Hot Topics in Ophthalmology
Authored by: Vanessa Lane, PhD, Senior Medical Writer, Touch Medical Media, UK
Anti-vascular endothelial growth factor (VEGF) therapy has dramatically revolutionized the management of age-related macular degeneration (AMD), diabetic macular edema (DMO) and retinal vein occlusion (RVO). However, demonstrating efficacy outcomes reported in clinical trials in the real world is challenging, possibly due to a lack of consensus on treatment regimens and lack of clarity regarding aims of treatment.1
Although effective, current anti-VEGFs require fixed monthly dosing, which is associated with a significant burden for the patient, physician, clinic and health system. Treatment with anti-VEGFs can also be associated with endophthalmitis risk and discomfort.2,3 Therefore, an unmet need exists in terms of a more durable approach to treating retinal disease.
When investigating different approaches to drug delivery, a number of challenges exist, including the ocular barrier to the macula, instability of larger molecules to heat and metabolism, ability to terminate drug administration once delivered and continuous versus pulsatile delivery routes. As a result, clinicians in everyday practice have treated pro re nata (PRN) or using treat-and-extend schedules,4–6 with treat-and-extend showing superiority over PRN.7 Other modes of drug delivery with potentially less intervention, reduced need for follow up and ability to extend the duration between treatments could offer a significant benefit to patients by reducing the burden of treatment while improving vision. Iontophoresis, which uses a mild electrical current to enhance the penetration of a drug through tissue, is being investigated for its capability of delivering large molecule anti-VEGFs to the posterior segment of the eye.8 Current research has quantified safe levels and this method is under further development in commercial applications. Suprachoroidal injection using a proprietary microinjector syringe has also been investigated. In the 3-month “Triamcinolone Acetonide with Intravitreal Aflibercept in Subjects with Macular Edema Due to Retinal Vein Occlusion” (TANZANITE) multicenter, masked Phase II study, triamcinolone acetonide plus intravitreal aflibercept significantly reduced the need for further anti-VEGF injections versus intravitreal injection of aflibercept followed by monthly intravitreal aflibercept injections PRN.9 A Port Delivery System (PDS), which is a durable intravitreal reservoir implant placed through a scleral incision in the pars plana in a one-time surgical procedure, is also under development.10 The device, roughly the size of a grain of rice, is loaded with ranibizumab via a custom needle and then inserted using standard vitreoretinal surgical techniques. The implant, which can hold a small volume of a highly concentrated drug that is slowly released, can then be refilled. A phase II study will investigate higher doses of ranibizumab in the device to more definitively evaluate the efficacy of the ranibizumab PDS, as well as the refill interval between doses, with a target of at least 4 months between refills.11
Promoter gene packaged in an adenoviral vector that causes cells to produce soluble fms-like tyrosine kinase-1 (FLT-1), a new chimeric protein that is a tyrosine kinase inhibitor and potently binds and inhibits VEGF, has been investigated.12,13 Early results suggest that this may reduce the frequency of anti-VEGF re-treatments.13 Studies are ongoing.
The topical route has also been explored. Squalamine, a small-molecule drug that targets both VEGF and platelet derived growth factor (PDGF), was investigated in the phase II IMPACT study (“Effect of squalamine lactate ophthalmic solution, 0.2% in subjects with neovascular age-related macular degeneration”).14 This randomized trial compared the experimental drug given topically twice daily in conjunction with routine ranibizumab injections versus ranibizumab monotherapy.14 Though it showed encouraging results, the phase III MAKO study “Efficacy and safety study of squalamine ophthalmic solution in subjects with neovascular AMD” failed to meet its primary endpoint of mean visual acuity (VA) gain at 9 months.15
The most commonly used anatomic endpoint for the study of late non-exudative AMD is the growth of geographic atrophy (GA).16 Best corrected VA (BCVA) by itself does not adequately capture the visual deficits experienced by patients with foveal-sparing GA.17 Quantification of changes in visual function and correlation with disease worsening requires additional endpoints that account for the underlying pathophysiological processes of the disease. In the early stages, characteristic findings such as drusen size and retinal pigment epithelium irregularities have been correlated with risk of progression of early AMD to intermediate and late stages.18 A higher prevalence of reticular pseudodrusen has also been reported in patients with GA versus early, intermediate or no AMD.19 In addition, the occurrence of GA with concomitant choroidal neovascularization (CNV) is not uncommon, and is associated with an even greater risk of severe vision loss than GA alone.20 A multimodal approach to the assessment of visual function may be more appropriate for clinical endpoints in trials involving patients with GA.
