What the Macular Degeneration Drug Trial Means

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How you see with advanced macular degeneration, National Eye Institute

Age-related macular degeneration is a leading cause of vision loss and blindness. The advanced form of the disease affects 1.6 million people in the United States.  That’s why results from the first year of a two-year clinical trial that tested medications for the wet form of age related macular degeneration (AMD) look promising for patients:
1.    In comparison with previous treatments, Avastin and Lucentis are the first treatments to ever improve vision in patients with age-related macular degeneration;
2.    Drugs used in the past (Macugen and Visodyne) only slowed the progression of age-related macular degeneration.
3.    Testing various regimens, including monthly injections versus variable (stopping the injection if no fluid builds up in retina), investigators learned that they could give injections into the eye less frequently than once a month because patients getting the injections did not build up fluid that quickly.  On average, patients needed injections into their eye 7 times during the year, instead of monthly (or 12 times).
4.    The two drugs had about the same effects on visual acuity, when administered on the same schedule.
5.    The drug’s cheaper formulation (Avastin), cost $50 per injection, compared with Lucentis, at $2,000 per dose.
6.    Safety considerations are still being evaluated. Serious adverse events (primarily hospitalizations) occurred in 24 percent of patients for patients on Avastin, compared with 19 percent for patients on Lucentis. According to the study, these safety concerns were not identified in previous studies of Avastin, when used to treat colon cancer. Patients are now being followed for a second year and safety will continue to be monitored.

A Patient’s View of the Clinical Trial

I spoke with Mara Coon, participant in the drug trial at the University of Wisconsin Madison site, for the Comparison of Age-related Macular Degeneration Treatments Trial (CATT). She is 74, was diagnosed with the wet form of age-related macular degeneration two years ago, and she told me that she let her first eye go before she entered the trial. She likes to do a lot of reading and knitting. Because the trial has a year to go, she does not know which drug she is taking. Her vision was 20/60 when she entered the trial, but after a year on the injections, it varies between 20/20 and 20/25. She was quick to tell me: “I am not sure whether everyone responds as well as I do,” a point of view that I think should be underscored. She likes participating in the trial, saying that “if it helps someone down the road, I am happy.” Suresh Chandra, MD, professor of ophthalmology at the University of Wisconsin, pointed out that is the “first time that we have seen a visual gain.”

Avastin’s History

Readers may recall that only a few years ago, Avastin, given at 500 times the dose for macular degeneration, was considered a miracle drug for advanced breast cancer. The drug costs for a year of treatment with Avastin average about $90,000 to $100,000. In the setting of breast cancer, Avastin has had a rocky road: to date, benefit in progression-free survival shown in the original study has not been replicated. Moreover, using disease-free survival, surviving without evidence of disease, not overall survival, or how long the patient actually lived, is a controversial measure of a drug’s effectiveness for terminal cancer.

Avastin was considered a breakthrough drug for treating cancer. It has been studied in a huge number of trials, both in cancer and for other diseases that depend on a rich blood supply. Avastin’s mechanism of action is to prevent new blood vessel growth that allows cancerous tumors to develop and and spread. In 2004, the FDA approved Avastin for the systemic treatment of metastatic colon cancer. In the course of using Avastin for colon cancer, investigators noticed that the drug also helped block blood vessel growth in age-related macular degeneration. Avastin was not approved by the FDA for the indication of AMD, but in 2005, Lucentis was established as highly effective for the treatment of wet AMD in clinical studies. Avastin was approved by the FDA in 2006 for AMD.

Cost Considerations

Cost and pricing are thorny issues. For macular degeneration, Avastin costs $50 per dose, compared with $2,000 per dose for Lucentis, but the outcomes are essentially the same. Many doctors do not want to discuss costs with patients. Perhaps patients also feel so removed from prices unless they have high out-of-pocket costs that they don’t think much about them either.

Several ophthalmologists declined to be interviewed for this story. The American Academy of Ophthalmology issued a press release the same day as the study was released, titled “New Study Offers Hope and Treatment Choices for Macular Degeneration.” The press release also states: “For unknown reasons, some wet AMD patients do not respond to one drug but get positive results with the other. Eye MDs need the flexibility to prescribe either medication to provide the best care for their patients.” This needs to be explained fully so the best decisions are made.

