Eylea's Roaring Rollout
Though questions remain on long-term dosing, aflibercept has taken the retinal world by storm.
By any fiscal reckoning, the launch of Eylea (aflibercept, Regeneron) exceeded expectations. Wall Street forecasters initially predicted sales of the new anti-VEGF agent for wet AMD would total $5 million in the final quarter of 2011. Instead, it took in $24 million. Huge demand convinced Regeneron to raise its 2012 sales prospects from $140-$160 million, first to $250-$300 million, and then more recently to $500-$550 million, and the company's stock price has soared accordingly. Regeneron's president was moved in the press to call the retina subspecialty's acceptance of Eylea “spectacular.”
Some may argue that enthusiasm is tempered by the second-year VIEW results and recent case reports of inflammation. They note that many had hoped Eylea would outperform Lucentis in anti-VEGF punch, a point as-yet unresolved by the data available in the literature.
Additionally, one of aflibercept's main selling points, its reduced dosing schedule — just five shots in the first year of treatment — wasn't maintained in the year 2 VIEW data submitted to the FDA. Finally, a cluster of post-injection inflammation events, though well within established incidence rates for intravitreal injections, prompted a company notification to the FDA and many to take a precautionary look at injection protocols.
However, it should also be noted that a closer look at the second year of VIEW reveals that on average only 1.2 additional injections were required over the mandated three injections in the Eylea groups, and this number was significantly different from the number of ranibizumab injections (although the numerical difference was small), indicating a possible artifact introduced by the study design that prevented a meaningful comparison of longevity between the two drugs, as true PRN dosing was not used.
Real-world testing will tell whether Eylea truly offers longer biologic activity. Furthermore, nine cases in the cluster of inflammation events occurred with one physician in one practice, a trend suggesting a localized problem and not a drug-specific issue. No other reports of such a cluster have since arisen.
In any case, none of this has done much to inhibit enthusiasm for the drug. Its verified year 1 dosing schedule and peripheral benefits, such as increased efficacy among pigment epithelial detachments, are proving more than sufficient for retinal specialists, who have waited six years for a new anti-VEGF option. Widespread first-line prescribing for new patients, along with its popularity in cases in which subretinal fluid persists despite a frequent dosing schedule, has made this exciting launch a huge success.
The largest AMD trials ever, VIEW 1 and VIEW 2 — two parallel phase 3 studies — involved some 2,500 patients worldwide. During the trials' first year, after three monthly loading injections, patients received three different Eylea dosing regimens: 0.5 mg every four weeks; 2 mg every four weeks; and 2 mg every eight weeks. Lucentis patients received 0.5 mg of the drug every four weeks. It should be noted that the VIEW trials did not include an arm of Lucentis patients on an eight-week dosing schedule; thus, it cannot be said how the two therapies would fare against each other on comparable dosing regimens.
In November 2011, the FDA approved a regimen for Eylea of 2 mg every eight weeks, based on maintenance of vision that was clinically equivalent at one year to monthly ranibizumab. In year two, patients were treated with the same doses per injection but were switched to a capped PRN schedule: All patients were treated PRN with monthly evaluations to determine the need for retreatment but were required to get an injection at least once every 12 weeks.
An integrated analysis of the VIEW studies found the visual acuity gain from baseline in the group receiving Eylea 2 mg every eight weeks was 7.6 letters at week 96, compared to 8.4 letters at week 52, with an average of 11.2 injections over two years and 4.2 injections during the second year.
The visual acuity gain from baseline in the monthly ranibizumab group at week 96 was 7.9 letters, compared to 8.7 letters at week 52, with an average of 16.5 injections over two years and 4.7 injections during the second year. The results surprised some, because mathematical models had predicted aflibercept's mechanism of action would yield a higher binding affinity for VEGF than ranibizumab.1
Subgroup analyses of difficult-to-treat patients may be enlightening and are part of the ongoing discussion. “If you look only at the patients who required more than the minimum number of injections, there was a full injection difference over the second year,” notes Michael Aberman, MD, vice president of strategy and investor relations at Regeneron. “Then, if you look at the top quartile of patients, the difference becomes approximately 1.5 injections over that second year, which we think is very meaningful. This demonstrates that the dosing benefit is more pronounced in the patients who are most difficult to treat.”
Whether these trends can be attributed to subject randomization or to factors inherent in the study medications and dosing regimens used cannot be determined post hoc. Real-world use will determine whether the mathematical models translate into greater longevity in patients, physicians say.
THE INFLAMMATION ANOMALY
In February, after injection of roughly 30,000 aflibercept doses, Regeneron learned of 14 cases of sterile intraocular inflammation. More notable than the number of cases — which factor to about a 0.05% rate, well within the incidence of inflammation established in the literature — was that 11 occurred at the same (Connecticut-based) group practice and nine under care of the same physician. According to a report the company submitted to the FDA, this practice received multiple shipments of different lots of the drug; vials from the same lots have been shipped and used nationwide; and the events could not be linked to a single lot or commercial vial delivery.
Some unknown factor in this practice's injection protocol likely contributed to the inflammation cluster, physicians believe. “They had all the same needles and drugs as everyone else. Something must have been done differently by the physician or his staff,” says Jason S. Slakter, MD, a partner at Vitreous Retina Macula Consultants of New York. “There is no evidence in my mind that this was a drug-related issue. But we do want to know what that practice was doing, so the rest of us can avoid doing the same thing.”
