What drugs are in development for Diabetic macular oedema?

Overview of Diabetic Macular Oedema

Diabetic macular oedema (DMO) is a vision‐threatening complication of diabetes mellitus that affects the central retina (the macula) and is the primary cause of visual impairment in diabetic patients. The condition results from the breakdown of the blood–retinal barrier, leading to accumulation of fluid and subsequent thickening of the macula. In recent decades, our understanding of DMO’s pathogenesis has evolved significantly; it is now clear that chronic hyperglycemia leads to a cascade of biochemical events, including oxidative stress, inflammation, and up‐regulation of vasoactive mediators like vascular endothelial growth factor (VEGF) that ultimately cause vascular leakage and fluid accumulation.

Definition and CausesDiabetic macular oedemama is defined as the abnormal accumulation of fluid in the macula secondary to increased vascular permeability. Its pathogenesis is multifactorial. Chronic hyperglycemia triggers a range of metabolic abnormalities such as activation of the polyol pathway and formation of advanced glycation end‐products, which promote inflammation and endothelial dysfunction. The consequent overexpression of cytokines and growth factors, particularly VEGF, increases vascular permeability, leading to oedema. In addition, inflammatory cytokines (e.g., interleukins, tumor necrosis factor‐alpha) further weaken the tight junctions of retinal vascular endothelial cells, reinforcing the leakage process. This cascade of events not only causes structural changes at the macula but also disrupts retinal neuronal function, thereby compromising visual acuity.

Current Treatment Landscape

Historically, grid or focal laser photocoagulation was the standard care for DMO, acting by reducing oxygen demand and decreasing the production of VEGF locally. However, laser treatment does not restore lost vision and may even lead to scotomas in some patients. Over the past decade, intravitreal injections of anti‐VEGF drugs (e.g., ranibizumab, aflibercept, bevacizumab) and corticosteroid implants (e.g., dexamethasone implant) have revolutionized DMO management by directly addressing the underlying pathophysiology. Although these therapies have achieved significant success and have become first‐line treatments, they require repeated intravitreal injections, carry a certain procedural burden, and in some cases may not achieve a favorable response in all patients. Consequently, there is strong interest in developing next‐generation, less invasive, more durable, and potentially combination or novel mechanism drugs to further improve treatment outcomes.

Drugs in Development

Given the unmet need to reduce injection frequency, improve patient convenience, and expand the therapeutic benefits beyond what current anti‐VEGF or corticosteroid agents offer, numerous drugs are in development for DMO. These candidate drugs are being explored from several angles: some aim to improve drug delivery (e.g., topical formulations), others target additional pathways beyond VEGF, and still others try to combine anti‐inflammatory, anti‐VEGF, and neuroprotective effects in one formulation.

Novel Drug Candidates

A number of novel candidates are emerging in the DMO space:

1. Topical Drug Candidates:
One of the most promising areas is the development of topical formulations that can deliver therapeutic concentrations to the posterior segment without the need for invasive injections. For example, OCS-01 is a topical eye drop formulation based on a high‐concentration dexamethasone preparation developed by Oculis. It is being evaluated in Phase 2 studies and has shown promising results in reducing macular thickness and improving visual acuity when compared with vehicle in diabetic macular oedema. Another promising topical candidate is OTT166, developed by OcuTerra Therapeutics. OTT166 is being assessed in a dose‐escalation clinical trial for DMO with the aim of providing a noninvasive alternative, which could substantially reduce the treatment burden on patients.

2. Intravitreal Candidate with Extended Durability:
New intravitreal formulations are also in development that combine sustained drug release with robust efficacy. Although anti‐VEGF agents (ranibizumab, aflibercept, bevacizumab) have already been approved, next‐generation formulations such as longer‐acting agents or port delivery systems are being designed to reduce the number of injections needed over time. Some agents, like brolucizumab or even KSI-301 (a novel anti–VEGF agent with an extended ocular half-life), are in development and are being evaluated for DMO in efforts to provide extended durability. Even though these agents were initially studied in the context of neovascular age‐related macular degeneration, similar kinetic and ocular pharmacodynamic profiles make them promising for DMO as well.

