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For better not for worse, combination therapy still finding its way for AMD
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Relevant observations on the complex pathologic pathways of age-related macular degeneration have laid ground for the concept of combination therapy in which multiple steps in the pathways are intervened concurrently. It is believed that combination therapy will eventually replace monotherapy as the treatment of choice for AMD due to the possibility of superior clinical benefits. The cover story in the latest issue of OSN APAO Edition explores results from recent studies of five therapeutic options in combination with the anti-VEGF agent ranibizumab for neovascular AMD.
Among the options, photodynamic therapy and the steroid implant Ozurdex (dexamethasone intravitreal implant, Allergan) have been commercially available for some time. Radiation therapy is not a new approach, but the new system of low-voltage external beam stereotactic radiotherapy (SRT) overcomes some limitations of the previous system, epimacular brachytherapy (EMBT). Fovista (pegpleranib, Ophthotech) and squalamine (Ohr Pharmaceutical) are based on relatively new targets in the pathologic pathways. It is difficult to compare the clinical benefits of these combined options due to differences in study design. In selected groups of patients, however, some of these options show promising clinical results.
Different study populations, methods of administration
It is not surprising that the studies of newer molecules, Fovista and squalamine, focus on naïve lesions of choroidal neovascularization (CNV) whereas the recent studies of earlier approaches, Ozurdex and radiation, focus on patients with persistent or recurrent lesions. The study of PDT still counts on a specific phenotype: polypoidal choroidal vasculopathy (PCV).
In terms of methods of administration, topical squalamine possibly provides the least treatment burden. Meanwhile, Fovista, if applied according to the study protocol, requires monthly intravitreal injections. If Fovista is approved for CNV, we may require more studies on better treatment regimens for real-world practice, such as as-needed or treat and extend, like we are studying for anti-VEGF monotherapy.
SRT requires only a single noninvasive administration without the need for vitrectomy, like in EMBT. The methods of Ozurdex implantation and PDT are familiar to most retina specialists today.
Promising options with clinical benefits
Interestingly, of the five options, SRT and PDT, which have effects on the whole vascular lesion of CNV, not only at specific steps in the pathologic pathways of AMD like other options, yield the most clinical benefits. Both treatments combined with Lucentis (ranibizumab, Novartis/Genentech) achieve better vision with fewer ranibizumab injections compared with ranibizumab monotherapy.
To achieve the clinical benefits of SRT, however, both lesion size (4 mm or smaller in greatest linear dimension) and macular fluid volume (greater than 7.4 mm3) of a CNV lesion count. The 1-year results of INTREPID (statistically significant reduction of the number of ranibizumab injections at 55% and improvement of vision at four to five letters) are carried over to 2 years for this specific group of patients.
For PDT in PCV, according to 12-month results of the EVEREST II study, the combination gives 3.2-letter superiority with two fewer ranibizumab injections and one fewer PDT re-treatment compared with ranibizumab monotherapy. A total of 61% of patients in the combination arm required PDT only once. However, the key benefit may be the rate of polyp regression, 70%, which is 50% more than monotherapy. It is still debatable whether polyp regression is needed in PCV treatment.
Both SRT and PDT may still have some concerns. SRT may carry the risk of microvascular changes in the treated area and need long-term monitoring. PDT can also cause massive hemorrhage, although the probability is low with combination therapy.
Possible visual benefits for specific patient groups
For squalamine, the best responders in terms of visual outcome may be patients with occult CNV less than 10 mm2 or classic CNV containing lesions. However, the data are based on results of a phase 2 trial. If this medication is approved for these specific groups, retina specialists may once again need to classify CNV lesions based on angiographic patterns. Agreement on the classification was not good previously. For Ozurdex, there is evidence showing that certain intraocular cytokines are related to disease activity of CNV and treating such lesions with Ozurdex decreases levels of the cytokines. However, no superiority in visual function was found.
Combination with other anti-VEGFs
Real-world experience tells us that responses to anti-VEGF agents by individual patients can be different. The option that provides better outcomes in combination with ranibizumab may not achieve similar results when combined with Eylea (aflibercept, Bayer/Regeneron) or Avastin (bevacizumab, Roche/Genentech). It is worth waiting for the results of the studies of Fovista combined with either aflibercept or bevacizumab, expected to be announced later this year.
Even though some combination therapy may become standard of care for neovascular AMD, the cost of the treatment is likely to be much higher than monotherapy, depending on the options combined. This economic impact can be a barrier for patient access to treatment, particularly in Asia where patients in many areas are currently able to access only off-label bevacizumab.
References:
Jackson TL, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2014.07.043.
Koh A. One-year efficacy and safety outcomes of ranibizumab in combination with verteporfin photodynamic therapy vs ranibizumab monotherapy in patients with polypoidal choroidal vasculopathy: results from EVEREST II. Presented at American Academy of Ophthalmology Retina Subspecialty Day; Oct. 15, 2016; Chicago.
Ophthotech announces results from pivotal phase 3 trials of Fovista in wet age-related macular degeneration. http://investors.ophthotech.com/releasedetail.cfm?ReleaseID=1003651. Published Dec. 12, 2016. Accessed Jan 16, 2016.
Rezar-Dreindl S, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.16-19772.
Zarbin MA, et al. Retina. 2010;doi:10.1097/IAE.0b013e3181f57e30.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; email: dennislam.gm@gmail.com.