New Developments for the Treatment of Exudative and Nonexudative AMD
A view of the pipeline
MARK R. BARAKAT, MD • PRAVIN U. DUGEL, MD
Over the last few years, great strides have been taken in the treatment of age-related macular degeneration. As the population ages, and the prevalence of AMD continues its steady, inexorable rise, the impact of anti-VEGF agents, as well as antioxidant supplementation (AREDS2) cannot be overstated. However, as clinicians treating AMD, we continue to face pressing problems, both for exudative and nonexudative AMD.
EXUDATIVE AMD
Although the advent of the three anti-VEGF drugs — bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY) — has ushered in an era with unprecedented visual benefit for patients with neovascular “wet” AMD, this benefit came at the cost of monthly, open-ended treatment.
With the ensuing variations in this treatment regimen, it comes as no surprise that a recent MarketScan study highlighted that the number of injections for AMD patients is significantly less than what the protocols of the pivotal clinical trials would call for.1 In fact, regardless of which specific anti-VEGF agent used, retina specialists are treating at approximately half that frequency.1 Unfortunately, poorer visual acuity outcomes with less frequent anti-VEGF treatments are a legitimate concern. In both the HORIZON and SECURE studies, VA declined with as-needed treatment.2,3
Mark R. Barakat, MD, practices with Retinal Consultants of Arizona in Phoenix. Pravin U. Dugel, MD, is managing partner of Retinal Consultants of Arizona and a founding member of Spectra Eye Institute in Sun City, AZ. Dr. Dugel reports financial interests as a consultant to Genentech, Regeneron, Allergan, Alcon, Novartis, Avalanche, and Acucela, as an investor in Neurotech, and as both in Ophthotech. Dr. Barakat reports financial interest in Ohr as a minor investor and speaker. He can be reached via e-mail at mark.barakat@gmail.com.
Several different approaches to addressing the issue of overwhelming treatment burden are currently employed, including finding better anti-VEGF agents, improving anti-VEGF delivery, and defining other targets of interest in addition to VEGF.
Novel Anti-VEGF Agents
New anti-VEGF agents could potentially address the treatment burden dilemma by offering longer duration of action and requiring less frequent treatment.
Allergan (Irvine, CA) is developing a DARPin (designed ankyrin repeat protein) product called abicipar, formerly AGN-150998. With its small molecular size and repeat structure (Figure 1), it can be designed for a target duration. Its affinity for VEGF is high, perhaps greater than the currently approved agents (data on file, Allergan). Because results from early phase trials were promising,4 a phase 3, randomized, double-masked investigation comparing abicipar to ranibizumab (the REACH study) is under way.
Figure 1. Designed ankyrin repeat proteins (DARPins) offer a small molecule and repeat structure that can be designed for a target duration.
Alcon (Fort Worth, TX) and Novartis (East Hanover, NJ), in turn, are developing brolucizumab, formerly RTH-258 and ESBA-1008. As a humanized, single-chain antibody fragment against all isoforms of VEGF-A, brolucizumab has a significantly smaller molecular size than the three currently available agents. In fact, at 26 kDa, it is almost half the size of ranibizumab, the smallest of these three agents.
Potential benefits of the smaller molecular size include better target tissue penetration with higher localized drug concentration and lower systemic exposure. Animal studies with brolucizumab have given credence to these potential benefits, with more brolucizumab than ranibizumab entering the retina and less of the compound encountered as systemic exposure.5
Early human trials in patients with neovascular AMD indicated that a single injection of brolucizumab may have more potent and longer-lasting effects than a single dose of ranibizumab. Not only was the VA better with brolucizumab, but the central subfield thickness on optical coherence tomography was also thinner. Furthermore, the median time to receive standard of care retreatment after the initial dose was 30 days longer for eyes treated with brolucizumab vs ranibizumab. There were no safety imbalances.5 Another trial showed similar results compared to aflibercept.6 A larger phase 3 trial is ongoing.
Another agent, conbercept (Chengdu Kanghong Pharmaceutical Group Co., Ltd., Chengdu, China), is a drug manufactured and approved in China. Akin to aflibercept, it is also a fusion of IgG and key domains of VEGF receptors (Figure 2, page 27). Phase 2 trials comparing conbercept to bevacizumab have shown possibly increased efficacy.7
Figure 2. Conbercept, like aflibercept, is a fusion of IgG and key domains of VEGF receptors.
Improving Anti-VEGF Delivery
A second potential strategy to address the problem we face in treating patients with neovascular AMD is to have a better anti-VEGF delivery system.
