ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR

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1 THE ROLE OF RANIBIZUMAB * Michael L. Klein, MD ABSTRACT The positive 1-year results of ranibizumab trials reported at the 23rd Annual Meeting of the American Society of Retina Specialists have generated considerable optimism that the drug would be approved for the treatment of neovascular agerelated macular degeneration (AMD) within the coming year. Similar to pegaptanib, which was approved for the treatment of AMD in December 2004, ranibizumab binds and inhibits vascular endothelial growth factor (VEGF), a potent inducer of the angiogenesis and increased vascular permeability that characterize neovascular AMD and other ocular disorders. This article reviews the anti- VEGF properties of ranibizumab and the reported 1-year results from 2 trials evaluating ranibizumab. The article also describes the aims of several ongoing and recently begun studies of ranibizumab in patients with AMD. (Adv Stud Ophthalmol. 2005;2(3): ) Ranibizumab (Lucentis; Genentech, Inc.; South San Francisco, Calif) for the treatment of neovascular age-related macular degeneration (AMD) is currently a topic of great interest among ophthalmologists. One-year results of trials evaluating the drug were reported at the 23rd Annual Meeting of the *This presentation is based on a roundtable symposium held in Whistler, British Columbia, Canada, on August 6, Professor of Ophthalmology, Director, Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon. Address correspondence to: Michael L. Klein, MD, Professor of Ophthalmology, Director, Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, 3375 SW Terwilliger Boulevard, Portland, OR kleinm@ohsu.edu. American Society of Retina Specialists in Montreal, Canada, 1,2 and they are positive. Published results are expected soon, and the outlook for approval from the US Food and Drug Administration (FDA) within the next year is optimistic. The role of ranibizumab in the treatment of neovascular AMD is rooted in its antiangiogenic properties specifically, its inhibitory effects on vascular endothelial growth factor (VEGF) 1,2 and in research findings that VEGF is a potent inducer of angiogenesis and increased vascular permeability. 3 This premise also applies to other antiangiogenic agents such as pegaptanib (Macugen; Eyetech Pharmaceuticals, Inc. and Pfizer Inc; New York, NY), which is approved for the treatment of AMD, 4 and bevacizumab (Avastin; Genentech, Inc.; South San Francisco, Calif), which is approved for the treatment of colorectal cancer, 5 but is still under study for treatment of AMD. 6 Because neovascular AMD and other ocular disorders are characterized by excessive angiogenesis and blood vessel leakage, it stands to reason that agents able to inhibit these processes by inhibiting VEGF would be effective in treatment of AMD. ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR PROPERTIES OF RANIBIZUMAB AND PEGAPTANIB Vascular endothelial growth factor comprises a family of proteins (eg, VEGF-A, VEGF-B, and VEGF-C) that are secreted by a variety of cells in the body in response to ischemia and other signals. 3 Within this family, VEGF-A, which has multiple isoforms, appears to be most responsible for increasing vascular permeability and neovascularization. Several therapeutic approaches targeting VEGF have been studied or are currently being studied as treatments for AMD and other angiogenic ocular disorders. The most familiar of these are pegaptanib, which was approved for AMD treatment in December Advanced Studies in Ophthalmology 107

2 2004, 4 and ranibizumab, which is expected to receive FDA approval within the coming year. Both agents bind VEGF-A and have considerable anti-vegf activity, are biologically active in the eye, and are given by intravitreal injection. However, there are key differences between them, as summarized in Table 1. Pegaptanib is an aptamer, or oligonucleotide that adheres to VEGF particles and blocks their action at the cellular level. 4,7 It is a string of RNA bases with a unique shape that conforms to a target protein molecule (ie, VEGF-A) to permit binding. Although it acts like an antibody, pegaptanib is not a protein or an immunoglobulin, nor is it part of the immune system. Ranibizumab, by comparison, is a humanized antibody fragment of bevacizumab, both of which bind to specific targets such as VEGF-A. Whereas bevacizumab, the parent molecule, is an immunoglobulin with a molecular weight of 150 kd, 5 ranibizumab is approximately 33% the weight and size, allowing it to pass through the retina and reach the subretinal space where neovascularization occurs. 