Philip J Rosenfeld MD, PhD
In 2003, the convergence of two “heavenly” technologies, optical coherence tomography (OCT) and vascular endothelial growth factor inhibitors (anti-VEGF), led to a revolution in treatment of neovascular age-related macular degeneration (nAMD). For the first time, vision loss from nAMD could be reversed and stabilised in many cases, and disease progress could be monitored using OCT to guide additional treatment, said Philip J Rosenfeld MD, PhD, in the Jackson Memorial Lecture at the AAO 2018 Annual Meeting in Chicago.
“OCT served as a VEGF meter and we could use it to determine when anti-VEGF therapy was needed. It was remarkable, we could see it work right away,” said Dr Rosenfeld, who participated in many of the early studies of OCT and anti-VEGF at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, USA.
Since then, many studies have demonstrated that OCT-guided anti-VEGF therapy can be just as effective as monthly dosing for treating wet AMD, including an investigator-sponsored trial sponsored by Genentech in 2006 (Fung ae et al.
Am J Ophthalmol 2007; 143:566-583. Lalwani GA et al.
Am J Ophthalmol 2008; 148:43-58).
Beyond reducing patient discomfort and risk, OCT-guided dosing saves big money – from 2008 through 2015 an estimated $16 billion saved for just nAMD treatments in the USA Medicare programme. OCT guidance is now by far the most frequently used dosing strategy throughout the world, according to the American Society of Retina Specialists (ASRS).
Even more money – an estimated $24.7 billion – was saved by the use of bevacizumab (Avastin, Genentech) in place of ranibizumab and aflibercept, the same study found. Approved for treating cancer in 2004, bevacizumab is derived from the same mouse monoclonal clones that were used to develop ranibizumab, but the molecule is about three times larger.
In part, because it is priced for systemic infusion in cancer patients, bevacizumab is much less expensive when compounded into miniscule doses for intravitreal injection – currently about $50 per dose compared with about $2,150 for ranibizumab in the USA. This dramatically lower cost makes anti-VEGF treatment available to many patients who otherwise could not afford it. However, the struggle to keep it available was long and difficult, Dr Rosenfeld said.
The idea to try bevacizumab for AMD came to Dr Rosenfeld in 2003 from his reading of the scientific literature describing its development. Systemic treatment might even have advantages over intravitreal ranibizumab.
“At the time, we didn’t expect patients to tolerate monthly injections in the eye. That was the thinking back then.”
Genentech would not sponsor a trial with systemic bevacizumab, so Dr Rosenfeld raised $200,000, mostly from patients, for a trial at the Bascom Palmer Eye Institute. After two-to-three systemic infusions of 5.0mg/kg bevacizumab two weeks apart, macular fluid cleared and vision improved in all 18 patients studied, lasting six months or longer in 12 (
Ophthalmol 2005;112(6):1035-1047).
Seeking a lower dose and reduced cardiovascular risks for a larger trial, Dr Rosenfeld had another epiphany. A 2004 article by Dennis P Han MD showed that intravitreally injected antibodies penetrated the retina (
Trans Am Ophthalmol Soc 2004; 102:305-320), contradicting an earlier Genentech study suggesting they may not (
Toxicol Pathol. 1999;27(5):536-544). Dr Rosenfeld had pharmacist Serafin Gonzalez PharmD compound bevacizumab for intravitreal injection following strict USP protocols.
“His guidelines are adopted by pharmacies all over the world to this day,” Dr Rosenfeld said.
By mid-2005, studies clearly established the efficacy of intravitreal bevacizumab for treating nAMD, and it was in use worldwide before ranibizumab was approved by the FDA a year later. Based on his earlier research, Dr Rosenfeld sought FDA approval for a prospective trial of intravitreal bevacizumab – but that endeavour was cut short when he was separately accused of scientific misconduct from an anonymous source. While he was eventually completely vindicated, “my life was turned upside down for 16 months”, Dr Rosenfeld said.
In 2007 Genentech tried to remove bevacizumab from the market for ophthalmic compounding after glass particles were found in some batches. After much conflict, the FDA finally ruled the contaminated product was not fit for any human use, and there was no reason to restrict compounding of properly manufactured bevacizumab. A report by Jack Mitchell, a US Senate committee investigator, and related media coverage were pivotal in the victory, Dr Rosenfeld said.
Around the same time, ophthalmic speciality societies in the USA and elsewhere led the US National Eye Institute to fund the prospective CATT study, which found no significant difference in outcomes between ranibizumab and bevacizumab for treating nAMD (
N Engl J Med 2011; 364:1897-1908).
Similarly, a 2008 cost report by Ross J Brechner MD, MS(Stat), MPH, of the agency operating the US Medicare programme, was finally published after much internal resistance (
Am J Ophthalmol 2011; 151: 887-895). Extending this research produced the 2008-2015 estimate of $24 billion-plus savings for AMD in the USA alone (
Am J Ophthalmol, July 2018).
“That’s a 123,500-fold return on the $200,000 investment from that initial patient clinical trial,” Dr Rosenfeld noted. This creates enormous pressure to keep bevacizumab available.
As a result, 70% of USA retina specialists now use bevacizumab for first-line treatment of wet AMD, as do 36% internationally, according to a 2018 ASRS survey (n=1,027). Thanks to several dedicated researchers and the support of ophthalmologists around the world, “we won that war”, Dr Rosenfeld said.
Philip J Rosenfeld: prosenfeld@med.miami.edu