The aflibercept solution has a higher viscosity than other anti-VEGF agents, and Dr. Slakter wonders whether this variable might have played a role in these events, which were not seen in the pivotal trials.
In any case, while the company and an ASRS surveillance committee continue to investigate the matter, Dr. Slakter is paying closer attention to his injection routine and urges colleagues to do likewise. “We are not changing anything,” he explains. “But we are now keeping better track of our technique, so it will be easier to isolate and change some particular factor if that becomes necessary.”
In addition to being an appealing first-line option, Eylea is viewed as a fresh strategy for suboptimal responders with persistent macular fluid despite monthly anti-VEGF therapy for a year or longer — a category that may include a great many patients, retina specialists say.
In the one-year CATT data, “among patients receiving monthly treatment, 55% in the Lucentis group still had fluid, and almost 70% still had fluid in the Avastin group,” says Rahul Khurana, MD, of Northern California Retina Associates. “Clearly that's a pretty high number. Some partners in our group practice were all sitting around a table and everyone was sort of saying, ‘No way, not in our practice.' But I put a lot of weight in these large trials. I think it's a bigger percentage of patients than we'd all like to imagine.”
Eylea's year 2 drop off in dosing advantage disappointed him, but Dr. Khurana notes that the VIEW studies' second-year minimum injection requirement (once every 12 weeks) may well have restrained the new drug's performance. “I still think it's an effective treatment,” he says. “If you look at both years of the study, it's 11 injections compared to 16, and that five-injection difference is a considerable benefit.”
Another concern is that all of the VIEW patients were treatment-naïve, so it is unclear whether converting existing anti-VEGF patients to Eylea will put them at risk for adverse effects or outcome lapses. Several ongoing studies are investigating this topic.
While practices like Dr. Khurana's move aflibercept to the forefront of prescribing algorithms, others let patients themselves decide which therapy would work best for them, taking risk and financial factors into account. Still others have adopted a wait-and-see approach.
Speaking for the latter, Pravin Dugel, MD, a Phoenix-based retinal specialist, cautions that a real-world, everyother-month regimen remains untested because VIEW patients all received monthly monitoring.
“We know from other studies that monthly surveillance is very important,” Dr. Dugel says. “For instance, if we look at the PIER study vs the EXCITE study and the SAILOR study vs the SUSTAIN study, the number of injections in these studies was not that different. What was different was surveillance. PIER patients did a lot worse visually than EXCITE, in part because they were not seen every month. And SAILOR had worse outcomes than SUSTAIN, in part for the same reason.”
Dr. Dugel currently reserves aflibercept for nonresponders to other anti-VEGF agents (and these patients are difficult to define) and for referred patients already receiving it. “While I think this drug is very interesting and encouraging, and I'm sure it will have a place in our armamentarium, we need to recognize that it's still very early in the game,” he says. “Eylea is not coming into a vacuum, the way Lucentis and Avastin did. We already have good drugs for these patients. So our standards now are higher. That's the difference. And I think we should not lose sight of that.”
Figure 1. A key binding domain of VEGFR1 and a key binding domain of VEGFR2 (left) are fused for tight binding affinity for both VEGF-A isomers and PlGF (center). Two dual-domain arms are used for one aflibercept molecule to mimic the natural receptor pairing necessary for growth factor signaling (right).
Figure 2. The Fc portion of IgG1 (left) is fused to the two dual-domain arms (center) resulting in the engineered molecule of aflibercept (right). This exemplifies how a molecule can be designed to possess specific properties of different naturally-occurring molecules with a goal of optimizing therapeutic activity.
Despite uncertainties, the Eylea launch probably would have enjoyed even greater success had the government given it a permanent reimbursement code — a so-called J-code. Without a J-code, private carriers inevitably require additional paperwork and often drag their heels on payments. In light of the expense, this has caused some practices to prescribe conservatively or, in some cases, not at all. A J-code for Eylea is expected no sooner than January 2013, not an unusual delay for a new drug.
To provide financial assistance, Regeneron instituted its Eylea 4 U program, which helps physicians navigate reimbursement issues and extends coverage to some uninsured patients. The company also allows practices 150 days to pay for Eylea, known as “extended dating” in the trade. The liberal payment policy has been well received by physicians.
“I've been pleased to see that if we follow the right channels, most of our patients do not incur significant out-of-pocket expenses,” says Alan J. Franklin, MD, PhD, a retina specialist in Mobile, AL, who prescribes aflibercept to many suboptimal responders. “Typically, the few individuals who don't qualify for co-pay assistance are relatively wealthy and are able to pay out of pocket.”
Reaction to the new drug as a fresh participant in the marketplace has been largely positive, observes Dr. Aberman, of Regeneron. “Being second to the market in this category has, we believe, worked to our advantage, as our perception is that the retinal community has long been eager to have a second source of drug product for wet AMD,” he says. The company priced Eylea $100 cheaper than Lucentis and consulted with practitioners and payers during the clinical development phase to incorporate their views into the launch.
Above all else, clinicians say they welcome the new drug's primary and irrefutable benefit of providing a third anti-VEGF option that, at the very least, matches the efficacy of the two established therapies and does hold the potential for a reduction in dosing frequency — a goal shared by clinicians and patients alike. RP
1. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92:667-668.