FDA approval of aflibercept for wet AMD gives clinicians, patients another option

While some retina specialists question the drug’s ability to extend the treatment interval, most are happy to have an additional option.

Recent approval of aflibercept by the U.S. Food and Drug Administration has clinicians theorizing about the drug’s role in retinal disease management.

Eylea (aflibercept, Regeneron Pharmaceuticals), also known as VEGF Trap-Eye, is a synthetic anti-VEGF agent that was approved for treatment of wet age-related macular degeneration in November. The decision followed positive feedback from the VIEW (VEGF Trap-Eye: Investigation of efficacy and safety in wet AMD) trials, sponsored by Regeneron and Bayer Healthcare. These studies suggest that aflibercept may be as efficacious as Lucentis (ranibizumab, Genentech) while extending the treatment interval to 8 weeks.

In line with such findings, early preclinical modeling indicated that aflibercept could show increased durability due to its potentially longer half-life and higher equimolar binding affinity.

“Instead of being a monoclonal antibody like Avastin or a monoclonal antibody segment like Lucentis, this is a synthetic fusion protein that has been specifically designed to act like an antibody, so it may have some potential advantages. Perhaps there is some durability advantage and potency advantage to being synthetic, and potentially less problems with the theoretical problem of tachyphylaxis,” Andrew A. Moshfeghi, MD, MBA, OSN Retina/Vitreous Board Member, told Ocular Surgery News.

Dr. Moshfeghi noted that while the FDA has approved a regimen of 2 mg every 8 weeks after three initial monthly injections, aflibercept’s label allows for some flexibility, enabling monthly injections for more recalcitrant cases. Consequently, he predicts two trends in usage.

“On one end of the spectrum, we have Eylea for those patients who were requiring monthly Avastin or monthly Lucentis and still showing signs of disease activity in terms of increased retinal fluid or subretinal fluid or macular hemorrhage,” he said. “Then, we have people who were doing well with Lucentis and Avastin with really no signs of disease activity who may be able to have longer intervals between injections, as a result of the theoretical benefit of a slightly longer durability.”

Predominantly classic subfoveal CNV.

Image: Moshfeghi AA

Treatment interval

Clinicians have expressed mixed feelings regarding aflibercept’s ability to extend the treatment interval. While some consider the VIEW data to be proof of aflibercept’s enhanced durability, others are waiting for widespread clinical affirmation or have stated that, given the patient population who will likely receive the drug first, the interval may not change initially.

“With any new drug entering the market where there are established, effective treatments already available, early use will be limited to failures and complicated cases in my practice,” Michael D. Ober, MD, FACS, said. “I am not certain that I will initially see a significant distinction in treatment interval between Eylea and Lucentis or Avastin because the Eyelea patients will be the most resistant to anti-VEGF treatment.”

Currently, Dr. Ober starts patients on Avastin (bevacizumab, Genentech) and switches them to ranibizumab if he does not achieve an optimal outcome after three to four injections, or if tachyphylaxis develops. Patients who will initially be prescribed aflibercept are those who are receiving ranibizumab monthly or for whom bevacizumab and ranibizumab have failed.

“The truth is, if clear advantage is seen for aflibercept in the early cases with these patients who are most resistant, I will soon be switching a lot faster and in a lot greater number. It is conceivable that I would use Eylea instead of Lucentis as second-line therapy,” Dr. Ober said.

Despite varying degrees of skepticism about aflibercept’s ability to extend the treatment interval, most retina specialists are grateful for the additional treatment option.

“What I really love about Eylea is that it is another choice. … It is sort of psychologically helpful for the patient to have options and to know that we have tried everything,” Dr. Moshfeghi said.

VIEW study

The largest study undertaken by neovascular AMD researchers, the phase 3 VIEW-1 and VIEW-2 trials analyzed nearly 2,500 patients across four continents. According to a press release from Regeneron and Bayer in December 2011, 96-week outcomes showed sustained visual acuity improvements for all patients receiving aflibercept.

“I think the VIEW study had a good sample size and gives us level 1 data on efficacy and safety,” Barbara Blodi, MD, said. “The year 2 dosing interval of every 3 months, however, makes it difficult to know if patients would actually need fewer injections with Eylea in the second year.”

Second-year regimens consisted of monthly evaluation and, if necessary, injection of the same dose received during the first year. All patients were re-treated at least every 12 weeks. Original regimens consisted of either 0.5 mg aflibercept every 4 weeks, 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks after three initial monthly injections, or 0.5 mg ranibizumab every 4 weeks.

