Drug Evaluation
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Pharmacokinetic evaluation of pegaptanib octasodium for the treatment of diabetic edema 1.
Introduction
2.
Present treatment guidelines
3.
Introduction to the compound
4.
Clinical efficacy of pegaptanib
5.
Conclusion
6.
Expert opinion
Rupal Morjaria & Ngai Victor Chong† †
Oxford University NHS Trust, Division of Ophthalmology, Healey Way, Oxford, UK
Introduction: Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy. Pegaptanib octasodium (Macugen) was the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration. It is a selective anti-VEGF agent, which only blocks VEGF. It has been shown to be safe and effective in treatment of DME in randomized controlled trials and it may be a safer first-line treatment in patients with diabetes with a predisposition to cardiovascular risk factors. Areas covered: This review covers the pharmacokinetics of pegaptanib octasodium. The authors also evaluate pegaptanib octasodium’s clinical efficacy, safety and tolerability in DME. Expert opinion: DME is the most common cause of visual loss in patients with diabetes. Pegaptanib has been found to be more effective than laser therapy alone for center-involving DME, its efficacy might be slightly worse than other pan-VEGF blockers, but the number of patients that have significant improvement of vision after treatment are similar to those treated with pan-VEGF blockers. As a selective VEGF blocker, it may have a better ocular and systemic safety profile than pan-VEGF blocking agents. It is reasonable to consider pegaptanib as the first-line treatment for center-involving DME with pan-VEGF blockers reserved for non-responders. Keywords: diabetic macular edema, expert review, Macugen, pegaptanib octasodium Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy (DR), and the most common cause of visual disability in working-age people [1-4]. The Wisconsin Epidemiologic Study of DR found the 14-year incidence of DME in type 1 diabetics to be 26% [5] and 27% of type 1 patients develop DME within 9 years of onset [6] An even higher incidence of macular edema has been reported in older patients with type 2 diabetes [7]. Treatments for DME are targeted to decreasing vascular leakage in order to allow for stabilization or improvement of visual acuity [4]. Focal photocoagulation has been the gold-standard treatment since the results of the Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1985, showed the reduction in risk of moderate visual loss by 50% (from 24 to 12% at 3 years) [8] following laser photocoagulation compared to no treatment [9]. The Diabetic Retinopathy Clinical Research Network (DRCRnet) indicates that even with tight glycemic and blood pressure control, 12 -- 13% of patients with foveal centered DME who undergo focal/grid laser lose 10 or more ETDRS letters after 2 -- 3 years of follow-up. The risks of laser photocoagulation include foveal damage due to inadvertent macular photocoagulation and post-operative expansion of treatment scars, both of which may result in a permanent decrease in visual 10.1517/17425255.2014.922543 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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R. Morjaria & N. V. Chong
Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Pegaptanib octasodium II, III trials Diabetic macular edema VEGF 165 receptor antagonist Parenteral, intraocular O
N H
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O O H3C
ht O x
H
H N
Pivotal trial(s)
ht O y
CH3
CH3
O P
N H O
Chemical formula
O
O
O– Na+
The chemical name for pegaptanib sodium is: RNA, ((2¢-deoxy-2¢-fluoro)C-Gm-Gm-A-A-(2¢deoxy-2¢-fluoro)U-(2¢-deoxy-2¢-fluoro)C-Am-Gm-(2¢-deoxy-2¢-fluoro)U-Gm-Am-Am-(2¢deoxy-2¢-fluoro)U-Gm-(2¢-deoxy-2¢-fluoro)C-(2¢-deoxy-2¢-fluoro)U-(2¢-deoxy-2¢-fluoro)UAm-(2¢-deoxy-2¢-fluoro)U-Am-(2¢-deoxy-2¢-fluoro)C-Am-(2¢-deoxy-2¢-fluoro)U-(2¢-deoxy-2¢fluoro)C-(2¢-deoxy-2¢-fluoro)C-Gm-(3¢!3¢)-dT), 5¢-ester with a, a¢-[4,12-dioxo6-[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1, 15-pentadecanediyl]bis [w-methoxypoly(oxy-1,2-ethanediyl)], sodium salt. The molecular formula for pegaptanib sodium is: C294H342F13N107Na28O188P28[C2H4O]n (where n is ~ 900), and the molecular weight is ~ 50 kDa [29] Preclinical and Phase IA clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration [15] A Phase II randomized double-masked trial of pegaptanib, an anti-VEGF aptamer, for diabetic macular edema [5] A Phase II/III, multicenter, randomized, double-masked, 2-year trial of pegatanib sodium for the treatment of diabetic macular edema [30]
Highlighted are the pivotal trials evaluating the efficacy of pegatanib.
acuity, indicating the need for improved treatment modalities [10-12]. Within the past 5 years, the use of intravitreal corticosteroids and intravitreal anti-VEGF agents have come into common clinical practice for the management of DME [9]. Pegaptanib octasodium (Box 1) is a selective anti-VEGF agent, which may have a better safety profile for use in DME. This paper provides an evaluation of the clinical usefulness, safety and tolerability of pegaptanib octasodium for the treatment of DME. A Medline search was performed using the terms ‘pegaptanib octasodium’, ‘Macugen’, and ‘diabetic macula edema’, ‘vascular endothelial growth factor’ ‘treatment’ or ‘tolerability’, ‘safety’, ‘pharmacokinetics’, ‘metabolism’.
unless there are contraindications. Pan-VEGF blockers and macula laser are used for the treatment of DME with a limited use of periocular/intraocular steroids. Overview of the market Several pharmacological as well as non-pharmacological treatment options are available for the treatment of DME. The greatest tool for preventing vision loss from DR is timely screening and identification of high-risk patients [18]. Focal laser treatment has been the gold standard treatment for DME, however its limitations have led to the use of other agents described in this article. 2.1
Corticosteroids The DRCRnet’s 3-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for DME showed laser treatment to be safer [11,18] At 3 years, central subfield thickness was < 250 µm in 67% eyes in the laser group, 43% in the 1 mg triamcinolone group and 51% in the 4 mg triamcinolone group [11]. Side-effects are a major drawback for the use of intravitreal triamcinolone. Four eyes in the 4 mg triamcinolone group had a procedure for glaucoma [11]. Among phakic eyes at baseline, the 3-year 2.2
2.
