It was really only a handful of few years ago that patients with ‘wet’ Aged-related Macular Degeneration were offered little more than counselling and support for a condition that would almost certainly leave them blind. In 2007, all that changed, with the introduction of a new drug – ranibizumab – to the Australian market.
It is not overstating it to say that ranibizumab – marketed in Australia as Lucentis – revolutionised the treatment of ‘wet’ Age-related Macular Degeneration (‘wet’ AMD) since its introduction five years ago.
Lucentis was the first medication shown in clinical studies to significantly improve visual acuity compared with sham or photodynamic therapy in a considerable proportion of patients with ‘wet’ AMD1,2 and was made widely available to Australian patients when it was first listed on the Australian Pharmaceutical Benefits Scheme (PBS) on 1 August 2007.3
AMD is still the leading cause of visual impairment in people over the age of 50 in the Western world. Nearly half of Australians who are blind have lost their sight due to AMD.4
Never in their lifetime, did they believe that they would be able to actually save sight, and here was a treatment that offered exactly that
Sydney retinal specialist Dr. Paul Beaumont said “thousands of Australians with wet AMD who would otherwise be legally blind have been treated with Lucentis and, if caught early enough, have had their sight saved”.
Before Ranibizumab
The listing of Lucentis on the PBS has dramatically changed the management of ‘wet’ AMD patients. Prior to its development, other available therapies had only slowed the decline of vision with the disease – not improved it.1,2
Neovascularisation and leakage are prominent features of the wet form of AMD and definitive clinical trials show that vascular endothelial growth factor (VEGF) is important in the progression of AMD. Intravitreal administration of Ranibizumab results in a marked suppression of neovascularisation and leakage.5
Ms. Julie Heraghty, CEO of the Macular Degeneration Foundation, says that only six years ago there were few options for people diagnosed with macular degeneration.
“We were educating the general public on the importance of early detection and checking for symptoms, but with no effective treatment available at that time, the end result for so many people was loss of sight, a really devastating outcome.
Ms. Heraghty said it seemed like medicine had just not been able to find an effective treatment “and then along came Lucentis and changed the landscape of ophthalmology”.
“There were so many stories of older Australians who had been looking forward to retired life with their friends and family, but whose hopes and dreams were shattered after their AMD diagnosis. For many of these people, reading and driving were especially important for their independence and quality of life, but with photodynamic therapy being the only treatment option at that time, these things… were lost to them,” Ms. Heraghty said.
Dr. Beaumont said the hardest thing for ophthalmologists at that time was not being able to offer patients with ‘wet’ AMD any reassurance that things would get better.
“Managing patients with ‘wet’ AMD was exhausting… we could only prepare them for the worsening situation that was to come,” he said.
Dr. Alex Harper, retinal specialist and senior lecturer on ophthalmology at the Royal Victorian Eye and Ear Hospital in Melbourne, agrees.
“For the previous decade of my professional career, patients with new onset ‘wet’ AMD invariably worsened and we could offer only counselling and support as they struggled to adapt to a life of low vision,” Dr. Harper said.
A New Regime
Ranibizumab is an anti-VEGF agent and it promised to provide a treatment solution for the management of ‘wet’ AMD because it was able to prevent the uncontrolled formation, growth and leakage of new blood vessels under the retina of the eye that lead to the development of the condition and subsequent vision loss.5
Ms. Heraghty said the introduction of anti-VEFG treatments was “amazing”.
“When Lucentis first appeared on the horizon, the medical community was amazed with the results that they were seeing. Never in their lifetime, did they believe that they would be able to actually save sight, and here was a treatment that offered exactly that.”
MARINA and ANCHOR Trials
The treatment has been the subject of numerous clinical trials and today it is the standard of care of therapy for ‘wet’ AMD around the world.1,2,6
Two major trials – the MARINA and ANCHOR trials – were designed to evaluate the effectiveness and safety of treatment with ranibizumab.
The two-year MARINA study group involved 716 patients. One third received monthly injections of Lucentis 0.3mg; one third with Lucentis 0.5mg and a third received sham injections.
The results indicated that approximately 95 per cent of patients receiving ranibizumab lost less than 15 letters, as opposed to more than 62 of the sham group that lost less than 15 letters, at 12 months.
In addition, up to 34 per cent of the patients receiving ranibizumab had an improvement in vision of 15 letters or more, compared to 4.6 per cent of the sham group at the 12 month mark. Mean visual acuity improved by 6.5 letters in the 0.3 mg group and by 7.2 letters in the 0.5 mg group. In contrast, vision reduced by 10.4 letters in the sham-injection group.