8 Another key difference between pegaptanib and ranibizumab is the number of VEGF-A isoforms each can bind and inhibit. With a binding site at the end of a string of 165 amino acids, pegaptanib easily binds VEGF-A isoform 165, but not the shorter isoforms 110 and 121. With a more proximal binding site, ranibizumab is able to bind and inhibit all 3 VEGF-A isoforms. Whereas the selective isoform inhibition of pegaptanib may be seen as an advantage in the treatment of neovascular AMD, it also may be argued that the ability of ranibizumab to bind all 3 biologically active isoforms may impart greater efficacy. Clearly, further study is needed to demonstrate the roles of various VEGF isoforms in the pathogenesis and treatment of AMD. safety, confirmed that ranibizumab was safe at all doses evaluated. 10 The study generated a good deal of attention because it also found that ranibizumab improved visual acuity by 12 to 15 letters at day 210 in treated patients as compared to those receiving placebo who lost an average of 5 letters at this time point. The study also demonstrated that ranibizumab was biologically active in the eye, resulting in reduced leakage on fluorescein angiography and a reduction in central retinal thickening on optical coherence tomography (OCT). The third study, which was a dose escalation trial, found that the dose of ranibizumab could be increased to 2 mg without increasing the risk of any major adverse events. 11 However, the trial did not demonstrate any advantage in using the higher dose. The FOCUS Trial. A fourth phase I/II study evaluating ranibizumab (formerly known as RhuFab) was the RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety 2 (FOCUS) trial. This multicenter, randomized, single-masked trial examined the use of ranibizumab plus photodynamic therapy (PDT) with verteporfin (Visudyne; Eyetech Pharmaceuticals, Inc. and Pfizer Inc; New York, NY) versus PDT alone in 162 patients with neovascular AMD. All patients had received 1 session of PDT before enrollment in the trial. The randomization scheme and primary and secondary endpoints of the trial are outlined in Table 2. At 12 months, patients randomized to ranibizumab injections and PDT gained an average of 5 letters in visual acuity from baseline, whereas those randomized to sham injections and PDT lost an average of 8 letters. 2 Thus, there was a 13-letter difference in mean change in visual acuity from study entry between the 2 treatment groups. CLINICAL TRIALS EVALUATING RANIBIZUMAB Several phase I/II clinical trials have evaluated or are currently evaluating ranibizumab in the treatment of AMD and its subtypes. PHASE I/II TRIALS Three phase I/II trials assessing the dosing and safety of ranibizumab have been conducted. The first of these determined that the maximum safe dose was 0.3 mg to 0.5 mg and established the dose range to be used in future studies of ranibizumab. 9 The second, a small multidose study that addressed Table 1. Key Differences Between Pegaptanib and Ranibizumab Pegaptanib Aptamer (antibody-like oligonucleotide) Nonimmunogenic Ranibizumab Humanized antibody fragment Immunoglobulin (protein produced by the immune system) Inhibits VEGF-A Inhibits VEGF-A isoforms 110, isoform , 165 VEGF = vascular endothelial growth factor. 108 Vol. 2, No. 3 December 2005

3 With respect to vision gain, 24% of patients treated with ranibizumab and PDT versus 5% of patients treated with sham injections and PDT improved vision by 15 or more letters or 3 or more lines compared to study entry. 2 The proportion of patients losing 15 or fewer letters was 90% in those treated with ranibizumab and PDT versus 67% in those treated with sham injections and PDT. Losses and gains in visual acuity in patients treated with PDT alone in the FOCUS trial were consistent with losses and gains observed in other PDT studies. PHASE III TRIALS At present, there are 3 phase III trials of ranibizumab that are nearing completion or still ongoing, and enrollment has begun for a fourth. One-year data have been reported for the first of these trials. The MARINA Trial. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) involved 716 patients with minimally classic or occult with no classic subfoveal choroidal neovascularization (CNV) secondary to AMD. 1 Lesion composition was confirmed by fluorescein angiography in all patients before study entry. The randomization scheme and primary and secondary endpoints for this multicenter, double-masked, sham-control study are outlined in Table 3. Patients who had received subfoveal laser treatment, PDT with verteporfin, or experimental therapies were excluded from the study. 1 However, patients could receive PDT if they converted to predominantly classic disease during the study or if they had small, active minimally classic or occult CNV lesions and lost 20 or more letters in visual acuity on 2 consecutive physician evaluations. It is worth noting that 11% of patients in the sham group, but only 1 patient receiving the 0.3-mg dose of ranibizumab and no patients receiving the 0.5-mg dose, had sufficient disease progression to require PDT. With respect to maintaining vision the primary endpoint 95% of patients treated with either dose of ranibizumab lost fewer than 15 letters from baseline at 1 year compared to 62% of patients receiving sham injections. 1 Secondary endpoint outcomes also favored ranibizumab, with 25% of patients receiving the 0.3-mg dose and 34% of those receiving the 0.5-mg dose gaining 15 or more letters or 3 or more lines in visual acuity from baseline to 1 year compared to 4.6% among patients receiving sham injections. 1 The same pattern was seen with respect to the proportion of patients achieving a visual acuity of 20/40 or better at 1 year nearly 40% in those receiving either dose of ranibizumab versus 11% in the sham group. Regarding the mean change in visual acuity from baseline to 1 year, patients treated with ranibizumab Table 2. FOCUS Trial: Randomization and Study Endpoints Randomization 162 patients with predominantly classic subfoveal neovascular AMD randomized 2:1 to receive photodynamic therapy with verteporfin, followed by monthly ranibizumab injections (0.5 mg) or sham injections for 23 months Primary Efficacy Endpoint Maintaining vision (losing <15 letters from baseline) at 1 year in patients with neovascular AMD Secondary Endpoints Mean change in visual acuity (in letters) from baseline at 1 year Difference in mean change in visual acuity (in letters) at 1 year between the treatment groups AMD = age-related macular degeneration; FOCUS = RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety. Data from Genentech, Inc. 2 Table 3. MARINA: Randomization and Study Endpoints Randomization 716 patients with minimally classic or occult neovascular AMD randomized 2:1 to receive monthly intravitreal injections of ranibizumab or sham injections for 2 years 478 patients randomized to ranibizumab further randomized to receive a 0.3-mg dose (n = 238) or a 0.5-mg dose (n = 240) Primary Endpoint Proportion of patients losing <15 letters at 1 year compared to baseline in the best corrected visual acuity score Key Secondary Endpoints Proportion of subjects gaining 15 letters in visual acuity at 1 year compared to baseline Proportion of patients with visual acuity of 20/200 or worse at 1 year Mean change from baseline in visual acuity over time to 1 year AMD = age-related macular degeneration; MARINA = Minimally Classic/Occult Trial of the Anti-Vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular AMD. Data from Genentech, Inc. 1 Advanced Studies in Ophthalmology 109

4 gained an average of 7 letters in visual acuity, whereas those given sham injections lost an average of 10.5 letters, a between-group difference of 17.5 letters. 1 Serious ocular adverse effects, such as uveitis and endophthalmitis, occurred in less than 1% of patients treated with ranibizumab, but in none of the patients in the sham group. 1 Systemic effects did not appear to be a significant factor because the incidence of serious nonocular adverse events, such as hypertension, nonfatal myocardial infarction, and nonfatal cerebrovascular accident, was similar in patients treated with either dose of ranibizumab and in patients given sham injections. There were 2 deaths in the group receiving the 0.5-mg dose of ranibizumab and 1 death in the group receiving the 0.3-mg dose, but no deaths in the sham group. Ongoing Trials. Two additional studies are nearing completion: the Anti-VEGF Antibody for the Treatment of Predominantly Classic CNV in AMD (ANCHOR) study and the phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection- Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal CNV with or without Classic CNV Secondary to AMD (PIER). 