Dry and neovascular “wet” age-related macular degeneration: Upcoming therapies

Abstract

The age-related macular degeneration (AMD) field is witnessing promising advancements in therapeutic options. Breakthrough drugs such as pegcetacoplan and avacincaptad have been FDA-approved for dry AMD, marking a significant development as there were no treatment options until August 2023. While several antivascular endothelial growth factor (VEGF) inhibitors have been approved for wet AMD, challenges persist with the need for frequent dosing. New treatments such as gene therapy, cell therapy, WNT pathway agonists, complement inhibitors, and anti-VEGF combination drugs are under development to address these issues. These developments are exciting and hold promise for transforming the field of medicine, offering hope for improved outcomes and enhanced patient care in managing AMD.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in those aged 60 years and above, projected to affect over 5 million people by 2050.[1] It is characterized by small deposits called drusen, containing lipids, polysaccharides, glycosaminoglycans, and proteins, and pigmentary changes at the macula, leading to a slow progressive deterioration of the retinal pigment epithelium (RPE).[2] Disease progression is classified into two types: (1) “dry” AMD, which can progress to geographic atrophy (GA), characterized by central vision loss due to the irreversible loss of RPE, photoreceptors, and choriocapillaris; and (2) “wet” or neovascular AMD (nAMD), marked by choroidal and/or retinal neovascularization, resulting in edema and hemorrhage, which can also lead to central vision loss [Fig. 1].[3,4]

Figure 1.

Underlying Mechanisms in AMD: Dry AMD involves the gradual thinning of the central retina and choriocapillaris with deterioration of the RPE, resulting in photoreceptor death and retina dysfunction. In Wet AMD, increased inflammation and complement activity lead to abnormal blood vessel growth with blood and fluid leakage and eventfully scar tissue formation beneath the neuro-epithelium and in the retinal stroma. From Li L, Yu Y, Lin S, Hu J. Changes in best-corrected visual acuity in patients with dry age-related macular degeneration after stem cell transplantation: systematic review and meta-analysis. Stem Cell Res Ther. 2022;13(1):237. Licensed for reuse via open access under the Creative Commons Attribution 4.0 International License

Risk factors include age, smoking, hypertension, and a diet high in saturated fat.[5] Vascular endothelial growth factor (VEGF), a signaling protein that stimulates new blood vessel creation, is critical in ocular neovascularization.[6] Treatments for dry AMD lacked before August 2023, relying on antioxidant vitamins and minerals such as vitamin E, vitamin C, beta-carotene, and zinc.[7] Several anti-VEGF drugs have been available since 2004 upon approval of the first anti-VEGF agent, pegaptanib sodium, a pegylated VEGF-A 165-specific aptamer.[8] These include ranibizumab (Lucentis), aflibercept (Eylea), brolucizumab (Beovu), bevacizumab (Avastin, off-label), and faricimab-svoa (Vabysmo). Recently, Susvimo was developed as a long-acting ranibizumab injection for intravitreal (IVT) use via an ocular implant. However, the drug previously faced a voluntary recall in 2022 due to septum dislodgment.[9]

Despite successes, challenges remain, including the burden of frequent clinical visits leading to undertreatment with lower visual acuity improvement in practice compared to clinical studies. Moreover, 35.2%–70.9% of patients with nAMD continued to present with intraretinal, subretinal, or sub-RPE fluid after one year of treatment.[9,10,11] About two-thirds of patients who initially had vision gain during the first 2 years ultimately lost this benefit by 5 or 7 years, even with the most rigorous anti-VEGF therapy regimens.[12,13] In addition, patients with nAMD who received anti-VEGF treatment for 2 years experienced a 38% occurrence of GA development discovered during their 5-year follow-up.[14] Lastly, patients with subretinal fibrosis, an advanced complication of nAMD, did not benefit from anti-VEGF therapy with progressive visual acuity deterioration.

Although there are still unmet needs, new strategies for treating AMD are beginning to emerge, including gene therapy, WNT agonists, anti-VEGF combination drugs, TK inhibitors, senescence-targeting drugs, and advancements in VEGF inhibitors.

Methods of Literature Search

The literature search was done from January 2024 to March 2024, using electronic databases including Google Scholar and PubMed, by searching the following keywords: gene therapy age-related macular degeneration, new treatments dry age-related macular degeneration, new treatments wet age-related macular degeneration, complement system inhibitors age-related macular degeneration, tyrosine kinase inhibitors age-related macular degeneration, and anti-VEGF injections. Articles were filtered to those published within the past 5 years. Many references were sought from news releases and non-peer-reviewed articles as the therapies are ongoing experiments. An extensive search was performed, and all relevant articles were retrieved, mainly written in the English language. The timeline of published articles ranged from 1996 to 2024.

