5
QUESTION
ANYTHING COMING DOWN THE PIKE YET FOR DRY AGE-RELATED MACULAR DEGENERATION?
Jose Mauricio Botto Garcia, MD, MSc
Philip J. Rosenfeld, MD, PhD
Age-related macular degeneration (AMD) is a leading cause of severe irreversible vision loss among the elderly worldwide.1–4 Severe vision loss is a feature of late AMD, which includes geographic atrophy (GA) and exudative AMD.1 The only approved, effective, injectable therapies solely target the exudative form of AMD, which comprises about 20% of late AMD.1 Exudative AMD is treated by injecting inhibitors of vascular endothelial growth factor into the eye, but even in the best of circumstances, the injections dry the exudative AMD, which may continue to slowly advance with significant vision loss over time.5 Currently, there are no effective therapies that are approved for the treatment of late, dry AMD (ie, GA) and there are no effective therapies that can slow the progression of intermediate dry AMD, which is characterized by drusen and pigmentary abnormalities.1–3,6,7
GA is characterized by the localized loss of macular photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris.2,6,8–11 While the focus of GA has been shown to arise from drusen12 and then enlarge over time, it is also possible for GA to develop in the absence of drusen.4 While the genetics of AMD suggest a role for the abnormal regulation of the complement pathway as an underlying cause of the disease,2,6 the exact mechanism by which complement causes AMD remains elusive.6 The most significant association exists between at-risk complement alleles and the presence and growth of drusen;3 however, large epidemiological studies have not yet found an association between at-risk complement alleles and the increased growth of GA.11 Despite the lack of a compelling association between complement at-risk alleles and the growth of GA, numerous studies have used complement inhibitors in an attempt to slow the enlargement of GA. In addition, other strategies have been studied in an attempt to slow the enlargement of GA,2,6,13 and these strategies include visual cycle modulation, beta-amyloid inhibition, protection against oxidative damage, and neuroprotection.2,7,14
The most frequently used clinical trial endpoint for the study of nonexudative AMD is to study a drug’s ability to slow the enlargement of GA over time.3 While other endpoints have been proposed that involve slowing the enlargement of drusen in intermediate AMD and slowing the progression of intermediate AMD to late AMD, only one drug study to date has investigated one of these alternative endpoints.3 While the limited scope of this review precludes a detailed description of all studied therapies to date, the drugs that follow are either currently in clinical trials or will soon enter trials for the treatment of dry AMD.
Complement Pathway Inhibition
As local inflammation and complement activation are implicated as a cause of AMD, inhibition of the complement pathway has been studied as a therapeutic approach.6,9,14,15 Genentech/Roche investigated lampalizumab, a monoclonal antibody fragment (Fab) against complement factor D that prevents the activation and amplification of the alternative complement pathway.15 The Phase II MAHALO (A Study to Evaluate the Long-Term Safety and Tolerability of Lampalizumab (FCFD4514S) in Patients With Geographic Atrophy Who Have Completed Genentech-Sponsored Lampalizumab Studies) study demonstrated a 20% reduction in the rate of GA progression after 18 months with monthly lampalizumab intravitreal injections (10 mg) compared to sham injections.3,6,16 While this result did not show conventional statistical significance, they did show a statistically significant reduction of 44% in a subgroup analysis of patients carrying an at-risk allele in the complement factor I locus. Given that this significant finding was found in a small subgroup, confirmation of this association between complement factor I, reduction in GA progression, and lampalizumab inhibition is needed.16 Two parallel, multicenter, international Phase III studies with lampalizumab, known as CHROMA (A Study to Assess the Efficacy and Safety of Lampalizumab Administered Intravitreally to Patients With Geographic Atrophy Secondary to AMD) and SPECTRI (A Study Investigating the Safety and Efficacy of Lampalizumab Intravitreal Injections in Participants With Geographic Atrophy Secondary to AMD), were performed. To be enrolled in these studies, patients had to have bilateral GA containing a banded pattern of hyperautofluorescence. These patients were then randomized to receive lampalizumab (10 mg) injections every 4 or 6 weeks or a sham injection. Unfortunately, Genentech/Roche announced that both SPECTRI and CHROMA failed to reach the primary endpoint and the studies were stopped.15
