Emerging treatments bring hope for patients with geographic atrophy
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New pharmacotherapies and novel approaches, such as gene therapy and cell therapy, are raising realistic hopes for patients with geographic atrophy, a condition that can lead to vision loss.
“There has been a tremendous amount of clinical research looking at different therapeutic avenues for geographic atrophy, and we have had some prominent disappointments over the last 10 years. But recently we had some very promising successes that bring a lot of hope and encouragement to a field that is continuing to drive innovation,” Charles C. Wykoff, MD, PhD, said.
Source: Robert Seale and Retina Consultants of Texas Research Centers
Geographic atrophy (GA) is an unmet need and a major public health problem, according to OSN Retina/Vitreous Board Member Carl D. Regillo, MD, FACS. With 5 million people worldwide and close to 1.5 million people in the U.S. having vision affected or threatened by GA, it accounts for approximately 35% of advanced age-related macular degeneration cases and is responsible for 10% to 20% of cases of AMD-related legal blindness.
“The most impactful statistic I have seen is that about one-third of the population will be affected by GA as they reach the age of 80 or older. Incidence goes up exponentially with age, and since patients are living longer, we are seeing more and more cases,” Regillo said. “While the initial stages are asymptomatic, more advanced stages steadily lead to irreversible central vision loss and eventual legal blindness in many cases, depending on how long the patient lives.”
The PROXIMA A and B studies, among others, have shown that that the natural history of GA is relentless progression.
“While in neovascular AMD patients can have a dramatic visual decline over days to weeks, in GA we see a progressive decline of approximately one line of vision on average per year, which cumulatively amounts to significant vision loss over time,” Wykoff said.
The slow, progressive nature of GA has been a key factor in making it difficult to find a treatment.
“There is no good animal model to test a potential therapeutic in the early stages, and any intervention requires a long follow-up to show a benefit, at least 6 to 12 months, while in nAMD, the potential benefits at a phase 1 level are visible within 3 months,” Regillo said. “Even more importantly, GA is multifactorial. There is no one dominant growth factor or target that appears to be a main pathophysiologic mechanism at play. There is a multitude of pathways and, therefore, potential treatment targets.”
Avacincaptad pegol
Genetic variants of a number of complement factor genes have been identified in studies as risk factors for the development of end-stage AMD. Two complement inhibitors that are currently in clinical trials, an anti-C5 and an anti-C3, are helping to confirm complement as a validated target.
Avacincaptad pegol (Iveric bio) is a C5-binding oligonucleotide designed to target and inhibit the complement protein C5 and the formation of its downstream fragments.
“By doing so, it blocks the formation of some cell-damaging components, such as membrane attack complex and inflammasomes,” Regillo said.
In the GATHER1 pivotal trial, avacincaptad pegol met the primary outcome at month 12, showing a highly statistically significant reduction in the mean rate of growth of GA as compared with sham with both the 2 mg and 4 mg doses administered monthly by intravitreal injection.
“At 18 months, we see an even greater effect, with 28% reduction in the 2 mg arm and 30% reduction in the 4 mg arm as compared to sham,” Regillo said.
From a safety standpoint, the drug was well tolerated, with no cases of intraocular inflammation or endophthalmitis. However, a dose-dependent increased incidence of choroidal neovascularization (CNV) was reported in the treated arms.
“CNV rate in 12 months was 2.7% in the sham arm, 9% in the 2 mg and 9.6% in the 4 mg arm. Rates were slightly higher at 18 months. Sham was still 2.7%, the 2 mg was 11.9%, and the 4 mg was 15.7%,” Regillo said.
GATHER2, a second phase 3 pivotal trial, will evaluate only the 2 mg dose injected monthly compared with sham. Following the same primary endpoint of GATHER1 at 12 months, during year 2, the avacincaptad pegol arm will be re-randomized to ongoing monthly vs. every other month therapy.
“Enrollment was completed in July 2021, and we expect the results of this confirmatory pivotal trial in the second half of 2022,” Regillo said.
Pegcetacoplan
C5 and C3 represent the core backbone of the complement cascade, Wykoff said. C3 is the molecule at which all three activation pathways converge, leading to downstream propagation of the inflammatory cascade.
“Pegcetacoplan (APL-2, Apellis Pharmaceuticals) is a pegylated peptide that binds to C3, inhibiting its cleavage and stopping downstream progression of the complement cascade,” he said.