Present treatment guidelines
Since the publication of ETDRS, the Diabetes Control and Complications Trial Research Group and the UK Prospective Diabetes Study have demonstrated that tight glycemic and blood pressure control decreases the risk of micro-vascular complications of diabetes, including DR and vision loss [13-17]. Patients should be started on statins and fenofibrates 2
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Pegaptanib octasodium
cumulative probability of cataract surgery was 31% in the laser group and 83% in the 4 mg group. Sustained release steroid delivery systems offer the possibility of less frequent dosing; however, they have the same problems with adverse events. The fluocinolone acetonide in macula edema trial assessed sustained delivery fluocinolone acetonide (FAc) non-biodegradable intravitreal insert in 956 patients with DME [19]. The mean improvement from baseline in best corrected visual acuity (BCVA) letter score at month 24 was 4.4 and 5.4 in the low- and high-dose groups compared with 1.7 in the sham group [19]. Cataracts occurred in 42.7% of the low-dose group, 51.7% of the high-dose group and 9.7% of the sham group [19]. Intraocular pressure (IOP)-related adverse events (AEs) were more frequent in the FAc insert groups than in the sham group (low dose, 37.1%; high dose, 45.5%; sham, 11.9%) [19] Laser trabeculoplasty was performed in 2.5% of the high-dose group, 1.3% of the low-dose group and 0% of the sham group and IOP-lowering surgery was performed in 8.1% of the highdose group, 4.8% of the low-dose group and 0.5% of the sham group [19] The lower dose FAc (Illuvien - Alimera Sciences, Alpharetta, GA, USA) is now approved for use in DME patients in several European countries but at the time of writing (April 2014) not in the US. The longer acting nature of Iluvien does potentially have a benefit in terms of treatment rate over regular intravitreal anti-VEGF treatments, but this benefit has to be balanced against the greater risk of side-effects [11]. A 700 µg dexamethasone intravitreal drug delivery system (DDS) (Ozurdex - Dexamethasone Impant, Allergan) was compared with a 350 µg dexamethasone intravitreal DDS and observation (171 eyes, 180-day follow-up) for eyes with DME [20] At 90-day follow-up, a statistically significant difference in the proportion of eyes achieving at least a 10-letter improvement in BCVA was evident between the 700 µg dexamethasone group and the observation group (33 vs. 12%; p = 0.007). This difference was not statistically significant at day 180 (30 vs. 23% respectively). The 350 µg dose showed a statistically significant effect at 60 days (23 vs. 9% 10-letter improvement), but not at 90 or 180 days. At day 90, there was also a statistically significant improvement in both central retinal thickness (CRT) (p < 0.01) and fluorescein leakage (p < 0.001) in eyes that received the 700 µg dexamethasone DDS compared with eyes in the observation group. The Phase III study of Ozurdex was presented recently, which showed that there were some efficacy compared with sham treatment, but cataract remains a problem. The risk of IOP rise seems to be less than that of Iluvien. The role of corticosteroids in DME might be restricted to the pseudophakic patients. Anti-VEGF therapy Several anti-VEGF agents are available. The first anti-VEGF agent used in ophthalmology was pegaptanib (OSI Pharmaceuticals, Long Island, New York, US), which is based on a 2.3
28-nucleotide RNA aptamer that binds to the VEGF-A165 isoform and was initially approved for the treatment of neovascular age-related macular degeneration (nAMD). This will be discussed further, later in the paper. Its use has largely been supplanted by the development of ranibizumab (Genentech, Inc., South San Francisco, California, US), a Fab anti-VEGF agent that neutralizes all isoforms of VEGFA. Ranibizumab, specifically designed for intravitreal use, was approved in European countries in 2007 for the treatment of nAMD, in 2010 for the treatment of visual impairment due to DME and in 2011 for the treatment of visual impairment due to macular edema secondary to retinal vein occlusion [21,22]. The randomized clinical trial Ranibizumab for Edema of the Macula in Diabetes (READ-2) and that of the DRCR.net along with pivotal studies RESOLVE and RESTORE in > 1000 patients have established the efficacy and safety of ranibizumab in DME. The 2-year report of the safety and efficacy of ranibizumab 0.5 mg in DME from the RESTORE found non-ocular AEs leading to study drug discontinuation in the second year; these included acute myocardial infarction and cerebrovascular accident, subarachnoid hemorrhage, chronic renal failure, pulmonary embolism and respiratory arrest [22]. Patients with diabetes are predisposed to cardiovascular risks and there was some evidence of increased risk of hypertension with ranibizumab: 10% (n = 12) in the ranibizumab arm; 9% (n = 10.8) in the ranibizumab and laser arm; 6% (n = 8) in the laser arm [22]. Bevacizumab (Genentech, Inc., South San Francisco, California, US), a humanized monoclonal antibody that binds to all isoforms of VEGF-A [23], was developed in 1996 and first used for the treatment of human cancers. It has also come into widespread off license clinical use in the treatment of retinal disease. The BOLT Study was a 2-year prospective randomized controlled trial comparing intravitreal bevacizumab (IVB) to laser therapy for center involving DME [23]. IVB was given at baseline, 6 weeks, 12 weeks and then at prn basis [23]. The mean visual acuity gain at 24 months in EDTRS letters was 9 in the bevacizumab arm compared to 2.5 letters in the laser arm (p = 0.005) [23]. The study was not large enough to make definitive statement on the safety of the drug in diabetic patients, with a predisposed risk of cardiovascular events [24]. IVB is used worldwide on a large scale because of its lower price in comparison to ranibizumab. Formal evaluation of the safety of IVB is lacking. Another anti-VEGF agent that has been developed is aflibercept (Regeneron, Tarrytown, New York, US), which consists of the VEGF binding portions of the human VEGFR-1 and VEGFR-2 fused to the Fc portion of the human Ig-G1. In addition to having high affinity to all isoforms of VEGF-A, it also binds to placental growth factor [25]. VEGF trap-eye has been evaluated in the Phase II Da Vinci study (n = 219). Aflibercept has a potentially longer duration of action than ranibizumab and bevacizumab in DME. Eyes treated with each aflibercept dosing regimen
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experienced statistically significant reductions in central retinal CRT compared with eyes undergoing laser treatment and improvements in visual acuity at week 52 [25]. Although the study was not large enough to be powered adequately to assess the significance of differences in safety, the most common systemic AEs were hypertension, nausea and congestive heart failure. [25]. Seven deaths occurred during the study. One patient in the laser group died of cardiac arrest compared to six in the aflibercept group [25].
the risk of adverse effects associated with more complete VEGF blockage. Pegaptanib blocked pathological neovascularization but not physiological neovascularization after intravitreous injection in mice; this may be attributed to its selective blockage of VEGFA-165 [27]. Intravitreal injection of pegaptanib has been shown to decrease neovascularization in patients with diabetes. 3.2
Pharmacokinetics Animal models
3.2.1
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3.