There are numerous obstacles to conducting high-quality clinical trials in uveitis, including the small number of patients with sight-threatening forms of disease and the array of distinct uveitis syndromes. There is currently little consensus regarding which of the wide range of outcome measures are relevant. Ocular flare is a critical measure in the assessment of patients with uveitis, and the activity of uveitis should be evaluated in part by grading the relative number of white cells (“cell”) and light scatter (“flare”) seen in the anterior chamber of the eye.21 The most common primary efficacy endpoints prioritize clinician-observed measures of disease activity, including visual haze, macular edema and visual acuity (VA).22
As early as 2005, a process of standardizing the approach to reporting clinical data in uveitis research was investigated.23 The Standardization of Uveitis Nomenclature (SUN) Working Group affirmed that an anatomic classification of uveitis should be used as a framework for subsequent work on diagnostic criteria for specific uveitic syndromes, and that the classification of uveitis entities should be on the basis of the location of the inflammation and not on the presence of structural complications.23 However, a 2016 study reported that different classifications were still being used despite efforts to standardize practice.24 Proposed methods for grading inflammatory activity have shown a high level of reproducibility for grading of anterior chamber cells and vitreous haze.25 In an attempt to quantitate this, the semi-quantitative preclinical ocular toxicology scoring (SPOTS ) system, a semi-quantitative ocular scoring system, could be considered as it includes criteria for the anterior segment, among others.26 Laser flare photometry could also potentially be used to assess flare as classification of its readings in patients with uveitis allows stratification of measurements into grades analogous to clinical flare grades and correlates well with conventional clinical flare grading.27 Swept-source (SS) optical coherence tomography (OCT) of the anterior segment has more recently been suggested as a tool to measure anterior chamber inflammation.28 Finally, fare photometry has been shown to be a quantitative and objective method for measuring the amount of flare in an eye,21,29 but it is limited by cost and lack of availability in many clinics.
New ophthalmic drug delivery systems are being developed to address the need for long-term drug delivery from a single procedure and to potentially reduce adverse events associated with some of the more potent therapies. Strategies for ocular drug delivery include ocular inserts that overcome physical barriers, position drugs where they are needed and enable posterior chamber diseases to be more effectively treated. Nanospheres provide the potential for drug delivery to the eye in the least volume, but along with this technology, a number of factors require consideration, including retrievability, tolerability of both the drug and the delivery device, ability of the device to stay in position once injected and durability in the eye beyond drug delivery.
1. Lanzetta P, Loewenstein A, Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti–vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255:1259–73.
2. Sachdeva MM, Moshiri A, Leder HA, Scott AW. Endophthalmitis following intravitreal injection of anti-VEGF agents: long-term outcomes and the identification of unusual micro-organisms. J Ophthalmic Inflamm Infect. 2016;6:2.
3. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013;27:787–94.
4. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148:43–58.
5. Silva R, Berta A, Larsen M, et al; TREND Study Group. Treat-and-extend versus monthly regimen in neovascular age-related macular degeneration: Results with Ranibizumab from the TREND study. Ophthalmology. 2018;125:57–65.
6. Wykoff CC, Croft DE, Brown DM, et al. Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results. Ophthalmology. 2015;122:2514–22.
7. Chin-Yee D, Eck T, Fowler S, et al. A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration. Br J Ophthalmol. 2016;100:914–7.
8. Higuchi WI. Novel method for the ocular iontophoretic delivery of avastin and Lucentis. 2010. Available at: http://grantome.com/grant/NIH/R43-EY020791-01 (accessed March 8, 2018).
9. Willoughby AS, Vuong VS, Cunefare D, et al. Choroidal changes after suprachoroidal injection of triamcinolone acetonide in eyes with macular edema secondary to retinal vein occlusion. Am J Ophthalmol. 2018;186:144–51.