Encapsulated cell technology. Neurotech (Cumberland, RI) has designed an implantable “protein factory” device, based on encapsulated cell technology (ECT).8 The implant (Figure 3) contains human retinal pigment epithelium cells genetically engineered to produce any variety of proteins. These cells are sheltered within a semipermeable capsule, with pores that allow for the free exchange of the oxygen and nutrients needed by these RPE cells into and the produced therapeutic protein out of the implant. However, the pores are sufficiently small to block entry to the host’s immune components, which could otherwise attack the RPE factory cells.9
Figure 3. Neurotech’s encapulated cell technology (ECT) contains human RPE cells engineered to produce a variety of proteins.
In a trial in which NT-501 (Renexus), an ECT device producing neurotrophic factor, was surgically implanted in patients with retinitis pigmentosa or geographic atrophy, and the level of the therapeutic factor remained constant over the course of five years.9 Subsequent explantation confirmed viable RPE cells within the devices.9
Dose-escalating trials of NT-503, a second ECT device producing a protein targeting VEGF, showed promise in patients with neovascular AMD. Successively better results were achieved with increasing doses, from low-dose generation 1 implants to higher-dose generation 2 implants, culminating in the best outcomes with the implantation of two generation 2 devices.
As a result, a generation-3 implant with increased an surface area–to–volume ratio was designed to attain a delivery rate six times that of the generation 2 implant.8 Phase 2 trials of this generation 3 implant vs aflibercept are currently under way.
Viral vectors. Another interesting line of drug delivery employs gene therapy with a viral vector. Adenovirus, which is the virus responsible for the common cold, has evolved to be highly effective at transmission and is thus an excellent candidate for a role as therapeutic vector (Figure 4, page 30).
Figure 4. Adenovirus, the virus responsible for the common cold, is an excellent candidate for a role as therapeutic vector.
By inserting specific sequences coding for therapeutic factors into this virus, two companies, Genzyme (Ridgefield, NJ) and Avalanche (Menlo Park, CA), hope to utilize the virus’s innate transfection abilities to deliver long-lasting gene therapy via intravitreal or subretinal administration, respectively.
The adenovirus is modified to contain the genetic sequence for sFLT01, a tyrosine kinase inhibitor. This agent blocks the VEGF cascade further downstream than typical anti-VEGF medications, and it could potentially be more effective as a result.10
In animal studies, intravitreal injection of the therapeutic vector resulted in sFLT01 expression in anterior-chamber fluid, as well as decreased growth of laser-induced choroidal neovascularization.11 Phase 1 trials have begun.
Using the same modified adenovirus but administering it subretinally, not intravitreally, the hope is to better transfect a localized target area with fewer side effects, particularly inflammation. After performing a core vitrectomy, a small caliber needle is used to inject the vector under the retina. The transfection effect of this approach has endured for more than 1.5 years without any safety signals or increased rate of GA in animal studies.12,13
Early human trials showed a reduction in central retinal thickness comparable to that seen with standard intravitreal anti-VEGF agents. However, the majority of patients did not require any rescue therapy for more than one year after subretinal injection.14
A 12-month phase 2a trial met its primary endpoint, showing a +11.5 letter difference between treatment and control, although mostly driven by a loss of -9.3 letters in the control arm. It also showed a greater likelihood of visual stability with two or fewer rescue treatments in the gene therapy group (42.9%) vs the control group (9.1%).15 Further studies are planned.
Other. Two additional delivery devices are the Replenish (Pasadena, CA) pump and the Genentech Port. The Replenish pump is a computer controlled, battery-powered device that is implanted much like a glaucoma shunt device.16 The Genentech Port (Figure 5) is a port that is placed under the conjunctiva.17 Both implants are refillable.
Figure 5. The Genentech port is a a refillable port placed beneath the conjunctiva. Using a custom refill needle, the port can be refilled via the subconjunctival opening.
Identifying Additional Targets
In addition to improving on currently available anti-VEGF agents or their delivery, modifying the course of neovascular AMD by identifying new molecular targets has been an approach of intense interest.
There has been increasing awareness of the complex array of factors apart from VEGF that are involved in the angiogenesis cascade leading to CNV formation. Many of these factors could represent novel therapeutic targets.
One agent taking aim at several components of this cascade is squalamine, a potent antiangiogenic molecule derived from the dogfish shark (Squalus acanthias), which Ohr Pharmaceuticals (New York, NY) has under development for wet AMD. Squalamine binds calmodulin intracellularly, preventing receptor activation and causing broad inhibition of multiple factors, VEGF and platelet derived growth factor (PDGF) chief among them.
Phase 2 trials of topical squalamine combined with intravitreal ranibizumab vs intravitreal ranibizumab alone showed VA improvements and reductions in retinal thickness on OCT.18
Patients in the phase 2 IMPACT trial with lesions that contained classic CNV demonstrated a visual improvement of +11 letters with squalamine combination therapy vs +5 letters with ranibizumab alone. Three line VA improvement was seen in 44% of these patients in the combination arm vs 29% in the ranibizumab control arm.19 A phase 3 trial is planned.