The ANCHOR study compared ranibizumab with an alternate macular degeneration treatment, verteporfin photodynamic therapy (PDT).
Of the 423 patients who participated in the study, 143 received PDT, 140 patients received 0.3mg ranibizumab, and 140 patients received 0.5 mg ranibizumab.
Patients were randomised to receive intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin PDT monthly or intravitreal sham injections plus PDT every three months, for two years.
The results of the study indicated that up to 96 per cent of patients treated with ranibizumab lost fewer than 15 letters, compared to just over 64 per cent of patients in the PDT group. The level of vision improved by 15 letters or more in 36-40 per cent of the patients receiving ranibizumab, and by 5.6 per cent in the PDT group. Mean visual acuity improved by 8.5 letters in the 0.3 mg group and by 11.3 letters in the 0.5 mg group. However, in the PDT group vision decreased by 9.5 letters.
Patients receiving Lucentis also experienced significant improvements in vision-related quality of life compared with sham or photodynamic therapy.7,8,9 People with ‘wet’ AMD were better able to complete everyday tasks as a result of Lucentis compared with baseline, including activities requiring distance vision – for example, negotiating steps and curbs, reading street signs and shop names and going to the movies – and also near-vision activities – such as reading the newspaper, cooking and recognising faces.8,9
Lucentis was also shown to minimise vision specific dependency compared with sham or photodynamic therapy,8,9 helping to remove the need to stay at home or rely on others.
Subsidised Access
Dr. Harper said the “PBS listing of Lucentis in August 2007 headlined a monumental change for patients with ‘wet’ AMD in Australia”.
“We have observed some remarkable improvements in Lucentis clinical trial patients and these became a reality when we had subsidised access to the drug.”
Dr. Beaumont said it is still “heartwarming” to see a patient reading a newspaper, knowing they’ve been receiving Lucentis injections for the past five years.
“Not only can we now save sight, but we are also saving on the societal costs of falls, fractures and nursing home care,” he said.
Beyond AMD
Late last year, Lucentis was approved by the TGA for two new indications: the treatment of visual impairment due to diabetic macular oedema (DME) and visual impairment due to macular oedema secondary to retinal vein occlusion (RVO) respectively.3
While not yet listed on the PBS for these conditions, Lucentis is the first medication approved to treat visual impairment due to DME, and the first anti-VEGF medication approved for the treatment of RVO in Australia.3
Laser therapy is currently the primary treatment for DME and macular oedema following branch RVO (BRVO). However, laser for DME is predominately associated with vision stabilisation only.11,12,13 BRVO patients with severe vision loss and who have had symptoms for more than a year are also unlikely to benefit from laser therapy.15,16
The RESTORE (Phase lll) trial, which involved 345 patients with type 1 or type 2 diabetes, and visual impairment due to DME,14 demonstrated that patients treated with Lucentis alone or Lucentis plus laser gained an average of 6.8 letters and 6.4 letters respectively in visual acuity at 12 months compared to baseline, while laser-treated patients gained an average of 0.9 letters as measured on a standard ETDRS eye chart.14
Results of two pivotal trials17,18 show some BRVO and central RVO patients had significantly superior
vision acuity gains after six months of Lucentis treatment compared with sham therapy, and this benefit was sustained for 12 months.17,18
Unresolved Issues
In 2010, approximately one million Australians had some evidence of AMD – four times as many as those who have dementia and more than half that of diabetes.4
Ms. Heraghty said despite the recent advances, there are “still unresolved issues at each stage of the disease management continuum”.
It is estimated that the number of people with late stage AMD and vision loss could double in the next 20 years in the absence of further advances in treatment and prevention measures.4
“The vast amount of research that has been conducted into Lucentis has paved the way for the development of future therapies,” said Dr. Beaumont.
“Different dosing regimens are now available to us, but these new treatments have no advantage in terms of vision.
The main thing is that for the past five years we have had access to anti-VEGF agents – that is what is stopping people from going blind.”
