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Combined options for improved AMD management continue to be explored through successes and failures
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Anti-VEGF agents are currently the gold standard in the treatment of neovascular age-related macular degeneration. The now long-term experience in randomized controlled trials as well as real-life clinical practice has shown their remarkable benefits but also their limitations.
“Only one-third of patients achieve a meaningful three-line vision improvement. Despite therapy, 15% to 20% lose vision, and the majority do not achieve 20/40 VA. In the HORIZON and SEVEN-UP studies, long-term results were not encouraging: After 4 to 5 years of therapy, vision falls below baseline,” Andras Papp, MD, PhD, said.
The problem, he said, is that anti-VEGFs treat the leakage but are not fundamentally addressing the multifactorial etiology of the disease.
Studies are currently exploring the possibility of combining anti-VEGF agents with new therapeutic modalities that target other specific components of AMD’s pathogenesis. There is hope that combination regimens may offer a new key to AMD treatment, but the road to success is not straight.
Is Fovista out of the game?
Image courtesy of Andras Papp, MD, PhD, reprinted with permission.
The recent news that Fovista, (pegpleranib, Ophthotech) failed to show significant benefit over anti-VEGF monotherapy in two phase 3 trials came as a surprise, in stark contrast with the highly encouraging phase 2 results.
Fovista inhibits PDGF, the growth factor involved in the recruitment of pericytes, the cells that envelope and protect blood vessels and at the same time contribute to the pathogenesis of fibrosis.
“The rationale behind PDGF inhibition was to make the new vessels more accessible and vulnerable to VEGF inhibitors and at the same time reduce fibrosis and scarring,” Papp said.
His site was involved in the phase 2b trial, in which the arm combining Lucentis (ranibizumab, Novartis/Genentech) with 1.5 mg Fovista achieved a 10.6 ETDRS letter gain at 24 weeks, while the Lucentis monotherapy arm gained 6.5 letters.
“This was a significant 62% improvement. We had great expectations from phase 3 trials,” Papp said.
The unexpected results in phase 3, which enrolled 1,245 patients, came from the leveling up of Lucentis outcomes, which achieved a 10.01 ETDRS letter gain, comparable with the 10.24 letter gain of combination therapy. No significant difference was shown in other secondary measurements.
“We are puzzled by the results because in phase 2 and phase 3 the patient population was the same. The design and protocol were similar. However, the phase 2 ended at 24 weeks while these are 12-month results, and this could be a reason for the difference. What I would very much like to know is what the results were at 24 weeks in the phase 3,” Papp said.
As the company said in a press release, further analysis will be done on the data of the two trials to better understand the results. Meanwhile, other phase 3 studies combining Fovista with Eylea (aflibercept, Bayer/Regeneron) and Avastin (bevacizumab, Roche/Genentech) are ongoing, with outcomes expected in mid-2017.
“Given the results with Lucentis, there are no great expectations on these studies,” Papp said. “However, the future of this approach remains in the balance. The concept is good, the safety profile is good, and what we may have to do is improve the molecule. Fovista already did better than the anti-PDGF molecule used in the Regeneron REGN2176-3 combination.”
“We should not rush to negative conclusions,” he said. “I still think that combination therapy has a role, and we should not give up on this approach but continue doing research, and research takes time.”
Addressing the inflammatory component with corticosteroids
A combination with corticosteroids could complement the action of anti-VEGFs by addressing the inflammatory component of neovascular AMD, according to some researchers. Studies found increased levels of cytokines and other inflammatory proteins in patients with recurrent choroidal neovascularization who do not respond to treatment.
“We thought that it might be possible to treat these cases by combining anti-VEGF with the Ozurdex dexamethasone implant (Allergan) and performed a prospective study which included 40 patients randomized to receive Lucentis combined with Ozurdex or ranibizumab alone,” Stefan Sacu, MD, said.
Ozurdex was injected at 6-month intervals, while ranibizumab was administered as needed in both groups. Functional and anatomical results did not differ significantly, but the re-treatment rate was lower in the group receiving combination therapy.
“Cytokine levels decreased significantly in this group as compared with baseline and with the group on Lucentis monotherapy,” Sacu said. “We concluded that the cases that don’t show a good response to anti-VEGF could be treated with Ozurdex, too, because inflammatory factors play an important role.”
However, Sacu said that there are limitations to the use of this combination in clinical practice because the analysis of cytokines is not yet possible in routine cases.
“It is an invasive method, and it is difficult to involve the laboratory in doing cytokine detection and analysis for thousands of patients. However, the study proved that a significant improvement could be obtained,” Sacu said.