Introduction to the compound
Pegaptanib (Macugen, Eyetech Pharmaceuticals; Box 1) is a pegylated anti-VEGF aptamer that selectively blocks the VEGF-165 isoform. It is based on a 28-nucleotide RNA aptamer that adopts a three-dimensional conformation that allows it to specifically bind to the extracellular VEGF-A165 in both diffusible and bound forms. The sugar back-bone of pegaptanib is modified to prevent degradation by endogenous endonucleases and exonucleases and two 20 kDA polyethylene glycol moieties are covalently attached to increase the half-life [15]. Intravitreous pegaptanib has emerged as a potential therapy for the treatment of DME, following completion of a Phase II trial [26], the first 2 years of a Phase III trial and several smaller uncontrolled trials. Chemistry and pharmacodynamics of pegaptanib DME and increased vascular permeability arise due to thickening of the capillary basement membrane, degeneration of capillary pericytes and adherence of leukocytes to the endothelium. As a pro-inflammatory mediator, VEGF may contribute to the development of DME by causing expression of cellular adhesion molecules and chemotaxia of leukocytes [27] Muller cell-derived VEGF depleted tight junction protein, increased capillary cellularity and inflammatory biomarkers, leading to retinal vascular leakage and macular edema in diabetic mice [27]. Intravitreal injection of VEGF induces a retinopathy that mimics DME in primates [27]. In addition, capillary non-perfusion leads to local hypoxia, producing angiogenic factors such as VEGF. Thus, VEGF is involved in both the development of DME as well as the maintenance of chronic DME via pro-inflammatory changes and/or loss of tight junctions in retinal capillaries [27]. VEGFA-165 is the predominant pathologic isomer in DR and may have the most potency in inducing blood-retinal barrier breakdown (VEGFA-164 in the mouse is analogous to VEGFA-165 in the human) [27] The isoforms vary in their affinity to bind heparin, causing some isoforms to be strictly bound to extracellular matrix (ECM) and other forms to be freely diffusible. VEGFA-165 has intermediate heparin binding ability. The isoforms that bind heparin and therefore have affinity for ECM can undergo proteolytic cleavage and become freely diffusible [27]. Selective blocking of VEGFA-165 via pegaptanib may decrease macular edema and also decrease 3.1
4
Pegaptanib has been evaluated in rabbits and rhesus monkeys. Bilateral intravitreal injection into rabbit eyes found it distributed in the vitreous, retina and aqueous within 24 h, slowly followed by the systemic circulation [28]. Rabbits injected with 0.5 mg pegaptanib per eye had vitreous humor samples collected over 28 days and assayed using HPLC and plasma levels detected using dual-hybridization assay [28]. Initial vitreous humor pegaptanib levels of ~ 350 µg/ml decreased to 1.7 µg/ml by day 28 by first-order elimination [28]. Estimated half-life for plasma levels was 84 h, with estimated plasma levels of 0.092 -- 0.005 µg/ml from days 1 to 21 [28]. In monkeys, the pharmacokinetics were measured using the vitreous aptamer concentrations with a binding assay and HPLC [28]. Varying doses of bilateral intravitreal injections of pegaptanib were administered as single doses (0.25, 0.5, 1, 1.5 or 2 mg each eye), 4 biweekly (0.1 mg each eye) followed by 2 biweekly (1 mg each eye) or 6 biweekly doses (0.25 or 0.5 mg each eye) [28]. Fully active pegaptanib was found in the vitreous after 7 -- 28 days [28]. For 1 and 2 mg doses the mean (SD) vitreous concentrations detected 2 days after intravitreal injections were 268 (86.8) and 499 (199.0) mg/ml, respectively [28]. The vitreous half-life based on first order kinetics was 98.7, 94.1 and 89.9 for the 0.5, 1 and 2 mg doses [28]. Human studies The pharmacokinetic study available on humans with nAMD used a 3 mg pegaptanib dose, 10 times the FDA approved dose. The mean Cmax was 80 ng/ml within 1 -- 4 days with a half-life of 10 days [28]. No literature could be found on the pharmacokinetic data for patients with renal or hepatic impairment or for patients aged ‡ 65 years or £ 18 years of age [28]. 3.2.2
4.
Clinical efficacy of pegaptanib
Intravitreous pegaptanib has emerged as an important therapy for the treatment of DME, following completion of a Phase II trial, the first 2 years of a Phase III trial and several smaller uncontrolled trials [6]. A Phase III trial of pegaptanib for the treatment of DME is now in an open-label extension through a planned 5 years [4]. Phase IA study in nAMD The Phase IA study was a multicenter open-label, dose escalation study of a single intravitreal injection of EYE001 4.1
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(pegaptanib) in patients with nAMD [14]. Doses of 0.5, 1, 2 and 3 mg were tested [14]. This study established safety of single doses of the anti-VEGF aptamer of up to 3 mg/eye [14]. No significant ocular or systemic side-effects were noted [14]. Phase II studies in DME A Phase II randomized double-blind masked trial of pegaptanib for patients with DME involving the center of the macula [26] at 0.3 mg, 1 mg and 3 mg doses were used compared to sham injections at week 6 and 12, with additional injections/focal photocoagulation as required for another 18 weeks [26]. There were better visual acuity outcomes (p = 0.04 in 0.3 mg group compared to sham), reduced central retinal thickness (p < 0.01 in 0.3 mg group compared to sham) and a reduced need for additional therapy with photocoagulation at 36 weeks when compared with sham injections (p = 0.042) [26,29].
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4.2
Phase III studies in DME A Phase III multicenter, randomized double-masked 2-year trial of pegaptanib [30] in DME has completed 2 years and is now in an open-label extension. The primary analysis included 260 patients who received 0.3 mg pegaptanib or a sham injection every 6 weeks for a total of nine injections in the first year [30]. In the second year, injections were given as often as 6 weeks according to reinjection criteria [30]. Up to three photocoagulation treatments a year were permitted beginning at week 18. The study found that 37% of patients treated with pegaptanib gained two lines (10 ETDRS letters) at 54 weeks versus sham (p = 0.0047). [30]. On average, patients treated with pegaptanib gained 5.2 letters of visual acuity at year 1 compared with 1.2 letters in the sham group (p < 0.05) [30]. At the end of year 2, patients receiving pegaptanib had gained an average of 6.1 letters, compared with 1.3 for patients in the sham arm (p < 0.01) [30]. 4.3
Safety and tolerability of ranibizumab versus pegaptanib
4.4
While serious failures in patient safety are uncommon, patient safety incidents or adverse health care events are a global concern. The role of VEGF in promoting vascular homeostasis leads to a theoretical risk of adverse thromboembolic events (ATEs) following the use of any VEGF inhibitor. When anti-VEGF agents are given systemically, there is a known risk of increased blood pressure and ischemic cardiac events. The long-term outcomes of ranibizumab for the use in DME from the RISE and RIDE study showed increased rates of stroke over 3 years in the 0.5 mg group (4.8%) compared to the 0.3 mg group (2.0%) [31]. The Antiplatelet Trialists’ Collaboration (APTC) classification was used to classify ATEs: vascular deaths (including deaths of unknown cause), nonfatal myocardial infarction and nonfatal stroke [31].
