Better Than a Sharp Stick in the Eye?

Frederic W. Grannis, Jr, MD

A trite modern metaphor for the absence of good options refers to those choices that are only “better than a sharp stick in the eye.” I was recently faced with a medical problem where I had to decide whether I had any option superior to a sharp stick in the eye. Let me explain.

Earlier in the year, at age 70, after a routine eye exam, an ophthalmologist at the University of California Irvine, informed me that she had observed drusen in both retinas, confirming a diagnosis of dry macular degeneration. She recommended vitamins and close follow-up. I made a follow-up appointment and began taking giant, difficult-to-swallow, AREDS 2 vitamins twice a day.

The new diagnosis was something that had concerned me for many years, given that my grandfather and his twin daughters, my mother and aunt, had all lost their vision to retinal disease. My brief review of the literature was encouraging. In most patients with dry age-related macular degeneration (AMD) visual loss progresses slowly over years and the AREDS vitamin regimen delays progression in many cases.

But a few months later, while driving, I noticed that my night vision was impaired. Everything seemed darker than normal. The same night, while watching TV, it was obvious that the vision in my right eye was impaired. When I looked at an Amsler grid, there were gray splotches on the right side in a number of locations and waviness in the previously straight lines.

Back at the Gavin Herbert Eye Institute at UC Irvine, optical coherence tomography and fluorescence retinal angiogram studies showed progression to wet macular degeneration.

I was well aware that, in the recent past, there had been no effective treatment for AMD, as exemplified by its course in my family members, who had spent their final years with major visual impairment. Was it time for me to start shopping for a guide dog and a white cane? Did I have any option that might be better than a sharp stick in the eye? The surprising answer provided by retinal surgeon Baruch Kuppermann, MD, of UC Irvine, was that a sharp stick in the eye was, in point of fact, my best therapeutic option. After discussion of alternatives, and the potential risks and benefits of multiple drug options (bevacizumab, aflibercept, and ranibizumab), I elected ranibizumab, and 0.5 mg of the drug was injected into the vitreous humor of my right eye via a 30-gauge needle. How terrible is a sharp stick in the eye? I would rate it a 1 (least painful) on a distress scale of 1 to 10. A paper cut sustained the same day actually hurt a little more.

By the time of the follow-up examination 1 month later, the night dimness had improved substantially, and the gray blotches were gone, although the Amsler grid lines still buckled slightly. On optical coherence tomography, the wet patch in the retina had completely resolved. The fluid has recurred at about 2 month intervals since then, but improves following each subsequent injection.

Well, you might muse, this is interesting, but why am I reading this on Cancer Network? This has nothing to do with cancer. Actually it does.

In the early 1970s, a molecular researcher in Boston, Judah Folkman, began investigating the biology of vascular supply in malignant tumors.[1] Presumably, because the transparent cornea provided a window through which retinal neovascularization and its response to treatment could be conveniently observed, much of this research was performed on intraocular tumor models.[2] From this basic science research emerged first information on vascular endothelial growth factors (VEGFs) controlling neovascularization and later, development of drugs, produced by molecular biological methods, designed to block cellular neovascularization receptors (VEGFR). Simultaneously, Folkman’s group and others were studying the effects of various anti-angiogenic molecules in non-malignant diseases of the eye characterized by neovascularization, including AMD and diabetic retinopathy.[3]

US Food and Drug Administration (FDA) approval and clinical availability of bevacizumab in early 2004 was greeted by tremendous hope and enthusiasm on the part of oncologists, patients, and investors. The enthusiasm was quickly tempered. The drug treatment manifested serious side effects. In some instances, the effect on tumor vascularization was so potent that tumor necrosis and organ perforation or bleeding occurred. Although a survival benefit was demonstrated, it was limited. In lung cancer, for example, the survival benefit of adding bevacizumab to standard chemotherapy was no more than a few months. Another blockbuster pharmaceutical had proved to be a costly disappointment in the war on cancer. Moreover, the cost was truly enormous. Bevacizumab could add as much as $70,000 to the price of cancer treatment.[4]

But there was an unanticipated benefit of treatment with the drug. Investigators noted that some cancer patients treated with systemic bevacizumab had clinical improvement in wet macular degeneration. Might patients with wet AMD benefit from planned treatment with bevacizumab? There were major potential problems with such an approach. First, as noted above, there were major potential side effects that, while acceptable in treatment of advanced cancer, would be daunting in treatment of elderly patients with eye disease. Next, the drug was not FDA-approved for such treatment. Finally, systemic treatment with bevacizumab was very expensive. For example, the standard dose for a 70 kg patient with non–small-cell lung cancer would be 15 mg/kg or 1,050 mg. Three vials of bevacizumab, containing 1,200 mg, cost approximately $8,250, according to the GoodRx Web site,[5] repeated at 3 week intervals.

