Panel Votes 10-0 for VEGF Trap
FDA approval expected by August
Jerry Helzner, Senior Editor
■ In wending its way through the lengthy FDA drug approval process, VEGF Trap took another giant step on June 17 when the FDA Dermatologic and Ophthalmic Drugs Advisory Committee voted 10 to 0 to recommend approval of the Regeneron/Bayer therapy for the indication of wet AMD. Moreover, the Committee offered a dosing schedule of 2 mg every eight weeks following three initial monthly intravitreal injections.
The current standard of care for wet AMD, Genentech's Lucentis, has a recommended dose of 0.5 mg, given monthly. The more patient-friendly and doctor-friendly dosing schedule for VEGF Trap (whose brand name will be Eylea) could make it a strong competitor for the treatment of a range of retinal diseases if and when it gains final approval. The drug has already shown positive trial results for the treatment of both RVO and DME.
In looking at the progression of VEGF Trap through the clinical trial and approval process, the drug has shown remarkably consistent results through very positive phase 2 trials, a little-noticed but compelling phase 2b extension study conducted by the highly respected Los Angeles retina specialist David Boyer, MD, and two phase 3 trials that confirmed the earlier optimism building around the potential of VEGF Trap.
“The positive recommendation by the advisory committee is an important step toward providing wet AMD patients with a new treatment option that could potentially reduce the burden that exists with current therapies,” said George D. Yancopoulos, MD, PhD, president of Regeneron Research Laboratories. “We look forward to continuing to work with the FDA as it completes its evaluation of the Eylea BLA.”
Still to be decided, if and when Eylea is approved, are questions of pricing. Because retina specialists currently use both costly Lucentis and far cheaper off-label Avastin to treat the same range of retinal diseases, Regeneron and Bayer might want to seek a middle-ground pricing that factors in the fewer number of injections required with VEGF Trap against the very low cost of the Avastin alternative.
In addition, Genentech has a study currently under way (HARBOR) that employs a 2 mg dose of Lucentis. Favorable results from HARBOR could level the playing field against Eylea. And the possibility of either competitor putting its drug in a sustained-release format is also a potential variable in the equation.
Meanwhile, investors who saw the potential in VEGF Trap moved Regeneron shares from a low of $20 about a year ago to a recent high near $70.
Bayer HealthCare will market Eylea outside the US, where the companies will share equally the profits from any future sales of Eylea. Regeneron maintains exclusive rights to Eylea in the United States.
Ozurdex Shows Continued Promise
Studies support the implant for ME therapy
Samantha Stahl, Assistant Editor
■ Enthusiasm for Ozurdex has been building among retina specialists seeking to treat macular edema patients without frequent injections. While traditional intravitreal injections clear relatively quickly, Allergan's sustained-release Ozurdex implant (sometimes combined with anti-VEGF) provides a more durable response, according to several studies demonstrating effective use presented at the recent ARVO meeting.
Baruch Kuppermann, MD, led researchers in a study seeking to evaluate efficacy of Ozurdex seven days after implant. While 427 patients received the dexamethasone implant, 426 received sham procedure. At day 7, mean improvement in BCVA was 5.3 letters for the implant patients, versus 1.6 letters for sham procedure.
Researchers at Washington University, led by Bryan Kim, MD, treated 15 RVO patients with an Ozurdex implant. After treatment, ETDRS vision and spectral domain OCT measurements were taken at weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24. OCT thickness decreased significantly as early as week 1 and peak visual acuity improvement occurred around week 9.
German researchers led by Stephan Thurau performed a retrospective case series with 18 patients who received an Ozurdex implant. Of the 13 eyes with CME, eight experienced a reduction in CME after a median of 35 days. Eleven patients had a history of immunosuppressive medication prior to the injection, and nine of the patients could reduce medication after the Ozurdex implant. The remaining two remained on medication because of uveitis in the second eye. Overall, the first loss of efficacy was observed three to four months after the injection.
Another study, led by Deniss Cornu, MD at the Valley Retina Institute in McAllen, Texas, evaluated the efficacy of a combination of Ozurdex with bevacizumab in patients with CME secondary to CRVO or BRVO. Twenty-three patients underwent Ozurdex combined with Avastin, as well as a posterior series of two bevicizumab 0.05 ml injections every four weeks.
The researchers concluded that “the combination of Avastin and Ozurdex proved to be beneficial, showing an improvement in VA and significant decrease in CMT at week 4, which correlates with the maximum effect of Avastin and the additional therapy provided by Ozurdex.”
At week 24, a significant increase in CMT and a lack of visual acuity improvement suggested that retreatment should be considered before month 6.
Two Approaches to Retinal Detachment
Comparing scleral buckling vs vitrectomy
■ To assess trends in primary rhegmatogenous retinal detachment (RRD) surgery, researchers from the Rudolf Foundation Clinic in Vienna and Weill Cornell Medical College in New York City retrospectively compared their treatment approaches and outcomes with a total of 230 patients over a two-year period from January 2007 to December 2008.
The researchers found that retinal reattachment after the primary surgical approach was achieved in 123 patients (88.49%) at the Rudolf Clinic and in 77 patients (84.62%) at Weill Cornell, and in all patients after one or more reoperations.
