Experts weigh-in on treatment options for neovascular AMD

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With several options available for improving vision in patients with neovascular age-related macular degeneration, the decision about which agent to use might take into account information on resolution of macular edema, cost, and safety.

By Cheryl Guttman Krader;

Reviewed by Victor H. Gonzalez, MD; Jeffrey S. Heier, MD; Dante Pieramici, MD; and Philip J. Rosenfeld, MD, PhD

At present, three anti-vascular endothelial growth factor (VEGF) agents are commercially available with an indication for treatment of neovascular age-related macular degeneration (nvAMD), and a fourth option is widely used off-label.

Recently, four ophthalmologists each outlined why they consider a particular agent to be the best.

Issue of safety

Dante Pieramici, MD, discussed reasons why ranibizumab (Lucentis, Genentech) is the treatment of choice. His focus was on safety, but first he reviewed clinical trial data on efficacy and durability.

Citing data from the CATT, IVAN, and VIEW trials, Dr. Pieramici noted that ranibizumab was associated with similar best-corrected visual acuity (BCVA) outcomes when compared with bevacizumab (Avastin, Genentech) or aflibercept (Eylea, Regeneron).

He discounted the idea that aflibercept provides a more durable effect by presenting data from the second year of the VIEW trials (the “prn” phase) during which the mean number of injections received was similar for patients in the ranibizumab and aflibercept groups.

“We also know from 2 years of follow-up in the HARBOR trial that after patients receive 3 loading doses, the average interval between prn ranibizumab injections is about 10 weeks,” said Dr. Pieramici, director, California Retina Research Foundation, and partner, California Retina Consultants, Santa Barbara, CA.

“Therefore, for the vast majority of patients, ranibizumab is given as a Q2month drug,” said Dr. Pieramici, who is also assistant clinical professor of ophthalmology, Doheny Eye Institute, Los Angeles.

Real-world market data corroborate that idea as well. According to Marketscan, the average AMD patient receives ~5.5 injections during the first year of anti-VEGF treatment whether being treated with ranibizumab or aflibercept.

Turning to safety, Dr. Pieramici noted that in multiple clinical trials, including CATT, MANTA, IVAN, and GEFAL, the rate of systemic serious adverse events (SAEs) was lower among patients treated with ranibizumab compared with bevacizumab.

Additionally, he explained there is a scientific foundation for that difference as ranibizumab is eliminated from the systemic circulation more quickly than bevacizumab and aflibercept causes less systemic inhibition of VEGF.

Furthermore, an analysis of safety data from the VIEW trials presented in the European Public Assessment Report found that the risk of stroke in patients aged 85 years and older was significantly higher in those receiving ranibizumab compared with aflibercept after both 1 year of treatment (1% versus 7%) and after 2 years (3% versus 9%).

Finally, Dr. Pieramici pointed out that use of bevacizumab is still accompanied by concerns about the safety of medication obtained from a compounding pharmacy.

“How many of your patients have asked you if the drug they are receiving comes from a compounding pharmacy?” Dr. Pieramici said. “Our patients are worried, and we are, too.”

Anatomic outcomes with aflibercept

Explaining why aflibercept is the best anti-VEGF agent for treating neovascular AMD, Jeffrey S. Heier, MD, director, vitreoretinal service, Ophthalmic Consultants of Boston, and assistant professor of ophthalmology, Tufts University School of Medicine, Boston, said that while bevacizumab, ranibizumab and aflibercept are all outstanding anti-VEGF agents, aflibercept has demonstrated consistently stronger anatomic outcomes.

In addition, aflibercept-due to its greater affinity-may have a more durable effect, and it provides these advantages without compromising safety.

Moreover, Dr. Heier noted that the peer-review literature is replete with articles discussing the benefits of aflibercept in patients who have not responded well to ranibizumab or bevacizumab.

Discussing efficacy, Dr. Heier pointed out that comparisons should take into account treatment effects on macular fluid since that is the parameter used to guide treatment decisions. Reviewing the anatomic data from the CATT and VIEW trials supports the conclusion that aflibercept has superior activity for eliminating fluid.

Better durability of aflibercept compared with ranibizumab derives from VIEW trials data where patients treated with aflibercept 2 mg Q8 weeks maintained similar improvement in BCVA compared with the controls receiving monthly ranibizumab.

Furthermore, during the second year prn phase, the aflibercept patients were much less likely than the ranibizumab-treated controls to need an injection before 3 months.

Dr. Heier noted that through week 96 in the VIEW trials, there was no difference between the aflibercept and ranibizumab arms in rates of arterial thromboembolic events (ATEs) or systemic SAEs, whereas in CATT, ranibizumab was associated with lower rates of systemic SAEs and hospitalizations compared with bevacizumab.

Focusing on the safety concerns that have been raised about aflibercept in the population of patients aged 85 and older based on the European Public Assessment Report, Dr. Heier pointed out that the meaning of the data are unclear considering:

1) the absence of a dose-response effect with aflibercept (adverse event rates were higher in patients treated with 0.5 mg than with 2 mg);

2) the lack of a consistent pattern (cerebrovascular accidents were more common with aflibercept than ranibizumab, but myocardial infarctions occurred more often among ranibizumab-treated patients); and

3) among patients aged 75 to 85 years old, who represented the largest age subgroup of the study population, both cerebrovascular accidents and myocardial infarctions were more common with ranibizumab than aflibercept.