1,2 The ANCHOR study is a randomized, multicenter, double-masked, active treatment controlled study comparing 2 different doses of ranibizumab to PDT in 423 patients in the United States, Europe, and Australia. 1,2 Results are expected by the end of PIER is comparing 1 of 2 doses of ranibizumab to sham injections in 184 patients in the United States, with ranibizumab injections given once a month for 3 months, and then once every 3 months thereafter for 2 years. 1,2 Results are expected in the first quarter of Another phase III trial is HORIZON, an openlabel extension study that permits eligible patients who completed certain other ranibizumab studies to continue therapy with this drug. 1,2 Enrollment in HORI- ZON, which will evaluate the safety and tolerability of this drug in these patients, recently began. CONCLUSIONS The role of ranibizumab and other antiangiogenic agents in the treatment of AMD centers on their ability to bind and inhibit VEGF, a potent inducer of neovascularization and vascular permeability that is biologically active in the eye. Several phase I/II and phase III clinical trials have evaluated or are currently evaluating ranibizumab in the treatment of AMD and its subtypes. One-year data from the phase I/II FOCUS trial and the phase III MARINA study were reported at the 23rd Annual Meeting of the American Society of Retina Specialists. The results were favorable, and published reports are expected soon. In the FOCUS trial, which examined the use of ranibizumab injections plus PDT versus sham injections plus PDT in 162 patients with neovascular AMD, 90% of patients receiving ranibizumab plus PDT lost 15 or fewer letters at 1 year compared to 67% of those receiving sham injections and PDT. Patients randomized to ranibizumab and PDT gained an average of 5 letters in visual acuity from baseline, whereas those randomized to sham injections and PDT lost an average of 8 letters. In the MARINA trial, 95% of patients treated with ranibizumab lost fewer than 15 letters at 1 year versus 62% of patients in the sham group, and 25% to 34% of those treated with ranibizumab gained 15 or more letters versus 5% of those receiving sham injections. All other vision outcomes also favored ranibizumab. There was a low rate of serious ocular adverse events, such as presumed endophthalmitis (0.6%) and uveitis (0.6%), and there were no apparent systemic safety concerns. As a whole, the initial clinical trial outcomes with ranibizumab are impressive. Pending further results and FDA approval, the drug is likely to have a major impact on the management of patients with neovascular AMD. The availability of an additional effective therapy would in turn lead to greater emphasis on earlier diagnosis and intervention, in addition to increased use of OCT and less dependence on lesion size and composition as determinants of therapy. The next challenge will likely involve the development of drugs that require less frequent intravitreal injections and the possibility of alternative drug delivery systems. DISCUSSION DRUG APPROVAL ISSUES Dr Olsen: The burning question is, When is ranibizumab going to be approved? Dr Klein: I don t know the answer to that. I can only guess from what I ve been hearing that it s going to be several months before anything like that happens. Dr MacCumber: The FDA often requests 2-year data. Do you think that s going to occur with this drug? Dr Klein: Again, I don t have any firsthand information, but I believe that is what the FDA usually asks for. Dr Bressler: I cannot speak for the FDA, but I pre- 110 Vol. 2, No. 3 December 2005