Patients should be aware that some ophthalmologists are consultants to drug companies or medical device manufacturers. Many doctors who work with industry do so because they want to participate in developing advances in their field. Yet these issues are not black-and-white. The public pays for these advances; drug companies invest in them, and reap the profits or take losses.

Pricing Macular Degeneration Drugs

Thus far, many articles and blogs have discussed the two drugs as if they are very different. However, they are made from the same monoclonal antibody; they are not different drugs at all. Ranibuzumab, the generic name for Lucentis, is made by customizing the molecule in bevacizumab (Avastin). According to the package inserts, they are manufactured in different cell cultures. The actual manufacture of Lucentis should not be that much more costly, according to several physicians, who asked that I not name them. What undoubtedly goes into price are research and development costs to bring the drug to market, including amortization costs (reduction in operational costs associated with evaluating the drug), patent life, and drug competition. Both eye medications are made by Genentech.

Pricing for this group of macular degeneration drugs and drugs with similar impacts, merits, and costs are likely to be debatable, both in the United States, which is struggling with health expenditures, as well as resource –poor countries.  The burden of having advanced macular degeneration is blindness. Around the world, numbers are enormous.

How will countries pay for drugs like this and many more in the pipeline? “Insurance companies are going to say: ‘Why do you want to use Lucentis?’” said Chandra. Even though he acknowledged that Genentech has invested in research, he added: “We are talking about billions versus millions.” He said that the trial results offer a “big sigh of relief for developing countries.”

Sean Tunis, the founder and director of an independent nonprofit organization, the Center for Medical Technology Policy, and a proponent of what is called “value-based” or “outcomes” pricing, does not think that the horse is out of the barn. In a nutshell, value-based pricing would consider payment for clinical outcomes. Tunis does not think that the “value-based price” for Avastin is $50, and he called reporters who stopped there in their cost discussion “hypocritical.”

“This is the first treatment to ever improve vision for macular degeneration,” said Tunis.” That is worth a lot more than $50 per dose.” The cost was figured, based on per milligram, not per outcome, he explained, proportional to say, how much less is needed to inject into the eye than is required for cancer indications.

There is a movement afoot in healthcare reform to pay for care, based on how well interventions do in achieving the best clinical outcomes, and paying attention to clinical outcomes that are most important to patients. Tunis also pointed out that there is a “small safety signal,” referring to the 24 percent versus 19 percent hospitalization rate in the trial.

This is a pretty complicated story. It is far from over. We have only seen safety and outcomes with these drugs for one year. It’s a start. What do you make of it?

This entry was posted in Age-related macular degeneration, Avastin, Blindness, Drug costs, Outcomes, Vision and tagged , , . Bookmark the permalink.

8 Responses to What the Macular Degeneration Drug Trial Means

  1. ebb says:

    One way insured patients feel the full cost of a drug is if they are on Medicare. The full cost of the drug is counted as they move toward the donut hole. When the costs exceed $2,840, insurees will have to pay full costs themselves. The second dose of a $2 thousand dollar drug will put you into the donut hole, no matter what you pay out of pocket for that first dose. Medicare patients must pay attention to drug costs.

  2. Bob Simpson says:

    There’s clearly a trade-off here if one risks going to the hospital as opposed to going blind. I think patients deserve to know the odds and be allowed to make those tough choices. The trick is to find reliable information admidst the deluge of propaganda that comes from the pharmaceutical industry.

  3. shana says:

    This is great! I can’t wait to what information comes out in further studies in this area, particularly since my spouse has been diagnosed with the early stages of macular degeneration. I hope that eye research continues to be funded and that we see more developments in this area.

  4. Sheila Buff says:

    Laura, nice article. My mom has dry AMD that so far isn’t really affecting her vision. Glad to know the trial results, because the issue could well arise for her. What was the primary reason for hospitalization in the trial? The dose is small, which would seem to limit the potential for some of Avastin’s known side effects. Allergic reactions?

  5. Laura Newman says:

    A few things: dry often changes to the wet form later in the course of the disease. The median age for patients in the study was over 80. Adverse events, include hospitalization, were distributed across many different conditions. According to the National Eye Institute, most were not associated with those found among patients in the Avastin cancer clinical trials. Also, overall the number of deaths, heart attacks, and strokes were low and similar for patients taking Avastin and Lucentis. So far, investigators have not been able to tell whether there is an association between a particular adverse event and treatment. They will be following safety throughout the trial.

