CONTROVERSIES IN CARE

Avastin vs Lucentis for Treatment of Neovascular AMD

EDITED BY MICHAEL COLUCCIELLO, MD

Retina specialists are seeing more patients with the wet form of age-related macular degeneration as the population ages and becomes more educated about the disease. More than 1.6 million people in the United States currently have one or both eyes affected by the advanced stage of AMD, and it is estimated that there are another seven million individuals at risk.

The anti-VEGF era has provided retina specialists with the potential to offer wet AMD patients improved vision. Ranibizumab (Lucentis, Genentech), a small anti-VEGF antibody fragment "designed" by Genentech for intraocular use to treat wet AMD, is FDA-approved based upon the results of the ANCHOR (predominately classic neovascularization) and MARINA (minimally classic/occult neovascularization) studies: These studies showed 25% to 40% visual improvement and >90% visual stabilization with Lucentis.

Bevacizumab (Avastin, Genentech), a full-length anti-VEGF antibody, has not undergone the rigorous studies required to obtain FDA approval for wet AMD, but small studies show apparent safety and efficacy for the treatment of wet AMD. Its use in the setting of wet AMD is offlabel but covered by Medicare.

A small (20 patients) comparative, prospective, doublemasked controlled Avastin vs Lucentis trial showed no difference in efficacy measured by visual acuity and foveal thickness response at a six-month follow-up.¹ Avastin costs about $50 a dose; Lucentis costs approximately $2,000 per dose. Considering that both drugs require multiple treatments, this cost differential is substantial, both from a microeconomic and macroeconomic perspective.

Retina specialists eagerly await the results of a large, multicenter clinical trial — the NEI's Comparisons of Agerelated macular degeneration Treatment Trials (CATT) — which may answer the question of superiority vs inferiority of Lucentis vs Avastin, determination of optimal treatment schedule, and long-term safety. However, the final results of this trial will not be known for a few years. In this new column, retina specialists Joshua Dunaief, MD, and Dan Will, MD, will comment on their current usage of these agents for the treatment of neovascular AMD.

REFERENCE

1. Subramanian ML, Ness S, Abedi G, et al. Bevacizumab vs Ranibizumab for Age-Related Macular Degeneration: Early Results of a Prospective Double-Masked, Randomized Clinical Trial. Am J Ophthalmol. 2009;148:875-882.

LUCENTIS

JOSHUA DUNAIEF, MD

In my academic practice at the Scheie Eye Institute, I have been caring for patients with AMD and researching the disease pathogenesis for 10 years, and I have witnessed firsthand the vast improvement in patient outcomes as treatment modalities have progressed from argon laser to PDT to pegaptanib sodium (Macugen, Eyetech) and now to Avastin and Lucentis.

Following publication of Philip Rosenfeld's ground-breaking case series on intravenous¹ Avastin and then case report on intravitreal² Avastin, many of us began using Avastin off-label for neovascular AMD. A consensus developed that it was probably safe and more effective than PDT. Dozens of mainly retrospective, short-term reports have supported this assertion. However, following completion of the ANCHOR and MARINA trials and FDA approval of Lucentis for exudative AMD, I have been recommending Lucentis to my patients because these prospective, randomized clinical trials provide evidence for the safety and efficacy of Lucentis.

Within about a year, we'll have some information about the safety and efficacy of Avastin vs Lucentis (for one year of therapy), based on the ongoing CATT trial. In this trial, 600 patients were randomized to receive Lucentis and 600 to Avastin. Within each of these groups, half were randomized to receive the drug every four weeks and half to get a single injection followed by repeat injections only if they have neovascular lesions with fluid.

There are theoretical reasons why Lucentis may prove more effective than Avastin. Avastin and Lucentis are both humanized anti-VEGF antibodies. Lucentis has a much higher affinity for VEGF than Avastin, so it may neutralize more VEGF protein. Lucentis is one-third the size of Avastin; while Avastin has been shown to penetrate the rabbit retina when injected into the vitreous, Lucentis may do so more readily, potentially achieving greater concentration at the site of neovascularization.

There are also theoretical reasons why Lucentis may be safer than Avastin. Lucentis lacks the potentially inflammation-promoting Fc portion of the antibody, which is retained in Avastin. While this structural dissimilarity does not result in significant inflammation in enough cases to be detectable in the retrospective studies, perhaps this will become apparent in the CATT trial, reported as either inflammation or "sterile endophthalmitis."

Intravenous Avastin use is associated with a slight increase in thromboembolic events in colon cancer patients. Could intraocular Avastin slightly increase stroke risk in AMD patients? In rabbits, small amounts of Avastin can be detected in the serum for weeks after injection, but Lucentis is not detected.^3,4 Again, the published studies on Avastin for AMD are insufficiently powered to detect a small increase in stroke risk.