3. Molecules Targeting Alternative Pathways:
In addition to VEGF antagonism, there is growing interest in drugs that target other inflammatory and metabolic pathways. Some preclinical candidates aim to inhibit cytokines, modulate the renin–angiotensin system, or target the Ang/Tie2 pathway to stabilize retinal vasculature. These molecules could be used alone or in combination with anti–VEGF therapies to address the multifactorial pathogenesis of DMO. For instance, compounds that inhibit hypoxia‐inducible factors (HIF) offer an alternative approach to reduce VEGF expression indirectly and might have additive effects when combined with current therapies.

4. Combination Therapies and Novel Delivery Systems:
Besides single‐agent candidates, combination therapies are being explored to achieve synergistic efficacy. These include candidates that combine anti–VEGF properties with corticosteroid delivery or other anti‐inflammatory actions. In parallel, novel drug delivery devices (such as sustained‐release microimplants and nanoparticle‐based systems) are under development to extend the release profile of these agents and improve the durability of the treatment effect without frequent interventions.

Mechanisms of Action

The drugs in development use several innovative mechanisms:

1. Direct VEGF Inhibition with Extended Durability:
Next-generation anti–VEGF candidates are designed not only to block VEGF binding to its receptors but to maintain therapeutic levels over longer periods. These agents may be engineered as larger molecules or antibody fragments with improved tissue retention, allowing for extended intervals between injections.

2. Topical Anti-Inflammatory and Anti-VEGF Activity:
Topical formulations such as OCS-01 deliver potent corticosteroids that work by reducing inflammation, stabilizing endothelial tight junctions, and decreasing VEGF expression. In turn, these changes reduce retinal vascular permeability and fluid accumulation. Similarly, OTT166 is being developed as a topical agent that can suppress proinflammatory mediators directly on the ocular surface and through posterior segment penetration.

3. Multi-targeted Approaches:
As the pathogenesis of DMO involves both inflammation and vascular leakage, some drug candidates are being designed to exert dual or multi-target actions. These drugs may combine VEGF inhibition with blockade of other cytokines such as IL-6 or TNF-α, or they might work by dampening the overall inflammatory milieu that contributes to barrier breakdown. Such multi-mechanistic strategies are thought to improve outcomes, especially in patients who show suboptimal responses to current monotherapies.

4. Alternative Delivery Platforms:
Novel delivery platforms (for example, sustained-release implants and nanocarriers) are being integrated with active drug molecules to enhance bioavailability in the retina. These platforms are designed to provide a more consistent drug level over time, reduce peak systemic exposure and local side effects, and ultimately decrease injection frequency. This approach represents an important shift from the conventional bolus intravitreal injection paradigm.

Clinical Trials and Research

Robust clinical research supports the development of these innovative therapies. A diverse range of ongoing clinical trials is evaluating the safety, efficacy, and treatment durability of these novel candidates. Both early-phase and later-phase studies are building an evidence base that will potentially expand the treatment armamentarium and offer less invasive or more durable therapies for DMO.

Ongoing Clinical Trials

Several clinical trials are currently underway:

1. Topical OCS-01 Trials:
Oculis’s Phase 2 clinical trial on OCS-01 has recently been published and presented at key ophthalmic congresses, showing statistically significant improvements in central macular thickness and visual acuity. This trial is particularly important for demonstrating that a noninvasive eye drop can achieve therapeutic drug levels in the posterior segment.

2. OTT166 Eye Drops Trials:
OTT166 is undergoing a Phase Ib/II dose-escalation study. The trial is designed to evaluate the safety, tolerability, and initial efficacy of this novel topical formulation in patients with centre-involved DMO. Early signals from this trial suggest that OTT166 may reduce retinal thickness and improve vision with a favorable safety profile.

3. Extended Release Anti–VEGF Formulations:
There are studies investigating next-generation anti–VEGF agents such as brolucizumab, KSI-301, and port delivery systems loaded with anti–VEGF molecules. These trials are aimed at extending the dosing intervals by achieving sustained intravitreal drug levels. The clinical endpoints typically focus on best-corrected visual acuity (BCVA) changes, central macular thickness (CMT) reductions, and durability of the treatment effect.

4. Combination and Multi-target Trials:
Several trials are testing combination therapies—either combining intravitreal anti–VEGF injections with adjunctive laser photocoagulation or with intravitreal corticosteroids—to determine whether a multi-targeted approach offers enhanced outcomes compared to monotherapy. These studies explore whether early integration of combination therapy can reduce the overall treatment burden and improve long-term visual outcomes.