  6. Irv Arons says:

    Laura,

    I’ve written about 60 articles on both the Avastin vs Lucentis controversy and on the CATT Study. Your readers might be interested in two of my recent postings — Avastin — The Rest of the Story (link: http://tinyurl.com/Avastin46) that relates how Dr. Phil Rosenfeld came up with the idea of using Avastin in the first place; and my most recent posting in the CATT Study Update series — Preliminary Two-Year Safety Data Presented at ARVO (link: http://tinyurl.com//CATTUpdate15) that discusses additional safety data that was presented in the Sunday afternoon session on the CATT Study.

  7. Norman says:

    Here’s the ARVO abstract on bevacizumab (Avastin) and ranibizumab (Lucentis):

    http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=3a667d20-f42d-421e-a859-e1b680de80ed&cKey=4e534aee-b678-4b9d-91dc-20a9d6ae0c56&mKey={6F224A2D-AF6A-4533-8BBB-6A8D7B26EDB3}

    Adverse Event Rates Following Intravitreal Injection of Avastin or Lucentis for Treating Age-Related Macular Degeneration

    They reviewed the Medicare database for patients who had been treated with both drugs for macular degeneration.

    Results: The primary analysis cohort includes 77,886 beneficiaries (46%Ran). HRs adjusted for baseline comorbidities, demographics and socio-economic status proxies showed an 11% higher risk in overall mortality (HR: 1.11; 99% CI: 1.01-1.23) and a 57% higher risk of hemorrhagic cerebrovascular accident (CVA) in the Bev group (HR: 1.57; 99% CI: 1.04-2.37)….

    Conclusions: Data from this Medicare claims analysis suggest differences in the safety profile of Bev vs Ran. However, this study is limited by incomplete information on some important confounding factors, e.g., smoking, lipid and blood pressure levels, which would further clarify the relative safety of these treatments in wet AMD.

    As the abstract says, the study was funded by Genentech, and most of the investigators seem to be affiliated with Genentech.

    Here’s Novartis’ take on it. http://www.novartis.com/newsroom/media-releases/en/2011/1512519.shtml As Wikipedia says, Novartis markets Lucentis in Europe. http://en.wikipedia.org/wiki/Ranibizumab

    These reviews of the Medicare database are retrospective studies. They have the benefits of huge numbers. They have the limitations of not being able to distinguish association from causation. The investigators said they adjusted for confounding factors, but as they admit, you can’t be sure you’ve adjusted for everything. For example, it seems plausible that low income people are less likely to use an expensive drug like Lucentis. Low-income people usually have worse outcomes in everything, and they’re more likely to smoke cigarettes.

    The original study in the NEJM, Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration http://www.nejm.org/doi/full/10.1056/NEJMoa1102673 looked at the incidence of stroke and death and found no difference between the two drugs, although you can’t reliably find a difference in events with a 1% incidence in 1,208 patients.

    In the accompanying editorial, Bevacizumab versus Ranibizumab — The Verdict, http://www.nejm.org/doi/full/10.1056/NEJMe1103334 Philip J. Rosenfeld says,

    “Ranibizumab, an antigen-binding fragment, is a smaller molecule that was specifically developed and approved to treat eye diseases and is derived from the same anti-VEGF mouse monoclonal antibody as bevacizumab. Both ranibizumab and bevacizumab bind VEGF at the same position; however, they differ in size, affinity for VEGF, speed of clearance from the eye, and cost.5 Ranibizumab, the FDA-approved treatment for neovascular AMD, costs approximately $2,000 per dose, whereas bevacizumab, the off-label treatment, costs approximately $50….

    “the study was insufficiently powered to identify differences in drug-related adverse events.7 Although bevacizumab persists longer than ranibizumab in the systemic circulation after an intravitreal injection,10 Martin et al. observed none of the expected adverse events associated with systemic anti-VEGF therapy. Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy….

    “Health care providers and payers worldwide will now have to justify the cost of using ranibizumab.”

    So it looks like that’s what Genentech and Novaris are trying to justify it.

    There were also a couple of letters in the NEJM on the cardiovascular and infectious risks of these treatments. http://www.nejm.org/doi/full/10.1056/NEJMc1013316 Market-based medicine always has its problems, so it’s interesting to see that the Chinese Communists also worry about inflammation with bevacizumab.

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