Retinal diseases: progress in treatment

Retinal Diseases

Retinal diseases take many forms, including age-related macular degeneration, diabetic macular oedema, retinal vein occlusions and uveitis, and according to a 2012 report for the US National Health Interview Survey, some 20.6 million US adults (8.5%) reported experiencing some kind of vision loss. By the age of 75, retinal disease affects around 1 in 5 of all adults. Worse, with populations ageing, the number affected is set to increase dramatically. In addition, there is a growing incidence in the key underlying causes of sight loss, such as obesity and diabetes. In the UK alone, it is predicted that by 2050, the number of people with sight loss will double to nearly four million (>5%). All this adds up to a clear need for new pharmaceutical interventions.

Age-related Macular Degeneration

One of the most common chronic retinal diseases is age-related macular degeneration (AMD), which is expected to affect around 3 million people in the US by 2020. AMD is a multifactorial degenerative disease, and this means there are a number of different approaches for treatment but the primary target is the blood vessels in the eye. For example, Visudyne (verteporfin) from Valeant Pharma, is used as a photosensitizer for photodynamic therapy to eliminate abnormal blood vessels associated with the wet form of macular degeneration. This approach whilst a major improvement over previous therapies has been overtaken by the anti-VEGF drugs. Eyetech/Valeant and Pfizer’s Macugen (pegaptanib) also targets blood vessels by binding to VEGF 165, a protein that plays a critical role in angiogenesis and increased leakage from blood vessels, two of the primary pathological processes responsible for vision loss in AMD.

Treatment for AMD was revolutionised in 2006 when Lucentis (ranibizumab), from Genentech/Roche and Novartis was approved by the FDA to treat the ‘wet’ type of AMD, a common form of age-related vision loss. Rather than just slow progression of vision loss, the new drug improved vision after 12 months. Like pegaptanib, this is an anti-angiogenic which targets VEGF-A, believed to trigger the growth of new vessels which may leak blood and fluid into the eye. Ranibizumab has proved extremely effective in trials: In one Phase III study, approximately 95% of patients treated with ranibizumab maintained visual acuity and up to 40% improved. This has led to stellar sales which totalled about $2.4 billion in 2012, though patents will begin to expire in 2020.

The drug’s market share came under attack in 2011 when Eylea (aflibercept) from Bayer Healthcare and Regeneron was first approved. Like ranibizumab, it binds VEGF-A and placental growth factor (PlGF), however aflibercept is only administered once every two months after three initial monthly doses. Other wet AMD treatments are dosed every month. Aflibercept has not proven as effective as ranibizumab, and two-year Phase III data suggested that aflibercept offered only a modest benefit in head-to-head comparison with ranibizumab. However. the eight week dosing schedule may cut by half the number of injections needed in anti-VEGF treatment, which is an attraction.

The other major competitor for sales is Avastin (bevacizumab), from Genentech/Roche. Both companies, together with Novartis, have discouraged the use of this drug for wet AMD since it is 30 times cheaper than Lucentis, which sells at around $2000 per dose. Both the French agency ANSM and the Cochrane Collaboration comparing the two drugs have found bevacizumab non-inferior to ranibizumab in efficacy and with no significant difference in systemic side effects and no increase in deaths. Bevacizumab is now approved in France and Italy for wet AMD and has seen worldwide usage for the indication, albeit off-label. Novartis and Roche have been fined by Italian authorities for blocking sales of bevacizumab but the companies are appealing the decision. The EU has launched an investigation into the procedures used by Roche and Novartis in the marketing of ranibizumab. A US study published in 2014 claimed that if Medicare patients were to receive Avastin for AMD instead of Lucentis, the healthcare system would save nearly $3 billion a year.

There are also plenty of therapy options on the horizon for AMD. Some dozen treatments are in early trials for AMD. For example, Fovista (pegpleranib), from Novartis and Opthotech is one of the few currently in Phase III trials. This anti-platelet-derived growth factor (anti-PDGF) therapy shows most promise when combined with anti-VEGF treatments and could end up as a combined formulation. Researchers expect to have top-line data from the late-stage study in 2016. Other combination treatments, such as photodynamic therapy with anti-VEGF have proved effective in trials and signal a possible trend for the future.

One objective has been to reduce or substitute injection treatment with less invasive means. Ohr Pharma has OHR 102 (squalamine) eye drops and combined it with ranibizumab to reduce the number of injections given, but in AMD the combination has been unsuccessful so far. The IRay radiotherapy system from Oraya Therapeutics has shown success in the INTREPID study, reducing the number of anti-VEGF injections required. On the lower-cost side there is Hospira/Pfizer with PF 582, a planned biosimilar to Lucentis currently in Phase II. It is set to be launched initially in markets where Lucentis patents do not restrict sales and may launch in 2018.