10. Rubio RG. Long-acting anti-VEGF delivery. Retina Today. 2014;July/August:78–80.
11. ClinicalTrials.gov. Study of the efficacy and safety of the ranibizumab port delivery system (RPDS) for sustained delivery of ranibizumab in participants with subfoveal neovascular age-related macular degeneration (AMD) (LADDER). Available at: https://clinicaltrials.gov/ct2/show/NCT02510794 (accessed 8 March 2018).
12. Tuo J, Pang JJ, Cao X, et al. AAV5-mediated sFLT01 gene therapy arrests retinal lesions in Ccl2(-/-)/Cx3cr1(-/-) mice. Neurobiol Aging. 2012;33:433.e1–433.e10.
13. Constable IJ, Pierce CM, Lai CM, et al. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine. 2016;14:168–75.
14. Ohr Pharmaceutical Inc. Ohr Pharmaceutical presents data from OHR-102 Phase II IMPACT study in wet-AMD at ARVO conference. 2015. Available from: https://www.ohrpharmaceutical.com/media-center/press-releases/detail/446/ohr-pharmaceutical-presents-data-from-ohr-102-phase-ii (accessed March 8, 2018).
15. Ohr Pharmaceutical Inc. Ohr Pharmaceutical announces efficacy results from the MAKO Study in wet-AMD. 2018. Available from: https://globenewswire.com/news-release/2018/01/05/1284092/0/en/Ohr-Pharmaceutical-Announces-Efficacy-Results-from-the-MAKO-Study-in-Wet-AMD.html (accessed March 8, 2018).
16. Schaal KB, Rosenfeld PJ, Gregori G, et al. Anatomic clinical trial endpoints for nonexudative age-related macular degeneration. Ophthalmology. 2016;123:1060–79.
17. Sadda SR, Chakravarthy U, Birch DG, et al. Clinical endpoints for the study of geographic atrophy secondary to age-related macular degeneration. Retina. 2016;36:1806–22.
18. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484–98.
19. Finger RP, Wu Z, Luu CD, et al. Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology. 2014;121:1252–6.
20. Kaszubski P, Ben Ami T, Saade C, Smith RT. Geographic atrophy and choroidal neovascularization in the same eye: A review. Ophthalmic Res. 2016;55:185–93.
21. Lam DL, Axtelle J, Rath S, et al. A Rayleigh scatter-based ocular flare analysis meter for flare photometry of the anterior chamber. Transl Vis Sci Technol. 2015;4:7.
22. Denniston AK, Holland GN, Kidess A, et al. Heterogeneity of primary outcome measures used in clinical trials of treatments for intermediate, posterior, and panuveitis. Orphanet J Rare Dis. 2015;10:97.
23. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–16.
24. Yeo TH, Ilangovan S, Keane PA, et al. Discrepancies in assessing anterior chamber activity among uveitis specialists. Jpn J Ophthalmol. 2016;60:206–11.
25. Kempen JH, Ganesh SK, Sangwan VS, Rathinam SR. Interobserver agreement in grading activity and site of inflammation in eyes of patients with uveitis. Am J Ophthalmol. 2008;146:813–8.
26. Eaton JS, Miller PE, Bentley E, et al. The SPOTS System: An ocular scoring system optimized for use in modern preclinical drug development and toxicology. J Ocul Pharmacol Ther. 2017;33:718–34.
27. Agrawal R, Keane PA, Singh J, et al. Classification of semi-automated flare readings using the Kowa FM 700 laser cell flare meter in patients with uveitis. Acta Ophthalmol. 2016;94:e135–41.
28. Invernizzi A, Marchi S, Aldigeri R, et al. Objective quantification of anterior chamber inflammation: measuring cells and flare by anterior segment optical coherence tomography. Ophthalmology. 2017;124:1670–7.
29. Konstantopoulou K, Del’Omo R, Morley AM, et al. A comparative study between clinical grading of anterior chamber flare and flare reading using the Kowa laser flare meter. Int Ophthalmol. 2015;35:629–33.
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