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Statement on Avastin
Position Statement Released by AMD Alliance International

The role, efficacy, and safety of anti-vascular endothelial growth factor (VEGF) therapies for use in the treatment of age-related macular degeneration (AMD) were first established by clinical trials of pegaptanib sodium, (Macugen, [OSI] Eyetech/Pfizer) and later by clinical trials for ranibizumab (Lucentis, Genentech, Inc.).

PEGAPTANIB SODIUM

Phase 3 clinical trials for pegaptanib sodium demonstrated that after 1 year of treatment, individuals who were treated with 0.3 mg and 1 mg pegaptanib sodium experienced less vision loss than those who were treated with a placebo. Individuals who were treated with pegaptanib sodium experienced lasting results for 2 years. The most common side effect (occurring in approximately 1.3% of cases) was endophthalmitis, which was caused by the injection.¹

RANIBIZUMAB

Phase 3 clinical trials for ranibizumab demonstrated superior results after 1 year of treatment, and showed that the majority of individuals who were treated with ranibizumab improved or maintained vision 2 years later. The improvement in visual acuity endpoints in the ranibizumab-treated groups (0.3 mg and 0.5 mg) was maintained at year 2, while individuals in the control group continued to experience vision deterioration. At
2 years, at least 90% of individuals who were treated with ranibizumab maintained or improved vision compared to approximately 53% of individuals who were treated with sham injections. Treatment side effects were mild to moderate, affected less than 3% of individuals, and included conjunctival hemorrhage, increased IOP, vitreous floaters, and endophthalmitis.²

BROADENING THE ANTI-VEGF THEORY

Ranibizumab was developed by Genentech, Inc. The company had previously developed bevacizumab (Avastin, Genentech, Inc.) an anti-VEGF drug that
is currently approved by the Food and Drug Administration (FDA) as an intravenous therapy for metastatic colorectal cancer patients. Bevacizumab for use in cancer therapy is currently being investigated. Ranibizumab is a molecular fragment of an antibody, and bevacizumab is a full-length antibody. They are
both thought to work by a similar principle — the drug blocks the production of VEGF. VEGF, which is also produced by cancer cells, prompts the abnormal growth of blood vessels, also known as angiogenesis. Bevacizumab binds with VEGF and interferes with its ability to stimulate blood vessel growth.

In early 2004, Philip Rosenfeld, MD, PhD, and colleagues at the Bascom Palmer Eye Institute in Miami, Fla, initiated the use of bevacizumab in the treatment of AMD. Their first study was called Systemic Avastin for Neovascular AMD (SANA). In this and subsequent studies, which consisted of intravitreal injections of bevacizumab, individuals who were clinically followed reported improvements in visual acuity comparable to ranibizumab with no
serious adverse events.³ It is important to note that these clinical studies were not conducted as randomized clinical trials.^4,5 Based on these results, the use of
bevacizumab for the treatment of AMD appears to have been broadly accepted by retinal specialists around the world.

The use of bevacizumab in the eyes, an indication for which it is not approved, is called off-label use. It is reasoned conjecture on the part of the AMD Alliance International that the off-label use of bevacizumab was first suggested for reasons of economy and availability in the face of a significant unmet need. Treatment with ranibizumab has not been available unless an individual is registered in a clinical trial, or, as is possible in some European countries, receives the treatment on what is called a 'named-patient' basis.

SAFETY AND EFFICACY OF BEVACIZUMAB

There is growing anecdotal evidence about the efficacy of the off-label use of bevacizumab. However, at this time, published reports on bevacizumab are limited to a number of human clinical case series in, and a few animal studies on, intravitreal injection. Most notable among the animal studies is one conducted by Anat Lowenstein, MD, who reported no safety issues in rabbit testing.⁶ Published human research on the safety and efficacy of bevacizumab is limited to the previously mentioned small human study at Bascom Palmer Eye Institute.

There have, however, been reports of serious life-threatening adverse events that can be attributed to bevacizumab when it is used in clinical trials on cancer patients. Most notably, a 4.4% risk of thromboembolic events has been referenced. It is noted that when used as a cancer treatment, bevacizumab is administered systemically rather than locally.

OUR POSITION ON BEVACIZUMAB

The off-label use of drugs is legal in North America, Europe, and Asia, and is a practice that is accepted by physicians, healthcare providers and institutions, and some insurers.

