Recent advances in the management of dry age-related macular degeneration: A review

Nutritional supplements

In recent years, there has been an enormous interest about nutrition and its relation to health. Many researchers demonstrated that food components are able to decrease the incidence of several diseases, including AMD. The AREDS study has shown that AREDS formula supplementation (a daily dose of 80 mg zinc oxide, 2 mg cupric oxide, 15 mg β-carotene, 500 mg vitamin C and 400 IU vitamin E) was effective in certain categories of patients affected by d-AMD, significantly reducing the risk of AMD progression²³. In particular, these results were achieved in patients with high-risk, using the late stage disease as the primary endpoint. Whether AREDS formula supplementation also has a beneficial effect in patients affected by the earliest stages of the disease is unknown²³. Also in GA patients these results were not confirmed; partially, this was due to the relative small sample size of GA patients included in the study²³. However, patients affected by a specific form of GA, involving the central area of the retina, were found to benefit from AREDS supplementation formula because they showed lower rates of progression to n-AMD, similarly to patients affected by a moderate stage of d-AMD²⁴. Since, β-carotene increases the incidence of lung cancer in smokers²⁵, a following study (AREDS2) evaluated the effect of β-carotene elimination from the original AREDS formula supplementation²⁶. AREDS2 demonstrated that β-carotene elimination or lower-dose zinc did not influence the progression to late AMD²⁶. However, a great incidence of lung cancer was recorded in patients treated with AREDS formula supplementation compared with patients treated with AREDS2 formula supplementation, mostly in former smokers²⁶.

A new active area of research is the association between the vitamin supplements and genetic profile: the interest was based on evidence that showed that genetic risk profile of a patient may influence the benefit of vitamin supplements²⁷. The results on this specific area will be available in the next years. However, there is general agreement that the AREDS and AREDS2 supplementation have a healthy effect mainly for their antioxidative action, and that they will play a great role in the treatment of d-AMD patients for a long period of time.

Anti-inflammatory therapy

Chronic inflammation is thought to be crucial for AMD pathogenesis^3,28. Currently, corticosteroids are being investigated for their antiangiogenic and antiinflammatory effect. Iluvien (Alimera Sciences, Alpharetta, GA, USA) is a sustained-release formulation of fluocinolone acetonide, just approved for the treatment of diabetic macular edema (DME), which could slow the progression of GA. A total of 40 patients affected bilaterally by GA were recruited in a phase II study (NCT00695318)²⁹. The study was completed, but the results are not yet available.

The histopathological identification of different complement complexes in patients with GA and the presence of variations in genes encoding complement proteins clarify several treatment strategies to study the contribution of systemic complement in the pathogenesis of the disease^30,31. Although different complement inhibitors are being studied to treat GA, none has been approved yet or has proven to be effective.

POT-4 (Potentia Pharmaceuticals, Louisville, KY, USA; ALcon, Hünenberg, Switzerland) is a C3 inhibitor administered by intravitreal injection, with 6 months duration of action. A phase I clinical trial (NCT00473928)³² was completed without safety concerns and a phase II clinical trial would be required to prove the safety and efficacy of this drug in d-AMD.

ARC1905 (Zimura; Ophthotech Corp., Princeton, NJ, USA) is an anti-C5 aptamer targeting C5, which has completed a phase I trial (NCT00950638)³³. Plans for initiating a phase II/III trial of ARC1905 are reported to be under way (http://www.ophthotech.com/product-candidates/arc1905/).

Another drug targeting C5 is Eculizumab (Soliris; Alexon Pharmaceuticals, Cheshire, CT, USA). The COMPLETE study showed no reduction of GA progression by Eculizumab, but the low luminance deficit at baseline was significantly correlated with the progression of GA over 6 months^34,35.

Lampalizumab (FCFD4514S; Genentech/Roche, San Francisco, CA, USA) is a humanized monoclonal antibody targeting complement factor D in the alternative complement pathway. The Lampalizumab phase II clinical trial (NCT02288559)³⁶ was the first study to demonstrate a positive effect in slowing growth of GA through complement inhibition. Two on-going phase III trials, Chroma (NCT02247479)³⁷ and Spectri (NCT02247531)³⁸ are under way to investigate the safety and efficacy of 10 mg Lampalizumab injections every 4 or 6 weeks vs sham injections.

Sirolimus (Rapamycin; MacuSight/Santen, Union City, CA, USA) is a macrolide immunosuppressive agent with antiinflammatory, antiangiogenic and antifibrotic activity. It was generally well tolerated, but no evidence of efficacy has been shown³⁹.

Glatiramer acetate (Copaxone; Reva Pharmaceuticals, Kfar-Saba, Israel) has been studied for its immunomodulatory effect altering T-cell differentiation in GA treatment. A phase I study (NCT00541333)⁴⁰ has demonstrated reduction of the drusen area in patients with drusen after weekly subcutaneous Glatiramer injections over 12 weeks. A phase II/III study (NCT00466076) is underway⁴¹.

In addition, amyloid-beta may play a role in AMD progression. RN6G (Pfizer, New York, NY, USA) and GSK933776 (GlaxoSmithKline, Brentford, UK), humanized monoclonal antibodies targeting amyloid-beta have been studied in phase II clinical trials (NCT01577381 and NCT01342926, respectively)^42,43, but results are not available.

Neuroprotective therapy

Another interesting area under development is neuroprotection. There are two drugs under investigation: ciliary neurotrophic factor-501 (CNFT) and Brimonidine.

