As a third-year medical student back in the early 2000s, I recall sitting in clinic as my attending supervisor explained a newly-developed treatment option for wet age-related macular degeneration (AMD): photodynamic therapy (PDT) with Visudyne (Bausch+Lomb, Inc, Bridgewater, NJ, USA). At the time I knew very little about the condition; however, I understood that it was a devastating disease that offered little hope for patients. The attending physician explained that PDT did not reverse the disease, but simply slowed its progression. It’s a scene reminiscent of our current quest to find a viable treatment for geographic atrophy (GA) associated with AMD, and, in particular, the unrealized promise of lampalizumab.
Similar to exudative AMD before anti-VEGF treatments, geographic atrophy is a disease process in desperate need of a new, effective treatment option. Like PDT for exudative AMD, many drugs being investigated for GA, including complement inhibitors like lampalizumab, simply hope to slow disease progression rather than reverse it.
It is important to educate patients on their disease prognosis and provide them with realistic expectations regarding their future visual function. Aside from a low vision evaluation, we currently have little to offer our progressive AMD patients with vision loss due to GA. Fortunately, new GA treatment options are on the horizon, and many potential treatment modalities are in various stages of research and development. These include injectable drugs that hope to slow disease progression as well as surgical transplantation of stem cells—potentially restoring lost retinal tissue.
This article will focus on new injectable drugs for GA treatment. Using the recent demise of lampalizumab, we’ll discuss the role of the complement cascade in the pathogenesis of GA, while highlighting points of potential intervention in the pathogenesis. With new GA treatment modalities in the pipeline, it is only a matter of time before an effective intervention comes to fruition.
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Prevalence of geographic atrophy
Geographic atrophy is a form of advanced AMD that accounts for up to 15% of severe vision loss associated with AMD. It affects five million people globally and accounts for about 25% of legal blindness in the United States. It is responsible for over a third of late-stage AMD cases and is found at significantly greater rates (four times higher) than wet AMD in patients over 85 years of age. The presence of GA imposes a significant burden on visual function and quality of life among the aging population. Approximately half of all patients with GA are considered legally blind in at least one eye.
It is characterized by progressive death of the macular retinal pigment epithelium (RPE) in discrete, well-circumscribed patches that enlarge over the course of years similar to slowly-growing bacterial colonies on an agar plate. As the RPE dies, the overlying neurosensory retina subsequently atrophies and an absolute central scotoma develops. Visual acuity may be relatively unaffected until the central fovea becomes involved, which occurs at a median time of two years after the initial GA diagnosis. Bilateral involvement is also common, with the second eye developing GA approximately seven years after first seen in the first eye. Nearly all GA lesions expand in a variable manner, typically faster toward the periphery than toward the central macula. Growth rates for GA range between 0.53 to 2.6 mm2 per year.
Clinically, our primary goal is to preserve the function of the macula/fovea. Future interventions that slow progression even just 20% could have a profound impact on preserving our patients’ visual function. This was the initial promise of lampalizumab.
Figure 1: Geographic atrophy shown in 80 y/o Caucasian Male with history of exudative AMD in both eyes. Photo courtesy of Kevin Cornwell, OD
Pathophysiology of geographic atrophy
Dysregulation of the complement cascade (our body’s innate immune system, typically activated by invading pathogens) leads to a pro-inflammatory/pro-apoptotic state within the retina. The complement system is implicated in the pathogenesis of GA and is a prominent target for therapeutic intervention research. This complex process consists of three separate pathways and multiple feedback loops. While the inhibition of a single, highly-upregulated, cytokine (VEGF) is effective in controlling exudative AMD, GA intervention via the complement pathway is significantly more challenging. It is yet to be determined where in the cascade intervention is most effective. We also do not fully understand the potential undesired implications of altering this delicate system.
Figure 2: Macular drusen shown in a 61 y/o Caucasian Male with dry AMD and longstanding history of smoking and hypertension. Elevated serum levels of complement factors have been shown in AMD patients. Increased levels of complement factors are also found in retinal drusen, Bruch’s membrane, and inner choroid—contributing to the breakdown of the blood-retinal barrier in AMD. Photo courtesy of Kevin Cornwell, OD
Potential treatments on the horizon
Investigators have identified several genetic polymorphisms in the alternative complement pathways that are associated with advanced AMD. One of these is complement factor H (CFH), where a deficiency can lead to abnormal amplification of the alternative pathway. Lampalizumab attempted to target the alternative complement pathway. As an anti-Factor D monoclonal antibody fragment, this drug inhibited a key feedback loop and rate-limiting step within this pro-inflammatory pathway.
The relatively small MAHALO study (2011) demonstrated a 20% reduction in mean change in GA growth at month 18 in patients treated with lampalizumab and a 44% reduction in patients with the complement factor I (CFI) risk allele, which is a negative regulator of the alternative complement pathway. This phase 2 clinical data was impressive.
The MAHALO study however was followed by two larger phase 3 trials, Spectri and Chroma. These studies were identical, two-year, multicenter, trials with nearly 2000 subjects randomized to one of four study arms: sham injection every four weeks, a 10mg lampalizumab injection every four weeks (Lq4), a sham injection every six weeks, and a 10mg lampalizumab injection every six weeks (Lq6). The primary outcome was the mean change in GA area measured by fundus autofluorescence (FAF) at 48 weeks with several secondary outcomes evaluating changes in visual function. The study prioritized enrollment of CFI+ subjects as well as subjects with diffuse or banded patterns on FAF (predictive of GA progression).