5 sume that if approval were granted on 1-year data, it would be conditional and subject to change based on 2-year data or 5-year safety data. We see drug labels changed all the time. This is a 2-year study and the protocol calls for 2-year data. But that doesn t mean that ranibizumab couldn t be approved on 1-year data with a change based on the 2-year data. Dr Klein: The primary endpoint was predefined as a 12-month endpoint. Would that make a difference in terms of wanting to have the 2-year data? Dr Bressler: One-year primary endpoints for ophthalmic products are often chosen so that a pharmaceutical company can find out quite quickly if its product is worthwhile for ophthalmologists and for our patients. If something works at 1 year, but it is useless or harmful at 2 years, that will influence us. If something works at 1 year and maintains that benefit at 2 years and beyond, then I think we re okay. Neovascular AMD, in my mind, seems to have the ability to continue to cause damage in some patients in the second year. I m much more comfortable if I see these results maintained out to 2 years, and we may even see better efficacy with prolonged use. It appears that the improvement that was seen, as suggested by the mean visual acuity change, was seen quite early on. That makes me think that we re not going to get more improvement between years 1 and 2. We may even lose some of the improvement in year 2 if atrophy occurs. Dr Mieler: The ranibizumab data that have been shown are very encouraging compared to the available data from other therapeutic trials. Certainly, the company that developed it would like to get it on the market. If the drug is approved right now, it would probably be for occult lesions or minimally classic lesions rather than across the board. With data from the ANCHOR study expected sometime in the next 6 months, I m wondering if the company may want to wait a bit longer to get an approval for all types of neovascularization. Dr Klein: If the results of the ANCHOR study, which involves predominantly classic lesions, are available by the end of the year, and the results are favorable, it would certainly make sense to get approval for all types of neovascular lesions. Dr Olsen: I would like to point out that MARINA is addressing a subgroup of exudative AMD in which prior studies typically had the hardest time showing a significant difference over the natural history or the current standard of care. The results are encouraging for ranibizumab treatment in a group that is probably the toughest to treat. RISK OF SYSTEMIC EVENTS Dr MacCumber: I was a little surprised by the mention of no significant systemic events. There may be a slight increase in death caused by cerebrovascular events, for instance, with the higher dose of ranibizumab. Perhaps there may be a very small risk that the drug is getting into the systemic circulation and causing an event. Dr Klein: I guess the deaths there were caused by small bowel infarction and asthma. Dr MacCumber: Certainly, cerebrovascular accidents can occur by chance, but can this study really determine that they were not caused by ranibizumab? Dr Bressler: The study cannot determine that there is no difference. You can t prove a negative. In general, safety is assessed by looking at the absolute numbers. Even if those numbers were the same, even if they were 1, 1, and 1, an event may be twice as common with, let s say, a ranibizumab dose of 0.5 mg, and the study population may not have been large enough to rule that out. The 95% confidence interval around the 1, 1, and 1 may be from 0% to 4% for each one, and that means that we re 95% confident that the real answer is between 0% and 4%. So, the real answer may be 2% for ranibizumab and 1% for sham, which would make treatment twice as risky. Because we don t have adequate numbers, we don t know that it is more risky, but we can t rule out that it isn t. Dr MacCumber: We know that bevacizumab has this potential risk when given intravenously in patients with cancer. I wonder if this might give the FDA pause to look at 2-year data. Dr Bressler: They should look at 2-year data and reports of post-injection deaths or heart attacks. That sort of reporting is exactly what s needed. That could be true after pegaptanib. Even though pegaptanib showed an equal number of deaths, that doesn t mean that the 95% confidence intervals are broader. It s just something that we should be paying attention to and continue collecting. USE OF OPTICAL COHERENCE TOMOGRAPHY Dr Bressler: I d like to expand on Dr Klein s comment that there will be more use of OCT and a greater emphasis on earlier diagnosis and intervention. Obviously, we want to catch patients when their visual acuity is 20/20, 20/25, 20/40, or at least not going lower than 20/64 for 95% of the time. However, Dr Olsen published an article in Ophthalmology a couple of years ago on lesions at presentation. 12 Most were subfoveal. Many had a visual Advanced Studies in Ophthalmology 111