Wet Macular Degeneration - Upcoming Therapy

Gene therapy

Gene therapy, proposed by Dr. Theodore Friedmann in 1972, offers a potential solution to the burden of repetitive anti-VEGF injections by introducing engineered genetic material into cells with deficient or absent gene function, typically facilitated by viral transduction.[15] This approach may provide long-term relief for patients requiring continuous therapeutic intervention. However, safety issues underscore the importance of rigorous safety measures in gene therapy trials, the chance of random insertion or mutagenesis, the potential mobilization of engineered vectors by endogenous retroviruses, and the possibility of germ cell alteration.[16,17]

Viral vector gene therapy

Most FDA-approved gene therapies utilize viral vectors, though advancements in non-viral vectors, such as synthetic or natural compounds, aid in the uptake and expression of genetic material within cells and are notable.[18] Viral vectors offer gene transfer efficiency with three fundamental requirements: the delivery system must be safe and immunologically inert, protect the genetic material from degradation, and encode an effective therapeutic gene.[17]

Adeno-associated viral (AAV) vectors provide superior gene transfer efficiency and safety due to their characteristics.[19] They are safe parent viruses that rely on a helper virus for replication.[18] The genome’s editability allows for precise control over genes.[20] AAV vectors offer non-genomic and genomic integration options, enabling sustained transgene expression.[15] In addition, multiple AAV serotypes with distinct capsid components enable tailored tissue targeting by optimizing transduction efficiency, immunogenicity, and cellular tropism.[21] Lastly, AAV vectors provoke a milder immune response than other viral vectors, enhancing safety and reducing the required vector dose for therapeutic efficacy.[22] Gene therapy holds promise for managing both rare genetic disorders and common conditions such as AMD.

New upcoming gene therapy for nAMD

New upcoming gene therapies for nAMD include RGX-314, ADVM-022, and 4D-150. Most of these clinical trials share similar eligibility criteria, requiring patients to have previously received treatment for nAMD and exhibited fluid on optical coherence tomography (OCT), along with documented responses to anti-VEGF therapy at the time of trial entry.

RGX-314

Non-integrating vector RGX-314 delivers a genetic code expressing a monoclonal antibody fragment similar to ranibizumab utilizing AAV8, with the goal of binding and neutralizing VEGF [Fig. 2].[23] Employing subretinal or suprachoroidal delivery, it is designed to be administered once to produce anti-VEGF therapy constantly. There are seven current or recently completed clinical trials [Table 1].

Figure 2.

Mechanism of Action of ABBV-RGX-314: Utilizing AAV8 to deliver a genetic code expressing a monoclonal antibody fragment[23]

Table 1.

Ongoing Clinical Trials of RGX-314

Type of Method	Clinical Trial #	Summary of Trial	State of Trial
Suprachoroidal	NCT04514653[23] NCT05210803 (long term)[24]	Three different doses of RGX-314 versus ranibizumab were studied based on efficacy, safety, and tolerability. Length: Initially 52 weeks. Now 5 years for long-term follow-up	Phase II, randomized AAVIATE trial Currently recruiting with completion in Jan/Feb 2024 Currently recruiting with completion in March 2028
Subretinal	NCT03066258[25] NCT04704921[26] NCT05407636[27] NCT03999801[24] NCT04832724[28]	Five different doses of RGX-314 studied based on safety and tolerability for 24 weeks (104 weeks for long-term follow-up). Two doses of each formulation (one used in a previous clinical trial vs. one made by commercial-ready manufacturing procedure) assessed in four cohorts for 1 year	Phase I/IIa open-label study Phase IIb/III (ATMOSPHERE) - Currently recruiting Phase III (ASCENT) - Currently recruiting 5-year follow-up on all participants Currently active, with recent completion in March 2024

A recent NCT04514653 trial showed that RGF-X314 through subchoroidal delivery was well tolerated across all three doses, with the highest dose level showing the most significant reduction in treatment burden [Table 1].[23] An 80% decrease in annual injection rate, with 50% of patients becoming injection-free, was noted. Treatment-emergent adverse effects (TEAEs) throughout 6 months were mild to moderate, which included conjunctival hemorrhage, increased intraocular pressure, episcleritis, and conjunctival hyperemia. No intraocular inflammation was seen with dose level 3, where patients were prophylactically treated with a short course of topical steroids following ABBV-RGX-314. Current trials are assessing 5-year long-term follow-up.[24]

Clinical studies are evaluating the subretinal delivery of RGX-314 [Table 1]. These trials involve assessing five doses of RGX-314 (3 × 10⁹, 1 × 10⁹, 6 × 10¹⁰, 1.6 × 10¹¹, and 2.5 × 10¹¹ vg/eye) in 42 patients.[25,26,27] Patients seem to tolerate the drug well across all dose cohorts, although there was one serious drug-related adverse effect in one receiving the highest dose. Impressively, subretinal RGX-314 reduced the need for supplemental anti-VEGF injections across 4 years, particularly for the three highest doses. All cohorts will have yearly check-ups for their 5-year observational follow-up study.[24] Promising long-term therapy results and better visual acuity have been noted among those enrolled in the long-term follow-up who were given 6 × 10¹⁰ and 1.6 × 10¹¹ vg/eye. The long-term study is anticipated to end by December 2028.[24,29]