Until we get the CATT results, I will doggedly prefer Lucentis, when available, over Avastin, due to concerns about safety and potentially inferior efficacy.

REFERENCES

1. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112:1035-1047.
2. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331-335.
3. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007;114:2179-2182.
4. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114:855-859.

AVASTIN

DAN WILL, MD

I see my neovascular AMD patients so often that they have become like extended family members. The anti-VEGF era of neovascular AMD treatment has improved our outcomes and brought us patients we frequently need to see six to 12 times per year or even more in severe bilateral cases. Yet there is no consensus as to whether Lucentis or Avastin should be first-line therapy. How do we guide these folks who we are seeing more often than some of our relatives?

The limitations of argon laser and PDT for neovascular AMD were obvious to patients and treating physicians, as vision too often continued to deteriorate over time despite repeated treatments. The introduction of anti-VEGF agents offered a new hope to a group of patients ripe for good news. Macugen was the first of these agents to be introduced, but the results were modest. Patients undergoing Macugen therapy needed faith in the level-one data to continue treatment as vision, OCT and angiography typically continued to worsen despite multiple injections.¹

As first reported by Rosenfeld et al.,² patients failing multiple Macugen injections could see improvement in their vision, OCT and angiography results with a single Avastin injection. The benefits were tangible to patients and physicians. Short-term studies demonstrated gains in vision for the typical AMD patient treated with Avastin.³

Lucentis quickly followed with more certain safety and efficacy demonstrated in the larger, more rigorous ANCHOR and MARINA trials.⁴ Clinically, patients treated with Lucentis responded as impressively as patients receiving Avastin. Fortunately, patients and physicians were left to choose between two molecularly and functionally comparable treatments that were both more impressive than previous options.

The 20 to one cost disparity between Lucentis and Avastin weighs heavily on everyone's minds, as patients and physicians alike are all too familiar with healthcare payment glitches. Two thousand dollars for a treatment given monthly could add up quickly and break a budget. The implications for the already runaway US healthcare spending also could not be ignored. Reconciling the concern of safety and efficacy with cost-consciousness became a regular topic of conversation as our patients and their families had many opportunities to consider all the facets of their frequent AMD treatment.

What about the evidence? The CATT trial is nearing completion and should ensure there is not some subtle difference in efficacy or safety between the two agents that was not apparent from clinical use, as well as provide data for dosing at less frequent intervals. As mentioned, Macugen has level-one evidence to support its efficacy and safety, but in studies and in practice it does not perform as well as Avastin or Lucentis. Lucentis has level-one evidence to support monthly use with excellent results in eyes meeting the study criteria. Avastin has level-two and level-three evidence demonstrating comparable safety and efficacy to Lucentis.⁵

Patients in ANCHOR and MARINA, who received injections every month, had better outcomes than patients injected every three months in the PIER trial. The "use the best evidence" argument in favor of Lucentis over Avastin weakens unless treatment adheres to strict monthly injections. What about our bilateral cases? What about usage longer than two years? We do not know the pros and cons of each drug under these circumstances.

The practical realities of a clinical trial dictate inclusion and exclusion criteria be developed so the outcome measures can be reasonably determined by limiting confounding variables. It is common for treatments, once established in trials, to be extrapolated back to patients who would have been excluded from the study. This requires judgment on the part of the physician and patient regarding the applicability of a treatment to a clinical situation outside the purviews of study inclusion/exclusion criteria. As a physician, it is critical to understand the limitations of anecdotal evidence and personal observations of patients, but it is equally critical to be aware of the limitations of clinical trials in medical decision making.

What about cost? The high cost of health care is well known. An impetus for healthcare reform has been the claim that, compared with other countries, our high spending does not result in comparably high outcomes. The two-year drug cost of Lucentis vs Avastin is roughly $48,000 vs $1,200 per patient, presuming monthly injections. Many patients cannot stop these injections even after two years and therefore our office schedules continue to book up with patients needing serial injections for wet AMD, placing an unsustainable burden on our healthcare system. So far, I have not been convinced Lucentis is any better than Avastin and cannot make the case for such an exorbitant cost difference.

Based on the performance of the drugs, I would not have a preference for Lucentis or Avastin if the cost were equal. I cannot ignore the cost difference and, therefore, I would choose Avastin therapy for myself if I needed treatment. RP

REFERENCES

1. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
2. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging.2005;36:331-335.
3. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab(Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:363-372.
4. Rosenfeld PJ, Brown DM, Heier JS, et al., Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
5. Ip MS, Scott IU, Brown GC, et al.; American Academy of Ophthalmology. Antivascular endothelial growth factor pharmacotherapy for age-related macular degeneration. A report by the American Academy of Ophthalmology. Ophthalmology. 2008;115:1837-1846.