Another complement inhibitor in clinical trials, which is known as LFG316 (Novartis), is an antibody against the complement component 5 (C5) of the complement pathway. C5 inhibition should effectively inhibit late stage complement activation and prevent membrane attach complex (MAC) formation. In a Phase IIb study, intravitreal LFG316 did not slow the enlargement of GA when compared with a sham injection. Then, LFG316 was combined with CLG561, a drug that inhibits another complement pathway protein known as properdin. Although no official report has been released, this combination therapy study apparently failed to meet its endpoint. Zimura (avacincaptad pegol) is another inhibitor of C5, but this drug is a chemically synthesized aptamer. Zimura is being evaluated currently in a Phase II/III study.7 APL-2 (Apellis Pharmaceuticals) is a pegylated peptide inhibitor of complement factor C3, which effectively inhibits both the classical and alternative pathways of complement activation. In the prospective, randomized, multicenter, sham-controlled, single-masked Phase II clinical trial, subjects were randomized to receive intravitreal APL-2 (15 mg) vs sham-injection every month or every other month over 12 months with final follow-up at 18 months. Apellis recently announced that APL-2 met its primary endpoint at 12 months.17 Monthly intravitreal injections of APL-2 showed a 29% (P = 0.008) reduction in the rate of GA lesion growth compared with sham. In the group treated every other month, a 20% (P = 0.067) reduction was observed. In addition, a post hoc analysis showed that APL-2’s effect was greater in the second 6 months of the study compared with the first 6 months, with a reduction in growth rate of 47% (P < 0.001) with monthly administration, and a reduction of 33% (P = 0.01) with every other month administration. Follow-up continued for 18 months and after 18 months, the growth rate of GA increased off therapy and returned to the rate observed with the sham treated group.18 A gene therapy strategy for the inhibition of complement activation is being investigated in a Phase I clinical trial that is using an adeno-associated virus that expresses a naturally occurring cell surface inhibitor of MAC known as CD59. This study, which is investigating a single intravitreal injection of HMR59 (Hemera BioSciences Inc.), is currently enrolling patients.19 The antibiotic doxycycline is also under study. This drug has demonstrated anti-inflammatory properties and has also been shown to prevent complement activation. This study, which is investigating 40 mg oral daily Oracea (doxycycline) for 24 months, is currently enrolling patients (Table 5-1).20
Neuroprotection
Brimonidine tartrate is a drug approved by the US Food and Drug Administration for the treatment of glaucoma and it has also been shown to have neuroprotection properties.7,14 Following a small Phase II study that showed encouraging results with brimonidine tartrate delivered through an intravitreal implant, a larger Phase II clinical trial was started. In this trial, patients will be treated with a 400 μg brimonidine implant, injected every 3 months for 24 months, and compared to a sham group.14 Unfortunately, the study has been stopped, but the results have not been released (Table 5-2).
Mitochondrial Bioenergetics
Elamipretide (Stealth BioTherapeutics) is a compound designed to selectively target cardiolipin involved with the electron transport chain and oxidative phosphorylation of mitochondria in an attempt to improve cellular bioenergetics. The ReCLAIM (An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of Subcutaneous Elamipretide in Subjects With Intermediate Age-Related Macular Degeneration) Phase I study is evaluating elamipretide for intermediate AMD and late AMD with nonsubfoveal GA. Eligible subjects will receive 40 mg of elamipretide administered as a once daily 1.0 mL subcutaneous injection for 12 weeks. Patients with any evidence of central GA will be excluded.21 This study is currently enrolling patients (Table 5-3).
Stem Cell Therapy
Another promising strategy in the treatment of GA is stem cell therapy.7 Stem cell transplantation could lead to prevention of disease progression, either by replacing damaged cells or providing trophic factors to prevent degeneration. Another less likely possibility is that stem cells could cause regeneration of RPE and photoreceptors that have been damaged. Currently, differentiated human embryonic stem cells (hESC) and the induced pluripotent stem cells are being investigated for the treatment of late-stage AMD.
In 2012, Schwartz and colleagues published the first description of hESC transplantation into human subjects with retinal disease.22 These cells had been fully differentiated into RPE prior to their transplantation into the subretinal space adjacent to the area of GA.10,21,23 Safety and tolerability of these subretinally transplanted hESC-derived RPE were confirmed in this Phase I study, which enrolled 9 patients with dry AMD who were followed up for approximately 22 months. The results of this study showed medium- to long-term safety, graft survival, and the possibility of biological activity based on improved visual acuity. This study demonstrated that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. A Phase II study is currently being organized. Cell Cure Neurosciences Ltd. is performing a similar trial using hESCs differentiated into RPE.
Table 5-1
Modulation of Inflammation
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