Subsequently, there is an ongoing phase IIb/III (ATMOSPHERE) and phase III (ASCENT) study, along with a 5-year follow-up involving all participants.[26,27,29,30] In addition, early findings from a phase II trial comparing pharmacodynamics behind a formulation utilized in earlier research with one generated by a manufacturing company show comparable safety and clinical profile.[30] Within 6 months, 60% of the high-dose cohort (clinical and commercial formulation) and 73% of the low-dose cohort were injection-free. Any TEAE, including postoperative conjunctival hemorrhage and inflammation, resolved within days to weeks, with all cases of mild retinal pigmentary changes. This trial is ongoing, and its completion was in March 2024.[28,30]

ADVM-022

Ixoberogene soroparvovec (ADVM-022) is a single-dose gene therapy using a novel vector capsid, AAV2.7M8. This vector carries a robust expression of a gene coding for the cDNA of the anti-VEGF aflibercept protein.[31]

A recent 2-year phase I study (OPTIC) [NCT03748784] and OPTIC-EXT [NCT04645212] aimed to assess ocular and systemic adverse effects, visual acuity, central subfield thickness (CST) changes, and number of injections.[32] Four cohorts were separated by dose (2 × 10¹¹ vs. 6 × 10¹¹ vector genomes) and prophylactic steroids (oral prednisone vs. topical difluprednate).[32] Results revealed no systemic adverse effects. Anterior chamber cells were reported as the most common adverse effect, although no anterior or vitreous chamber cells were seen in 2 × 10¹¹ vg/eye patients. Reported intraocular inflammation responded well to topical corticosteroids. Over 2 years, vision and CST remained constant, and yearly anti-VEGF injections were reduced by 80% in 2 × 10¹¹ vg/eye and 98% in 6 × 10¹¹ vg/eye cohorts.[32] These participants will be evaluated for 3 more years. In addition, a phase II trial (LUNA) [NCT05536973] is currently studying 2 × 10¹¹ vg and 6 × 10¹⁰ vg, along with an enhanced corticosteroid regimen.[32]

4D-150

4D-150 is a single-dose IVT AAV vector (R100) that carries two transgenes: one encoding aflibercept (AFLB) and the other targeting VEGF-C with a miRNA sequence.[33] As of now, this is the first retinal gene therapy hoping to inhibit all four VEGF-related molecules driving angiogenesis: VEGF A, B, C, and PIGF.[33]

A phase I/II dose escalation and a randomized controlled trial have been underway. In the phase I dose exploration stage, the safety and tolerability of three doses (3E10, 1E10, and 6E9 vg/eye) were assessed.[34] In the phase II dose expansion stage, patients were randomly assigned to receive either 3E10 vg/eye or 1E10 vg/eye dose escalation of 4D-150 or aflibercept.[34,35] The objective was to study the safety and efficacy of phase I doses and to compare 4D-150 with an established treatment. In April 2023, 4DMT announced positive interim data for phase I, indicating a good safety profile and clinical activity with significant decreases in the burden of anti-VEGF treatment across all dose levels, with the highest dose (3E10 vg/eye) demonstrating superiority. Following a single IVT dose of 4D-150, about 80% of patients in the 3E10 vg/eye high-dose cohort did not need another injection within 36 weeks.[34] As of February 5, 2024, positive data from the phase II dose expansion stage showed a favorable safety profile with no new inflammation and no change in steroid status.[36] Participants in the high-dose cohort continued to show decreased need for additional anti-VEGF injections and decreased CST. 4DMT plans for the phase III study to be a BCVA non-inferiority study versus aflibercept 2 mg every 8 weeks with 3E10 vg/eye as the study dose.[36]

Anti-VEGF combination drugs

Efdamrofusp alfa (IBI302) is a novel bispecific fusion protein targeting both VEGF and complement pathways, addressing the multifactorial nature. Studies have shown genetic variants of complement factor H (CFH), C2, complement factor B, C3, C9, and complement factor I (CFI) associated with increased disease incidence and progression.[6,37,38,39,40] Many components, such as C3a, C4a, C5a, complement factor P, CFH, and membrane attack complex (MAC) [Fig. 3], are involved in forming drusen bodies and complement activation in aqueous humor in AMD patients.[41,42,43,44,45] Complement components C3a, C5, and sublytic MAC have also been found to induce VEGF expression, promoting choroidal neovascularization.[46,47]

Figure 3.

