabetic macular oedema in phakic patients. Eye (Lond). 2024;38(2):292-298. doi:10.1038/s41433-023-02706-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764926/

12. Karger Publishers. The Association between Retinal Thickness Fluctuations and Visual Outcomes under Anti-Vascular Endothelial Growth Factor Therapy: A Systematic Review and Meta-Analysis. Ophthalmologica. 2024;247(4):261. doi:10.1159/000539474. https://karger.com/oph/article/247/4/261/909043/

13. Funatsu H, Kitano S, Nishikawa S, et al. Relationship Between Macular Thickness and Visual Acuity in the Treatment of Diabetic Macular Edema With Anti-VEGF Therapy: Systematic Review. JAMA Ophthalmol. 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954155/

14. Oculis Holding AG. Oculis Completes Enrollment in Both DIAMOND Phase 3 Trials of OCS-01 in Diabetic Macular Edema. GlobeNewswire. April 10, 2025. https://investors.oculis.com/news-releases/news-release-details/oculis-completes-enrollment-both-diamond-phase-3-trials-ocs-01