Results from Recent Studies

Recent research findings underscore the benefits and limitations of these emerging drugs:

1. Topical Drug Efficacy:
In early Phase 2 studies for OCS-01, patients treated with the eye drop demonstrated statistically significant improvements in visual function compared to those receiving a vehicle control. The data indicated a between-group difference in improvement of BCVA and a reduction in central macular thickness. Such results are promising because they open the possibility of noninvasive, self-administered treatment that could revolutionize how DMO is managed.

2. Dose-Escalation and Safety Data for OTT166:
Preliminary data from the OTT166 trials reveal that the drug is well tolerated, with few adverse events. Early efficacy signals, such as a measurable decrease in retinal thickness and modest improvements in visual acuity, have been encouraging enough to support further investigation in larger cohorts.

3. Extended Durability of New Anti–VEGF Formulations:
Clinical trials testing extended-release anti–VEGF candidates have reported that some new formulations extend the duration of action beyond that of standard agents. For example, preliminary outcomes have shown sustained BCVA improvement with fewer injections over a year, suggesting that these drugs may reduce the injection frequency and thus lessen the patient burden and risk for injection-related complications.

4. Combination Therapy Outcomes:
Combination therapies, which integrate anti–VEGF agents with focal/grid photocoagulation or corticosteroids, have demonstrated a potential for additive benefits. Some pilot studies have observed that patients receiving a combined regimen require fewer injections while achieving superior or equivalent visual improvements compared to those receiving standard care, suggesting that combining treatment modalities could be an effective strategy in resistant cases.

Future Directions and Challenges

The field of DMO drug development is moving toward novel therapeutic approaches that promise to overcome some of the limitations associated with current therapies. However, many challenges remain—from optimizing drug delivery to navigating regulatory pathways.

Emerging Therapies

Emerging therapies are not limited to just reformulating existing drugs; they involve entirely new strategies such as:

1. Novel Anti–VEGF and Multi-target Agents:
Researchers are exploring dual-action molecules that inhibit VEGF as well as inflammatory cytokines. These agents aim to address the multifactorial nature of DMO by simultaneously targeting two or more pathogenic pathways. Early preclinical and clinical evidence supports the notion that blocking both VEGF and inflammatory mediators leads to an improved therapeutic effect compared to VEGF inhibition alone.

2. Gene Therapy and Molecular Modulation:
Beyond protein-based drugs, gene modulation techniques are being tested in preclinical models to down-regulate the expression of key mediators such as VEGF, HIF, or inflammatory chemokines. Gene therapies that aim to restore the integrity of the endothelial barrier or reduce the chronic inflammatory state in the retina are in very early development and hold promise for long-term disease modification.

3. Advanced Drug Delivery Systems:
The development of sustained-release implants, nanoparticle carriers, and novel ocular delivery platforms is a rapidly evolving field. These systems promise to maintain therapeutic drug concentrations in the posterior segment for extended periods and may allow for personalized dosing regimens based on pharmacokinetic modeling. Their design represents a fusion of innovative drug molecules with advanced technologies that overcome the inherent challenges of crossing the ocular barriers.

Regulatory and Approval Processes

For novel therapies in DMO, the regulatory landscape is challenging:

1. Rigorous Safety and Efficacy Assessments:
New drugs must prove not only that they work better or as well as existing therapies but that they provide advantages in safety, convenience, or durability that justify their development and potential higher cost. Regulatory agencies such as the FDA and EMA require extensive clinical data from randomized controlled trials (RCTs) to ensure that new candidates hold up against these standards.

2. Innovative Clinical Endpoints:
Because of the treatment burden associated with intravitreal injections, regulatory bodies are beginning to look for endpoints beyond just change in BCVA and retinal thickness. Measures of treatment persistence, quality of life improvement, and patient satisfaction are increasingly important. Novel biomarkers derived from advanced imaging (such as OCT angiography) might also play a role in regulatory decision-making in the future.

3. Translating Topical and Extended-release Therapies:
For topical formulations like OCS-01 and OTT166, demonstrating that a noninvasive route can achieve therapeutic levels in the posterior segment remains a significant regulatory hurdle. Clinical trial designs must include robust pharmacokinetic and pharmacodynamic studies to overcome skepticism about drug penetration. Furthermore, bridging studies that compare these new delivery methods with established intravitreal injections are essential.