Graphical Representation of Complement Cascade: The complement cascade pathway can be activated by three proteolytic pathways: the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP). All three pathways converge on C3 and C5, leading to the terminal pathway and the formation of the membrane attack complex (MAC), which leads to cell lysis. From Qin S, Dong N, Yang M, Wang J, Feng X, Wang Y. Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option. J Immunol Res. 2021;2021:9945725. Licensed for reuse via open access under the Creative Commons Attribution 4.0 International License

The U.S. Food and Drug Administration (FDA) has not yet approved any complement inhibitors for nAMD treatment. To reduce complement amplification, IBI302 was designed to neutralize multiple isoforms of the VEGF and bind C3b/C4b to reduce complement amplification.[48] Phase I trials showed promising safety and efficacy profiles in BCVA and anatomic aspects, leading to phase II studies.[48] In a phase II trial presented at the AAO Annual Meeting, both 2 mg and 4 mg doses of IBI302 demonstrated noninferiority to 2 mg aflibercept in improving BCVA at 36 weeks, with potential benefits in preventing macular atrophy and fibrosis.[49] In February 2024, Innovent initiated a phase III clinical trial evaluating IVT IBI302 8 mg for nAMD [NCT05972473].[45] The continued robust efficacy and safety profiles of IBI302 suggest it is a potential alternative treatment.[45] In March, the primary endpoint of the second phase II study was met, with non-inferior BCVA gains observed, particularly in the 8.0 mg IBI302 group compared to 6.4 mg IBI302 or aflibercept 2.0 mg. Over 80% of subjects within the 6.4 mg or 8.0 mg group could extend the dosing interval to every 12 weeks. Based on these successful results of long-term benefits, the phase III study STAR has added an every 16-week dosing interval regimen for IBI302.[50]

WNT pathway agonist

Subretinal fibrosis, an end-stage complication of nAMD, poses a risk of irreversible visual impairment, with about one-third of patients progressing to this stage despite anti-VEGF treatment.[51] The Wnt pathway, crucial for embryogenesis, tissue homeostasis, and cancer development, operates through three main pathways: the canonical Wnt/β-catenin pathway, the Wnt-planar cell polarity pathway, and the Wnt-calcium pathway.[52,53,54,55] Studies have shown that Wnt1 and Wnt3a inhibit the destruction complex, allowing β-catenin to accumulate and activate fibrosis-related gene expression.[55]

Norrin, a secreted protein emitted by Müller cells and endothelial cells in the developing retina, activates the β-catenin pathway by binding to FZD4 and LRP5/6 co-receptors.[55,56] Studies have shown that VEGF, which disrupts the blood-retinal barrier (BRB), induces retinal vascular permeability, and enables endothelial cells to respond to norrin, restoring BRB function.[57] Norrin has demonstrated the ability to prevent and restore BRB dysfunction in animal models through TSPAN12 co-activator facilitating FZD4 receptor response and β-catenin activation.[57] These findings suggest the potential therapeutic use of norrin in VEGF-related pathologies, including nAMD and diabetic retinopathy (DR).

Restoret, a WNT agonist antibody, is the first of its kind in clinical use. In the phase Ib/IIa AMARONE trial, Restoret was studied in those with diabetic macular edema (DME) and nAMD.[58] Mimicking the natural ligand Norrin, Restoret aims to restore and maintain the integrity of the blood-retinal barrier by activating the Wnt pathway, preventing or reducing leakage from abnormal blood vessels, a hallmark of nAMD.[56,57] The trial consisted of an open-label multiple ascending dose safety study and a comparative safety and preliminary efficacy study.[58] Patients with DME received IVT Restoret monotherapy, while nAMD patients received Restoret in combination with aflibercept. The 12-week data presented by EyeBio on February 13, 2024, indicated that Restoret was tolerated with no adverse effects. Patients with DME who received Restoret alone showed a mean improvement in vision of 11.2 letters and a reduction in retinal thickness.[58] Similar outcomes were observed in nAMD patients receiving Restoret in combination with aflibercept, suggesting promising safety and efficacy profiles for Restoret in treating retinal diseases.

Senescence targeting drugs

The pathogenesis of macular degeneration involves various processes, including senescence triggered by factors such as oxidative stress. In 2021, Chae et al.[59] discovered several senescent RPE cells in mouse models of both dAMD and nAMD, leading to the creation of senescence-targeting medications.

