What drugs are in development for Wet age-related macular degeneration?

Overview of Wet Age-related Macular DegenerationDefinitionon and Pathophysiology
Wet age-related macular degeneration (wet AMD) is defined as the advanced, neovascular form of AMD that is characterized by the growth of abnormal new blood vessels from the choroid into the subretinal space. These newly formed vessels are fragile and tend to leak fluid, blood, and lipids into the macular region, ultimately causing rapid and irreversible damage to central vision. The pathophysiology of wet AMD involves a complex interplay between vascular, inflammatory, genetic, and environmental factors. At the cellular level, the dysfunction of the retinal pigment epithelium (RPE) and breakdown of the blood‐retinal barrier trigger an increase in vascular endothelial growth factor (VEGF) levels. VEGF, a potent angiogenic mediator, stimulates the formation of choroidal neovascularization (CNV) while also increasing vascular permeability. Oxidative stress, chronic inflammation, and complement system dysregulation further contribute to the disease cascade, accelerating the neovascular process and leading to photoreceptor loss and fibrotic scar formation in the macula. Recent studies have also suggested that mounting an inflammatory response and alterations in the extracellular matrix set the stage for the abnormal angiogenic response observed in wet AMD. These molecular and structural changes explain not only the rapid progression of vision loss but also the challenges in reproducing long‐term efficacy with existing treatments.

Current Treatment Landscape
The current treatment paradigm for wet AMD is dominated by intravitreal injections of anti-VEGF agents such as ranibizumab, aflibercept, and the more recently introduced brolucizumab. These drugs work by neutralizing VEGF–which is central to the neovascular process–and thus prevent the growth and leakage of abnormal vessels. Despite the dramatic improvement in visual outcomes provided by anti-VEGF therapies, these treatments are burdened with limitations. Frequent monthly or bi-monthly injections are typically required to maintain therapeutic benefit, leading to substantial patient inconvenience, increased risk of injection-related complications, and high healthcare costs. Moreover, real-world studies have revealed that efficacy in routine practice often lags behind the results of tightly controlled clinical trials, largely due to under-treatment and non-adherence. These challenges have inspired robust research activity; as the understanding of wet AMD progresses, there is a significant push to discover or develop novel therapeutic candidates that not only target the VEGF pathway more durably but also act on complementary or alternative targets to overcome the intrinsic limitations of current therapies.

Drugs in Development

Promising Drug Candidates
A diverse range of drugs is currently in development for wet AMD, spanning several therapeutic modalities and mechanisms of action. Among these, several classes of drugs are emerging as particularly promising:

•  ADVM-022 (also known as ixoberogene soroparvovec or Ixo-vec) is a gene therapy product candidate developed by Adverum. Administered as a single intravitreal injection, ADVM-022 uses an adeno-associated viral (AAV) vector to deliver a gene cassette encoding aflibercept. Its aim is to provide sustained production of the anti-VEGF protein by retinal cells, potentially overcoming the need for repetitive intravitreal injections. Early-phase clinical studies have focused on determining the appropriate dosing regimen and evaluating the long-term durability and safety of this approach.

•  OPT-302 is another promising candidate currently in development. Unlike traditional anti-VEGF agents that primarily neutralize VEGF-A isoforms, OPT-302 is designed to inhibit VEGF-C and VEGF-D. These isoforms are thought to contribute to angiogenesis when VEGF-A is already under suppression, thereby representing a complementary mechanism. The use of OPT-302 in combination with existing anti-VEGF therapies is being explored to achieve enhanced vision gains and extend dosing intervals. Key Phase III registrational trials, including the ShORe and COAST studies, are underway to evaluate its efficacy and safety in patients with wet AMD.