Sixty-eight patients at Rudolf (48.9%) and 43 patients at Weill Cornell (47.3%) achieved a BCVA at final follow-up of at least 0.3 logMAR. The choice of the primary RRD procedure was significantly different between the two centers. Scleral buckling was the primary RRD procedure at Rudolf (87.77%) while vitrectomy was the most common primary procedure at Weill Cornell (83.52%). The main outcome measures—retinal reattachment and BCVA at final follow-up—were not significantly different between the two centers.
The researchers, who presented at the 2011 ARVO meeting, concluded that “good and comparable anatomic and visual outcomes, which were not significantly associated with the selection of the primary RRD procedure, were achieved in both centers.”
They noted that scleral buckling seems to remain the primary RRD procedure in the center in Vienna, particularly in phakic and young RRD cases. There is an agreement on the use of primary vitrectomy in pseudo-phakic RRD cases in both centers. In addition, there is now an increasing trend towards primary vitrectomy for the treatment of phakic and pseudo-phakic RRD patients in both centers.
|■ Head-to-head BRVO study: Ozurdex vs. Lucentis. Allergan Ltd. announced in the UK recently that the first head-to-head study in BRVO will take place in Europe and Israel. Called the COmparison of intravitreal dexamethasone implant and ranibizumab for Macular Oedema in BRVO (COMO), the study will assess the relative effectiveness of two different therapies for BRVO, Ozurdex (dexamethasone 0.7 mg intravitreal implant) versus ranibizumab. Recruitment for the COMO 12-month study is now under way from at least 36 sites across Europe and Israel.|
About 400 patients with macular edema following BRVO of less than 90 days duration will be enrolled into the COMO study and randomized to receive treatment with either Ozurdex or ranibizumab. Patients in the Ozurdex group will receive an intravitreal injection on day one and another at five months, with a further injection at month 10 or 11, if required. Patients in the ranibizumab group will receive six intravitreal injections on a monthly basis from day one to six months, and then monthly as needed from month six through to month 11. The primary endpoint will be the mean change from baseline in BVCA at month 12.
Interestingly, the study design does not include an arm that uses Ozurdex and Lucentis in combination, a regimen now favored by some retina specialists.
■ NLP rate in wet AMD patients. Researchers from LSU-Ochsner, Lake Erie College and Wills Eye Institute reviewed more than 20 years of Wills wet AMD cases, a total of 9,017 patients, to determine how many of these cases directly resulted in no light perception (NLP).
The researchers systematically excluded all other possibilities of severe vision loss and found five cases (0.06%) of NLP directly attributable to the effects of wet AMD. Of these patients, three had received anti-VEGF injections and two had not. All five patients possessed a distinct 360-degree fibrous elliptical disciform scar surrounding both the macula and the optic nerve, which the researchers called “a newly described and unique posterior pole finding in patients with exudative age-related macular degeneration.”
The researchers concluded that the progression of wet AMD to NLP is “very low.”
■ Regeneron/Bayer seek EU approval for wet AMD drug. Regeneron Pharmaceuticals and Bayer HealthCare said that Bayer has submitted an application for marketing authorization in Europe for VEGF Trap-Eye for the treatment of wet AMD. Regeneron and Bayer are collaborating on the global development of VEGF Trap-Eye for the treatment of a range of retinal diseases.
The VEGF Trap-Eye submission is based on positive results from two phase 3 trials, the VIEW 1 study and the VIEW 2 study. In these trials, all regimens of VEGF Trap-Eye, including 2 mg VEGF Trap-Eye dosed every two months (following three loading doses), successfully met the primary endpoint of non-inferiority, compared to the current standard of care, Lucentis 0.5 mg dosed every month.
■ Dropped nucleus: refer or attempt rescue? In a presentation at the recent Euretina conference in London, Ferenc Kuhn, MD, stated strongly that a dropped nucleus during cataract surgery requires immediate referral to a vitreoretinal specialist unless the lens fragments are very few and superficial. Some cataract surgeons, beginning with the late cataract surgery pioneer Charles Kelman and later Sina Sabet, MD, have developed lasso and wire net-type devices that have been used by cataract surgeons with varying degrees of success to remove lens fragments after a dropped nucleus.
Dr. Kuhn asserted that lens fragments left in the eye can lead to inflammation, followed by cystoid macular edema, and retinal detachment. He advised that a complete pars plana vitrectomy performed in a timely manner by a vitreoretinal surgeon can eliminate the source of inflammation. The vitrectomy should be complete and include detachment and removal of the posterior cortical vitreous, Dr. Kuhn noted.
■ Residency training in ROP. Not sufficient? A nationwide survey of residency training for ROP, encompassing 33 program directors and 82 third-year residents, indicated that the majority of residents perform fewer than 20 ROP examinations during residency and that only 14% of third-year residents felt competent to perform ROP exams. This despite the fact that 60% of respondents said that all bedside examinations were supervised by an attending physician. In addition, only 4% of respondents acknowledged having a formal assessment of ROP competency during residency.
The researchers, who presented their data at this year's ARVO meeting, said their findings “raise concerns about ROP training during residency and should promote discussion on ways to improve ROP education.”
■ UK drug review recommends Ozurdex for RVO. The UK's National Institute for Health and Clinical Excellence said that its draft guidance backed Allergan's Ozurdex implant as a cost-effective treatment for macular edema related to retinal vein occlusion.
Allergan estimates that up to 25,000 patients in the UK every year need treatment for macular edema associated with RVO and may be suitable for treatment with Ozurdex. RP