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‘Triple therapy’ shows promising results for AMD treatment
Combination of PDT, bevacizumab and dexamethasone aims at increased safety, fewer re-treatments for patients, doctor says.
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As age-related macular degeneration treatments progress, many surgeons are looking toward combining existing therapies to provide more effective and longer-term solutions for their patients. “Triple therapy” showed promise in preliminary studies by combining photodynamic therapy, bevacizumab and dexamethasone, according to a study recently published in Retina.
“If you look at all other monotherapies, they are either not as good as we thought concerning visual acuity outcome or you need a lot of re-treatments,” said Albert J. Augustin, MD, who developed triple therapy about 6 years ago.
“Our final goal should be a combination treatment that helps to reduce the number of re-treatments and makes everything safer,” he said.
Why a combination?
This combination draws on the strengths of each component to better treat patients, Dr. Augustin said in the study and during a subsequent interview with Ocular Surgery News.
“Anti-VEGF [vascular endothelial growth factor] and PDT with verteporfin possess different mechanisms of action that may work synergistically, with their combination potentially improving VA with a limited and finite number of treatments,” Dr. Augustin’s study concluded. “In addition, verteporfin therapy has been combined in practice with steroids such as intravitreal triamcinolone and dexamethasone, which have a third anti-inflammatory complementary mechanism of action.”
When PDT was first released, Dr. Augustin said he felt that it was counterintuitive because light toxicity and photodynamic reactions are thought to play a role in the pathogenesis of AMD. It also does not address the inflammation and edema of choroidal neovascularization, he said.
Anti-VEGF treatments are not as effective as desired because they do not treat the existing tissue, producing worse results when the CNV is older or larger, Dr. Augustin said.
“You need a CNV eraser because the tissue that is already present doesn’t disappear,” he told OSN. “This is one of the major reasons we need so many anti-VEGF re-treatments. We only take away a major part of the growth stimulation, but the CNV is still present and is doing harm to the adjacent neurosensory tissues.”
Peter K. Kaiser |
Ideally, he said, a combination treatment should incorporate an anti-VEGF drug, an anti-inflammatory drug and a treatment directly counteracting the CNV. An additional advantage of adding an anti-inflammatory drug is the antifibrotic effect of those agents.
Peter K. Kaiser, MD, weighed in on the issue of which anti-inflammatory steroid to choose: dexamethasone or triamcinolone.
“The big difference is that dexamethasone has a much quicker onset of action and a much higher potency, but it doesn’t last as long. Kenalog (triamcinolone, Bristol-Meyers Squibb) isn’t as potent but lasts considerably longer,” he said. “The nice thing about dexamethasone is it is clear, so it does not usually cause floaters or disrupt vision. In addition, by breaking down faster, you have less cataract and glaucoma issues.”
Dr. Kaiser also said many physicians are concerned with the purity of Kenalog and its intraocular use. This leads them to use a purified version or to wash it before injection, steps that dexamethasone does not require despite its off-label use.
The study
Dr. Augustin and colleagues performed a prospective noncomparative study of 104 patients receiving triple therapy. All patients, regardless of lesion size or fibrotic composition, were included.
The therapy was given in steps, with verteporfin PDT first administered with a reduced light dose. About 16 hours after PDT, dexamethasone and bevacizumab were injected intravitreally.
“We administered the dexamethasone 16 hours after PDT because PDT’s efficacy depends upon immunologically/inflammatory mediated processes, which are established within a 16-hour period,” the researchers said. “Delaying 16 hours before administering dexamethasone ensures PDT’s therapeutic effects, but prevents PDT mediated over-activation of the inflammatory cascade.”
Patients returned every 6 weeks for follow-up appointments and were tested for VA and IOP and underwent slit-lamp, ophthalmoloscopic and optical coherence tomography (OCT) testing. Every 3 months, or earlier if OCT showed significant edema, the patient received fluorescein angiography.