•  D-4517.2 is an investigational oral and subcutaneously administered small molecule that functions as a VEGF receptor tyrosine kinase inhibitor (TKI). Formulated with hydroxyl dendrimer technology, D-4517.2 is designed to cross the blood–retinal barrier and target activated microglia, macrophages, and hypertrophic RPE cells that contribute to CNV development. Preclinical studies in Vldlr knockout mice have demonstrated significant reduction in the number of CNV lesions with D-4517.2 treatment, suggesting its potential as an adjunct or alternative to intravitreal injections.

•  In addition to these candidates, the current pipeline includes several other novel agents such as KSI-301, RGX-314, AKST4290, GB-102 (Sunitinib Malate), RBM-007, Lytenava (a bevacizumab variant), UBX1325, PAN-90806, and CLS-AX (Axitinib). These candidates represent a variety of approaches including sustained-release formulations, gene therapy vectors, novel antibody derivatives, and small molecules. For instance, RGX-314 is a gene therapy candidate engineered to deliver a continuous supply of a soluble VEGF inhibitor directly from retinal cells. Similarly, KSI-301 is a large molecule anti-VEGF therapeutic that promises extended durability compared to current options. The inclusion of GB-102, an injectable microparticle formulation of sunitinib, aims to provide long-lasting VEGF inhibition with fewer injections. Although detailed efficacy and safety data for each of these candidates are still emerging, the breadth of the pipeline indicates a strong consensus in the industry regarding the need to develop therapies that address the limitations of current anti-VEGF treatments.

•  Other investigational agents under exploration include bispecific antibodies and dual-target approaches. For example, while faricimab—a bispecific antibody targeting both VEGF-A and angiopoietin-2—is already approved, next-generation bispecifics are being refined to further extend dosing intervals and reduce systemic exposure. Complement inhibitors such as POT-4 and ARC1905, although originally studied primarily for inflammatory or complement-mediated pathways, are being revisited as potential adjunctive therapies in wet AMD. There is also interest in targeting novel angiogenic factors such as secretogranin III (Scg3), which appears to drive pathological angiogenesis independent of VEGF, offering an alternative therapeutic target to tackle resistance to standard anti-VEGF treatment.

Mechanisms of Action
The drugs under development for wet AMD employ a range of mechanisms of action that can be grouped into several broad categories:

•  Gene Therapy Approaches – Candidates like ADVM-022 and RGX-314 aim to exploit the potential of gene therapy by delivering transgenes that enable the host retinal cells to produce therapeutic proteins continuously. These therapies typically use AAV-based vectors to introduce genes encoding anti-VEGF proteins (e.g., aflibercept) into the retinal cells. The goal of this strategy is to achieve durable inhibition of VEGF with a single administration, thereby substantially reducing the treatment burden.

•  Targeting Alternative VEGF Isoforms – Traditional anti-VEGF agents focus on inhibiting VEGF-A; however, some patients continue to experience CNV progression despite such treatments. OPT-302 addresses this gap by specifically neutralizing VEGF-C and VEGF-D. These isoforms may have compensatory roles when VEGF-A is inhibited, and their suppression can lead to more complete attenuation of pathological angiogenesis.

•  Small Molecule Inhibition – Drugs like D-4517.2 are small molecule inhibitors that target intracellular signaling pathways downstream of VEGF receptors. By inhibiting the tyrosine kinase activity of VEGF receptors, these agents prevent the cascade of intracellular signals that lead to angiogenesis, vascular leakage, and inflammation. The use of novel formulations, such as hydroxyl dendrimer conjugates, may enhance tissue penetration and improve pharmacokinetic profiles.

•  Sustained-Release and Extended-Duration Formulations – Some drug candidates are designed not only to target angiogenic pathways but also to improve the duration of their therapeutic effect. KSI-301, for example, is engineered as a large molecule with an extended half-life, which may allow for dosing intervals that surpass those of current monthly regimens. Similarly, injectable microparticle formulations like GB-102 are designed to slowly release an active drug over an extended period.