AMD Facts |
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Microneedles May Aid In Eye-Related Illnesses |
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Ophthalmologists may soon have a more effective way to treat diseases such as macular degeneration that affect tissues in the back of the eye. New research, from the Georgia Institute of Technology and Emory University, has shown that microneedles less than a millimetre in length can deliver drug molecules and particles to the eye in an animal model. The injection targets the suprachoroidal space of the eye, which provides a natural passageway for drug injected across the white part (sclera) of the eye to flow along the eye’s inner surface and subsequently into the back of the eye. The minimally-invasive technique could represent a significant improvement over conventional methods that inject drugs into the centre of the eye – or use eyedrops, which have limited effectiveness in treating many diseases. The study was reported in the journal Investigative Ophthalmology & Visual Science. The research was supported by the US National Eye Institute. “This research could lead to a simple and safe procedure that offers doctors a better way to target drugs to specific locations in the eye,” said Samirkumar Patel, the paper’s first author and a postdoctoral researcher at Georgia Tech. “The design and simplicity of the microneedle device may make it more likely to be used in the clinic as a way to administer drug formulations into the suprachoroidal space that surrounds the eye.” Dr. Patel, who is now director of research for a startup company formed to commercialise the technology, said the study also showed that the suprachoroidal space could accommodate a variety of drugs and microparticles. That could open the door for the use of timed-release drugs that could reduce the need for frequent injections to treat chronic eye diseases. The new study showed that injections of fluids containing molecules and particles into that space “The study showed that if we inject non-degradable particles into the suprachoroidal space and wait as long as two months, the particles remain,” said Professor Mark Prausnitz, from Georgia Tech’s School of Chemical and Biomolecular Engineering. “That means there is no natural mechanism to remove the particles from the eye. Knowing this, we can design biodegradable particles with drugs encapsulated in them that can slowly release those drugs over a period of time that we could control.” Henry Edelhauser, a professor of ophthalmology at Emory School of Medicine, said pharmaceutical companies are now developing new compounds to treat eye diseases. Those drugs will be most effective if they can be delivered directly to the portion of the eye that requires treatment, such as the choroid and retina that this new delivery method targets. “With this technique, we are keeping the drug right where it needs to be for most therapies of interest in the back of the eye,” he said. The microneedles used in the technique are made of stainless steel and are less than one millimetre long. The researchers believe that they will cause less trauma to the eye than the larger hypodermic needles, and reduce the risk of infection. Professor Edelhauser said, the compounds studied were not drugs, so the next step will be to study how well the microneedle technique can get real drugs to the eye structures of interest. |
References
1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. NEJM 2006; 355: 1432-1444.
2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. NEJM 2006; 355: 1419-1431.
3. www.health.gov.au/internet/main/publishing.nsf/Content/lucentis.htm
4. ‘Eyes on the future – A clear outlook on age-related macular degeneration’. Report by Deloitte Access Economics & Macular Degeneration Foundation, 2011.
5. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26: 859-870.
6. Dhoot DS, Kaiser PK. Ranibuzumab for age-related macular degeneration. Expert Opin Biol Ther 2012; 12(3):371–81.
7. Bressler NM, Chang TS, Suñer IJ, Fine JT, Dolan CM, Ward J, Ianchulev T; MARINA and ANCHOR Research Groups. Vision-related function after ranibizumab treatment by better- or worse-seeing eye: clinical trial results from MARINA and ANCHOR. Ophthalmology. 2010 Apr;117(4):747-56.e4.
8. Bressler NM, Chang TS, Fine JT, Dolan CM, Ward J; Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) Research Group. Improved vision-related function after ranibizumab vs photodynamic therapy: a randomized clinical trial. Arch Ophthalmol. 2009 Jan;127(1):13-21
9. Chang TS, Bressler NM, Fine JT, Dolan CM, Ward J, Klesert TR; MARINA Study Group. Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 2007 Nov;125(11):1460-9.
10. Mitchell P, Annemans L, White R et al. Cost effectiveness of treatments for wet age-related macular degeneration. Pharmacoeconomics. 2011; 29 (2):107–131.
11. The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-77.
12.Massin P, Bandello f, Garweg J et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled, double-masked, multicentre phase II study. Diabetes Care. 2010;33:2399-2405.
13. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796-806.
14. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE Study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011; 118:615-625.
15. Laouri M et al. The burden of disease of retinal vein occlusion: review of the literature. 2011. Eye 2011;25(8):981-8.
16. Wong TY, Scott IU. Retinal-vein occlusion. N Engl J Med. 2010;363:2135-2144.
17. Brown DM et al. Sustained Benefits from Ranibizumab for Macular Edema Following Branch Retinal Vein Occlusion: 12-Month Outcomes of a Phase III Study. Ophthalmology. 2011; 118: 1594–1602.
18. Campochiaro PA et al. Sustained Benefits from Ranibizumab for Macular Edema following Central Retinal Vein Occlusion: Twelve-Month Outcomes of a Phase III Study. Ophthalmology. 2011. 118: 2041–9.
19. http://clinicaltrials.gov/ct2/show/NCT01318941.
20. www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-ranibizumab-mar07.