The first program to validate pegcetacoplan was the FILLY trial, a single-masked phase 2 program in which meaningful reduction in the growth rate of GA was achieved. The phase 3 program consisted of two trials, OAKS and DERBY. Combined, these trials enrolled 1,258 patients randomly assigned equally to receive pegcetacoplan 15 mg monthly, pegcetacoplan 15 mg every other month or sham.
In OAKS, the primary endpoint was met. With monthly and every other month dosing, 22% and 16% reductions in the growth of GA were found, with P values of .0003 and .0052, respectively. DERBY did not meet the primary endpoint, with a percentage of reduction of GA growth of 12% with monthly dosing and 11% with every other month dosing. Combining the data sets of OAKS and DERBY, pegcetacoplan decreased the growth of GA by 17% with monthly dosing and 14% with every other month dosing, obtaining P values of less than .05.
“While the field would certainly like to see a much larger reduction in growth, I see this as an important start, a move in the right direction,” Wykoff said.
Eleonora M. Lad, MD, PhD, found the results of DERBY and OAKS “very impressive overall.”
“I believe that these data are a breakthrough in GA,” she said.
She was particularly impressed with the results in extrafoveal lesions, in which monthly and every other month dosing led to 26% and 23% reductions in growth, respectively, in combined studies.
“These lesions progress faster than foveal, and the results showed even greater in this subpopulation. To me, that’s key as a clinician because we are trying to protect the fovea,” she said.
Although DERBY results did not achieve the same statistical significance of OAKS, the drug reduced lesion growth in the study, and Lad hopes that the combined data of the two studies will still support the approval of pegcetacoplan for GA. Apellis plans to submit a new drug application to the FDA in the first half of 2022.
A safety analysis showed that pegcetacoplan was overall well tolerated, but over the 18-month course of the FILLY study, including a 6-month off-drug follow-up period, new-onset neovascular AMD was diagnosed in 20.9% of the eyes receiving the treatment monthly and 8.9% of the eyes receiving the treatment every other month vs. 1.2% of the eyes in the sham arm.
“This finding has significantly impacted the entire field of sponsors investigating pharmacotherapies targeting GA. Every company now is considering this as a possible side effect of manipulating the complement cascade,” Wykoff said.
Combined data from DERBY and OAKS showed a significantly lower percentage of cases: 6% in the monthly arm, 4.1% in the every other month arm and 2.4% in the sham arm.
Such a discrepancy might be at least partially related to the percentage of fellow eyes with neovascular AMD at baseline, which was approximately 35-40% in the phase 2 population vs. approximately 20% in the phase 3 population.
“We know that fellow eye history of exudative AMD is a strong predictor of exudative AMD development in the study eye. The other important factor to consider here is the prospectively integrated imaging modalities that were used to confirm the presence of exudative AMD in phase 3, as a lesson learned from phase 2,” Wykoff said.
Discussing outcomes
Lad commended the study design of OAKS and DERBY, which was different from other trials. While GATHER1 and GATHER2 recruited only patients with extrafoveal lesions in the treated eye, DERBY and OAKS included foveal lesions, too.
“They included a broad GA population that was reflective of the real-world setting. GA is a complex disease, very heterogeneous, so it is promising to see a drug that reduced lesion growth and has this favorable safety profile in a broad population,” she said.
Regillo said that the efficacy and safety outcomes of the two drugs targeting the complement cascade were similar at the phase 2 level. “And we await the confirmatory phase 3 GATHER2 trial results for avacincaptad pegol to know if there will be a meaningful difference in efficacy or safety when comparing the larger registration trials for both drugs,” he said.
“However, we have now two drugs both shutting down the complement cascade, and the results at least thus far look comparable,” he said.
“Complement inhibition seems to be working. We must make sure we have the right target and the right drug to engage the target,” Arshad M. Khanani, MD, MA, an OSN Retina/Vitreous Board Member, said.
GATHER2 data are expected to come out next year, and if they are positive, the pathway to approval will be straightforward for avacincaptad pegol. On the other hand, the mixed trial results might jeopardize the approval of pegcetacoplan, according to Khanani.
“Historically, the FDA requires two positive phase 3 trials for approval. Since GA is an unmet need, the FDA might still consider approval or require another trial from Apellis to look only at the extrafoveal lesions. However, since the pooled efficacy was only 17% in 1 year with 12 injections, I doubt that any of us will use APL-2 for central lesions even if it is approved. Personally, I would only treat extrafoveal lesions in patients who have lost the other eye to central GA,” he said.