In addition, he noted that whereas in the RISE and RIDE studies of ranibizumab treatment for diabetic macular edema, potential safety signals emerged with use of ranibizumab 0.5 mg, there appears to be no increased risk of ATEs or deaths among patients with diabetes treated with aflibercept.

Quality and value of bevacizumab

Philip J. Rosenfeld, MD, PhD, argued that bevacizumab is the best treatment, because it offers the best quality and value. He supported his opinion with data from the Preferences and Trends survey presented at the 2013 American Society of Retina Specialists meeting.

“When asked about their management choice for a patient with 1 disc area of subfoveal CNV due to AMD and visual acuity of 20/100, 61% of respondents said they would pick bevacizumab,” said Dr. Rosenfeld, professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami.

Addressing potential concerns related to obtaining bevacizumab from a compounding pharmacy, he pointed out this should not be an issue if physicians are careful about choosing their supplier.

“You have to take control of the situation,” Dr. Rosenfeld said. “Compounding bevacizumab is safe as long as Chapter 797 guidelines are followed, and at Bascom Palmer Eye Institute, where we have administered [more than] 80,000 doses, we have had no problems with contamination.”

He also argued against concerns that bevacizumab is associated with more ATEs, noting that there have been no increase in vascular deaths, myocardial infarctions, or cerebral vascular accidents from the use of bevacizumab compared with the other anti-VEGF drugs, and these are the adverse events associated with high dose systemic use of anti-VEGF agents.

The increase in systemic SAEs associated with bevacizumab in CATT was not seen in multiple other clinical trials (IVAN, BRAMD, GEFAL, and LUCAS).

“In addition, the systemic SAEs in these studies were not the SAEs most commonly associated with systemic bevacizumab,” Dr. Rosenfeld said. “If the higher rate of systemic adverse events with bevacizumab was the result of systemically achieved drug levels, than the types of adverse events that occurred should be similar to those seen in oncology trials of systemic bevacizumab treatment, especially hypertension, and they were not.”

Finally, when it comes to cost, there is a clear difference in favor of bevacizumab. Considering data on the Medicare allowable reimbursement, there is a 40-fold difference comparing bevacizumab against both ranibizumab and aflibercept, ~$50 versus ~$2,000.

Pegaptanib for neovascular AMD

Victor H. Gonzalez, MD, founder, Valley Retina Institute, McAllen, TX, discussed the role of pegaptanib sodium (Macugen, Valeant Pharmaceuticals) in the management of neovascular AMD.

He suggested that rather than trying to tease out possible differences in systemic safety risks between ranibizumab, bevacizumab, or aflibercept, retinal specialists should recognize there is potential risk associated with each-particularly in vulnerable patients, and especially because continuous therapy is necessary for maximizing outcomes.

Compared with the other anti-VEGF agents, pegaptanib has a better systemic safety profile because it is selective for the VEGF isoform involved in pathological ocular neovascularization.

Therefore, it may offer a better option for use in a maintenance regimen in high-risk populations-i.e., patients aged 85 and older or those with a recent history of a cerebrovascular accident or cardiovascular event.

“After induction with one of the other anti-VEGF agents, ongoing treatment every 6 weeks with pegaptanib seems to be a promising approach for maintaining vision benefits with a better safety profile,” Dr. Gonzalez said.

Evidence on the systemic safety of ongoing treatment with pegaptanib derives from 4 years of follow-up for patients enrolled in the VISION trial.

Findings from the LEVEL trial support the use of pegaptanib in an induction/maintenance regimen. In LEVEL, patients who had a positive response to initial treatment with a nonselective anti-VEGF agent were switched to pegaptanib 0.3 mg every 6 weeks as maintenance. At the end of 1 year of follow-up, mean visual acuity improvement remained stable.

“The visual outcomes for these patients maintained with pegaptanib sodium after successful control of the neovascular membrane with a nonselective anti-VEGF were very much equivalent to those associated with monthly injections in the pivotal ranibizumab trials, and there was no evidence of increased systemic or ocular side effects,” Dr. Gonzalez said.

Victor H. Gonzalez, MD

E: maculadoc@aol.com

Dr. Gonzalez is a consultant to Regeneron Pharmaceuticals and Valeant Pharmaceuticals and does contracted research for Genentech, Regeneron, and Valeant.

Jeffrey S. Heier, MD

E: jsheier@mac.com

Dr. Heier is a scientific advisor for and has received research funding from Genentech and Regeneron Pharmaceuticals. He served as the Steering Committee Chair for the VIEW 1 trial.

Dante Pieramici, MD

E: dpieramici@yahoo.com

Dr. Pieramici did not indicate any financial interest in the subject matter.

Philip J. Rosenfeld, MD, PhD

E: prosenfeld@med.miami.edu

Dr. Rosenfeld has no financial interests in any of the anti-VEGF drugs or their related manufacturers.