Priority for the sharp-stick-in-the-eye strategy probably should go to ophthalmologists, who first began using aflibercept and then bevacizumab in tiny dosages injected locally into the eye.[6] Bevacizumab in such doses was affordable, and striking improvement or stabilization of wet AMD was quickly demonstrated in small series. Starting in 2005, there began to appear a flurry of publications reporting striking success of off-label use of bevacizumab for intravitreous injection in the treatment of retinal vein thrombosis, diabetic retinopathy, and wet AMD.[7]

Larger trials demonstrated minimal adverse effects, and a high percentage of patients had improvement or stability in retinal changes and vision.[8] In the intervening years, many clinical studies have confirmed long-term efficacy of bevacizumab in treatment of AMD with either fixed regimen or as-needed administration. What’s more, because only a small dose of the drug was sufficient, cost was relatively low; only 1.25 mg of bevacizumab is typically injected intravitreal, a cost of approximately $80.

But, we must remember that nothing is ever simple in our dysfunctional American system of health care. Could we accept manna in the form of a highly-cost effective miracle treatment?

Of course not. That is not how we do things.

Genentech advised ophthalmologists not to use bevacizumab, off-label, for AMD treatment. Neither would the company do the clinical research necessary to obtain FDA approval to sell bevacizumab for intravitreal injection, nor would they compound bevacizumab in low unit-dosage. Doctors who wanted to use the drug would have to compound it themselves-with the accompanying risk of possible contamination and endophthalmitis. Why?

Ranibizumab, a smaller molecule, also produced by Genentech under the trade-name Lucentis, and specifically designed for intraocular use, demonstrated similar benefits in clinical trials starting in 2006 and was approved by the FDA.[9] When Genentech advised against intravitreal injection of bevacizumab there was major blowback, as ophthalmologists accused the company of trying to drive doctors and patients to use a drug that was no safer or more effective, in order to enhance profits from sales of the far more expensive option-ranibizumab.[10] Genentech relented and both drugs have been in use for the past 7 years. Multiple studies show only a small difference of fewer complications with ranibizumab and minor improvements in visual function.[11]

And there the story should end, with a major advance in medicine in the form of understanding of molecular pathophysiology followed by a triumph of molecular drug design leading to new drugs that palliate disease and markedly slow progression of visual loss.

Then I opened the envelope containing the bill for my treatment.

The charge for a single 0.5 mg dose of ranibizumab from UC Irvine was $11,700-a fivefold markup over the going price. That adds up to $23,400,000 per gram and $23.4 billion for a kilogram of the drug. Again, because we are talking about the modern American system of billing, my insurance company only paid UC Irvine approximately 1/ 20, and including my co-pay, Genentech got only about $700.

Am I selfish for opting for the more expensive drug that offers only a small additional visual benefit and a slight reduction of serious complications like endophthalmitis? Considering the recent epidemiologic catastrophe arising from deficiencies in safety at the New England Compounding Center, I made a decision to go with ranibizumab and later aflibercept, but I am uneasy about my decision. What would happen to an uninsured patient with wet AMD?

The obvious first solution would be for the pharmaceutical company to put profits on the back burner and sell bevacizumab in unit doses of 1.25 mg at a reasonable price. The clear need is for our society to work out a system of payment for medical treatment that prevents outlandish and irrational gouging. Will we see such changes anytime soon? I seriously doubt it.

To finish on a high note, my vision is intact over a year post treatment, and I am very grateful to Dr. Kuppermann and his team, and to the research scientists and companies that make his care possible. Would that the bean-counters, nabob-CEOs, wonks, and politicos who put together our Rube Goldberg–style healthcare delivery policies functioned at the same high level.

References:

1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-6.

2. Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J. Tumor angiogenesis: iris neovascularization at a distance from experimental intraocular tumors. J Natl Cancer Inst. 1973;50:219-28.

3. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445-50.

 4. Fojo T, Grady C. How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst. 2009;101:1044-8.

5. Avastin. GoodRx. http://www.goodrx.com/avastin. Accessed 7 April 2015.

6. Folk JC, Stone EM. Ranibizumab therapy for neovascular age-related macular degeneration. N Engl J Med. 2010;363:1648-55.

7. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36:336-9.

8. Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study. Invest Ophthalmol Vis Sci. 2006;47:4569-78.

9. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113:633.e1-4.

10. Haddrill M. All About Vision: Lucentis vs Avastin: a macular degeneration treatment controversy. All About Vision. http://www.allaboutvision.com/conditions/lucentis-vs-avastin.htm. Accessed 7 April 2015.

11. Chen G, Li W, Tzekov R, et al. Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a meta-analysis of randomized controlled trials. Retina. 2015;35:187-93.