Diabetic Macular Oedema

With the number of diabetes patients increasing, one of the other most common retinal diseases is diabetic macular oedema (DMO or DME). In 2010, the estimated healthcare cost for DMO in England alone was £92 million. For more than 2 decades, laser photocoagulation applied to microaneurysms in the eye has been the main treatment for DMO. However, success with trials of anti-VEGF drugs has led to a dramatic shift away from laser therapy, which suffered from unwelcome side-effects.

Just as with AMD, the primary anti-VEGF drugs for DMO are aflibercept and ranibizumab, which were approved in 2014 and 2011 respectively. Again, bevacizumab has been used as a therapy though this is not officially licensed in the indication. Regeneron executives have commented that ‘off-label’ bevacizumab accounts for more than 60% of the market. So which treatment has proved most effective? A recent comparative study published in the NEJM shows hints that unlike with AMD, aflibercept provides a significantly greater improvement on the primary endpoint (mean visual acuity letter score change at one year: aflibercept +13 letters; bevacizumab +10; ranibizumab +11), with similar levels of adverse effects for the three drugs. Other researchers are following up this trial. The eight week dosing schedule for aflibercept also contributes to its potential success.

Besides anti-VEGFs, there are a number of non-steroidal anti-inflammatory treatments available, including Nevanac (nepafenac), from Alcon and Novartis, which was first approved in 2005. Another anti-inflammatory Ozurdex (dexamethasone) from Allergan and Actavis, addresses problems associated with administering NSAIDs to the eye. Ozurdex is a sustained-release intravitreal injectable therapy which has proven able to deliver corticosteroid for 4 to 6 months in clinical trials. This therapy was approved in the EU and US in 2014. Also following this strategy is Iluvien (fluocinolone acetonide) from Alimera Sciences and pSivida. Approved in the EU in 2012 and in the USA in 2014, it uses an extended release implant to deliver sustained levels of fluocinolone acetonide at the back of the eye. Alimera executives believe that some 50% of all DME patients are not adequately managed by current standard of care.

Retinal Vein Occlusion (RVO)

Blockage to the eye’s central veins can lead to severe damage to the retina and blindness, and just as with AMD and DMO, anti-VEGF therapies have proven effective. Ranibizumab was EU approved for RVO in 2007 and in the USA in 2010. In trials, approximately 60% of branch RVO and 48% of central RVO patients treated with monthly ranibizumab gained at least 15 letters of visual acuity at six months, compared with 29% and 17% of those treated according to current standard practice.

Ranibizumab approval was followed last year by aflibercept. The recommended treatment approach in the EU – where aflibercept’s approval is for macular oedema secondary to central and branch retinal vein occlusion - is to initiate the therapy with one injection per month, continuing monthly treatment until maximum visual acuity is achieved. Finally, Ozurdex was FDA approved for branch RVO in 2009 and in the EU the following year.

Other Indications

Treatments are available for a number of other retinal diseases, including uveitis and retinitis pigmentosa. Ozurdex was approved for uveitis in 2010, and Opsiria (sirolimus injection), from Santen, has been filed for approval in the EU while it remains in Phase III in the USA. At least two other therapies are in Phase II trials.

For retinitis pigmentosa, the transcorneal electrical stimulation of the retina has been shown to offer some improvement. This is believed to stimulate neuroprotective systems. Small scale trials of OkuStim Electrotherapy, from Okuvision, reveal some improvements and the device is CE-Mark approved in the EU, where it is one of the first forms of outpatient treatment for retinitis pigmentosa. Trials are ongoing.

Therapies on the Horizon

One focus for future therapeutics is delivery, since topical application and periocular and intravitreal injections of anti-VEGF medications and corticosteroids have been shown to lead to the development of cataract and glaucoma. Options such as suprachoroidal delivery are under investigation, including the surgical catheterization of the suprachoroidal space with a microcatheter such as the iTrack 400 from iScience Interventional Corp. Other companies are investigating the use of hollow microneedles, as well as micropumps for anti-VEGF drugs, and nano-delivery systems like Verisome drug delivery platform for IBI-20089 and IBI-10090 from Icon Bioscience.

Finally, in cases where treatment has not proven effective, it may eventually be possible to replace the retina altogether. Second Sight’s Argus II Retinal Prosthesis System was approved for use via CE Mark in retinitis pigmentosa in the EU in 2012 and in the US the following year. Also approved for retinitis pigmentosa in the EU via CE Mark is the Alpha IMS sub-retinal chip, from Retinal Implant. Both systems rely on external cameras to stimulate signals on a chip inserted into the skull, and while they offer revolutionary step-change, their performance in terms of visual acuity remains limited. That is expected to change rapidly with advances in the miniaturization of electronics.

References:

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. N Engl J Med 2015;372:1193-1203.

Antibody therapies and their challenges in the treatment of age-related macular degeneration. Volz C, Pauly D. Eur J Pharm Biopharm 2015 S0939-6411(15)00102-2.

Age related macular degeneration – challenge for future: Pathogenesis and new perspectives for the treatment. Michalska-Ma?ecka K, Kabiesza A, Nowakb M, ?piewaka D, et al. Eur Geriatr Med 2015;6:69–75.