Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study

Since posting this update on October11th, I have obtained further information about the upcoming clinical trial to be held to compare Lucentis with Avastin. For the details, see the Addendum below.

Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study

On October 6th, after the New England Journal of Medicine had gone to press, the National Eye Institute and the National Institute of Health announced that they will proceed with a comparative study of Avastin and Lucentis.

As noted in my previous three updates (see links below in the Author’s Note), I and others felt that common sense dictated that a comparative study be undertaken particularly because of the disparity in price between the two drugs – Lucentis priced at $1950 per dose, and Avastin (used off-label) at about a tenth of that price.

As stated on their web site: “The National Eye Institute (NEI) of the National Institutes of Health (NIH) will fund a new multicenter clinical trial to compare two drugs currently used to treat advanced age-related macular degeneration (AMD)... Lucentis (ranibizumab) and Avastin (bevacizumab).”

In addition, the announcement said: “In advanced AMD, abnormal new blood vessels grow beneath the retina. These abnormal blood vessels can leak blood and fluid, and can cause severe vision loss. NEI-supported research has helped establish that VEGF is an important part of the biological pathways involved in triggering and sustaining the growth of new blood vessels in the retina. Research also demonstrated that VEGF is present in higher levels in a number of eye diseases, such as AMD. NEI has supported more than 300 research studies at a cost of nearly $95 million to better understand the role of VEGF in eye diseases.”

At this point, two anti-VEGF therapies, Macugen (pegaptanib sodium) and Lucentis, have already been approved by FDA specifically for the treatment of advanced AMD. Paul A. Sieving, M.D., Ph.D., director of NEI, said, "We are pleased that NIH-supported research is stimulating the development and testing of new, effective treatments for AMD."

I contacted the NEI and learned that patient enrollment will begin after the first of the year.

As I learn more about this important clinical trial, I will continue to update my web site.

ADDENDUM

According to a report in the New York Times, if the drugs prove to be equivalent in treating age-related macular degeneration, it would probably mean that many eye doctors would switch to the cheaper drug, hurting Genentech's sales but saving the Medicare program hundreds of millions of dollars a year.

Both Avastin and Lucentis work in a similar way, and some eye doctors say they believe Avastin is equally as effective. However Avastin has not been tested in rigorous clinical trials as Lucentis has. So interest has been growing for a trial to compare the drugs. It is estimated that there are 200,000 new cases each year of the type of macular degeneration for which Lucentis is approved.

Dr. Maryann Redford, the administrator of the NEI grant for the study, said it will involve a two-year trial costing about $16 million. The trial will follow about 1,200 people divided into four groups: one group will get a Lucentis injection every four weeks, one group will get an Avastin injection every four weeks; and two groups will get either Lucentis or Avastin on an as-needed basis. Redford said the study will take four years to complete.

Dr. Redford added that cost is not the primary reason that NEI decided to fund the study. "Right now there is an uncontrolled experiment being done, in that many clinicians are using Avastin, but its safety and efficacy for this use hasn't been tested," adding, "If the fallout also is that it can be done much less expensively, great."

Hal Barron, Genentech's chief medical officer, said the company is not interested in paying for a study comparing Lucentis and Avastin because it is unlikely that Avastin is a superior treatment and because the company prefers to spend money developing new treatments. Barron added that 81% of patients pay less than $50 out of pocket for each Lucentis dose because they have Medicare or other insurance.


Author’s Note on Avastin

Since posting the original article on January 31, 2006, I have now posted eight updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD (January 2006)

Avastin Update: Medicare not Likely to Cover its Use (March 2006)

Avastin Update II: AAO supports Medicare Coverage for Off-label Avastin Use (April 2006)

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD (July 2006)

Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)

Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them (October 2006)

Newer Updates

Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting (November 2006)

Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)

Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them

Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them

This week’s issue (October 5, 2006) of the New England Journal of Medicine (NEJM) contains several articles on the use of Lucentis to treat age-related macular degeneration (AMD). The lead article, “Ranibizumab and Age-Related Macular Degeneration”, relates the latest test results that led to the drug’s approval on June 30th of this year, while a second article, "The Price of Sight -- Raninbizumab (Lucentis), Bevacizumab (Avastin), and the Treatment of Macular Degeneration" calls for a clinical trial between them because of the price differential.