Overall APTC-classified AEs occurred in 7.2, 10.8 and 10.4% of patients in the sham/0.5, 0.3 and 0.5 mg groups, respectively. Among APTC-classified events occurring over 36 months, deaths due to vascular and unknown causes occurred in 2, 3.6, and 3.6% of patients in the sham/0.5, 0.3 and 0.5 mg ranibizumab groups, respectively [31]. The overall incidence of deaths through 36 months, including deaths from nonvascular causes, was 4.4% (11 patients) in the monthly 0.3 mg group, 6.4% (16 patients) in the 0.5 mg group and 2.8% (7 patients) in the sham/0.5 mg group [31] Causes of death were mostly consistent with those typical of patients with advanced complications of diabetes. Although the APTC classification system provides useful insight into the systemic safety of intraocular anti-VEGF therapy, a more thorough understanding of systemic anti-VEGF safety has developed over the last several years, primarily because of the use of intravenous agents in oncology. Categorizing SAEs demonstrated that the overall incidence of SAEs potentially related to systemic VEGF inhibition was higher in patients who received 0.5 mg ranibizumab compared with 0.3 mg ranibizumab or sham/0.5 mg: 49 of 249 (19.7%) versus 42 of 250 (16.8%) and 33 of 251 (13.1%) [22] The incidence of several categories (CNS and cerebrovascular hemorrhage, congestive heart failure, hypertension, gastrointestinal perforation, proteinuria and wound-healing complications) appeared to increase in a dose-dependent fashion in patients with DME treated with intravitreal ranibizumab [31]. As for pegaptanib, no new safety concerns were identified compared with the Phase II trial, the clinical trials of pegaptanib in patients with nAMD [32] and experience in clinical practice. Ocular events included conjunctival hemorrhage (22%), eye pain (10%), punctate keratitis (11%) and diabetic retinal edema (11%) [32]. Increased IOP was noted in 17 patients treated with pegaptanib and in 7 patients treated with sham injection [32]. Cardiac disorders were reported in 6.9% of pegaptanib patients and 5.6% of patients in the sham arm. No deaths were related to the injection procedure or the study drug. 5.
Conclusion
VEGF levels have been found to be higher in patients with diabetes than non-diabetic patients. The pathological process in diabetic patients differs from that in AMD patients. Most of the safety data for pan-VEGF blocker ranibizumab have been done on neovascular AMD and some safety concerns arise with the use of these medications for DME patients. The population with diabetes tends to be younger, with more cardiac and renal disease. Diabetic eyes can have neovascularization and fibrous tissue that can contract and cause tractional retinal detachments [18]. Pegaptanib is not currently approved for treatment of DME, making it an off-label treatment for DME. However, it is unclear if it plays a role
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in ischemic diabetic maculopathy [33]. There have been reports of ischemic events following bevacizumab and ranibizumab, including non-arteritic ischemic neuropathy, retinal venous circulation, retinal artery occlusion, hemorrhagic macular infarction and ocular ischemic syndrome [33]. It is hypothesized that these side-effects would not be seen with pegaptanib, which avoids complete VEGF blockade.
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6.
Expert opinion
DME is the most common cause of visual loss in working-age people. Thus it is important to identify treatments that will allow prompt improvement of visual function. Pegaptanib has the potential to improve visual acuity quickly with an excellent long-term risk-to-benefit ratio. Phase III data support the beneficial effect of pegaptanib on visual acuity and central macular thickness. Systemic adverse effects of pegaptanib are potentially minimized compared with those of pan-VEGF-A blockers such as ranibizumab and bevacizumab. Patients with diabetes are more likely to have an underlying increased risk for systemic vascular events such as stroke and myocardial infarction. As patients with DME may require long-term treatment with intravitreal injections, it is important to consider potential systemic effects in a population prone to vascular events when deciding between agents with varying levels of VEGF-blockage. In addition, deleterious local adverse effects may occur from complete blockage of VEGF after intravitreal injection. In patients with DR, excessive VEGF blockage may increase the risk of adverse effects such as macular ischemia, retinal vascular occlusion, geographic atrophy and/or systemic vascular events. It will be particularly important to contrast the adverse effect profiles of pegaptanib and ranibizumab in their Phase III trials. Although this is no substitute for a direct comparative controlled trial, it is unlikely that such a trial would be designed. In terms of efficacy, ranibizumab appears to have slightly better visual outcome, however, 37% of patients treated with pegaptanib had over 10-letter gain in the Phase III study. Unlike in neovascular age-related macular degeneration, a short delay in receiving ranibizumab is unlikely to have
6
long-term deleterious effect. In the RESTORE extension study, the patients in the laser-treated group were given ranibizumab after 12 months, and the final visual acuity at 36 months was not significantly different from that of the two groups who had ranibizumab from the beginning [34,35], suggesting that a 12-month wait is acceptable. One can propose that physicians can use pegaptanib as an initial therapy and if it has not achieved the desired result, one can then convert to a pan-VEGF blocker, as pegaptanib is potentially safer. However, as pegaptanib is not approved for DME, it can potentially create a regulatory hurdle. On the other hand, bevacizumab is unlicensed for intraocular use, but it is often used in practice; so the use of pegaptanib in DME should not be prohibited, particularly in places where bevacizumab use is widespread. A long-acting version of pegaptanib is currently under development. Pegaptanib is an aptamer, they are more stable with temperature changes, which is commonly required in compacting them into drug delivery medium. Biologics such as ranibizumab can be denatured by the increased temperature and slow delivery might be more difficult to achieve. Furthermore, a long-term pan-VEGF blockade might also be harmful. In summary, VEGF is an important molecule in the pathophysiology of DME, and VEGF blockade is an effective treatment for DME. It is possible to block either the VEGF-165 isoform alone or to block all isoforms of VEGF, depending on the agent used. Selective blockade has the advantage of less potential risk as normal VEGF-mediated physiological functions are more preserved.