Senescence, caused by factors such as oxidative stress, results in irreversible cellular arrest and contributes to chronic inflammation and tissue degeneration. While this mechanism is essential in embryonic development and wound healing, its buildup due to aging or continuous stress can cause chronic inflammation and tissue degeneration, aided by proinflammatory molecules known as senescence-associated secretory phenotype (SASP).[60]

UBX1325 is a senescence-targeting drug currently being studied for the treatment of nAMD and DME. This medication targets Bcl-xL, a protein essential to the survival of senescent cells.[61] In September 2023, UNITY released results from the phase II ENVISION study showing that patients who switched from aflibercept to UBX1325 and aflibercept maintained their visual gain after 24 weeks.[61] Switching to UBX1325 alone also preserved visual acuity, although a minimal decrease was noted, at week 48.[61] Many patients also did not require additional anti-VEGF treatment. Despite the drug’s potential, UNITY intends to prioritize the development of UBX1325 for DME treatment due to more significant improvements in visual acuity.

5.0 VEGF inhibitors

Aflibercept (Eylea), a well-known anti-VEGF inhibitor, binds to all VEGF-A isoforms and placental growth factor (PIGF) via a fusion of the second Ig domain of VEGFR1 and the third Ig domain of VEGFR2 fused to the Fc region of human IgG1.[62] EYLEA HD, a high-dose formulation (8 mg) approved in August 2023, offers longer-acting treatment and reduced treatment burden. Administered once every 8–16 weeks for nAMD and DME, it provides an alternative to the usual Eylea regimen. It is typically administered every 4 weeks, which may be extended to once every 8 weeks, depending on the condition. The recent PULSAR trial in October 2023 presented 2-year results, demonstrating sustained visual and anatomic improvements among patients receiving EYLEA HD requiring fewer injections compared to standard.[63]

Lytenava, also known as ONS-5010, is a formulation of bevacizumab being developed as an IVT injection. Bevacizumab-vikg, a recombinant humanized monoclonal antibody (mAb), binds to all isoforms of VEGF tightly, blocking the binding to their receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), located on the surface of endothelial cells.[64] There are currently no FDA-approved ophthalmic formulations of bevacizumab, leading clinicians to use repackaged IVT bevacizumab, products with a high risk of contamination and inconsistent potency.[64] They have also utilized off-label IVT Avastin (bevacizumab), originally used as an anticancer agent for multiple solid tumors such as colorectal and lung.[65] Despite positive pivotal trials, Lytenava faced rejection by the FDA in August 2023 stemming from concerns, questionable observations from manufacturing inspections, and the need for more confirmatory clinical evidence.[66] However, ongoing efforts to evaluate Lytenaya’s potential continue with the NORSE EIGHT trial, aiming to improve visual acuity. The trial recently achieved a significant milestone by dosing its first patient on January 31, 2024 [Table 2].[64]

Table 2.

Current clinical trials of anti-VEGF injections

Anti-VEGF Inhibitor & Trial	Summary of Trial	State of Trial
OPT-302 (Sozinibercept) NCT 04757636 (COAST)[67] NCT04757610 (ShORe)[67]	OPT-302 in combination with aflibercept OCT-302 in combination with ranibizumab Primary endpoint: Average change in BCVA across 52 weeks, evaluated for safety and tolerability over a 2-year period	Phase III. Enrollment completed February 2024 Phase III. Enrollment is to be completed in Q2 2024. Results from both trials aimed to be released in mid-2025
Faricimab NCT04777201 [AVONELLE-X][68]	Long-term safety and tolerability of faricimab 6 mg to patients who completed parent study	Phase III Active, not currently recruiting. Awaiting data.
Ranibizumab (Lucentis) NCT05476926 [VOYAGER][69] NCT04853251 [BELVEDERE][69] NCT04657289 [VELODROME][70] NCT03683251 [PORTAL][70]	Efficacy, safety, and clinical signs in those received Tx with PDS w/RBZ versus faricimab over 5 years Studying treatment response participants receiving PDS with RBZ 100 mg/mL refilled every 24 weeks Efficacy, safety, and pharmacokinetics of PDS with refill-exchange every 9 months compared to every 6 months Extension study, evaluating long-term safety and tolerability of PDS in patients from Ladder [GX28228], Archyway [GR40548], and Velodrome [WR42221]	Expected to end in 2027. Phase IV Expected to end in 2024 Expected to end in 2026 Expected to end in 2026
Lytenava (ONS-5010) NORSE EIGHT[64]	Subjects receiving 1.25 mg Lytenava or 0.5 mg Lucentis IVT injection every 4 weeks. Primary endpoint: Visual acuity improvement	First subject dosed on January 31, 2024

BCVA- Best Corrected Visual Acuity, PDS- Port Delivery System, RBZ- Ranibizumab, nAMD- (neovascular age-related macular degeneration

Yesafil is a biosimilar to aflibercept. Biosimilars offer more affordable alternatives to expensive biologic medications, fostering competition in the market and driving down prices with comparable efficacy, safety, and quality. The biosimilar was authorized by the European Commission in September 2023, marking a significant advancement in patient access to life-saving therapies.[71]