6 acuity of 20/100 and 50% had a visual acuity of 20/200 or worse. That s not when we want to avoid a 3-line loss. Even if we gain 3 lines at a visual acuity of 20/200, we re only bringing the visual acuity back to 20/100. That s good, but it s hardly a success. The key is earlier diagnosis and intervention. Increased use of OCT will need to be justified by studies that demonstrate that information we find on OCT will change our management for the better. In other words, if we see fluid on OCT in 1 patient and decide to treat, but don t see fluid on OCT in another patient and decide not to reinject, we need to know that making treatment decisions based on OCT resulted in better outcomes than if we did not have the OCT data. In MARINA, which did not allow OCT findings to influence the retreatment decision, monthly injections resulted in 95% of treated subjects avoiding 3- or more line loss at 1 year. We need to know that if we adjust treatment decisions based on OCT, at least 95% of patients will not lose 3 or more lines of vision. If 85% of patients lose fewer than 3 lines because treatment decisions were based on OCT findings, is the diminished treatment benefit worth it to that person? Would we ever recognize in our practice that we got slightly worse outcomes when making treatment decisions based on OCT rather than following the protocol in MARINA? No. This is a common problem and a big public health problem. Decisions regarding certain interventions require studies demonstrating that withholding treatment if no fluid is seen on OCT is an option as long as the outcome is non-inferior to what we already have when OCT data are not part of the decision-making process. Dr Klein: I think there will be a greater emphasis on OCT than fluorescein in patient follow-up because we are dealing with a treatment of which spot sizes and lesion composition are not as important and because OCT is easier to do and less invasive. Dr Bressler: We may need that OCT instead of fluorescein, which wasn t even used in the decision to retreat again in MARINA. What we ll have to find out is whether you get the same outcome if you don t see fluid on OCT or on fluorescein angiography. I think these studies could be done fairly easily and economically at eye centers. Until then, ophthalmologists who say, I think I can withhold treatment because I don t see leakage on fluorescein, or I think I can withhold treatment because I don t see fluid on OCT, may be right. But I would say, Are you certain your outcome isn t 80% for avoiding 3- or more line loss and only 15% for gaining 3 or more lines? You just can t see that in the 100 or so patients that you treat. Dr Klein: I agree that that needs to be determined, just as in the pegaptanib data, in which most of us were looking to see if we had a better way of determining whether to continue treatment. The same will be true of ranibizumab. REFERENCES 1. Genentech, Inc. Phase III study shows Lucentis improved vision in patients with wet age-related macular degeneration [press release]. Available at: news/press-releases/display.do?metho&d=printid=8727. Accessed September 7, Genentech, Inc. Preliminary Phase I/II study showed Lucentis improved vision in patients with wet age-related macular degeneration when used in combination with Visudyne [press release]. Available at: gene/news/press-releases/display.do?method= print&id=8728. Accessed September 7, Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992;13: Gragoudas ES. Pegaptanib sodium for the treatment of age-related macular degeneration. 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Presented at: 19th Annual Meeting of the Vitreous Society; November 27-December 1, 2001; Fajardo, Puerto Rico. 10. Heier JS. The VEGF antibody approach: the RhuFab Collaborative Trial. RhuFab V2 for the treatment of wet AMD. Paper presented at: American Academy of Ophthalmology, Subspecialty Day; November 15, 2003; Anaheim, Calif. 11. Puliafito CA, Rosenfeld PJ, McCluskey ER. RhuFab V2 dose escalating trial: safety and tolerability of 3 escalating dosing regimens in subjects with age-related macular degeneration. Presented at: 36th Annual Scientific Meeting of the Retina Society; September 18-21, 2003; Chicago, Ill. 12. Olsen TW, Feng X, Kasper TJ, et al. Fluorescein angiographic lesion type frequency in neovascular age-related macular degeneration. Ophthalmology. 2004;111: Vol. 2, No. 3 December 2005