Declaration of interest V Chong is a consultant for Allergan, Bayer, Novartis and Quantel Medical. His department has received grant support from Allergan, Novartis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Diabetic Retinopathy Clinical Research Network. Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127(3):245-51 Diabetic Retinopathy Clinical Research Network. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117(6):1064-77.e35 Agency EM. EPARs for authorised medicinal products for human use: Macugen. Available from: http://www. emea.europa.eu/humandocs/Humans/ EPAR/macugen/macugen.htm [cited 23 January 2009] Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an antiVEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina 2002;22(2):143-52 Gragoudas ES Adamis AP, Cunningham ET, Feinsod M, et al. Pegatanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805-16 Wenick AS, Bressler NM. Diabetic macular edema: current and emerging therapies. Middle East Afr J Ophthalmol 2012;19(1):4-12 Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Ophthalmol 2013;7:495-501 Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch clin exp ophthalmol 2010;248(7):915-30 Peter A, Campochiaro PA, Brown DM, et al. FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Opthalmology 2012;119:2125-32
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20.
Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010;128(3):289-96
21.
Frampton JE. Ranibizumab: in diabetic macular oedema. Drugs 2012;72(4):509-23
22.
Lang GE, Berta A, Eldem BM, et al. Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study. Ophthalmology 2013;120:2004-12
23.
Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol 2012;130(8):972-9
24.
van der Reis MI, La Heij EC, De Jong-Hesse Y, et al. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. Retina 2011;31(8):1449-69
25.
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF. Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119(8):1658-65
26.
Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112(10):1747-57
27.
Doggrell SA. Pegaptanib: the first antiangiogenic agent approved for neovascular macular degeneration. Expert opin pharmacother 2005;6(8):1421-3
28.
Kourlas H, Schiller DS. Pegaptanib sodium for the treatment of neovascular age-related macular degeneration: a review. Clin ther 2006;28(1):36-44
29.
Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113(1):23-8
30.
Sultan MB, Zhou D, Loftus J, et al. Macugen Study G. A phase 2/3, multicenter, randomized, double-
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1996 US Preventive Services Task Force Recommendation. U.S. Agency for Healthcare Research and Quality, Rockville, MD; 2009. Report No.: 09-05135-EF-1. U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. PMID: 20722170
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masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118(6):1107-18 31.
Wolfensberger TJ, Gregor ZJ. Macular edema -- rationale for therapy. Dev ophthalmol 2010;47:49-58
32.
Sivaprasad S, Hykin P, Saeed A, et al. Intravitreal pegaptanib sodium for choroidal neovascularisation secondary to age-related macular degeneration: panEuropean experience. Eye(Lond) 2010;24(5):793-8
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Chong V. Biological, preclinical and clinical characteristics of inhibitors of vascular endothelial growth factors. Ophthalmologica 2012;227(Suppl 1):2-10
34.
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Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE Extension Study. Ophthalmology 2014;121(5):1045-53 The RESTORE 3-year results evaluate long-term safety and efficacy profiles with ranibizumab treatment for DME. The commonest non-ocular adverse event was hypertension (7.9%) in the extension study. It can be speculated that this is a subtle side-effect of pan-
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VEGF blockade on the vascular status, and pegatanib may be safer as a firstline treatment.
Affiliation
Rupal Morjaria1,2 & Ngai Victor Chong†1,3,4 † Author for correspondence 1 Oxford University NHS Trust, Division of Ophthalmology, Healey Way, Oxford, OX3 9DY, UK Tel: +01865 234736, +0845 556 1253, +0207 467 5470, +01865 234 987; E-mail: [email protected], [email protected], [email protected] 2 Sandwell and West Birmingham NHS Trust, Division of Ophthalmology, City Road, Birmingham, B18 7QH, UK 3 Visiting Professor of Ophthalmology, University of Aston, Birmingham, UK 4 Visiting Professor of Ophthalmology, University of Hong Kong, Hong Kong, UK
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Pharmacokinetic evaluation of pegaptanib octasodium for the treatment of diabetic edema 1.
Introduction
2.
Present treatment guidelines
3.
Introduction to the compound
4.
Clinical efficacy of pegaptanib
5.
Conclusion
6.
Expert opinion
Rupal Morjaria & Ngai Victor Chong† †
Oxford University NHS Trust, Division of Ophthalmology, Healey Way, Oxford, UK
Introduction: Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy. Pegaptanib octasodium (Macugen) was the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration. It is a selective anti-VEGF agent, which only blocks VEGF. It has been shown to be safe and effective in treatment of DME in randomized controlled trials and it may be a safer first-line treatment in patients with diabetes with a predisposition to cardiovascular risk factors. Areas covered: This review covers the pharmacokinetics of pegaptanib octasodium. The authors also evaluate pegaptanib octasodium’s clinical efficacy, safety and tolerability in DME. Expert opinion: DME is the most common cause of visual loss in patients with diabetes. Pegaptanib has been found to be more effective than laser therapy alone for center-involving DME, its efficacy might be slightly worse than other pan-VEGF blockers, but the number of patients that have significant improvement of vision after treatment are similar to those treated with pan-VEGF blockers. As a selective VEGF blocker, it may have a better ocular and systemic safety profile than pan-VEGF blocking agents. It is reasonable to consider pegaptanib as the first-line treatment for center-involving DME with pan-VEGF blockers reserved for non-responders. Keywords: diabetic macular edema, expert review, Macugen, pegaptanib octasodium Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy (DR), and the most common cause of visual disability in working-age people [1-4]. The Wisconsin Epidemiologic Study of DR found the 14-year incidence of DME in type 1 diabetics to be 26% [5] and 27% of type 1 patients develop DME within 9 years of onset [6] An even higher incidence of macular edema has been reported in older patients with type 2 diabetes [7]. Treatments for DME are targeted to decreasing vascular leakage in order to allow for stabilization or improvement of visual acuity [4]. Focal photocoagulation has been the gold-standard treatment since the results of the Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1985, showed the reduction in risk of moderate visual loss by 50% (from 24 to 12% at 3 years) [8] following laser photocoagulation compared to no treatment [9]. The Diabetic Retinopathy Clinical Research Network (DRCRnet) indicates that even with tight glycemic and blood pressure control, 12 -- 13% of patients with foveal centered DME who undergo focal/grid laser lose 10 or more ETDRS letters after 2 -- 3 years of follow-up. The risks of laser photocoagulation include foveal damage due to inadvertent macular photocoagulation and post-operative expansion of treatment scars, both of which may result in a permanent decrease in visual 10.1517/17425255.2014.922543 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Pegaptanib octasodium II, III trials Diabetic macular edema VEGF 165 receptor antagonist Parenteral, intraocular O
N H
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O O H3C
ht O x
H
H N
Pivotal trial(s)
ht O y
CH3
CH3
O P
N H O
Chemical formula
O
O
O– Na+
The chemical name for pegaptanib sodium is: RNA, ((2¢-deoxy-2¢-fluoro)C-Gm-Gm-A-A-(2¢deoxy-2¢-fluoro)U-(2¢-deoxy-2¢-fluoro)C-Am-Gm-(2¢-deoxy-2¢-fluoro)U-Gm-Am-Am-(2¢deoxy-2¢-fluoro)U-Gm-(2¢-deoxy-2¢-fluoro)C-(2¢-deoxy-2¢-fluoro)U-(2¢-deoxy-2¢-fluoro)UAm-(2¢-deoxy-2¢-fluoro)U-Am-(2¢-deoxy-2¢-fluoro)C-Am-(2¢-deoxy-2¢-fluoro)U-(2¢-deoxy-2¢fluoro)C-(2¢-deoxy-2¢-fluoro)C-Gm-(3¢!3¢)-dT), 5¢-ester with a, a¢-[4,12-dioxo6-[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1, 15-pentadecanediyl]bis [w-methoxypoly(oxy-1,2-ethanediyl)], sodium salt. The molecular formula for pegaptanib sodium is: C294H342F13N107Na28O188P28[C2H4O]n (where n is ~ 900), and the molecular weight is ~ 50 kDa [29] Preclinical and Phase IA clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration [15] A Phase II randomized double-masked trial of pegaptanib, an anti-VEGF aptamer, for diabetic macular edema [5] A Phase II/III, multicenter, randomized, double-masked, 2-year trial of pegatanib sodium for the treatment of diabetic macular edema [30]
Highlighted are the pivotal trials evaluating the efficacy of pegatanib.