OPT-302, also known as Sozinibercept, is a novel recombinant “trap” immunoglobulin G1 (IgG1) Fc-fusion protein intended to target and block VEGF C and D.[72] These ligand mediators play crucial roles in angiogenesis and vascular leakage in retinal vascular disorders. Administered via IVT injection, OPT-302 is intended to be used with typical anti-VEGF-A therapy, such as aflibercept or ranibizumab.[72] The average changes in BCVA are currently being investigated from day 0 to week 52 in two concurrent phase III pivotal trials, COAST and ShoRe. Patients will be followed beyond week 52 for an additional year to evaluate extended safety and tolerability over 2 years [Table 2].[67] The phase IIb trial, administering OPT-302 combined with ranibizumab, demonstrated a statistically significant improvement in visual acuity compared to ranibizumab alone.[72] Patients receiving OPT-302 showed statistically superior gains at 24 weeks, with more participants experiencing improvements in vision of 10 or more letters and reductions in swelling and microvascular permeability. A largely positive safety profile was also exhibited.[72]

Faricimab is the first and only bispecific antibody with a strong affinity for VEGF-A and Ang-2. It is administered intravitreally and was licensed by the FDA and EMA in January 2022 after TENAYA and LUCERNE trials.[73] Faricimab treatment results in quicker retinal fluid drying with fewer injections than aflibercept. Patients on faricimab required fewer injections than those on aflibercept, as evidenced by the absence of intraretinal fluid (IRF) occurring at 48 weeks with faricimab versus 84 weeks with aflibercept. Recent updates include the AVONELLE-X phase III trial, studying the long-term safety and tolerability of Faricimab in those who completed the parent studies (TENAYA or LUCERNE) [Table 2].[68]

Ranibizumab (Lucentis) is a humanized, immunoglobulin G1 monoclonal antibody fragment targeting VEGF-A.[74] It inhibits VEGF-A’s interaction with its receptor on endothelial cells, thereby preventing endothelial proliferation, vascular leakage, and neovascularization. Derived from bevacizumab, its antigen-binding fragment (Fab) exhibits a higher affinity to VEGF-A.[62] The recent approval of Suvimo, a port delivery system (PDS) for ranibizumab, allows for constant drug distribution into the vitreous chamber for over 6 months.[75] On-going clinical trials such as VOYAGER, BELVEDERE, VELODROME, and the PORTAL expansion study assess PDS’s effectiveness, safety, and pharmacokinetics with ranibizumab [Table 2].[69,70] The DIAGRID trial, evaluating PDS with RBZ 100 mg/mL, was suspended due to voluntary recall in October 2022 after septum dislodgement issues were identified and many implants did not perform as per the quality standard.[76]

Tyrosine kinase inhibitors (TKI)

Tyrosine kinases are critical in cellular signaling, including cell proliferation and migration, with some involved in angiogenesis, such as VEGF receptors. Several drugs inhibiting angiogenic tyrosine kinase receptors have been developed, primarily for cancer treatment, as tumors rely on angiogenesis for progression. Axitinib, a targeted drug for metastatic renal cell carcinoma, which blocks both VEGF and PDGF receptors, is being evaluated using human retinal microvascular endothelial cells (HRMVECs) and human brain vascular pericytes (HBVRs), as well as using a rat model of laser-induced choroidal neovascularization (CNV).[77,78] Results suggest inhibiting the VEGF and PDGF pathways could benefit patients with nAMD. Axitinib has also shown strong efficacy in the rat model at low doses, indicating its potential utility in nAMD therapy.

AXPAXLI, also shown as OTX-TKI, is a bioresorbable hydrogel implant containing axitinib, a tyrosine kinase inhibitor, for the treatment of nAMD and DR.[79,80] The preservative-free implant, aiming for sustained release for at least 6 months, received FDA approval for a phase III SOL trial in November 2023. The trial, which started in September 2023, aims to enroll approximately 300 treatment-naïve subjects with nAMD, with participants receiving either aflibercept injections or Axpaxli implants.[80] As of February 15, 2024, the first three participants received aflibercept injections for the trial.[79]

Vorolanib is a newer tyrosine kinase receptor inhibitor with anti-angiogenic properties.[81] Although primarily studied in cancer, it is being explored as a potential therapy for nAMD due to its action on VEGF and PDGF receptors.[82] The DAVIO trial investigated EYP-1901, a sustained delivery system of vorolanib via IVT injection, designed to last at least 6 months. In phase I, involving 17 patients with nAMD, a single dose of EYP-1901 was administered after standard anti-VEGF therapy, showing a significantly reduced need for additional anti-VEGF injections over 12 months. No adverse effects related to EYP-1901 were reported. Positive results from the phase II DAVIO 2 trial with 2 mg and 3 mg doses demonstrated statistical non-inferiority to aflibercept control, supporting advancement to phase III trials expected to start in the second half of 2024.[83]