Gene therapy
Gene therapy targeting the complement system is still in the early stages of development, but the potential impact may be big in GA, according to Khanani.
“It is a one and done procedure that overcomes the burden of multiple injections and the problem of compliance,” he said.
GT005 (Gyroscope Therapeutics) is a one-time AAV-based gene therapy designed to rebalance the complement system by expressing the complement factor I (CFI), a natural inhibitor of the complement system.
The FOCUS phase 1/2 open-label study is investigating safety, tolerability and dose response of three doses of GT005 administered as a single subretinal injection. Two methods of administration are being evaluated: standard transvitreal procedure and injection via Gyroscope’s proprietary Orbit subretinal delivery system.
“The latest data update from the FOCUS trial has shown elevation of the CFI protein, and evidence of its downregulating effect has been confirmed by 46% decrease in levels of the Ba and C3 proteins in the vitreous. These results are sustained at 1 year after administration, and data in two patients have suggested sustained expression to over 18 months. We still have to learn if the level of these biomarkers remains stable in the long term,” Khanani said.
In addition to FOCUS, GT005 is being evaluated in the phase 2 EXPLORE and HORIZON trials. The first includes patients with rare variants in the CFI gene and low levels of CFI protein in the blood, while the second includes a broad population with GA.
“Both these trials will provide efficacy as well as safety data and will be followed by extension trials and maybe phase 3 trials in a few years. At present, we are still in the early stages, and we need at least 5 years down the road to see if the drug can be approved,” Khanani said.
Cell therapy
Stem cell transplantation to replace the diseased retina is another potential treatment avenue still in the early stages of development. In September, Lineage Cell Therapeutics reported updated interim results from its ongoing phase 1/2a clinical trial of OpRegen, a single subretinal injection of human embryonic stem cell-derived retinal pigment epithelium (RPE) cells.
“Patients with GA lose their RPE cells. If we can replace those cells, the hope is that we can restore the photoreceptor outer segment function and consequently restore some vision,” Christopher Riemann, MD, said.
OpRegen has only been evaluated in a phase 1 trial, in which it was shown to be safe in terms of not causing any inflammatory or immune response. In one of the four cohorts of the trial in which eyes with better visual potential, from 20/60 to 20/200, were included, other exciting signals were observed.
“Those patients, many of them, had significant increases in visual function, 10 letters on average and up to 24 letters in some patients, something we have never seen before in a treatment for GA. The possibility to reverse visual loss from GA is super exciting,” Riemann said.
Two of his patients were included in the trial, and both of them now see better out of the treated eye.
“One of them called me a few months after we did the surgery. She was crying, and whenever a phase 1 patient calls and is crying, my investigator’s heart is in my throat because we always worry that something horrible is going to happen. When I got her to stop crying and talk to me, she said, ‘Doctor, you don’t understand. I can see.’ That was a really big deal,” Riemann said.
The other patient did not improve initially, but over several months, he is slowly gaining vision.
To exclude a placebo effect, OCT was performed to evaluate if there were structural changes that correlated with the visual gain. Changes were found in many patients, but not all.
“We are seeing restoration of the RPE, the external limiting membrane and the outer nuclear layer in the area of the cell transplant,” Riemann said.
CNV developed as a side effect in both of his patients, at the site of the puncture, possibly as a result of microscopic fractures to Bruch’s membrane caused by the insertion of the cannula in the subretinal space.
“Both were responsive to anti-VEGF treatment with a T&E regimen. They are doing beautifully well, their vision has improved, and they are both glad to have enrolled in the trial,” Riemann said.
In the study, two ways of delivering the cells were evaluated: by injection in the subretinal space after vitrectomy or by using the Orbit delivery system. While CNV appears to be related to the use of the Orbit system, 15 of the 17 patients treated with the vitrectomy and retinotomy approach developed macular pucker, and two had retinal detachment.
“We’ll have to work out whether we prefer to deal with the surgical complications of macular pucker and RD or to deal with CNV, making a lot of these patients anti-VEGF dependent,” Riemann said. “More importantly, we should be able, with improvement in surgical techniques, to improve the safety profile of the delivery itself. The good news is that ERM, RD and CNVM all have effective treatment options.”
