COVER STORY
`
`Intravitreal
`VEGF Trap for AMD:
`An Update
`
`The CLEAR-IT 2 Extension Study was presented at the annual meeting of the Association
`for Research in Vision and Ophthalmology.
`
`BY JEFFREY S. HEIER, MD
`
`T he CLEAR-IT 2 trial was a phase 2 study of the
`
`safety and efficacy of VEGF Trap-Eye
`(Regeneron Pharmaceuticals) in patients with
`neovascular age-related macular degeneration
`(AMD). The results of the phase 2 trial were presented
`at the 2008 Retina Society meeting.1 An extension of
`the CLEAR-IT 2 trial followed patients from the original
`trial; 6-month results of the extension stage of the study
`
`were presented at the Association for Research in Vision
`and Ophthalmology (ARVO) earlier this year.2 This arti-
`cle reviews results of the initial CLEAR-IT 2 as well as
`data from the extension stage.
`
`CLE AR-IT 2
`VEGF Trap-Eye is a purified formulation of VEGF Trap,
`a vascular endothelial growth factor (VEGF) receptor
`
`
`
`
`Image courtesy of Jeffrey S. Heier, MD
`
`Figure 1. VEGF Trap-Eye is a fusion protein designed to bind all forms of the proteins VEGF-A and PLGF, which both play a part
`in abnormal growth of new blood vessels.
`
`44 I RETINA TODAY I OCTOBER 2009
`
`Apotex Exhibit 1015
`Page 1 of 2
`
`

`

`COVER STORY
`
`fusion protein that binds all forms of VEGF-A (Figure 1).
`VEGF Trap-Eye, formulated for intraocular use, is being
`developed for the treatment of neovascular AMD, dia-
`betic macular edema, and other ocular pathologies.
`CLEAR-IT 2 was a double-masked multicenter trial
`in which patients with neovascular AMD were ran-
`domly assigned to receive monthly intravitreal injec-
`tions of VEGF Trap-Eye 0.5 mg or 2.0 mg or quarterly
`injections of 0.5, 2.0 or 4.0 mg for an initial 3-month
`fixed-dose period, after which they received the same
`doses on an as needed basis at monthly visits out to 1
`year. Subgroups of patients were established based on
`age, best-corrected visual acuity (BCVA) at baseline,
`lesion size at baseline, and previous treatment for neo-
`vascular AMD.
`
`At 1 year, for all treated groups
`combined, there was a significant
`improvement in BCVA from baseline.
`
`At 1 year, for all treated groups combined (n=157),
`there was a significant improvement in BCVA from
`baseline (mean improvement 5.3 letters; P<.0001).
`Patients who received three monthly doses of 2.0 mg
`followed by as-needed dosing achieved mean improve-
`ments in BCVA of 9.0 letters from baseline (P<.0001 vs
`baseline). Those who received three monthly doses of
`0.5 mg followed by as-needed dosing achieved mean
`improvements of 5.4 letters from baseline (P<.085 vs
`baseline) at the end of 1 year. Patients who received ini-
`tial quarterly dosing followed by as-needed dosing also
`achieved gains in BCVA, but they were generally not as
`robust as those achieved with initial monthly dosing.
`Patients receiving initial monthly doses of VEGF Trap-
`Eye achieved mean decreases in retinal thickness vs
`baseline at 1 year. In addition, treatment with VEGF
`Trap-Eye was associated with a reduction in the size of
`the total active choroidal neovascular membrane
`(CNV).
`Subgroup analyses were presented at this year’s
`ARVO meeting. Patients 75 years old or less achieved
`greater BCVA gains than those older than 75 years.
`Other differences between subgroups did not achieve
`statistical significance.
`
`E XTENSION STUDY
`Six-month results for 117 patients who elected to
`enter the extension stage of the CLEAR-IT 2 study were
`also presented at this year’s ARVO. All patients received
`
`2.0 mg VEGF Trap-Eye on an as-needed basis.
`In the original study, the mean gain in BCVA from
`baseline for the 117 patients who entered the extension
`stage was 7.3 letters (P<.0001 vs baseline) at the
`3-month primary endpoint of the original study, 8.4 let-
`ters (P<.0001 vs baseline) at 1 year, and 7.1 letters
`(P<.0001 vs baseline) at month 6 of the extension study.
`Over the 15-month course of the PRN dosing phase,
`from month 3 of the original study to month 6 of the
`extension phase, patients received a mean 3.5 injections
`of VEGF Trap-Eye.
`The treatment was generally well tolerated through-
`out the study, and there were no drug-related serious
`adverse events. One case of culture-negative endoph-
`thalmitis/uveitis was reported in a study eye, and there
`were two arterial thrombotic events that were deemed
`not to be related to the drug. Three deaths were report-
`ed, two related to cancers and one in a patient with
`pre-existing pulmonary hypertension. The most com-
`mon adverse events were those typically associated
`with intravitreal injections, including conjunctival hem-
`orrhage at the injection site and transient increased
`intraocular pressure following injection.
`
`CONCLUSION
`The extension study demonstrates that patients with
`neovascular AMD achieved and maintained significant
`improvement in BCVA for 18 months with initial fixed
`dosing followed by 15 months of as-needed administra-
`tion. On average, only 3.5 injections were given during
`the PRN dosing phase. Patients continue to be seen and
`treated in the extension stage of the CLEAR-IT 2 study. ■
`
`Jeffrey S. Heier, MD, is a Clinical
`Ophthalmologist specializing in diseases of the
`retina and vitreous at Ophthalmic Consultants
`of Boston. He reports that is a consultant or
`Regeneron, Inc. Dr. Heier is a member of the
`Retina Today Editorial Board. He can be reached at
`jsheier@eyeboston.com.
`
`1. Brown D. One year results of a phase 2, randomized, controlled dose- and interval-
`ranging study of intravitreal VEGF Trap-Eye in patients with neovascular age-related
`macular degeneration. Paper presented at: Retina Society annual meeting; September
`25-28, 2008; Scottsdale, AZ.
`2. Heier JS, CLEAR-IT 2 Investigators. CLEAR-IT 2: Phase 2, randomized, controlled
`dose-and interval-ranging study of intravitreal VEGF Trap Eye in patients with neovascu-
`lar age-related macular degeneration: predictive factors for visual acuity outcome at one
`year. Paper presented at: Association for Research in Vision and Ophthalmology annual
`meeting; May 4, 2009; Fort Lauderdale, FL.
`
`CONTACT US
`
`Send us your thoughts via e-mail to
`letters@bmctoday.com.
`
`OCTOBER 2009 I RETINA TODAY I 45
`
`
`
`
`Apotex Exhibit 1015
`Page 2 of 2
`
`