acuity, indicating the need for improved treatment modalities [10-12]. Within the past 5 years, the use of intravitreal corticosteroids and intravitreal anti-VEGF agents have come into common clinical practice for the management of DME [9]. Pegaptanib octasodium (Box 1) is a selective anti-VEGF agent, which may have a better safety profile for use in DME. This paper provides an evaluation of the clinical usefulness, safety and tolerability of pegaptanib octasodium for the treatment of DME. A Medline search was performed using the terms ‘pegaptanib octasodium’, ‘Macugen’, and ‘diabetic macula edema’, ‘vascular endothelial growth factor’ ‘treatment’ or ‘tolerability’, ‘safety’, ‘pharmacokinetics’, ‘metabolism’.
unless there are contraindications. Pan-VEGF blockers and macula laser are used for the treatment of DME with a limited use of periocular/intraocular steroids. Overview of the market Several pharmacological as well as non-pharmacological treatment options are available for the treatment of DME. The greatest tool for preventing vision loss from DR is timely screening and identification of high-risk patients [18]. Focal laser treatment has been the gold standard treatment for DME, however its limitations have led to the use of other agents described in this article. 2.1
Corticosteroids The DRCRnet’s 3-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for DME showed laser treatment to be safer [11,18] At 3 years, central subfield thickness was < 250 µm in 67% eyes in the laser group, 43% in the 1 mg triamcinolone group and 51% in the 4 mg triamcinolone group [11]. Side-effects are a major drawback for the use of intravitreal triamcinolone. Four eyes in the 4 mg triamcinolone group had a procedure for glaucoma [11]. Among phakic eyes at baseline, the 3-year 2.2
2.
Present treatment guidelines
Since the publication of ETDRS, the Diabetes Control and Complications Trial Research Group and the UK Prospective Diabetes Study have demonstrated that tight glycemic and blood pressure control decreases the risk of micro-vascular complications of diabetes, including DR and vision loss [13-17]. Patients should be started on statins and fenofibrates 2
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Pegaptanib octasodium
cumulative probability of cataract surgery was 31% in the laser group and 83% in the 4 mg group. Sustained release steroid delivery systems offer the possibility of less frequent dosing; however, they have the same problems with adverse events. The fluocinolone acetonide in macula edema trial assessed sustained delivery fluocinolone acetonide (FAc) non-biodegradable intravitreal insert in 956 patients with DME [19]. The mean improvement from baseline in best corrected visual acuity (BCVA) letter score at month 24 was 4.4 and 5.4 in the low- and high-dose groups compared with 1.7 in the sham group [19]. Cataracts occurred in 42.7% of the low-dose group, 51.7% of the high-dose group and 9.7% of the sham group [19]. Intraocular pressure (IOP)-related adverse events (AEs) were more frequent in the FAc insert groups than in the sham group (low dose, 37.1%; high dose, 45.5%; sham, 11.9%) [19] Laser trabeculoplasty was performed in 2.5% of the high-dose group, 1.3% of the low-dose group and 0% of the sham group and IOP-lowering surgery was performed in 8.1% of the highdose group, 4.8% of the low-dose group and 0.5% of the sham group [19] The lower dose FAc (Illuvien - Alimera Sciences, Alpharetta, GA, USA) is now approved for use in DME patients in several European countries but at the time of writing (April 2014) not in the US. The longer acting nature of Iluvien does potentially have a benefit in terms of treatment rate over regular intravitreal anti-VEGF treatments, but this benefit has to be balanced against the greater risk of side-effects [11]. A 700 µg dexamethasone intravitreal drug delivery system (DDS) (Ozurdex - Dexamethasone Impant, Allergan) was compared with a 350 µg dexamethasone intravitreal DDS and observation (171 eyes, 180-day follow-up) for eyes with DME [20] At 90-day follow-up, a statistically significant difference in the proportion of eyes achieving at least a 10-letter improvement in BCVA was evident between the 700 µg dexamethasone group and the observation group (33 vs. 12%; p = 0.007). This difference was not statistically significant at day 180 (30 vs. 23% respectively). The 350 µg dose showed a statistically significant effect at 60 days (23 vs. 9% 10-letter improvement), but not at 90 or 180 days. At day 90, there was also a statistically significant improvement in both central retinal thickness (CRT) (p < 0.01) and fluorescein leakage (p < 0.001) in eyes that received the 700 µg dexamethasone DDS compared with eyes in the observation group. The Phase III study of Ozurdex was presented recently, which showed that there were some efficacy compared with sham treatment, but cataract remains a problem. The risk of IOP rise seems to be less than that of Iluvien. The role of corticosteroids in DME might be restricted to the pseudophakic patients. Anti-VEGF therapy Several anti-VEGF agents are available. The first anti-VEGF agent used in ophthalmology was pegaptanib (OSI Pharmaceuticals, Long Island, New York, US), which is based on a 2.3
28-nucleotide RNA aptamer that binds to the VEGF-A165 isoform and was initially approved for the treatment of neovascular age-related macular degeneration (nAMD). This will be discussed further, later in the paper. Its use has largely been supplanted by the development of ranibizumab (Genentech, Inc., South San Francisco, California, US), a Fab anti-VEGF agent that neutralizes all isoforms of VEGFA. Ranibizumab, specifically designed for intravitreal use, was approved in European countries in 2007 for the treatment of nAMD, in 2010 for the treatment of visual impairment due to DME and in 2011 for the treatment of visual impairment due to macular edema secondary to retinal vein occlusion [21,22]. The randomized clinical trial Ranibizumab for Edema of the Macula in Diabetes (READ-2) and that of the DRCR.net along with pivotal studies RESOLVE and RESTORE in > 1000 patients have established the efficacy and safety of ranibizumab in DME. The 2-year report of the safety and efficacy of ranibizumab 0.5 mg in DME from the RESTORE found non-ocular AEs leading to study drug discontinuation in the second year; these included acute myocardial infarction and cerebrovascular accident, subarachnoid hemorrhage, chronic renal failure, pulmonary embolism and respiratory arrest [22]. Patients with diabetes are predisposed to cardiovascular risks and there was some evidence of increased risk of hypertension with ranibizumab: 10% (n = 12) in the ranibizumab arm; 9% (n = 10.8) in the ranibizumab and laser arm; 6% (n = 8) in