October 2016

 

RETINA

 

Slowing down dry AMD progression


by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer

 
 

“The problem is that clinical trials need a control group, but you can’t ethically deny patients with wet AMD anti-VEGF for possibly a 5-year duration, since we know the treatments halt wet progression and even restore vision in some cases. That is why, at the moment, we have more of a clinical impression surrounding neovascular-associated GA, but lack studies to prove it.” –Sylvia Bopp, MD

 
Geographic atrophy

AMD
Geographic atrophy due to AMD with soft and crystalline drusen; color fundus photograph (left) and corresponding fundus autofluorescence image (right) Source: Frank Holz, MD

Retina specialists take a realistic look at their options at the German Ophthalmic Surgeons (DOC) Congress in Nuremberg, Germany

Geographic atrophy (GA) is a devastating late-stage manifestation of age-related macular degeneration (AMD). While some preventive measures are well in place for persons with early and intermediate AMD, an effective treatment for delaying progression in those who have developed advanced dry AMD with atrophy seems more challenging. The increasing prevalence of blindness in today’s ever-aging population lends urgency to finding effective therapeutic approaches. EyeWorld spoke with retinal specialists Frank Holz, MD, Department of Ophthalmology, Bonn University Eye Clinic, Bonn, Germany, and Sylvia Bopp, MD, Augenklinik Universitätsallee, Bremen, Germany, for an updated perspective on the disease and current research efforts.

Terminology

Current AMD classification distinguishes early and intermediate AMD on the one hand, in which central vision is usually maintained, and late stage AMD, which is either associated with neovascularization (wet) or GA with areas of central vision loss, on the other. According to Dr. Holz, who spoke about treating GA at the German Ophthalmic Surgeons (DOC) Congress in Nuremberg, Germany, “Dry AMD is a term we are now trying to modify because it causes a lot of confusion. Dry AMD can be everything from a single little drusen associated with aging but with no functional deficit whatsoever, to geographic atrophy, which can lead to complete disability with loss of central vision. Geographic atrophy is late-stage disease, which was formerly labeled late dry AMD.”

Slow it down

Retinal specialists think that slowing down the unrelenting forward progression of AMD is the physician’s best chance to preserve patients’ eyesight. However, unlike antivascular endothelial growth factor (anti- VEGF) therapy, which has shown high efficacy in halting progression of exudative AMD, there are no approved treatments for GA, as yet. Dr. Holz discussed the results and expectations of two current trials that take two very different approaches to the problem.

The S.E.A.T.T.L.E. study implemented an investigational visual cycle modulator emixustat hydrochloride to reduce A2E, a vitamin A-based toxin thought to have deleterious effects on RPE cells, to slow progression in GA patients. The randomized study enrolled 508 patients with GA to receive oral emixustat for 24 months. The study failed to meet its primary endpoint with none of the treatment groups demonstrating a significant difference in lesion growth rates. The lesion growth rates over 24 months for the 10 mg, 5 mg, 2.5 mg, and placebo groups were 1.84 mm2/year, 1.83 mm2/year, 1.69 mm2/year, and 1.69 mm2/year, respectively.

“There are several lines of evidence to indicate that toxic byproducts of the visual cycle play a role in aging of the retina, the retinal pigment epithelium, and in AMD. The hope was that by slowing down the visual cycle and having lower amounts of these toxic byproducts that it would help to slow disease progression. Following the study outcomes, emixustat will not be pursued for this phenotype of AMD, as the drug unfortunately did not influence the course of the disease,” Dr. Holz said.

On a far more promising front, investigators in the dual CHROMA and SPECTRI studies are focusing on intervening in the complement pathway responsible for inflammation and cell death in GA through the use of lampalizumab. This humanized mouse anti-factor D monoclonal antibody is designed to limit the rate-limiting step in the alternative complement pathway, by binding to factor D, a protein in the complement cascade. In a Phase 2 trial that investigated the role of lampalizumab in GA (MAHALO), a 20% reduction in GA growth rate was achieved at 18 months, with monthly intravitreal lampalizumab injections. In a subgroup analysis of patients with the complement factor I biomarker, a 44% reduction in GA growth rate was observed. These results sparked the currently recruiting Phase 3 multicenter, randomized, double- masked, sham injection controlled CHROMA and SPECTRI studies that will investigate the drug’s efficacy and safety. This approach also represents the potential therapy for GA furthest in clinical development to date. Dr. Holz thinks that lampalizumab may present a promising option to slow down GA and prevent severe visual loss. “There is evidence that complement hyperactivity plays an important role in the pathogenesis of the disease. By intervening here, we may be able to slow down atrophy. The CHROMA and SPECTRI trials are recruiting almost 2,000 patients to see if the drug can slow the expansion of atrophic patches. Atrophic lesions will always continue to grow if there is no treatment given, so results will be telling. However, it is too early to say—the data are in the final analysis,” he said.

Recruitment will end around Q3 2016 and patients will be followed for 24 months. Dr. Holz expects to see first results sometime in 2018.

Neovascular-associated GA

According to Dr. Bopp, neovascular- associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. She explained, “Treatment with VEGF inhibitors early in the course of the neovascular disease is of great clinical benefit. However, we suspect that anti-VEGF treatment may actually strengthen development of geographic atrophy with continuous use. We are still not certain if it’s caused by the treatment with anti-VEGF or if it is a progression of the disease itself.” Dr. Bopp said that AMD research has certain limitations that are hard to get around. “The problem is that clinical trials need a control group, but you can’t ethically, with a good conscience, deny patients with wet AMD anti-VEGF for possibly a 5-year duration, since we know the treatments halt wet progression and even restore vision in some cases. That is why, at the moment, we have more of a clinical impression surrounding neovascular-associated GA, but lack studies to prove it.”

Prevention

According to Dr. Bopp, while preventive treatment for AMD has proven effective in slowing disease progression in the Age-Related Eye Disease Study (AREDS), it also presents certain limitations in daily practice, due to patient adherence and a variety of other factors. Dr. Bopp explained, “We recommend the AREDS vitamin cocktail to our patients, but a little half-heartedly. On the one hand, AREDS is the only study that has proven that we can affect progression in dry AMD patients, so it lets us offer some hope and give patients something to work toward. But on the other hand, you would have to follow a patient’s nutritional plan closely and also determine the patient’s nutritional deficits to fully understand if the supplements are working. Sometimes statistically significant study outcomes are not quite as clinically relevant.” While ineffective in individuals with early AMD, AREDS investigated 3,500 people with AMD over 10 years and proved efficacy in slowing AMD progression by 25% and slowing visual loss by 19% in persons with intermediate AMD. AREDS2 validated the efficacy of 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc, 2 mg copper, and added 10 mg lutein and 2 mg zeaxanthin to the mix, as an increased intake of these macular carotenoids has been associated with a decreased risk of neovascular AMD and a lower AMD degeneration risk.

Editors’ note: Drs. Holz and Bopp have no financial interests related to their comments.

Contact information

Bopp
: s.bopp@retina.to
Holz: Julia.Moroni@ukb.uni-bonn.de

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