At 96 weeks, visual gain for patients receiving 2 mg aflibercept every 8 weeks was 7.6 letters from baseline, compared with 8.4 letters at week 52. This group received an average of 11.2 injections over 2 years, with a mean 4.2 injections during the second year.

For those treated with ranibizumab, a gain of 7.9 letters, compared with 8.7 letters at 52 weeks, was achieved. Patients averaged 16.5 injections over 2 years and 4.7 injections in the second year.

“If you compare ranibizumab, which is the optimal gold standard, you see that the [every 8 weeks] interval obtains the same level of significant improvement,” Ursula M. Schmidt-Erfurth, MD, said in a presentation at the American Academy of Ophthalmology meeting. “This practical strategy with reduced treatment and monitoring need provides an opportunity for optimal visual benefit with less burden to patients, their families and clinicians and a lower cumulative risk for injection-related side effects.”

Dr. Schmidt-Erfurth also noted that optical coherence tomography evaluations performed monthly during VIEW-2 illustrated that patients receiving aflibercept every 8 weeks had the lowest central retinal thickness and a higher rate of completely dry retina at endpoint.

“I think the most significant finding about Eylea is that it can reliably go 8 weeks in between injections for the average patient undergoing maintenance therapy,” Dr. Moshfeghi said. “It is possible that there will be a subset of patients, a significant subset of Eylea patients, out of the clinical trial world that we might be able to treat every 9 or 10 or 11 weeks.”

Reimbursement coding, expanding indications

Notably, aflibercept is approximately $100 cheaper per injection than ranibizumab and could substantially reduce the annual cost of treatment if given less frequently.

In the absence of a specific reimbursement code, which is not projected to be available until January 2013, efficient insurance reimbursement is difficult. This roadblock may dissuade ophthalmologists, particularly individual practitioners, from purchasing large quantities of the drug.

“We have to use a generic J-code in the meantime, which typically results in a rejection of the billing claim until it is manually reviewed by an insurance company or Medicare,” Dr. Moshfeghi said. “Because there are so many of these injections and they are performed so frequently, there will be a long logjam of billing claims not being repaid. … That is a lot of money to put on the line before we are reimbursed.”

In a presentation at Hawaiian Eye 2012, Kevin J. Corcoran, COE, CPC, FNAO, OSN Practice Management Board Member, said practices should use code 67028, intravitreal injection, for aflibercept along with J3590, unclassified biologics. It is eligible for separate payments in an ASC or a hospital outpatient department.

Medicare reimbursement for the single-use vial is $1,961 per vial.

Researchers are also investigating additional indications for aflibercept. Dr. Blodi noted diabetic macular edema and retinal vein occlusion as prime targets, as supported by the DA VINCI and COPERNICUS studies.

“Because of Eylea’s possible enhanced potency and durability, there is reason to believe that it could be effective in those diseases, Dr. Moshfeghi said.

“I do not think aflibercept will replace what we currently have,” Dr. Blodi said. “But it is something that we definitely need.”

Dr. Ober projects that if no serious complications arise, aflibercept will gradually take a portion of ranibizumab’s market within the next couple of years.

“Despite the fact that we have an FDA-approved option and a non-FDA-approved option, which are each functioning well for patients, AMD is still a target of innovation by the pharmaceutical industry,” he said. “We still have new drugs coming to market. And who could want anything more than that?” – by Michelle Pagnani

Reference:

Schmidt-Erfurth UM, Heier JS, Anderesi M, et al. VEGF trap-eye vs. ranibizumab in wet AMD: integrated analysis of the VIEW 1 and VIEW 2 studies. Paper presented at: American Academy of Ophthalmology meeting; October 2011; Orlando, FL.

Barbara Blodi, MD, can be reached at Department of Ophthalmology and Visual Sciences, University of Wisconsin, 2870 University Ave., Suite 206, Madison, WI 53705; 608-263-7290; email: bablodi@wisc.edu.

Andrew A. Moshfeghi, MD, MBA, can be reached at University of Miami Miller School of Medicine, 7101 Fairway Dr., Palm Beach Gardens, FL 33418; 561-355-8608; fax: 561-355-8601; email: amoshfeghi@med.miami.edu.

Michael D. Ober, MD, FACS, can be reached at Retina Consultants of Michigan, 29201 Telegraph Rd., Suite 606, Southfield, MI 48034; 248-356-8610; fax: 248-356-6473; email: obermike@gmail.com.

Disclosure: Drs. Blodi and Ober have no relevant financial disclosures. Dr. Moshfeghi has received consulting revenue from Genentech.