the laser arm [22]. Bevacizumab (Genentech, Inc., South San Francisco, California, US), a humanized monoclonal antibody that binds to all isoforms of VEGF-A [23], was developed in 1996 and first used for the treatment of human cancers. It has also come into widespread off license clinical use in the treatment of retinal disease. The BOLT Study was a 2-year prospective randomized controlled trial comparing intravitreal bevacizumab (IVB) to laser therapy for center involving DME [23]. IVB was given at baseline, 6 weeks, 12 weeks and then at prn basis [23]. The mean visual acuity gain at 24 months in EDTRS letters was 9 in the bevacizumab arm compared to 2.5 letters in the laser arm (p = 0.005) [23]. The study was not large enough to make definitive statement on the safety of the drug in diabetic patients, with a predisposed risk of cardiovascular events [24]. IVB is used worldwide on a large scale because of its lower price in comparison to ranibizumab. Formal evaluation of the safety of IVB is lacking. Another anti-VEGF agent that has been developed is aflibercept (Regeneron, Tarrytown, New York, US), which consists of the VEGF binding portions of the human VEGFR-1 and VEGFR-2 fused to the Fc portion of the human Ig-G1. In addition to having high affinity to all isoforms of VEGF-A, it also binds to placental growth factor [25]. VEGF trap-eye has been evaluated in the Phase II Da Vinci study (n = 219). Aflibercept has a potentially longer duration of action than ranibizumab and bevacizumab in DME. Eyes treated with each aflibercept dosing regimen
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experienced statistically significant reductions in central retinal CRT compared with eyes undergoing laser treatment and improvements in visual acuity at week 52 [25]. Although the study was not large enough to be powered adequately to assess the significance of differences in safety, the most common systemic AEs were hypertension, nausea and congestive heart failure. [25]. Seven deaths occurred during the study. One patient in the laser group died of cardiac arrest compared to six in the aflibercept group [25].
the risk of adverse effects associated with more complete VEGF blockage. Pegaptanib blocked pathological neovascularization but not physiological neovascularization after intravitreous injection in mice; this may be attributed to its selective blockage of VEGFA-165 [27]. Intravitreal injection of pegaptanib has been shown to decrease neovascularization in patients with diabetes. 3.2
Pharmacokinetics Animal models
3.2.1
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3.
Introduction to the compound
Pegaptanib (Macugen, Eyetech Pharmaceuticals; Box 1) is a pegylated anti-VEGF aptamer that selectively blocks the VEGF-165 isoform. It is based on a 28-nucleotide RNA aptamer that adopts a three-dimensional conformation that allows it to specifically bind to the extracellular VEGF-A165 in both diffusible and bound forms. The sugar back-bone of pegaptanib is modified to prevent degradation by endogenous endonucleases and exonucleases and two 20 kDA polyethylene glycol moieties are covalently attached to increase the half-life [15]. Intravitreous pegaptanib has emerged as a potential therapy for the treatment of DME, following completion of a Phase II trial [26], the first 2 years of a Phase III trial and several smaller uncontrolled trials. Chemistry and pharmacodynamics of pegaptanib DME and increased vascular permeability arise due to thickening of the capillary basement membrane, degeneration of capillary pericytes and adherence of leukocytes to the endothelium. As a pro-inflammatory mediator, VEGF may contribute to the development of DME by causing expression of cellular adhesion molecules and chemotaxia of leukocytes [27] Muller cell-derived VEGF depleted tight junction protein, increased capillary cellularity and inflammatory biomarkers, leading to retinal vascular leakage and macular edema in diabetic mice [27]. Intravitreal injection of VEGF induces a retinopathy that mimics DME in primates [27]. In addition, capillary non-perfusion leads to local hypoxia, producing angiogenic factors such as VEGF. Thus, VEGF is involved in both the development of DME as well as the maintenance of chronic DME via pro-inflammatory changes and/or loss of tight junctions in retinal capillaries [27]. VEGFA-165 is the predominant pathologic isomer in DR and may have the most potency in inducing blood-retinal barrier breakdown (VEGFA-164 in the mouse is analogous to VEGFA-165 in the human) [27] The isoforms vary in their affinity to bind heparin, causing some isoforms to be strictly bound to extracellular matrix (ECM) and other forms to be freely diffusible. VEGFA-165 has intermediate heparin binding ability. The isoforms that bind heparin and therefore have affinity for ECM can undergo proteolytic cleavage and become freely diffusible [27]. Selective blocking of VEGFA-165 via pegaptanib may decrease macular edema and also decrease 3.1
4
Pegaptanib has been evaluated in rabbits and rhesus monkeys. Bilateral intravitreal injection into rabbit eyes found it distributed in the vitreous, retina and aqueous within 24 h, slowly followed by the systemic circulation [28]. Rabbits injected with 0.5 mg pegaptanib per eye had vitreous humor samples collected over 28 days and assayed using HPLC and plasma levels detected using dual-hybridization assay [28]. Initial vitreous humor pegaptanib levels of ~ 350 µg/ml decreased to 1.7 µg/ml by day 28 by first-order elimination [28]. Estimated half-life for plasma levels was 84 h, with estimated plasma levels of 0.092 -- 0.005 µg/ml from days 1 to 21 [28]. In monkeys, the pharmacokinetics were measured using the vitreous aptamer concentrations with a binding assay and HPLC [28]. Varying doses of bilateral intravitreal injections of pegaptanib were administered as single doses (0.25, 0.5, 1, 1.5 or 2 mg each eye), 4 biweekly (0.1 mg each eye) followed by 2 biweekly (1 mg each eye) or 6 biweekly doses (0.25 or 0.5 mg each eye) [28]. Fully active pegaptanib was found in the vitreous after 7 -- 28 days [28]. For 1 and 2 mg doses the mean (SD) vitreous concentrations detected 2 days after intravitreal injections were 268 (86.8) and 499 (199.0) mg/ml, respectively [28]. The vitreous half-life based on first order kinetics was 98.7, 94.1 and 89.9 for the 0.5, 1 and 2 mg doses [28]. Human studies The pharmacokinetic study available on humans with nAMD used a 3 mg pegaptanib dose, 10 times the FDA approved dose. The mean Cmax was 80 ng/ml within 1 -- 4 days with a half-life of 10 days [28]. No literature could be found on the pharmacokinetic data for patients with renal or hepatic impairment or for patients aged ‡ 65 years or £ 18 years of age [28]. 3.2.2
4.