Platelet-derived growth factor. Other compounds are taking aim exclusively at PDGF, a target of particular interest because it addresses an unmet need in our current treatment of neovascular AMD. Treatment of neovascular lesions with anti-VEGF agents causes remodeling of the pathologic vasculature, resulting in less tortuous, less leaky vessels that are better covered by pericytes.20 These pericytes cover the neovascular lesion in a protective shell (Figure 6), leaving only the tip cells, found at the leading edge of the vascular complex, uncovered.21
Figure 6. Treatment of AMD with anti-VEGF causes remodeling of the pathologic vasculature, resulting in vessels covered by pericytes (left). Anti-PDGF treatment can strip these pericytes from the neovascular complex (right).
Only these unprotected tip cells, in turn, are susceptible to anti-VEGF treatment, and they are destroyed, allowing the bulk of the endothelial cells to continue to mature. In essence, anti-VEGF monotherapy prunes off the exposed tips and matures the neovascular complex.
Because these pericytes that confer resistance to anti-VEGF treatment are maintained by PDGF, and anti-PDGF treatment strips them from the neovascular complex, combined treatment with both anti-VEGF and anti-PDGF holds promise. In theory, the anti-PDGF agent would remove the pericyte armor from the neovascular lesion, exposing the endothelial cells beneath it to the anti-VEGF agent, killing these endothelial cells. This approach has the potential for neovascular regression, establishing a paradigm shift from disease maintenance to disease modification.
Fovista. Multiple companies are developing anti-PDGF agents, including Ophthotech (Princeton, NJ), Santen Inc. (Emeryville, CA), Allergan, and Regeneron. The particular compound arguably furthest along in development is Ophtotech’s Fovista (formerly E10030), with the largest phase 2b trial (449 patients) performed in retina to date.22
When comparing 0.3 mg or 1.5 mg of Fovista combined with ranibizumab vs ranibizumab alone with a primary endpoint of mean change in VA, the combination with the higher dose of Fovista led to greater VA improvement than ranibizumab alone. There were no local or systemic safety imbalances noted.22
At the higher Fovista dose, VA improved by 62% more from baseline than with ranibizumab monotherapy, with a classic dose-response curve that continued to outpace monotherapy over the six-month course. Prespecified subgroup analyses of both baseline lesion size and vision demonstrated that the groups benefited equally, without any influencing the results disproportionately.22
In terms of visual improvement, patients were 71% and 190% more likely to enjoy greater than 4 lines and 5 lines of visual improvement with Fovista, respectively. Combination therapy with the anti-PDGF agent also resulted in a 119% relative benefit towards achieving a VA of 20/25 or better, with a lower rate of vision loss compared to ranibizumab monotherapy.22
Biomarker analysis of the patients that did gain 4 and 5 lines with ranibizumab monotherapy suggested a robust antipermeability effect, as seen by improvements of intraretinal, subretinal, and sub-RPE fluid on OCT. However, only small neovascular membranes, presumably not completely ensconced by pericytes, shrank with treatment.
In contrast, patients gaining the same vision with combination therapy actually had significant regression of subretinal hyper-reflective material (SHRM) on OCT, in addition to the same fluid reduction seen in the control arm. This effect on SHRM, thought to represent the neovascular lesion, has not been previously described in clinical trials of any anti-VEGF product.22
For patients who lost vision, eyes treated with ranibizumab monotherapy demonstrated fibrosis and disciform scarring, whereas eyes receiving combination therapy showed little, if any, scarring.22,23 Because PDGF is a potent fibrotic agent, it is certainly biologically plausible that its blockade has a direct impact on the degree of fibrosis and scar formation, as seen in this subgroup.
In short, the combined inhibition of VEGF and PDGF has shown strong potential for synergy by going a step beyond simple reduction of exudation from CNV and actually attacking the neovascular complex directly.
Targeting fibrosis. Perhaps our focus on the increased permeability and ensuing exudation of CNV as the main pathology of neovascular AMD should broaden to encompass the ultimate fibrotic process as well. Indeed, a possibly more apt model of the neovascular process in AMD is that of wound-healing, in which PDGF-regulated fibrosis and scarring play integral roles. Subsequently, addressing both VEGF- and PDGF-regulated processes may have profound disease-modifying effects for this condition.
For now, there are three different approaches to improving on our current, seemingly unsustainable treatment strategy for neovascular AMD: finding new anti-VEGF agents with potential for greater potency and duration (brolucizumab, abicipar), improving anti-VEGF delivery with genetic engineering (Genzyme, Avalanche) or implantable devices (Neurotech), and developing other targets of interest for combination therapy (Ophthotech, Ohr). As new trial data are released in the years ahead, there will certainly be new developments with real potential to impact the way treat neovascular AMD.
