Ranibizumab According to Need: A Treatment for Age-related
`Macular Degeneration
`
`RICHARD SPAIDE
`
`A GE-RELATED MACULAR DEGENERATION (AMD) IS
`
`increasing in incidence and prevalence among the
`world’s population. Inhibition of the vascular com-
`ponent of AMD has been attempted with a variety of
`approaches, but the development of the pan-vascular
`endothelial growth factor (VEGF)-A blocker, ranibizumab
`(Lucentis, Genentech, South San Francisco, California,
`USA), for the treatment of choroidal neovascularization
`(CNV) has been a triumph of modern medicine.1 Ranibi-
`zumab is an antibody fragment that binds all active
`isoforms of VEGF-A, rendering them inactive. It was
`developed through an exhaustive process that required
`modifying a murine monoclonal antibody to derive an
`antibody fragment, and affinity maturing the fragment to
`restore and even improve VEGF binding. Patients with
`neovascular AMD treated in phase 3 trials using this
`medication experienced an improvement in visual acuity.
`In the MARINA trial, which examined minimally classic
`or occult with no classic disease, patients receiving 0.5 mg
`of intravitreal ranibizumab on a fixed monthly schedule
`had a mean improvement of 7.2 letters, while sham-treated
`controls lost 10.4 letters over the course of the first year.2
`In the ANCHOR trial, patients receiving 0.5 mg of
`intravitreal ranibizumab on a fixed monthly schedule had
`a mean improvement of 11.3 letters, while controls treated
`with photodynamic therapy that used verteporfin had a
`mean loss of 9.5 letters over the first year.3
`Along with the triumph of ranibizumab comes the bill.
`The drug charge per injection costs patients, or their
`insurance company, $2,000. The costs estimate increases
`when the charges for the injection procedure, the ophthal-
`mic examination, and associated tests are added. Econo-
`mists would add in the costs incurred by the family
`members taking off work to accompany the patient and
`lost opportunity costs. The total cost over a year for a
`single patient is stunning; the cost projections for the
`United States are staggering. Although economists can
`convert burdens into the equivalent economic ones, pa-
`tients and doctors alike often pigeonhole costs. Returning
`every month for injection and follow-up within two to
`seven days after the injection, as recommended in the
`
`See accompanying Article on page 566.
`Accepted for publication Feb 9, 2007.
`From the Vitreous, Retina, Macula Consultants of New York, New York,
`New York.
`Inquiries to Richard Spaide, Vitreous, Retina, Macula Consultants of
`New York, 460 Park Ave, 5th Floor, New York, NY 10022; e-mail:
`rickspaide@yahoo.com
`
`product insert, is a cost, but also is an emotional and
`psychological burden for the patient, family, and even the
`doctor. In medicine, risk of treatment is usually associated
`with the intensity of treatment. Mandated monthly treat-
`ment may incur increased risks, particularly if the patient
`really doesn’t really “need” the treatment each month.
`In this issue appears an important article by Anne Fung
`and associates at Bascom Palmer Eye Institute.4 This study,
`known as the Prospective Optical Coherence Tomography
`Imaging of Patients With Neovascular AMD Treated
`With Intraocular Ranibizumab (Lucentis), or PrONTO,
`study, led by Phil Rosenfeld, examined a strategy of giving
`patients ranibizumab on a schedule dictated by a carefully
`considered list of criteria. At baseline and each visit
`thereafter, patients had their visual acuity measurements
`performed with an Early Treatment Diabetic Retinopathy
`Study (ETDRS) chart at 2 m when a refraction protocol
`was used. Patients then were given three injections of
`ranibizumab at monthly intervals. Five criteria were used
`to determine whether a patient needed an additional
`injection at each monthly follow-up examination. Patients
`were treated again if they had a visual acuity loss of at least
`5 letters on the ETDRS chart with optical coherence
`tomography (OCT) evidence of fluid in the macula, an
`increase in OCT central retinal thickness of at least 100
`␮m, new macular hemorrhage, new area of classic CNV
`seen by fluorescein angiography, or evidence of persistent
`fluid on OCT at least one month after the previous
`injection. After one year of follow-up, the patients had a
`mean visual acuity improvement of 9.3 letters. With the
`usual caveats about comparing studies, the visual acuity
`results were similar to those seen in ANCHOR and
`MARINA. However, patients in the PrONTO study
`required only 5.6 injections over the first year. The reduced
`drug costs per patient amount to about half the mean per
`capita yearly income for older people in the United
`States.5 Multiply this dollar amount by the number of
`patients with CNV that results from AMD and the
`potential savings are enormous.