A topical adjunct
Squalamine lactate ophthalmic solution 0.2% (Ohr-102, Ohr Pharmaceutical) is a topically delivered, small-molecule anti-angiogenic drug with a novel intracellular mechanism of action. The drug acts against the development of aberrant neovascularization by inhibiting multiple protein growth factors of angiogenesis, including VEGF, PDGF and basic fibroblast growth factor, which has also shown to be elevated in retinal vein occlusion and neovascular AMD patients.
The phase 2 IMPACT trial enrolled treatment-naïve neovascular AMD patients at more than 20 clinical sites in the U.S. who were randomly assigned to treatment with squalamine or placebo eye drops for a 9-month period, along with ranibizumab injections as necessary, following an initial baseline ranibizumab injection.
“Data from the study demonstrated that in the prespecified group of patients with classic CNV containing lesions, 42% of the patients receiving squalamine along with Lucentis achieved a gain of three or more lines of vision at 9 months as compared to 28% in the Lucentis monotherapy group. Mean gains in visual acuity were +10.5 letters for the squalamine combination arm and +5.4 letters with Lucentis monotherapy, a clinically meaningful benefit of +5.1 letters. The positive effect on visual acuity in classic CNV was seen early in the course of treatment and continued to increase through the end of the study,” Jason Slakter, MD, said.
Further analyses showed that the best responders were patients with occult CNV less than 10 mm2. According to Slakter, in this population, 40% of squalamine combination treated patients gained three or more lines of vision compared with 26% with Lucentis monotherapy, and mean gains in visual acuity compared with baseline were +11 letters with squalamine combination and +5.7 letters with Lucentis monotherapy, a clinically meaningful benefit of +5.3 letters (P = .033). This optimized patient population is now being enrolled in the phase 3 program.
Squalamine used in combination with an anti-VEGF agent may provide several potential advantages over other combination therapy approaches currently being investigated in clinical studies.
“The obvious benefits are those of a daily topical therapy compared to additional intravitreal injections,” Slakter said. “There is a great unmet need for a noninvasive, topical therapy that provides better visual outcomes and maintains these gains over the long term, which is critical for a chronic disease like AMD.”
Due to the contained manufacturing costs and ease of administration, squalamine drops could also be highly cost-effective and greatly reduce the burden of AMD treatment.
Radiation for selective destruction of proliferating cells
Radiation therapy is also an option in combination with anti-VEGF agents. The idea comes from oncology: Radiation therapy selectively targets the proliferating neovascular cells, as it does with cancer cells, and acts synergistically with anti-VEGF agents.
“With radiation, we aim to kill off cells that are proliferating, and because they are proliferating, they are more vulnerable than mature retinal cells. Hence, it is a relatively selective treatment,” Timothy L. Jackson, FRCOphth, PhD, said.
The main evidence base comes from the INTREPID study comparing stereotactic radiotherapy with ranibizumab vs. ranibizumab monotherapy. A significant reduction in the number of anti-VEGF injections was achieved in the radiotherapy arms of the study. A subsequent analysis found that the best responders were patients with active leakage whose lesions fit fully within the 4-mm radiation area.
“One of the advantages of the stereotactic radiotherapy device is that it has a very collimated beam of radiation which falls on a 4-mm disc on the macula, with a very rapid fall of radiation beyond that area. Cases with active lesions within the diameter of the beam had a 55% reduction in the number of injections required and VA that was 5.3 letters superior to the ranibizumab-only treatment. There are not many treatments out there that offer the prospect of fewer injections and better vision,” Jackson said.
A new, larger study, named the STAR study and funded by the U.K. National Institute for Health Research, will analyze the outcomes of stereotactic radiotherapy in 411 patients classified as potential best responders according to the findings of the INTREPID study. The follow-up of the study will be 4 years.
“If the STAR study confirms the subgroup analysis of the INTREPID, we’ll have a treatment with obvious advantages for selected patients and for the NHS. A reduced number of injections allows reduction of monitoring cost and injection cost,” Jackson said.
Although safety appears satisfactory, the main risk is that post-radiation microvascular changes might occur at the fovea in a small number of cases, so it is important to monitor safety in the long term.
“Microvascular changes are typically very subtle and may only be picked up on angiography. The good thing is that we have reasonably long-term follow-up now, which is reassuring,” Jackson said.
PDT has a role in selected cases
Patients with the polypoidal choroidal vasculopathy (PCV) subtype of AMD may benefit from adjunctive photodynamic therapy, a relatively old procedure that has regained a role in combination with anti-VEGF in these cases.
PCV is common in Asia, where it affects 25% to 60% of AMD patients, leading to an even higher burden of recurrences and injections.