D4517.2 (Ashvattha Therapeutics) is a Sunitinib analog conjugated to a hydroxyl dendrimer for wAMD, DME, and DR. Sunitinib is a multi-kinase angiogenesis inhibitor with selectivity for PDGF receptors (PDGFRalpha and PDGFRbeta), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), FLT-3, colony-stimulating factor receptor type 1 (CSF-1R), and proto-oncogene proteins ckit and c-ret.[84] The first-in-class home medication initiative was developed to address the challenges patients face, including the necessity of a retinal ophthalmologist, the need for caregivers to assist with transportation to and from medical visits, and the high cost. Patients would administer the drug at home with an autoinjector subcutaneously up to once per month at a lower price, manufactured at up to 1/10 the cost of other approaches. In phase I and phase II trials, single doses of D-4517.2 were safe and tolerable.[84,85] The phase II Chronic Dose trial [NCT05387837] aims to evaluate the safety, dosing regimens, and the time to anti-VEGF rescue following initial dosing.[84,86] Results are expected in the first half of 2024, with the first patient dosed on November 1, 2023.

Dry Macular Degeneration - Upcoming Therapy

Gene therapy

JNJ-1887, formerly HMR59 and AAVCAGsCD59, is an AAV2 gene therapy designed as an IVT injection to enhance the expression of soluble CD59 (sCD59), directly inhibiting the MAC, the final step of the complement cascade.[87] MAC is associated with the formation of GA and the upregulation of VEGF; therefore, JNJ-1887 is intended to treat GA. The phase I trial involved a dose-escalating study of a single IVT injection in those with GA.[88] Seventeen patients were randomly assigned to three dosage cohorts. Patients who received the high IVT dose were found to have decreased GA progression compared to the placebo group. Treatment across all groups was tolerated over a 2-year follow-up period, with no dose-limiting toxicity observed. None of the patients experienced a conversion to nAMD. A phase IIb double-masked dose-ranging study [NCT05811351] involving 300 patients is ongoing with the estimated completion date for this trial in November 2025 [Table 3].[89]

Table 3.

Current clinical trials of new dry AMD therapy

Type of Therapy	Trial Summary	Trial State
Gene Therapy: JNJ-1887: NCT05811351[89]	Summary of Trial One of two doses of gene therapy or control over 18 months, including prophylactic steroids	State of Trial Phase IIb. Estimated to be completed November 2025.
Cell Therapy: RG6501: NCT05626114[90] ASP7317: NCT03178149[91]	Assessing safety and feasibility of subretinal delivery method Evaluating improvements in retinal structures using OCT imaging 3 months post-surgery Assessing safety and tolerability over a 52-week period. Changes in GA lesion area and BCVA from baseline to week 52	Phase II Estimated to be completed September 2029. Phase Ib clinical Actively recruiting participants
Other Therapies: ALK-001[92]	GA growth rate from baseline to 24 months. Safety, tolerability, incidences of conversion to wet AMD, and changes in visual acuity	Phase II/III trial Currently active, awaiting data.

GA: Geographic atrophy, BCVA: Best corrected visual acuity

GT-005 (Novartis) uses an AAV vector to increase the expression of complement factor I (CFI) for treating GA. A phase I/II FOCUS trial enrolled 56 patients with interim safety data indicating the drug’s safety and tolerability, with no treatment-related serious adverse effects.[93] Researchers observed increased CFI levels in 11 out of 13 treated patients that sustained beyond week 29. A phase II HORIZON trial was estimated to finish by September 2023, while a phase II EXPLORE trial was estimated to finish by November 2024, with some participants from both clinical trials to take part in a long-term follow-up trial ORACLE.[94,95] However, in September 2023, Novartis decided to discontinue the development of GT005 following a recommendation from an independent data-monitoring committee.[96] The decision came after an overall benefit-risk assessment of data from the clinical trials. While Novartis reported no new safety signals, the therapy did not demonstrate sufficient efficacy to warrant its further development.

Cell therapy

Compared to other approaches, cell therapy holds multiple advantages as it replaces the degenerated cell types (s) in a biologically relevant way. There is a chance that a single therapeutic intervention could provide long-term effects lasting years or even decades. Within the retinal world, this approach mainly focuses on RPE cell transplantation to treat GA.

RG6501 (OpRegen) is an allogeneic RPE cell therapy developed to treat GA. Preliminary results from phase I/II studies have shown improvements in outer retinal structure and visual function. Patients gained an average of 7.6 letters in visual acuity at 12 months, with 25% achieving 15 letters or more.[97] Improvements in outer retinal structure improvement observed to persist for up to 4 years of follow-up. A phase II [NCT05626114] study is underway and actively recruiting participants.[90] Patients in this study will receive subretinal delivery of RG6501 at a dose of about 200,000 cells. The estimated completion date is September 2029 [Table 3].

