CATT findings support use of Avastin as alternative to Lucentis
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between two drugs for the treatment of neovascular age-related macular
degeneration (AMD). Vascular endothelial growth factor (VEGF), the
cytokine primarily responsible for blood-vessel growth, is inhibited
when anti-VEGF drugs are injected repeatedly into the eye, and
blindness is prevented in most patients. The majority of treated
patients go on to have some improvement in vision.
The two anti-VEGF drugs most commonly used are bevacizumab (Avastin)
and ranibizumab (Lucentis), both developed by Genentech. Avastin, a
full-length humanized monoclonal antibody, has been approved by the
Food and Drug Administration (FDA) for the systemic treatment of
certain cancers. Lucentis, 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 Avastin. Both Lucentis and Avastin bind VEGF at the same
position; however, they differ in size, affinity for VEGF, speed of
clearance from the eye, and cost. Lucentis, the FDA-approved treatment
for neovascular AMD, costs approximately $2,000 per dose, whereas
Avastin, the off-label treatment, costs approximately $50. This cost
difference, along with the perceived clinical similarities between
these two drugs, has led to the widespread use of Avastin in the
absence of level I evidence.
Martin and colleagues provide such evidence in their findings from the
first year of the Comparison of AMD Treatment Trials (CATT), a large,
prospective, multicenter, randomized clinical trial comparing Avastin
and Lucentis. Despite formidable obstacles, the investigators
successfully compared the two drugs and two different dosing regimens:
a monthly regimen versus an as-needed regimen (i.e., drug
administration only when signs of exudation are present). An
OCT-guided as-needed regimen has been shown to result in improved
visual acuity, but CATT is the first prospective approach to directly
compare a monthly regimen with an as-needed regimen.
Martin et al. found that the monthly use of either Avastin or Lucentis
results in the same visual acuity outcome. This finding holds true for
the mean visual acuity and the proportion of patients who gain 15
letters (which represents a doubling of the visual acuity), lose 15
letters, or remain stable. Critics will argue that the OCT outcomes
suggest differences between these two drugs. Although the OCT retinal
thickness measurements favor Lucentis, this difference is not
reflected in any of the visual-acuity or angiographic outcomes.
In addition, Martin et al. observed equivalent visual-acuity outcomes
with both the monthly and the as-needed regimens of Lucentis. This
result is particularly good news for patients. The success of the
as-needed regimen in a multicenter clinical trial cannot be
overstated, given the intrinsic difficulties associated with the
training of investigators to agree on OCT interpretation and
retreatment guidelines. Given deficiencies that were reported by the
reading center, it is likely that visual acuity and anatomic outcomes
would have been even better with improved investigator compliance.
Although the as-needed regimen with Avastin appeared similar to the
as-needed regimen with Lucentis, the as-needed Avastin regimen
compared less favorably with monthly regimens for either Avastin or
Lucentis. One possibility may be that Avastin has a less durable
treatment effect in a subgroup of patients and thus more frequent
administration may be required. If the frequency of administration
were increased, then the outcomes in such patients should approach the
outcomes observed with monthly treatments.
Although CATT addresses the question of efficacy, the study was
insufficiently powered to identify differences in drug-related adverse
events. Although Avastin persists longer than Lucentis in the systemic
circulation after an intravitreal injection, Martin et al. observed
none of the expected adverse events associated with systemic anti-VEGF
therapy. Although more patients receiving Avastin had multiple
systemic serious adverse events and hospitalizations than those
receiving Lucentis, these events were not associated with organ
systems typically identified with systemic anti-VEGF therapy. The
results from the second year of CATT and from five other large,
ongoing, multicenter comparative clinical trials in Europe should help
to clarify whether these adverse events are related to intravitreal
anti-VEGF therapy.
The CATT results, together with the totality of global experience,
support the use of either Avastin or Lucentis for the treatment of
neovascular AMD. An as-needed regimen is an acceptable alternative to
a monthly regimen, but strict compliance on the part of both the
clinician and the patient is required. Health care providers and
payers worldwide will now have to justify the cost of using Lucentis.
Regulators in certain countries will be forced to reconsider their
policies that make it illegal to use drugs off-label, particularly
when so many of their citizens cannot afford Lucentis. The CATT data
support the continued global use of intravitreal Avastin as an
effective, low-cost alternative to Lucentis.
N Engl J Med. 2011 May 19;364(20):1966-7. Epub 2011 Apr 28.
http://www.ncbi.nlm.nih.gov/pubmed/21526924
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