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.).
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
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
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
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
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
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
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
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/
Eligible patients are not able to access these clinical trials outside the United
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
►What is my exact diagnosis?
►What is the typical progression for an
individual with my eye condition?
►What treatment options and/or care do
►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?
www.amdalliance.org is continually updated. Please
check back frequently for updated details as developments occur in future. RP
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:
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:
Accessed March 30, 2006.
3. Rosenfeld P. An Update on Bevacizumab. Review of Ophthalmology.
[serial online]. 2005;12. Available at:
Accessed March 30, 2006.
4. The Medicines and Healthcare Products Regulatory Agency (MHRA).
The Medicines for Human Use (Clinical Trials) Regulations. 2003. Available at
5. Clinical Trials. A Service of the U.S. National Institutes
of Health (NIH). Developed by the National Library of Medicine. Available at
6. Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and
retinal penetration studies following intravitreal injection of bevacizumab (Avastin).
7. American Medical Association (AMA). Professional Resources.
Informed Consent. March 7, 2005. Available at:
Accessed March 30, 2006.
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
Retinal Physician, Issue: July 2006