As stated earlier, there is growing anecdotal evidence about the efficacy of the off-label use of bevacizumab. However, there have been no randomized controlled clinical trials, nor are there any broad, scientifically-accepted published reports in this regard. In fact, due to the fact that bevacizumab is a full-length antibody, some researchers assert that it will not be as effective in the long term because it cannot penetrate all layers of the eye as well as the fragment antibody ranibizumab. Answers to all of the questions about bevacizumab will only be known following the completion of clinical trials and publication of the results. Genentech, Inc., has stated that it is not planning to conduct any clinical trials involving the medication.

On April 20, 2006, the American Academy of Ophthalmology (AAO) issued a statement declaring their support for Medicare reimbursement consideration for the cost of bevacizumab usage in cases where individuals who are deemed by their treating physician to have failed FDA-approved therapies and/or are likely to have greater benefit from the use of intravitreal bevacizumab.

Individuals also have access to a clinical trial of ranibizumab, sponsored by Genentech, Inc., the makers of bevacizumab. The trial, known as Safety Assessment of Intravitreal Lucentis for AMD (SAILOR), is a 1-year, phase 3b study that is designed to evaluate the safety of ranibizumab, the VEGF inhibitor, which, as discussed above, has not yet been approved by the FDA. The trial provides access to the drug for eligible individuals in advance of the FDA's response and is open to individuals with all subtypes of new or recurrent active subfoveal wet AMD. For more information, see "Clinical Trials Update" on page 88 or go to http://www.clinicaltrials.gov/ct/show/
NCT00251459?order=2. Eligible patients are not able to access these clinical trials outside the United States.

Meanwhile, until options such as ranibizumab become widely available, individuals are desperately seeking options and answers. Our position is that individuals must make an informed decision about treatment in consultation with their own retinal specialist. According to the American Medical Association, informed consent refers to significantly more than the process of signing a 'consent to treat' form. Rather, informed consent refers to the communication that takes place between individuals and their physician.⁷

The process of arriving at an informed decision includes questions such as:

►What is my exact diagnosis?

►What is the typical progression for an individual with my eye condition?

►What treatment options and/or care do you recommend?

►How will each of these treatments and/or care options help me?

►What are the risks and side effects for my unique eye condition?

►What are the proven and unproven benefits of treatment for my unique eye condition?

►Are the differences in the evidence gathered through randomized clinical trials versus clinical studies significant for me?⁴

►Regardless of cost or coverage by my insurance, what are some alternative treatments?

Our website, www.amdalliance.org is continually updated. Please check back frequently for updated details as developments occur in future. RP

REFERENCES

1. Pfizer. News Releases 2006. European Commission Approves Macugen for Treatment of All Types of Wet Age-Related Macular Degeneration; First Treatment to Target Underlying Disease Process of Wet AMD. February 2, 2006. Available at: http://www.pfizer.com/pfizer/are/news_releases/2006pr/mn_2006_0202.jsp. Accessed March 30, 2006.

2. Genentech. Genentech Granted Six-Month Priority Review for Lucentis for the Treatment of Wet Age-Related Macular Degeneration. February 28, 2006. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=9427. Accessed March 30, 2006.

3. Rosenfeld P. An Update on Bevacizumab. Review of Ophthalmology. [serial online]. 2005;12. Available at: http://www.revophth.com/index.asp?page=1_857.htm. Accessed March 30, 2006.

4. The Medicines and Healthcare Products Regulatory Agency (MHRA). The Medicines for Human Use (Clinical Trials) Regulations. 2003. Available at http://www.mhra.gov.uk/home/groups/comms-ic/documents/publication/con007627.pdf.

5. Clinical Trials. A Service of the U.S. National Institutes of Health (NIH). Developed by the National Library of Medicine. Available at http://www.clinicaltrials.gov.

6. Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina. 2006;26:262-269.

7. American Medical Association (AMA). Professional Resources. Informed Consent. March 7, 2005. Available at: http://www.ama-assn.org/ama/pub/category/4608.html. Accessed March 30, 2006.

AMD Alliance International is the only international organization in the world dedicated exclusively to promoting awareness, treatment and research into macular degeneration, the leading cause of vision loss in the developed world. With 55 members in 21 countries, we are a membership organization comprised of the worlds' leading vision and research organizations.