All patients received at least one triple therapy cycle and were followed for a mean 40 weeks. Of these patients, 39.4% gained three or more lines, and 3.8% lost three or more lines. Mean VA significantly improved by 1.8 lines. There were no adverse events, including increased IOP, the study authors said.
“In most patients with CNV due to AMD, triple therapy resulted in significant and sustained VA improvement after only one cycle of treatment,” they said. “In addition, the therapy offers a good safety profile, potentially lowering costs compared with therapies that must be administered more frequently, and convenience for patients.”
After the first round of therapy, five patients received a complete second round, while 18 patients received an additional injection of bevacizumab.
“The results suggest that similar benefit may be gained from one triple therapy cycle compared with up to three anti-VEGF monotherapy courses, with sustained benefit from the triple therapy, in contrast to the likely need for continued additional anti-VEGF monotherapy cycles to maintain the observed benefit,” Dr. Augustin and colleagues said.
The researchers acknowledged that this case series is limited by the low number of patients and lack of a control arm. They said the regimen itself is experimental, and dosages and time intervals may need to be refined.
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Clinical observations
Drs. Augustin and Kaiser have used this approach in their practices, although Dr. Kaiser said he is not yet doing so regularly. They said it is effective and could possibly help with the increased volume in retina practices.
“In oncology, we became successful when we switched from monotherapies to combination treatments, and I think it’s comparable to an oncologic approach,” Dr. Augustin said.
In the study, he compared the PDT to a surgeon removing a cancerous mass before moving on to chemotherapy.
“[Triple therapy] appears to be delivering better results than with any of these drugs alone and even better than PDT and Avastin,” Dr. Kaiser said.
Thus far, Dr. Kaiser said, he has seen a dramatic decrease in the number of treatments triple therapy patients need, while still delivering results comparable with the gold standard of Lucentis (ranibizumab, Genentech). He added that there is still a need for randomized studies.
“The results that we’ve been seeing with the triple therapy, and especially Dr. Augustin’s work, have shown nice stability after only one treatment,” Dr. Kaiser said. “With ranibizumab or bevacizumab monotherapy, we are getting good results, but we have to administer a lot of treatments to get there. We also do not know when we can stop the treatments. Ideally, we’d have a similar efficacy with combination treatment, but considerably fewer treatments.”
If this ideal situation were implemented, the increased volume in retina practices could be spread out, helping physicians and patients, he said.
Future developments
Although results have been promising, both physicians cautioned that this treatment is experimental.
Dr. Augustin also emphasized that the vitrectomy used during the study may not be a necessary step, but might actually increase the risk of endophthalmitis.
“We did the vitrectomy for volume reasons only,” he said. “If you are able to concentrate the drugs that have to be applied after PDT, then a vitrectomy is not necessary and … might do harm.”
He said a vitrectomy could increase the inflammation of the disease process, as well as the risk of endophthalmitis. It was only added in the study because of lack of access to concentrated medications.
“This is an experimental treatment that is not proven yet, but the results appear promising and certainly warrants further investigation,” Dr. Kaiser said.
For more information:
- Albert J. Augustin, MD, can be reached at Moltkestrasse 90, 76133 Karlsruhe, Germany; 49-721-974-2001; fax: 49-721-974-2009; e-mail: 106020.560@compuserve.com. He serves on the scientific advisory boards for Alcon, Novartis, QLT, Zeiss, Pfizer and Allergan. The Department of Ophthalmology at Karlsruhe, his employer, has received research grant support for his work from Alcon, Allergan, Novartis and QLT.
- Peter K. Kaiser, MD can be reached at the Cole Eye Institute, Division of Ophthalmology, A31, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702; e-mail: pkkaiser@aol.com. Dr. Kaiser serves on the scientific advisory boards for Genentech, Alcon, Novartis, QLT, Bausch & Lomb, Occulogix and Allergan. The Cole Eye Institute, his employer, has received research grant support for his work from Alcon, Allergan, OSI/Eyetech, Genentech, Novartis, QLT and Sirna Therapeutics.
Reference:
- Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27:133-140.
- Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.