Multiple options in the pipeline
Among other treatments under investigation for GA, GEM103 (Gemini Therapeutics) is a recombinant complement regulator targeting complement factor H, currently being investigated in the phase 2a ReGAtta study. NGM621 (NGM Biopharmaceuticals) is a humanized IgG1 monoclonal antibody engineered to potently inhibit complement C3, being investigated in the phase 2 CATALINA study. Janssen Pharmaceuticals has acquired the rights to Hemera Biosciences’ investigational gene therapy HMR59.
“There are many important ongoing programs evaluating various pharmacotherapies including gene therapy approaches, subcutaneous delivery mechanisms, oral approaches and intravitreal injections that cumulatively hold tremendous promise of bringing new therapeutics to patients with GA and ultimately intermediate AMD in order to prevent GA development. There are a lot of fascinating studies ongoing, and there is much to learn,” Wykoff said.
“I think we are getting closer to the goal of finding a treatment,” Riemann said. “If I look at the enormous amount of energy and effort that has been put into treating this disease, I think that the ultimate goal will be some effective combination therapy and multiple treatment modalities to suit individual patients.”
“Geographic atrophy is a devastating disease where we see our patients lose vision over time. It is exciting to see research progressing in so many directions to find efficacious and safe treatment options for our patients,” Khanani said.
Editor's note: On November 18, 2021, this article was updated to more closely reflect the findings of the OAKS study. Healio editors regret the error.
- References:
- Friedman DS, et al. Arch Ophthalmol. 2004;doi:10.1001/archopht.122.4.564.
- Halawa OA, et al. J Clin Med. 2021;doi:10.3390/jcm10122580.
- Jaffe GJ, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2020.08.027.
- Keenan TDL, et al. Adv Exp Med Biol. 2021;doi:10.1007/978-3-030-66014-7_1.
- Kim BJ, et al. Prog Retin Eye Res. 2021;doi:10.1016/j.preteyeres.2020.100936.
- Kim JB, et al. Drugs Aging. 2021;doi:10.1007/s40266-020-00822-6.
- Liao DS, et al. Ophthalmology. 2020;doi:10.1016/j.ophtha.2019.07.011.
- Lin JB, et al. J Clin Med. 2021;doi:10.3390/jcm10132890.
- Madheswaran G, et al. BMJ Open. 2021;doi:10.1136/bmjopen-2020-047861.
- Mahmoudzadeh R, et al. Curr Opin Ophthalmol. 2021;doi:10.1097/ICU.0000000000000746.
- Park YG, et al. Int J Mol Sci. 2021;doi:10.3390/ijms22136851.
- Rudnicka AR, et al. Ophthalmology. 2012;doi:10.1016/j.ophtha.2011.09.027.
- Sadda SR, et al. JAMA Ophthalmol. 2021;doi:10.1001/jamaophthalmol.2021.1414.
- Samanta A, et al. Asia Pac J Ophthalmol (Phila). 2021;doi:10.1097/APO.0000000000000355.
- Steinle NC, et al. Am J Ophthalmol. 2021;doi:10.1016/j.ajo.2021.02.031.
- Wong WL, et al. Lancet Glob Health. 2014;doi:10.1016/S2214-109X(13)70145-1.
- Wong WT, et al. Ophthalmology. 2020;doi:10.1016/j.ophtha.2019.09.008.
- Wykoff CC, et al. Am J Ophthalmol. 2021;doi:10.1016/j.ajo.2021.08.018.
- Wykoff CC, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2021.02.025.
- Yu HJ, et al. BioDrugs. 2021;doi:10.1007/s40259-021-00481-y.
- For more information:
- Arshad M. Khanani, MD, MA, can be reached at Sierra Eye Associates, 950 Ryland St., Reno, NV 89502; email: arshad.khanani@gmail.com.
- Eleonora M. Lad, MD, PhD, can be reached at Duke Eye Center, 2351 Erwin Road, Durham, NC 27705-4699; email: nora.lad@duke.edu.
- Carl D. Regillo, MD, FACS, can be reached at Wills Eye Hospital, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; email: cregillo@aol.com.
- Christopher D. Riemann, MD, can be reached at Cincinnati Eye Institute, 1945 CEI Drive, Cincinnati, OH 45242; email: criemann@cincinnatieye.com.
- Charles C. Wykoff, MD, PhD, can be reached at Retina Consultants of Houston, 6560 Fannin St., Suite 750, Houston, TX 77030; email: ccwmd@houstonretina.com.
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