•  Dual-targeting and Bispecific Antibodies – Given that VEGF is not the sole driver of CNV, therapies that target additional pathways are being developed. Next-generation bispecific antibodies aim to simultaneously inhibit multiple targets (for example, VEGF-A and Angiopoietin-2) to enhance efficacy and durability. Although faricimab has paved the way, ongoing research is focused on optimizing these constructs to minimize adverse events and improve patient outcomes.

•  Complement Inhibition and Novel Angiogenic Factor Blockade – Recent research has highlighted the role of the complement system and other non-VEGF angiogenic factors in the pathogenesis of wet AMD. By inhibiting components such as complement factor C3 or novel factors like Scg3, these agents may offer an alternative route to mitigate neovascularization and inflammation, either as stand-alone therapies or in combination with established anti-VEGF treatments.

Clinical Trials and Research

Key Ongoing Clinical Trials
Several pivotal clinical trials are underway to evaluate the efficacy and safety of these emerging therapies in wet AMD:

•  ADVM-022 – Early-phase (Phase I/II) trials of ADVM-022 have been initiated to assess the safety profile, dosage parameters, and long-term durability of this gene therapy product. The design of these studies involves a single intravitreal injection with subsequent monitoring of aflibercept expression levels, visual acuity outcomes, and potential inflammatory responses in the treated eyes.

•  OPT-302 – The OPT-302 clinical development program includes two key registrational Phase III trials, the ShORe and COAST studies. These trials are investigating the combination of OPT-302 with standard anti-VEGF therapy in treatment-naïve patients with wet AMD. Primary endpoints include improvements in best-corrected visual acuity (BCVA) and reductions in central retinal thickness. The data being collected will provide insights into whether dual inhibition of VEGF isoforms yields superior clinical outcomes compared to anti-VEGF monotherapy.

•  D-4517.2 – Though still in preclinical to early clinical phases, trials investigating D-4517.2 are evaluating its ability to reduce CNV lesions as demonstrated by imaging markers and visual acuity improvements. Animal model studies using Vldlr knockout mice have provided promising results that warrant further evaluation in human subjects.

•  4D-150 – Another gene therapy candidate, 4D-150, which combines a transgene cassette expressing aflibercept with a VEGF-C inhibitory RNA interference (RNAi) molecule, is currently being evaluated in a Phase 2 dose expansion study. Interim clinical data presented in these trials focus on safety parameters, dosing frequency, and preliminary efficacy endpoints such as BCVA improvements and central retinal thickness reduction.

•  Other Trials – In addition to the above trials, several other Phase II and Phase III studies are exploring candidates like KSI-301, RGX-314, and microparticle formulations like GB-102. Although detailed public data from all of these trials are not yet available, they are being closely monitored due to their potential to extend treatment intervals and enhance visual outcomes. Moreover, combination therapy studies that integrate new agents with established anti-VEGF drugs are also ongoing, reflecting the trend toward multifactorial treatment approaches in wet AMD.

Efficacy and Safety Data
Preliminary data emerging from these clinical investigations suggest several encouraging trends:

•  OPT-302 Combination Therapy – Early results from the OPT-302 registrational trials indicate that when used in combination with an anti-VEGF agent, OPT-302 can yield statistically significant improvements in BCVA compared with anti-VEGF monotherapy. In these studies, patients receiving the combination therapy showed not only superior visual gains but also a potential reduction in injection frequency, which is a critical factor in reducing treatment burden.

•  ADVM-022 Gene Therapy – Phase I/II data on ADVM-022 have demonstrated that a single intravitreal injection can lead to sustained expression levels of aflibercept in the retina. Patients have exhibited stabilization of visual acuity over extended follow-up periods, and although there are concerns regarding inflammation and immune responses, these events appear manageable with appropriate prophylactic regimens. Safety profiles remain a focal point of ongoing analysis, with dose optimization studies being crucial to striking a balance between efficacy and tolerability.

•  D-4517.2 Preclinical Evidence – Data derived from animal models have shown that D-4517.2 can effectively reduce the number of CNV lesions, thereby supporting its potential utility as a non-invasive therapeutic option. While human data are still awaited, the promising preclinical efficacy and the favorable safety signals reported in these studies underscore the need for further clinical evaluation.

