Ophthalmic Use of Bevacizumab Runs into
Controversy
by David W. Sharp
Medicine Top Ten
Papers
Rank
Papers
Cites Jul-Aug
07
Rank
May-Jun 07
1
C.L. Ogden, et al., "Prevalence of
overweight and
obesity
in the United States, 1999-2004,"JAMA, 295(13): 1549-55, 5 April 2006. [Ctrs.
for Disease Control, Atlanta, GA] *028RG
81
1
2
J.A. Dormandy, et al., "Secondary
prevention of macrovascular events in patients with type 2
diabetes
in the PROactive Study (PROspective pioglitAzone
Clinical Trial In macroVascular Events): a randomised
controlled trial,"Lancet, 366(9493):
1279-89, 8 October 2005. [13 U.S. and European
institutions] *971ST
44
5
3
C. Baigent, et al. (Cholesterol Treatment
Trialists’ [CTT] Collaborators), "Efficacy
and safety of cholesterol-lowering treatment: prospective
meta-analysis of data from 90 056 participants in 14
randomised trials of statins,"Lancet,
366(9493): 1267-78, 8 October 2005. [Correspond. addresses:
Clin. Trial Serv. Unit and Epidem. Stud. Unit, Oxford,
U.K.; Natl. Hlth. & Med. Res. Council Clin. Trials
Ctr., Sydney, Australia] *971st
42
†
4
R.L. Avery, et al., "Intravitreal
bevacizumab (Avastin) for neovascular age-related macular
degeneration,"Ophthalmology, 113(3):
363-72, March 2006. [Correspond. address: California Retina
Consultants, Santa Barbara] *017LD
37
†
5
M.J. Piccart-Gebhart, et al., "Trastuzumab
after adjuvant chemotherapy in HER2-positive
breast
cancer,"New Engl. J. Med.,
353(16): 1659-72, 20 October 2005. [26 institutions
worldwide] *975IC
34
†
6
E.H. Romond, et al., "Trastuzumab plus
adjuvant chemotherapy for operable HER2-positive breast
cancer,"New Engl. J. Med., 353(16):
1673-84, 20 October 2005. [19 U.S. institutions] *975IC
34
6
7
D.M. Harper, et al., "Sustained efficacy
up to 4·5 years of a bivalent L1 virus-like particle
vaccine against human papillomavirus types 16 and 18:
follow-up from a randomised control trial,"Lancet, 367(9518): 1247-55, 15 April 2006. [9
institutions worldwide] *034FC
34
†
8
P.J. Rosenfeld, A.A. Moshfeghi, C.A. Puliafito,
"Optical coherence tomography findings after an
intravitreal injection of bevacizumab (Avastin) for
neovascular age-related macular degeneration,"Ophthal. Surg. Lasers & Imaging, 36(4): 331-5,
July/August 2005. [U. Miami Sch. Med., FL] *968DA
34
†
9
J.A. Lieberman, et al., "Effectiveness of
antipsychotic drugs in patients with chronic
schizophrenia,"New Engl. J. Med., 353(12): 1209-23, 22
September 2005. [8 U.S. institutions] *966DS
33
2
10
B. Dahlof, et al., "Prevention of
cardiovascular events with an antihypertensive regimen of
amlodipine adding perindopril as required versus atenolol
adding bendroflumethiazide as required, in the
Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure
Lowering Arm (ASCOT-BPLA: a multicentre randomised
controlled trial,"Lancet, 366(9489):
895-906, 10 September 2005. [13 institutions worldwide]
*962YR
The eye has not featured much among the highly cited clinical papers
tracked by ScienceWatch.com, but at #4 this time there is
something from an ophthalmological journal. Macular degeneration is an
important cause of blindness; being age-related, the disease is likely to
increase in importance over the years. In the "wet" form, which is the more
serious variety, new growth of vessels behind the retina adversely affects
vision, so one approach to treatment might be to try and stop this
neovascularization.
Inhibitors of vascular endothelial growth factors (VEGF) have been
attracting much interest across the spectrum of medical research, most
obviously perhaps in cancer treatment—indeed, this column has
recently covered one of these agents, the monoclonal antibody bevacizumab
(Avastin), in the context of colon cancer (see ScienceWatch.com,
16[6]: 5,
November/December
2005).
Ranibizumab (Lucentis) is related to bevacizumab but is about two-thirds
smaller in molecular size. Unlike its companion, ranibizumab is licensed
for the treatment of age-related macular degeneration, but ophthalmologists
have been using bevacizumab "off label," which involves pharmacists making
up bevacizumab in a form suitable for direct injection into the eye.
Last October Genentech, which has developed both drugs, said that from
January 1, 2008, it would no longer allow compounding pharmacies to
purchase bevacizumab from wholesalers. In reaching this decision ("not made
lightly") the company cited concerns over the safety for ophthalmic use of
a product designed for intravenous injection.
Genentech said that it had had to destroy $200 million worth of the drug
that would have met the standards for systemic use, but added that it would
be willing to reverse its policy if the Food and Drug Administration
authorized such action. This development can only have heated up an already
lively debate about the intravitreal use of bevacizumab—see, for
example, the review by Tien Wong and colleagues (Lancet, 370
[9583]: 204-06, 2007) and subsequent correspondence (Lancet, 370
[9597]:1479-81, 2007).
Because ranibizumab is much more expensive than the other drug, some
critics see the company’s unwillingness to seek a license for the
intravitreal use of bevacizumab as profit-driven, which Genentech strongly
denies. On the other hand, unwanted cardiovascular effects of anti-VEGF
agents are a concern, and there is uncertainty about how much of the drug
injected into the eye reaches the general circulation.
Head-to-head clinical trials of the two Genentech drugs should help to
resolve issues of safety and efficacy, and two such studies are in the
pipeline. In the U.K. the National Institute for Health Research is
recruiting 600 patients for a randomized trial of bevacizumab and
ranibizumab, and the U.S. National Eye Institute has announced that it will
fund a similar study.
From 2005 the interest of both the ophthalmological community and patients
in bevacizumab has been fuelled by non-randomized evidence such as that in
the paper by Dr. Robert L. Avery and his colleagues (#4). Avery et
al. studied 79 patients (81 eyes) given monthly intravitreal
injections of bevacizumab 1.25 mg, and recorded, among other variables,
changes in retinal thickness and visual acuity. Both improved. No
significant systemic or ocular adverse effects were seen.
In a much larger study of 716 patients, with sham injection as the control,
Dr. Philip J. Rosenfeld and coworkers used ranibizumab doses of 0.3 and 0.5
mg (P.J. Rosenfeld, et al., New Engl. J. Med., 355[14]:
1419-31, 2006). Visual acuity improved with both doses of ranibizumab while
it deteriorated in the sham-injected patients.
Six months separate these two papers, and Rosenfeld’s randomized
trial of the other drug has not yet made it to the Top Ten (with 50 total
cites and 17 in the latest counting period). Has bevacizumab been given
intravenously to patients with neovascular macular degeneration? Yes. For
example, Rosenfeld’s group (A.A. Moshfeghi, et al.,
Ophthalmology, 113[11]: 2002-11, 2006) gave 5 mg/kg injections to
18 such patients with "impressive results." However, they think it unlikely
that a large trial of this approach will be done because of the "potential
risks associated with systemic anti-VEGF therapy."
A former deputy editor of The Lancet, David W. Sharp, M.A.
(Cambridge), is a freelance writer living in Minchinhampton,
Gloucestershire, U.K.