`If patients can meet the entry criteria of the study and
`are treated according to the methods used in the study,
`they would have a reasonable expectation of having similar
`results. The confidence of this expectation is influenced by
`a number of factors, including the number of patients in
`the study. The ANCHOR and MARINA studies both had
`large numbers of patients, whereas the PrONTO study had
`40 patients and no controls. In actuality, PrONTO would
`
`0002-9394/07/$32.00
`doi:10.1016/j.ajo.2007.02.024
`
`© 2007 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
`679
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`Regeneron Exhibit 2031
`Page 01 of 02
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`be difficult to implement for many practices. An ETDRS
`visual acuity measurement with protocol refraction is a
`requirement for a rigorous trial and is a time-consuming
`test administered by a certified visual acuity examiner.
`This test is not practical for many busy practices. Dropping
`the need for ETDRS visual acuity measurement as part
`of the criteria would make the study easier to implement,
`but at the cost of widened confidence intervals for the
`expected outcomes.
`The reduction in intraocular injections was not associ-
`ated with marked reduction in visits by the patient to the
`ophthalmologist’s office. Patients still required monthly
`examinations with monthly OCTs and quarterly fluores-
`cein angiograms to look for classic CNV. An alternative
`approach would be to look for a method to decrease both
`the injections and visits in general. In the PIER trial,
`patients were provided three injections at monthly inter-
`vals and then quarterly injections, except the patients were
`given a final injection at month 11. Even though the
`patients should have had a fairly good 12-month visual
`acuity because they had a mandated injection at 11
`months, the mean visual acuity dropped by 0.2 letters in
`the 0.5-mg group. So giving the patients a reduced number
`of injections—a therapy not based on objective factors of
`need—appeared to result in a less favorable outcome.6 In
`our office, we treat some patients with a technique we call
`“inject and extend.” Patients are provided three monthly
`injections and then told to return in six weeks. They
`undergo an ophthalmic examination, including biomicros-
`copy and OCT. If the patients have no new hemorrhage or
`
`signs of exudation such as edema or subretinal fluid they
`are injected and instructed to return in eight weeks. If they
`have edema or other signs of exudation, they are given an
`injection and told to return in four weeks. Patients
`returning at eight weeks are given the same examination.
`If there are no signs of disease activity, they are given an
`injection and told to return in 10 weeks. If they have
`exudation, they are given an injection and told to return in
`six weeks. Patients with this strategy would go only a few
`weeks, at most, of having any sign of exudation. The
`optimal examination and treatment
`interval may be
`quickly established.
`It is obvious that monthly treatment is an expensive and
`burdensome ordeal. The good news is that it works. The
`PrONTO approach obviates the need for six injections,
`but still has the cost of monthly examinations. The good
`news about PrONTO is that it suggests that patients can be
`treated according to need and have a good outcome. We
`need to determine and consider what the patient’s needs
`are in aggregate. How can we best address the patient
`needs, both for good visual outcome and decreased burden
`to the patient and the patient’s family? What are the best
`criteria to use for retreatment? Is an inject and extend
`strategy better because it reduces patient visits? These are
`interesting questions that need to be answered. They could
`not have been asked without the groundbreaking work of
`the Bascom Palmer group with the PrONTO study, which
`to their credit was partly funded by Genentech, the maker
`of ranibizumab.
`
`THE AUTHOR RECEIVED CONSULTING FEES AND RESEARCH SUPPORT FROM GENETECH (SOUTH SAN FRANCISCO, CALIFORNIA,
`USA) and Novaritis (East Hanover, New Jersey, USA). The author was involved in design and conduct of study; data collection; analysis and data
`interpretation; and preparation and manuscript writing and approval.
`
`REFERENCES
`
`1. Ferrara N, Damico L, Shams N, Lowman H, Kim R.
`Development of ranibizumab, an anti-vascular endothelial
`growth factor antigen binding fragment, as therapy for
`neovascular age-related macular degeneration. Retina 2006;
`26:859 – 870.
`2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for
`neovascular age-related macular degeneration. N Engl J Med
`2006;355:1419 –1431.
`3. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus
`
`verteporfin for neovascular age-related macular degeneration.
`N Engl J Med 2006;355:1432–1444.
`4. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An OCT guided,
`variable dosing regimen with intravitreal ranibizumab (Lucen-
`tis) for neovascular age-related macular degeneration. Am J
`Ophthalmology 2007;143:566 –583.
`5. Wu KB. Sources of income for older persons 2003. Available
`at: http://assets.aarp.org/rgcenter/econ/dd125_income.pdf. Ac-
`cessed Date: February 9, 2007.
`6. Genentech press release concerning the PIER study. Available
`at: http://www.gene.com/gene/news/press-releases/display.do?
`method⫽detail&id⫽9747. Accessed Date: February 9, 2007.
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`AMERICAN JOURNAL OF OPHTHALMOLOGY
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`APRIL 2007
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