•  4D-150 Interim Results – The Phase 2 dose expansion study for 4D-150 has thus far indicated that the dual-transgene strategy can produce sustained therapeutic protein levels with acceptable adverse event profiles. Visual outcomes, measured by changes in BCVA and central retinal thickness, are trending in the positive direction, although longer-term data are necessary for a comprehensive assessment.

•  Overall Safety Trends – One consistent theme across emerging therapies is the emphasis on reducing treatment burden while maintaining or enhancing efficacy. Extended durability, whether achieved through gene therapy, novel sustained-release formulations, or combination therapies, is a central aim. Safety data that continue to emerge from these trials have generally suggested that when compared with monthly intravitreal injections, newer modalities have the potential to reduce the frequency of invasive procedures and ultimately lower the risk of injection-related complications.

Future Directions in Treatment

Innovations in Drug Development
The current research landscape is witnessing several innovative developments that promise to transform the way wet AMD is managed:

•  Gene Therapy as a Paradigm Shift – The use of gene therapy in wet AMD represents one of the most exciting advances in drug development. By enabling retinal cells to produce anti-VEGF proteins continuously, therapies such as ADVM-022 and RGX-314 could potentially eliminate the need for repeated intravitreal injections. This “one-and-done” approach may lead to improved patient compliance and a more sustained therapeutic effect. Future innovations may focus on refining vector design, optimizing transgene expression, and further minimizing immune-related adverse events.

•  Extended-release Formulations and Delivery Devices – In addition to gene therapy, drug developers are working on novel delivery strategies designed to prolong the duration of therapeutic effect. Agents like KSI-301 and GB-102 aim to reduce the dosing frequency by incorporating molecular modifications or sustained-release formulations into their design. Such strategies include microparticle-based delivery systems and implantable devices that gradually release the active drug into the vitreous, thus potentially doubling or even tripling the intervals between treatments.

•  Dual-target and Multitarget Strategies – Recognizing that VEGF is not the sole driver of CNV, there is a trend toward designing therapies that target additional angiogenic or inflammatory mediators. OPT-302, which neutralizes VEGF-C and VEGF-D, and bispecific antibodies which simultaneously block VEGF-A and angiopoietin-2 are examples of this approach. These dual-target strategies have the potential to overcome resistance mechanisms that may limit the long-term efficacy of conventional anti-VEGF therapy and may lead to more robust and durable visual outcomes.

•  Non-Invasive Treatment Modalities – Future drug development is also exploring non-invasive or minimally invasive alternatives that could further reduce the burden of frequent clinic visits. Agents such as D-4517.2, which can be administered orally or subcutaneously, represent a novel paradigm that shifts away from the conventional intravitreal injection model. The convenience and safety of non-invasive delivery could revolutionize the management of wet AMD, particularly in elderly patients who face significant challenges with frequent office visits.

•  Personalized Medicine and Biomarker-Driven Strategies – As our understanding of the genetic and molecular underpinnings of AMD deepens, future therapies are likely to incorporate biomarker-based patient stratification. Predictive markers, as described in some patents, can help identify patients who are likely to respond to specific therapies. This personalized approach will allow clinicians to tailor treatments to the individual, thereby maximizing efficacy while minimizing adverse effects and unnecessary treatments.

Potential Impact on Patient Outcomes
The ultimate goal of these innovative therapeutic strategies is to dramatically improve the clinical outcomes and quality of life for patients with wet AMD:

•  Reduced Treatment Burden – One of the most significant frustrations in wet AMD management is the need for frequent, often monthly, intravitreal injections. The development of longer-acting therapies—be it through gene therapy, extended-release formulations, or non-invasive delivery—promises to ease this burden considerably. For patients, fewer injections mean less anxiety, reduced risk of injection-related complications (such as endophthalmitis, retinal detachments, or hemorrhage), and lower overall healthcare costs.

