AMD pipeline

[caption id="attachment_7692" align="alignnone" width="200"] Pravin Dugel MD[/caption] Like the smell of imminent rain in the desert, change is coming in age-related macular degeneration 
(AMD) therapy, Pravin Dugel MD told the Ophthalmology Futures European Forum 2016 in Copenhagen, Denmark. “We’ve hit the ceiling with monthly anti-VEGF-A injections. We all smell the rain coming,” said Dr Dugel, Managing Partner of Retinal Consultants of Arizona, Phoenix, and Clinical Professor at the University of Southern California Keck School of Medicine, Los Angeles, USA. Drugs targeting non-VEGF biological pathways, combination therapies, extended release devices and formulations that keep AMD drugs at therapeutic levels longer, are all on the horizon, according to a panel of clinical and industry experts led by Dr Dugel. However, to be viable, any new treatment for AMD faces significant hurdles demonstrating efficacy that justifies its extra treatment burden and expense, particularly to insurance companies and other healthcare payers, they said. BEATING THE CHAMPION Perhaps the biggest hurdle to both regulatory approval and insurance coverage for new AMD drugs is the success of anti-VEGF compounds, said Eugene de Juan Jr MD, founder and Managing Partner of ForSight Labs, Menlo Park, California, and Jean Kelly Stock Distinguished Professor of Ophthalmology at University of California, San Francisco, USA. It’s not likely that a new drug will better the immediate 10 letter+ visual acuity improvement seen in some trials, and demonstrating long-term improvement is expensive and technically challenging. Still, there is plenty of real-world evidence that current anti-VEGF treatment approaches are not enough. “Even though it seems that 95% of patients stabilise, if you look at the long-term in the SEVEN-UP trial and others, after five years there is a significant decline in visual acuity,” said Anat Loewenstein MD, Chairman of the Division of Ophthalmology, Tel Aviv Medical Center, Israel. The burden on patients and health facilities of frequent intravitreal injections over the typical 10 to 15 years expected lifespan of AMD patients is almost impossible to sustain on a large scale, she added. Many patients do not reach optimal anti-VEGF treatment levels because monthly monitoring and treatment is difficult and expensive, agreed Andreas Wenzel PhD, of Novartis Institutes for BioMedical Research, Basel, Switzerland. Even treat-and-extend, which lengthens monitoring and treatment intervals to as long as 12 weeks after retinal oedema is initially stabilised, does not work for all patients. “The ceiling has been reached in randomised controlled clinical trials and well controlled patients, but in real life the ceiling is not reached,” said Dr Wenzel. Long-acting anti-VEGF drugs would help, Dr Wenzel said. Adding more drug to the eye, increasing the affinity of anti-VEGF, increasing molecule size or making the compound 'sticky' all might increase residence time in the eye. The goal is a drug that lasts three, four months, maybe even longer. Extended-release devices, such as the port delivery device in clinical trials by Genentech, are another way anti-VEGF-A might better fulfil its potential, said Dr de Juan. In addition to reducing treatment intervals, continuous anti-VEGF suppression might reduce the need for long-term administration in some patients, he suggested. “Every once in a while you give a patient one treatment, particularly an early patient, and 5/10% don’t need another injection. What’s going on with that? I think with sustained delivery we will see a lot more of that,” said Dr de Juan, whose ForSight Labs developed the depot device Genentech is testing. He also emphasised the value of early diagnosis for treatment success, when abnormal blood vessels are most susceptible to anti-VEGF. EXPANDED TARGET However, as dramatic as anti-VEGF’s impact may be, it actually is more effective in reducing retinal oedema than reversing abnormal blood vessel growth, noted José-Alain Sahel MD, Director of The Vision Institute, Paris, France, Professor at Sorbonne Universities Medical School in Paris, and Chairman of Ophthalmology at University of Pittsburgh Medical Center, USA. “The vascular component effect is weak. The vessels are still there,” he said. Dr Dugel agreed the wound healing process in AMD is very complex and should be attacked in many ways, as with complex oncology targets. Potential broader spectrum treatments include anti-VEGF-A combined with ANG-2 TIE inhibitors, in development by several manufacturers; and pan-VEGF inhibitors that target VEGF-C and D as well as A. However, the recent failure of clinical trials sponsored by two excellent companies (Ophthotech and Regeneron) targeting anti-PDGF combination treatment gives us pause, noted Dr Dugel. This, said Dr Dugel, shows us how formidable anti-VEGF-A monotherapy is, despite its limitations. However, new compounds must show they add enough benefit to justify the added treatment burden, Dr Lowenstein said. This can be difficulty when they treat later-stage patients, as do anti-PDGF and ANG-2 inhibitors. Demonstrating efficacy to payers is a particular challenge, Dr Wenzel said. While payers may accept an improvement of 5+ letters of visual acuity as a meaningful outcome, he doesn’t think anatomic improvements such as regression of neovascularisation of fibrosis will be enough. This creates huge economic uncertainty that must be addressed to justify the development cost of new AMD treatments.   Anat Loewenstein: anatl@tlvmc.gov.il José-Alain Sahel: j.sahel@gmail.com Pravin Dugel: pdugel@gmail.com Andreas Wenzel: andreas.wenzel@novartis.com Eugene de Juan: edejuan@forsightlabs.com

Tags: AMD