The ASP7317 comprises human embryonic stem cell-derived RPE cells and is intended to treat GA. A phase Ib [NCT03178149] clinical trial is actively recruiting participants who will receive low, medium, or high cells/dose through subretinal injections.[91] They will also receive immunosuppressive therapy [Table 3].

Lastly, Eyecyte-RPE is a pluripotent stem cell therapy being initiated in India. Approval has been granted in April 2024 for the first human trial of this therapy, targeting those with medium- and late-stage geographic atrophy.[98] This therapy aims to be provided at a fraction of the cost of most cell and gene therapy products.

Complement inhibitors

Until recently, no approved therapies existed for individuals living with GA. However, two new drugs targeting the complement cascade have gained FDA approval, to stop its attack on the retina and slow GA progression. The FDA approved the first drug, SYFOVRE™ Pegcetacoplan, in February 2023, targeting the C3 protein.[99] The second drug, Izervay (formerly known as Zimura), avacincaptad pegol, was FDA-approved in August 2023, targeting the C5 protein.[100] In a phase II trial, Zimura demonstrated significant improvement in visual acuity when used in combination with ranibizumab for nAMD.[101] Patients received monthly 2 mg Zimura alongside anti-VEGF 0.5 mg, with approximately 60% achieving visual acuity improvement more significant than or equal to three lines, surpassing typical anti-VEGF monotherapy. Clinical trials have demonstrated SYFOVRE and Izervay’s remarkable ability to slow down the rate of GA progression with a monthly administration of SYFOVRE decreasing the rate of lesion growth by 18%–22% over 2 years and Izervay decreasing the rate by 14% over 1 year.[102,103] While patients receiving either drug face an increased risk of developing nAMD, therapies to treat nAMD have proven effective.[99,100] Administration of SYFOVRE has also been associated with a rare but potentially severe inflammatory reaction known as occlusive retinal vasculitis. Both drugs are still very novel therapies and, therefore, require follow-up studies to fully understand their long-term effects and risks. Additional research is vital to identify the patient population who may benefit from this treatment relative to the risk, considering the location of damage in the eye and its impact on vision.

Other therapies

Luminate (risuteganib) is a novel integrin regulator that targets intermediate dAMD, addressing oxidative stress pathways, including mitochondrial dysfunction. The FDA recently approved the design of a phase IIb/III clinical trial in April 2023, following a successful phase IIa study.[104] Results from the phase IIa study showed that 48% of patients who received two risuteganib injections at week 28, compared to 7% in the sham group at week 12, gained more than eight letters from their baseline. The safety profile was relatively high, with no reported drug-related serious adverse effects. The phase IIb/IIIa study is designed to study continued efficacy at 52 weeks and safety through 96 weeks.[104] Patients will receive five IVT injections 12 weeks apart with continued IVT treatment during the follow-up safety portion of the study. The main objectives include improvement in BCVA at 52 weeks in the risuteganib versus sham control cohort.

ALK-001 is a modified form of vitamin A, designed to slow the formation of dimers as the accumulation of vitamin A in the RPE and Bruch membrane has been associated with retinal aging and degeneration.[92] ALK-001 specifically targets individuals with GA secondary to AMD and is intended to be taken as a once-daily oral medication. A phase II/III trial [NCT02402660] is currently ongoing, with results yet to be published [Table 3].[92]

Conclusion

Several new AMD treatments are being developed, but more research is needed to assess long-term effects, safety, and tolerance. Physicians must stay up to date with advancements to make well-informed treatment decisions that consider patient preferences, safety, and efficacy. While the future looks bright, the complexity of selecting the most appropriate treatment options remains a significant challenge for clinicians.

More attention should shift toward earlier stages of dry AMD as current treatments focus heavily on GA. Understanding safety concerns in gene therapy is critical as pigmentary changes in subretinal areas, intraocular inflammation with IVT injections, and signs of inflammation with suprachoroidal gene therapy have been noted. This raises important questions: Are we exposing proinflammatory tissues to the eye, or are these effects due to insufficient prophylaxis? If the latter, how long should prophylaxis be given, and should it be IVT, topical, or oral? These factors are critical for improving the safety and efficacy of AMD gene therapy.

Beyond typical anti-VEGF treatments, there is significant promise for investigating therapies that target general inflammatory markers, such as WNT pathway agonists, senescence-targeting drugs, and complement inhibitors. It will be interesting to explore if these broader anti-inflammatory drugs can treat other inflammation-related ocular diseases such as DR and uveitis, highlighting their potential for therapeutic uses across a range of retinal diseases.

Whether these novel treatments will complement or eventually replace anti-VEGF medications is also within question. Could these new treatments outperform and reduce the frequency of injections at a comparable or lower cost? The future of AMD treatment lies in integrating these innovative therapies to offer more comprehensive and effective management of this challenging condition.

Conflicts of interest:

There are no conflicts of interest.

Funding Statement

Nil.