Genentech, the manufacturer of both drugs, commented about the release of the first article:

Genentech, Inc. (NYSE: DNA) announced today the publication of data from the two randomized, controlled pivotal Phase III clinical trials of LUCENTIS (ranibizumab injection) in the New England Journal of Medicine. The published findings include two-year efficacy and safety data from the MARINA trial and one-year efficacy and safety data from the ongoing ANCHOR trial. Based on these studies, LUCENTIS was granted U.S. Food and Drug Administration (FDA) approval on June 30, 2006 for the treatment of patients with the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness in people over 55.

The MARINA and ANCHOR clinical trials met the primary efficacy endpoint of maintaining vision (defined as a loss of less than 15 letters in visual acuity) at one year in patients with wet AMD. In these studies, nearly all patients (approximately 95 percent) treated with LUCENTIS maintained or improved vision at one year compared with 62 percent of patients in the MARINA control group and 64 percent of patients in the ANCHOR control group. Importantly, up to 40 percent of patients experienced an improvement in vision of three lines (15 letters) or more on the study eye chart compared with 5 percent and 6 percent of patients in the MARINA and ANCHOR control groups, respectively. The improvement in visual acuity endpoints among patients treated with LUCENTIS in the MARINA study was maintained at year two, while patients in the control group continued to decline.

"The results of these Lucentis studies have changed the way we approach the treatment of wet AMD by demonstrating, for the first time, improvements in vision in more than one-third of patients treated," said David Brown, M.D., lead author for the ANCHOR study and retina specialist at Vitreoretinal Consultants, The Methodist Hospital in Houston, Texas.

"What makes this publication particularly significant is that the visual acuity benefits after one year of treatment in the MARINA study were maintained through two years and associated with anatomic improvements consistent with the changes in visual acuity observed," said Philip J. Rosenfeld, M.D., Ph.D., professor of ophthalmology, Bascom Palmer Eye Institute in Miami and lead author for the MARINA study. "In this study, Lucentis had a favorable safety profile and did not appear to put patients at an additional risk for systemic adverse events and the ocular adverse event rates were similar to what we would expect among people in this age group who receive an injection in the eye."

However, perhaps more importantly, Dr. Robert Steinbrook commented in his article, "The Price of Sight -- Raninbizumab (Lucentis), Bevacizumab (Avastin), and the Treatment of Macular Degeneration" on the need for a direct clinical trial between Lucentis and Avastin because of the price disparity between the two drugs, as I have related previously in my web Journal. (See the Author’s notes at the end of this article.)

As Doctor Steinbrook noted in his “Perspectives” article, “Before the FDA approved ranibizumab, some ophthalmologists began using another monoclonal antibody, bevacizumab, that is closely related to ranibizumab to treat patients who have neovascular macular degeneration or other chorioretinal diseases mediated by vascular endothelial growth factor. Marketed as Avastin and also manufactured by Genentech, bevacizumab is a full-length antibody that is derived from the same mouse monoclonal antibody precursor as ranibizumab (see Figure 1), neutralizes vascular endothelial growth factor, and costs considerably less than ranibizumab when administered as an intraocular injection.”

Figure 1. Relationship between Ranibizumab and Bevacizumab.

Ranibizumab is a recombinant humanized monoclonal IgG1 kappa-isotype antibody fragment (with a molecular weight of about 48 kD). It is produced in an Escherichia coli expression system (and thus is not glycosylated) and is designed for intraocular use. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody (with a molecular weight of about 149 kD). It is produced in a Chinese-hamster-ovary mammalian-cell expression system (and thus is glycosylated) and is designed for intravenous infusion. Both the antibody fragment and the full-length antibody bind to and inhibit all the biologically active forms of vascular endothelial growth factor (VEGF) A and are derived from the same mouse monoclonal antibody. However, ranibizumab has been genetically engineered through a process of selective mutation to increase its affinity for binding and inhibiting the growth factor. The Fab domain of ranibizumab differs from the Fab domain of bevacizumab by six amino acids, five on the heavy chain (four of which are in the binding site) and one on the light chain. Not all the intermediate Fabs between the mouse monoclonal antibody and ranibizumab are shown.