“Combination therapy has been used a lot for the last 10 years and has been quite successful in reducing the number of injections in these cases. The injections, on the other hand, reduce the side effects of PDT, including increased VEGF expression,” Timothy Lai, MD, said.
The EVEREST and EVEREST II trials have shown that PCV patients who undergo combined treatment do significantly better than patients on ranibizumab monotherapy. The established protocol was one PDT treatment initially in combination with the first of three monthly loading dose injections of ranibizumab, followed by monitoring and as-needed treatment.
Another study recently presented at the congress of the Asia-Pacific Vitreo-retina Society in Bangkok, the PLANET study, is looking into the use of aflibercept plus PDT as a rescue therapy in PCV patients.
“In this study PDT is not performed initially, but rather you have three loading doses of aflibercept and then decide on specific criteria if the patient needs PDT or not,” Lai said.
One of the limitations with this study is that aflibercept is administered at fixed intervals in the first year before switching to treat-and-extend in the second year. This results in a higher number of injections as compared with the schedule proposed by EVEREST.
“Asia is very diverse. In places with wealthy economies such as Japan, the government provides the drug and patients may need to copay maybe 5% to 10%, sometimes nothing. But in other places like Singapore and Hong Kong, treatment is mostly paid by the patient out of pocket,” Lai said.
In his routine practice, he uses combined therapy in most PCV cases. “Never in type 1 or 2 AMD, never for retinal angiomatous proliferation lesions, where it could cause RPE rip,” he said.
“PDT can be quite damaging,” Lai said. “PCV patients have a thick choroid — that’s why they are more suitable for PDT because PDT on a thick choroid is less likely to cause damage.”
“I perform PDT first and injection on the same day after about 1 hour. Others do the injection 7 days after PDT, or before PDT and PDT later, but there is some evidence that the closer the two are, the better the visual outcome,” he said. – by Michela Cimberle
- References:
- Connolly B, et al. Ophthalmol Clin North Am. 2006;doi:10.1016/j.ohc.2006.05.003.
- Jackson TL, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2013.02.016.
- Jackson TL, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2014.07.043.
- Jackson TL, et al. Retina. 2015;doi:10.1097/IAE.0000000000000283.
- Jaffe GJ, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2015.09.004.
- Jaffe GJ, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.10.010.
- Koh A, et al. Retina. 2012;doi:10.1097/IAE.0b013e31824f91e8.
- Lai TY, et al. Retina. 2011;doi:10.1097/IAE.0b013e31820d3f3f.
- Ophthotech announces results from pivotal phase 3 trials of Fovista in wet age-related macular degeneration. http://files.shareholder.com/downloads/AMDA-25HR8L/3450877743x0x920784/f8ce0d38-79ff-411a-a65a-96f10245d1fc/OPHT_News_2016_12_12_General_Releases.pdf. Published Dec. 12, 2016.
- Rezar-Dreindl S, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.16-19772.
- Rezar-Dreindl S, et al. Retina. 2016;doi:10.1097/IAE.0000000000001264.
- Wong RL, et al. J Ophthalmic Vis Res. 2013;8(4):359-371.
- For more information:
- Timothy L. Jackson, FRCOphth, PhD, is a consultant ophthalmic surgeon at King’s College Hospital, London, and Reader in Retinal Research at King’s College London. He can be reached at email: t.jackson1@nhs.net.
- Timothy Lai, MD, is an honorary clinical associate professor of the Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong. He can be reached at email: tyylai@cuhk.edu.hk.
- Andras Papp, MD, PhD, is an associate professor at the Department of Ophthalmology, Semmelweis University, Budapest, Hungary, and the secretary of the retina section of the Hungarian Ophthalmic Society. He can be reached at email: papp.andras1@med.semmelweis-univ.hu.
- Stefan Sacu, MD, is an associate professor at the Medical University of Vienna, Austria. He can be reached at email: stefan.sacu@meduniwien.ac.at.
- Jason Slakter, MD, is a clinical professor of ophthalmology at New York University School of Medicine and CEO at Ohr Pharmaceutical. He can be reached at email: jslakter@aol.com.
Disclosures: Jackson reports his employer receives free use of the IRay device for participants enrolled in the STAR study; he received an unrestricted educational grant from Novartis for an unrelated study; and his employer receives site payments for studies sponsored by Bayer and Ophthotech. Lai reports he has received honorarium for consultancy and/or lecture fees from Allergan, Bayer, Genentech and Novartis. Papp reports he is a consultant for Bayer, Novartis and Roche. Sacu reports no relevant financial disclosures. Slakter reports he is CEO of Ohr Pharmaceutical.
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