Unfortunately, the drug did not meet its endpoints. In Spectri, all three groups demonstrated GA enlargement by approximately 2mm2 over 48 weeks, with no significant differences between the groups (Lq4 2.089mm2, Lq6 2.019 mm2, sham 1.932 mm2). Moreover, there was no benefit in the CFI+ subgroup (CFI+ Lq4 2.057 mm2, CFI+ Lq6 2.032 mm2, CFI+ sham 2.007 mm2). There were no new safety signals, including a low rate of endophthalmitis.
Almost half of all phase 3 clinical trials fail, despite sound pre-clinical and positive phase 2 data. These results were unexpected and disappointing, yet hope still remains. The Chroma and Spectri studies enrolled over 600 patients in the sham arms, providing the largest data set of its kind on the natural history of GA, including data on ETDRS visual acuity (both best-corrected and low-luminance), objective assessments of visual function with reading speed and macular microperimetry, subjective assessments of function with the NEI VFQ 25 and Functional Reading Independence Index (FRI Index), high-quality serial imaging with color photography, FAF, spectral-domain optical coherence tomography (SDOCT), near-infrared, and fluorescein angiography. It is exciting to consider what we will learn over the next few years as this data is more closely scrutinized.
While lampalizumab was ineffective, several other complement inhibitors for GA are currently being developed, including a peptide against C3, an antibody against properdin and C5, gene therapy directed toward the culmination of the cascade, the membrane attack complex, and an aptamer against C5. These are all in various stages of development, including phase 1 and 2 clinical trials.
An anti-C3 peptide may be more effective, as it is a central inhibition of complement: C3 is involved in all three complement pathways (lectin, classical, and alternative). In a phase 2 study of APL-2 by Apellis (Crestwood, KY, USA), the drug was given monthly (n=84) or every other month (n=78) with GA lesion growth compared to sham over 12 months. The treatment groups showed a 20% and 29% reduction, respectively, with little to no difference in visual outcomes between groups. One point of concern was that treated eyes appeared to have a higher incidence of new choroidal neovascular membrane (CNVM) formation, up to 30% over 12 months with monthly treatment and a history of CNVM in the fellow eye. Potentially more concerning, there was also a higher incidence of endophthalmitis in the treatment groups: 2.3% in the monthly arm and 1.3% in the arm treated every other month. It is difficult to know the clinical significance of this given the small size of the trial.
Another agent in development by Novartis (LFG316, Basel, Switzerland) is an anti-C5 antibody. C5 is cleaved into 5a and C5b, which activate different parts of the complement cascade. This drug did not meet the primary endpoint as monotherapy in a phase 2 trial, but is now being evaluated in combination with an anti-properdin antibody. Properdin is a molecule that perpetuates the effect of the C3 enzyme and greatly amplifies activation of the alternative pathway. Blocking properdin may blunt an important amplification loop and may be synergistic with blockage of C5.
An anti-C5 aptamer (Zimura, Ophthotech Corp., New York, NY, USA) also hopes to slow the rate of GA progression, and was studied in a 48-week phase 1b/2a trial with two dose levels, 0.3mg (n=24) and 1mg (n=23) and injections per eye. There were no safety signals, including no new CNVM formation seen, and a trend toward a dose-response treatment benefit. A phase 2 randomized study is being planned with a target of 200 subjects in three cohorts (2mg/eye, 4mg/eye, sham).
Finally, another target is the culmination of the complement cascade: the membrane attack complex (MAC). This intriguing approach from Hemera Biosciences Inc. (Boston, MA, USA) involves gene therapy to induce the expression of soluble CD59. CD59 is a natural membrane-bound protein that inhibits MAC formation by blocking incorporation of C9. A phase 1 dose-escalation study has completed enrollment of 17 subjects with no safety issues noted and stable vision. If this approach works, a single intravitreal injection may enable long-term protection through protein expression.
The ongoing search for GA therapy
In summary, the complement cascade appears to be a strong candidate for therapeutic intervention in preventing irreversible vision loss due to geographic atrophy. As in the case with lampalizumab, other investigational drugs will likely suffer the same fate. Given the complexity of this system, we’ll likely encounter additional dead ends before reaching our goal. Why is an effective therapy so elusive? Treating GA is not like exudative AMD with a single significant target. Successful GA treatment and intervention will likely require a multifaceted approach.
At present, there is not a good pre-clinical model on which to base GA trials, further increasing uncertainty. Finally, there is the issue of stoichiometry. The intraocular concentration of complement components can be significantly higher (up to a million times greater) than levels of VEGF—making continuous, long-term inhibition a potentially daunting task.
As Thomas Henry Huxley (1825-1895) once stated, “The great tragedy of science—the slaying of a beautiful hypothesis by an ugly fact.” These “ugly facts” may continue to pile up in our quest to find a therapy for geographic atrophy. Nevertheless, we must stay up to date on the current clinical research for GA and AMD, while redirecting the inevitable frustration of inconclusive data. As eye care practitioners on the frontlines of ocular diseases like AMD, striving to help patients maintain their visual function and quality of life is our highest priority.