“In February 2004, the FDA approved bevacizumab for the treatment of metastatic cancer of the colon or rectum. Although the typical price of bevacizumab as part of a chemotherapy regimen is $4,400 a month, a 4-ml vial containing 100 mg has a wholesale acquisition cost of $550. Thus, physicians and compounding pharmacies can prepare small aliquots in syringes for intraocular injection at a cost to the physician of $17 to $50, depending on the dose and the efficiency of the process. In some instances, charges to patients may be considerably higher. On a molar basis, the typical dose — 1.25 mg (0.05 ml) — of bevacizumab is similar to the approved dose of ranibizumab.”

“Intraocular administration of bevacizumab is entirely off-label; the drug is formulated for intravenous infusion, not intravitreal injection. Nonetheless, and though data from controlled trials are lacking, bevacizumab appears to be safe and effective in the short term. And ophthalmologists frequently use medications off-label.”

“As of mid-September 2006, ranibizumab had been approved in the United States and Switzerland (where it is marketed by Novartis, which has commercialization rights outside the United States). Bevacizumab has already brought Genentech billons of dollars in sales; ranibizumab will soon do so as well.”

“The good news for patients is that there are two new medications for neovascular age-related macular degeneration, both of which appear to work better than the alternatives. But since they have never been directly compared, physicians can only speculate about which drug is superior with regard to safety, efficacy, and frequency of administration. The price difference is also too big to ignore.” (Emphasis added by this author.)

“In many parts of the world, a medication that costs $1,950 for a monthly injection is unaffordable. In the United States, under Medicare, ranibizumab is covered through Part B; patients are responsible for a 20% copayment for each injection. In some instances, supplemental insurance, Medicaid, or support programs for the poor or uninsured that are funded by the manufacturer or others cover most or all of the patients' costs. But regardless of who pays the bill, sales of ranibizumab generate revenue for Genentech, the drug's high price contributes to the overall cost of health care, and the drug may sometimes still be unaffordable.”

“It is possible that bevacizumab would prove to be superior for neovascular age-related macular degeneration. For example, the molecule is about three times as large as ranibizumab and may remain in the eye longer, decreasing the frequency with which injections are required. At present, intraocular pharmacokinetic data are lacking. However, ranibizumab could also prove to be better. In addition to its smaller size, ranibizumab is genetically engineered to have greater affinity for vascular endothelial growth factor and is formulated for intraocular use; more of the drug may therefore penetrate all the layers of the retina. Moreover, ranibizumab that leaks out of the eye into the circulation has a half-life of hours; the half-life of a full-length antibody such as bevacizumab is longer. For this reason, ranibizumab could theoretically be associated with less systemic toxicity than bevacizumab, but it is not known whether this is in fact the case. As an antibody fragment, ranibizumab lacks an Fc portion, so it may be less likely to induce inflammation within the eye. However, according to Rosenfeld, no apparent inflammation has been seen with bevacizumab, even with the highest dose that has been administered.”

“Since late 2005, the National Eye Institute has been considering a proposal for a prospective multicenter trial that would compare ranibizumab directly with bevacizumab. Although the institute has signed off on the need for a trial, as of mid-September it was still considering the research design and how to pay for the study, which would probably cost tens of millions of dollars. If the study is to go forward, the federal government will probably have to buy both drugs from Genentech. And the investigators will probably have to submit to the FDA an investigational new drug application for intravitreal bevacizumab. Such a comparison might not ultimately affect the difference in price between the drugs, but it is certainly the only way to determine which drug is better for patients.”


In addition to the two articles noted above, two additional articles are included in this week’s edition of the NEJM. They are:

Ranibizumab versus Verteporfin in Age-Related Macular Degeneration, a discussion of the clinical trial showing the differences between using Lucentis and verteporfin PDT in treating AMD; and a general discussion of AMD: Age-Related Macular Degeneration.

All of the articles can be found at:

http://content.nejm.org/cgi/content/full/355/14/1409

however, only Dr. Steinbrooks article can be read in full without a subscription to the NEJM.


Author’s Note on Avastin

Since posting the original article on January 31, 2006, I have now posted eight updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD (January 2006)

Avastin Update: Medicare not Likely to Cover its Use (March 2006)

Avastin Update II: AAO supports Medicare Coverage for Off-label Avistan Use (April 2006)

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD (July 2006)

Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)

Newer Updates:

Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study (October 2006)

Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting (November 2006)

Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)