NONEXUDATIVE AMD
Nonexudative “dry” AMD is becoming ever more prevalent, with advanced cases consisting of GA affecting more than five million people worldwide.24 Current treatment strategies for this condition focus on antioxidant supplementation, specifically the AREDS2 formulation.25
Unfortunately, there are no approved treatments for dry AMD or for the GA commonly associated with it. However, two main treatment strategies are currently being explored: protection of photoreceptors and suppression of inflammation.
Protecting Photoreceptors
One strategy for the treatment of dry AMD consists of protecting photoreceptors and the RPE by various means. Neuroprotective agents exhibit therapeutic potential by preventing apoptosis. Ciliary neurotrophic factor (CNTF), previously mentioned as Neurotech’s NT-501, prevented photoreceptor apoptosis in an animal model of retinal degeneration and has shown constant output and viable factory cells in its ECT implant five years after implantation.9
Alternatively, another way to promote the survival of photoreceptors in dry AMD lies in modulating photoreceptor metabolism to reduce the buildup of toxic metabolites, including lipofuscin and the retinal fluorophore A2E in particular. Acucela’s (Bothell, WA) emixustat, formerly ACU-4429, is a nonretinoid molecule that modulates the isomerase that converts all trans-retinol to 11-cis-retinal in the RPE. This process effectively slows the visual cycle in rod photoreceptors, reducing the metabolic rate of the photoreceptors and the accumulation of vitamin A toxins.
Early human trials showed emixustat to be well tolerated in an oral form, with a significant, dose-dependent suppression of rod photoreceptor sensitivity as measured by electroretinography (ERG).26 In phase 2 trials, no cone ERG changes were noted, and adverse visual events, such as chromatopsia and delayed dark adaptation, were typically tolerable, consistent with emixustat’s mechanism of action, and were reversible upon discontinuation of the agent.26
A phase 2b/3 study has been designed to evaluate the long-term safety and efficacy of this visual cycle modulator in slowing the growth of GA in patients with dry AMD.
Suppressing Inflammation
Another approach to addressing nonexudative AMD generating great interest is directed against the inflammatory component of this condition. In particular, the complement cascade, part of the innate immune system, has been closely linked to AMD.27-30 The three different pathways within the complement system are triggered by various molecular cues, primarily serving to combat infection and modulate inflammatory responses.
Complement components have been found at the level of Bruch’s membrane and implicated in the process of drusen formation.31 It is thought that, given the right combination of oxidative stress, genetic predisposition, and environmental exposure, these accumulations of complement factors lead to focal areas of tissue damage that continue to expand, affect neighboring RPE cells, and ultimately culminate in GA.32
Genentech’s lampalizumab is an agent that inhibits factor D, a rate-limiting enzyme in the alternative pathway of the complement system. In so doing, it both halts the amplification feedback effect intrinsic to that pathway, greatly reducing inflammation and the production of membrane attack complex, and allows the other two pathways (classical and lectin) to mount an appropriate immune response to pathogens.33
In a phase 2 trial, MAHALO, 129 patients with bilateral GA were randomized to receive 10 mg of lampalizumab monthly, 10 mg of lampalizumab every other month, or sham (monthly or bimonthly) for 18 months. The primary endpoint was mean change in GA from baseline to month 18 as measured by fundus autofluorescence.
The agent was well tolerated, without any safety imbalances. Starting at month 6, there was a clinically significant 20% reduction in the rate of GA progression in the monthly lampalizumab group, compared to the pooled sham group.34
On subsequent biomarker analysis of genes expressed in the alternate complement pathway, there appeared to be a significant correlation with complement factor I (CFI). Those patients positive for the biomarker (CFI+) enjoyed a 44% reduction in GA formation at the end of the trial, compared to CFI+ patients in the sham arm.
Conversely, patients negative for CFI demonstrated no apparent treatment effect.34 As a result, CFI status may be predictive of treatment response to lampalizumab. Further data are forthcoming from the phase 3 trial, currently under way.35
CONCLUSION
In summary, while there are no currently approved treatments for dry AMD, an area of looming unmet need, early trial results appear promising. The two main approaches taken are the protection of photoreceptors and RPE cells (emixustat, NT-501 ECT) and the suppression of inflammation (lampalizumab).
As with agents in development for neovascular AMD, we look forward to more robust data from larger trials in the near future. It is encouraging, however, that agents currently being explored for both dry and wet AMD have the potential to revolutionize the way that we approach and treat both aspects of this dichotomous condition. RP
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