Challenges in Drug Development

Several challenges hamper the development of new DMO therapies:

1. Patient Heterogeneity and Nonresponse:
One of the principal challenges in DMO therapy is the variability among patients. Up to 30% or more of patients may be nonresponders or partial responders to standard anti–VEGF therapies. New drugs must not only work for the average patient but also target this subgroup. Personalized medicine approaches based on genetic, systemic, and ocular biomarkers are being investigated to stratify patients and guide treatment choices.

2. Long-Term Safety:
New treatments must be safe over the long term. Chronic exposure to corticosteroids, for example, is associated with cataract formation and elevated intraocular pressure. Similarly, repeated intravitreal injections carry risks of endophthalmitis and retinal detachment. Developing drugs with fewer injections and lower systemic exposure is a priority.

3. Economic and Logistical Considerations:
The high cost and logistical burden associated with current intravitreal treatments have driven interest in less invasive options. However, production costs for novel molecules and sustained-release systems can be high. Thus, there is a delicate balance between innovation and affordability in drug development for DMO.

4. Integration of Combination Therapies:
While combination therapies appear promising, determining the optimal timing and dosing for multi-targeted strategies is complex. Clinical trials must be designed carefully to assess the additive or synergistic effects of drug combinations, while also monitoring for unforeseen adverse interactions.

5. Bridging the Gap Between Preclinical Success and Clinical Efficacy:
Many promising drug candidates show excellent efficacy in preclinical models but fail to translate these benefits in clinical trials. This translational gap is a significant hurdle, emphasizing the need for improved animal models and early phase clinical trial designs that accurately predict human outcomes.

Detailed Conclusion

In summary, diabetic macular oedema is a multifactorial retinal condition originating from chronic hyperglycemia, inflammation, and abnormal vascular permeability. Current therapies—primarily intravitreal anti–VEGF agents and corticosteroid implants—have significantly improved visual outcomes but carry a heavy treatment burden and do not work optimally in all patients. This unmet need has spurred the development of a host of innovative drug candidates for DMO.

On one hand, novel topical formulations such as OCS-01 and OTT166 are showing promise by potentially offering noninvasive treatment options that can alleviate the burdens associated with repeated injections. These candidates capitalize on anti-inflammatory and barrier-stabilizing properties to reduce retinal oedema. On the other hand, next-generation intravitreal agents with extended durability—such as advanced anti–VEGF formulations and drug delivery systems like port delivery implants—are being developed to reduce injection frequency. In addition, multi-targeted molecules that block not only VEGF but also inflammatory cytokines are emerging, addressing the complex interplay of pathogenic mechanisms in DMO.

Clinical trials are currently underway to establish the safety, efficacy, and durability of these new candidates. Early-phase data have been encouraging, with some studies showing significant anatomical and functional improvements compared with baseline or vehicle controls. Ongoing trials are exploring extended-release strategies and combination therapies that could potentially enhance efficacy while reducing treatment burden. At the same time, researchers are working under challenging regulatory frameworks that demand robust evidence of both short-term and long-term benefits, which include not only vision outcomes but also improvements in quality of life and treatment persistence.

Future directions in DMO drug development are likely to emphasize personalized medicine, where a patient’s specific biomarker profile (obtained from advanced imaging and other systemic parameters) could inform the choice of therapy. Moreover, there is a growing emphasis on combination regimens that integrate the anti–VEGF, anti-inflammatory, and neuroprotective pathways. However, these developments come with challenges such as ensuring long-term safety, managing economic burdens, and overcoming the translational gap between preclinical success and clinical efficacy.

In conclusion, the pipeline for diabetic macular oedema is robust and multifaceted. Novel drug candidates like OCS-01, OTT166, extended-release anti–VEGF formulations, and multi-targeted agents are under active development. These innovations promise to reduce the treatment burden, offer noninvasive alternatives, and address patient subgroups that are currently inadequately served by existing therapies. At the same time, integration of advanced drug delivery systems and combination therapy strategies highlights the future direction of DMO management. With continued rigorous clinical research and careful regulatory navigation, these emerging therapies hold the potential to substantially improve outcomes for the millions affected by diabetic macular oedema worldwide.

Each perspective—from mechanism of action and clinical durability to economic and regulatory challenges—provides an insight into the complexities and innovations in DMO drug development. The future of DMO therapy lies in a more personalized, less invasive, and more durable treatment approach that addresses not only the immediate anatomical abnormalities but also the broader inflammatory and metabolic derangements underlying the disease.