CNFT, a member of the IL-6 cytokine family, has been shown to protect photoreceptors in animal models⁴⁴. Neurotech Pharmaceuticals (Cumberland, RI, USA) developed a well-tolerated intraocular encapsulated cell technology (ECT), which when combined with CNTF in a sustained-release platform (NT-501), releases the substance for more than one year⁴⁵. A randomized, double-masked, phase II trial (NCT00447954)⁴⁶ studied the 2-year results of the NT-501 implant in GA patients with promising results. In total, 51 patients were randomized and treated by high-dose or low-dose NT-501 implants or sham treatment. Zhang et al.⁴⁷ showed a dose-dependent stabilization of visual acuity, evaluated as a loss of <15 letters on the ETDRS chart, in high-dose patients (96.3%) versus low-dose (83.3%) and sham treatment (75%) at 12-month evaluation. The stabilization of visual acuity was related with a retinal thickness increase at structural OCT.

Brimonidine, a member of α-2 agonists, which is frequently used in glaucoma patients, has also demonstrated a neuroprotective effect on retinal cells in animal models^48,49. A multicenter, phase II, double-masked, randomized study (NCT00658619)⁵⁰ evaluated the efficacy and the safety of Brimonidine administered by an intravitreal biodegradable implant (Allergan, Irvine, CA, USA). The study evaluated the changes of GA area and BCVA in 119 patients with bilateral GA, randomly divided and treated by 200 or 400 μg of Brimonidine or a sham therapy every 3 months through month 21. The results did not show reliable data and for this reason a second multicenter trial (NCT02087085)⁵¹ is currently ongoing. The primary outcome measure of this trial is the GA area change from baseline to 24-month evaluation in the 311 study eyes treated by 400 µg Brimonidine implant or sham treatment. The estimated study completion date is March 2019.

Lipofuscin and visual cycle inhibitors

The rationale for using visual cycle inhibitors in the treatment of GA is the documented phototoxic and proinfiamamtory effect of lipofuscin accumulated at the sites of RPE atrophy in patients with GA⁵².

Fenretinide (Sirion Therapeutics, Tampa, FL, USA) is a synthetic retinoid that competitively prevents the uptake of retinol by the RPE with downregulation of visual cycle. A phase II clinical trial (NCT00429936)⁵³ demonstrated that 100 mg and 300 mg daily Fenretinide did not reduce the growth rate of GA, but patients seemed to tolerate it well.

Emixustat (ACU-4489; Acucela, Seattle, WA, USA) is a non-retinoid visual cycle modulator of the isomerase (RPE65) preventing conversion of all-trans-retinol to 11-cis-retinalin in the RPE, with minor accumulation of lipofuscin. A phase IIa trial (NCT01002950)⁵⁴ showed a biological effect in GA eyes. Phase II/III study (NCT01802866)⁵⁵ was completed, but results are not available.

Choroidal blood flow restoration agents

The choroid is diminished in thickness in older age patients and for this reason a new target therapy in d-AMD could lead to the restoration of a higher choroidal blood flow⁵⁶. Choroidal circulation plays an important role in providing nutrients and removing wastes from the RPE and retina layers⁵⁷. Many vasodilators are currently under investigation in clinical trials with the rationale that the use of these drugs may increase the blood flow of the choroid, and thus may delay the progression of d-AMD.

A phase 3, multicenter, controlled, randomized study (NCT00619229)⁵⁸ proved that Alprostadil (UCB Pharma, Berkshire, UK) was superior to placebo treatment in patients affected by d-AMD⁵⁹. Patients treated with Alprostadil showed a best-corrected visual acuity superior of 0.94 lines compared with patients treated by placebo after 3 months, increasing to 1.51 lines at 6-month follow-up. However, further trials are strongly recommended to evaluate the long-term effects and safety of Alprostadil, and to understand the role that this drug could play in d-AMD therapy.

A small pilot trial (NCT01922128)⁶⁰ studied a new vasodilator called MC-1101, and demonstrated not only a safe and well tolerated profile for topical administration, but also a choroidal blood flow increase. MC-1101 has also shown an anti-inflammatory and an antioxidant profile. The safety and efficacy of MC-1101 will be evaluated by a randomized phase II/III trial (NCT02127463)⁶¹ that is currently ongoing and includes 60 patients affected by mild to moderate d-AMD.

Moxaverine, a nonselective phosphodiesterase inhibitor, showed contradictory results in different studies: Schmidl et al.⁶² reported that oral administration of Moxaverine is not effective in increasing choroidal blood flow, while Resh et al.⁶³ and Pemp et al.⁶⁴ demonstrated that intravenous administrated Moxaverine increases choroidal blood flow compared with placebo. These different results may be due to the different mode of administration, but further studies are necessary to investigate the clinically efficacy of Moxaverine in patients affected by d-AMD.

Sildenafil (Viagra; Pfizer Inc, New York, NY, USA) is a known vasodilator, but its role in the treatment of d-AMD is not clear. Metelitsina et al.⁶⁵ reported that this drug was not effective in improving the choroidal blood flow of the fovea in patients affected by AMD.

Stem cell-based therapy

Stem cell therapy represents a promising new approach for AMD. Evidence suggests that RPE and photoreceptors are primarily affected in GA, their transplantation seems to be an interesting therapeutic option⁶⁶. Thus, human pluripotent stem cells, embryonic (hESC) or induced (iPSC) are currently being investigated in clinical trials for AMD^67–69.

However, stem-cell-based therapy carries a long-term and multi-disciplinary approach. Therefore, the pros and cons of therapy must be analyzed in order to fully develop these new attractive approaches.