•  Sustained Visual Improvement – Current anti-VEGF therapies have been successful in stabilizing vision, but often do not lead to significant long-term visual gains in all patients. The emerging drugs in development are designed not only to halt the progression of wet AMD but also to promote meaningful improvements in best-corrected visual acuity (BCVA) and retinal anatomy. Combination therapies that inhibit multiple angiogenic pathways have the potential to achieve more significant and sustained improvements in vision compared to monotherapy.

•  Enhanced Safety Profiles – Extended durability of therapeutic effect may also translate into enhanced safety for patients. With fewer injections required, there is a proportionate reduction in cumulative injection-related risks and patient discomfort. Furthermore, advanced drug delivery systems are being engineered to minimize systemic exposure, potentially reducing the risk of systemic adverse effects that have been observed with some anti-VEGF agents in certain patient populations.

•  Personalized Therapeutic Approaches – The integration of predictive biomarkers into clinical practice could radically change treatment algorithms by allowing for the selection of the most appropriate therapy based on an individual’s genetic and molecular profile. This personalized approach means that patients are more likely to receive therapies that are effective for their particular disease subtype, further enhancing treatment outcomes and patient satisfaction.

•  Long-term Cost-effectiveness and Healthcare Impact – By reducing the frequency of invasive procedures and potentially offering one-time treatments (such as with gene therapies), these innovations may lead to significant cost savings for healthcare systems. In the long run, improving patient adherence and reducing the recurrence of wet AMD-induced vision loss could help mitigate the enormous economic and social burden associated with the disease.

Conclusion
In summary, the pipeline for drugs in development for wet age-related macular degeneration is both diverse and robust. The current landscape is moving beyond the traditional VEGF-A inhibition paradigm with several innovative approaches under investigation. Gene therapies such as ADVM-022 and RGX-314 promise to deliver a long-term, one-time treatment solution by enabling the retinal cells to produce anti-VEGF proteins continuously, potentially liberating patients from the cycle of frequent intravitreal injections. Meanwhile, OPT-302 represents a strategic shift by targeting VEGF isoforms VEGF-C and VEGF-D, especially in combination with standard anti-VEGF therapy, to address the shortcomings of current treatments. Similarly, small molecule inhibitors like D-4517.2 are being developed as non-invasive alternatives that may complement or even replace intravitreal injections in the future. Additionally, the development of extended-release formulations (such as those seen with KSI-301 and GB-102) and dual-targeting bispecific antibodies aims to address both efficacy and durability issues, further optimizing patient outcomes.

Clinical trials have already provided promising preliminary data in terms of visual acuity improvements and reduced treatment frequency, with key ongoing studies such as the OPT-302 registrational trials, ADVM-022 Phase I/II studies, and 4D-150 trials leading the way. Future directions in wet AMD treatment are set to capitalize on these advances by embracing innovations in gene therapy, sustained-release drug delivery, non-invasive administration routes, and personalized medicine strategies. These approaches are anticipated to not only improve the overall efficacy and safety of treatment but also to significantly reduce the treatment burden on patients, thereby enhancing adherence, quality of life, and long-term cost-effectiveness for healthcare systems.

In conclusion, the emerging drug candidates for wet AMD are being developed from multiple perspectives: from advanced gene therapies that promise long-term efficacy to innovative small molecules and extended-release formulations that reduce the need for frequent injections, and from combination therapies targeting multiple angiogenic pathways to biomarker-driven personalized treatment strategies. While many of these candidates are in various stages of clinical investigation, the overall trend is clear—future treatments for wet AMD will likely offer more durable responses, improved safety profiles, and a substantial reduction in the clinical and socioeconomic burden of this sight-threatening disease. These innovations have the potential to usher in a new era in wet AMD management where the balance between efficacy, safety, and patient convenience is significantly improved, ultimately transforming patient outcomes and quality of life.