Clinical efficacy of pegaptanib
Intravitreous pegaptanib has emerged as an important therapy for the treatment of DME, following completion of a Phase II trial, the first 2 years of a Phase III trial and several smaller uncontrolled trials [6]. A Phase III trial of pegaptanib for the treatment of DME is now in an open-label extension through a planned 5 years [4]. Phase IA study in nAMD The Phase IA study was a multicenter open-label, dose escalation study of a single intravitreal injection of EYE001 4.1
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Pegaptanib octasodium
(pegaptanib) in patients with nAMD [14]. Doses of 0.5, 1, 2 and 3 mg were tested [14]. This study established safety of single doses of the anti-VEGF aptamer of up to 3 mg/eye [14]. No significant ocular or systemic side-effects were noted [14]. Phase II studies in DME A Phase II randomized double-blind masked trial of pegaptanib for patients with DME involving the center of the macula [26] at 0.3 mg, 1 mg and 3 mg doses were used compared to sham injections at week 6 and 12, with additional injections/focal photocoagulation as required for another 18 weeks [26]. There were better visual acuity outcomes (p = 0.04 in 0.3 mg group compared to sham), reduced central retinal thickness (p < 0.01 in 0.3 mg group compared to sham) and a reduced need for additional therapy with photocoagulation at 36 weeks when compared with sham injections (p = 0.042) [26,29].
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4.2
Phase III studies in DME A Phase III multicenter, randomized double-masked 2-year trial of pegaptanib [30] in DME has completed 2 years and is now in an open-label extension. The primary analysis included 260 patients who received 0.3 mg pegaptanib or a sham injection every 6 weeks for a total of nine injections in the first year [30]. In the second year, injections were given as often as 6 weeks according to reinjection criteria [30]. Up to three photocoagulation treatments a year were permitted beginning at week 18. The study found that 37% of patients treated with pegaptanib gained two lines (10 ETDRS letters) at 54 weeks versus sham (p = 0.0047). [30]. On average, patients treated with pegaptanib gained 5.2 letters of visual acuity at year 1 compared with 1.2 letters in the sham group (p < 0.05) [30]. At the end of year 2, patients receiving pegaptanib had gained an average of 6.1 letters, compared with 1.3 for patients in the sham arm (p < 0.01) [30]. 4.3
Safety and tolerability of ranibizumab versus pegaptanib
4.4
While serious failures in patient safety are uncommon, patient safety incidents or adverse health care events are a global concern. The role of VEGF in promoting vascular homeostasis leads to a theoretical risk of adverse thromboembolic events (ATEs) following the use of any VEGF inhibitor. When anti-VEGF agents are given systemically, there is a known risk of increased blood pressure and ischemic cardiac events. The long-term outcomes of ranibizumab for the use in DME from the RISE and RIDE study showed increased rates of stroke over 3 years in the 0.5 mg group (4.8%) compared to the 0.3 mg group (2.0%) [31]. The Antiplatelet Trialists’ Collaboration (APTC) classification was used to classify ATEs: vascular deaths (including deaths of unknown cause), nonfatal myocardial infarction and nonfatal stroke [31].
Overall APTC-classified AEs occurred in 7.2, 10.8 and 10.4% of patients in the sham/0.5, 0.3 and 0.5 mg groups, respectively. Among APTC-classified events occurring over 36 months, deaths due to vascular and unknown causes occurred in 2, 3.6, and 3.6% of patients in the sham/0.5, 0.3 and 0.5 mg ranibizumab groups, respectively [31]. The overall incidence of deaths through 36 months, including deaths from nonvascular causes, was 4.4% (11 patients) in the monthly 0.3 mg group, 6.4% (16 patients) in the 0.5 mg group and 2.8% (7 patients) in the sham/0.5 mg group [31] Causes of death were mostly consistent with those typical of patients with advanced complications of diabetes. Although the APTC classification system provides useful insight into the systemic safety of intraocular anti-VEGF therapy, a more thorough understanding of systemic anti-VEGF safety has developed over the last several years, primarily because of the use of intravenous agents in oncology. Categorizing SAEs demonstrated that the overall incidence of SAEs potentially related to systemic VEGF inhibition was higher in patients who received 0.5 mg ranibizumab compared with 0.3 mg ranibizumab or sham/0.5 mg: 49 of 249 (19.7%) versus 42 of 250 (16.8%) and 33 of 251 (13.1%) [22] The incidence of several categories (CNS and cerebrovascular hemorrhage, congestive heart failure, hypertension, gastrointestinal perforation, proteinuria and wound-healing complications) appeared to increase in a dose-dependent fashion in patients with DME treated with intravitreal ranibizumab [31]. As for pegaptanib, no new safety concerns were identified compared with the Phase II trial, the clinical trials of pegaptanib in patients with nAMD [32] and experience in clinical practice. Ocular events included conjunctival hemorrhage (22%), eye pain (10%), punctate keratitis (11%) and diabetic retinal edema (11%) [32]. Increased IOP was noted in 17 patients treated with pegaptanib and in 7 patients treated with sham injection [32]. Cardiac disorders were reported in 6.9% of pegaptanib patients and 5.6% of patients in the sham arm. No deaths were related to the injection procedure or the study drug. 5.
Conclusion
VEGF levels have been found to be higher in patients with diabetes than non-diabetic patients. The pathological process in diabetic patients differs from that in AMD patients. Most of the safety data for pan-VEGF blocker ranibizumab have been done on neovascular AMD and some safety concerns arise with the use of these medications for DME patients. The population with diabetes tends to be younger, with more cardiac and renal disease. Diabetic eyes can have neovascularization and fibrous tissue that can contract and cause tractional retinal detachments [18]. Pegaptanib is not currently approved for treatment of DME, making it an off-label treatment for DME. However, it is unclear if it plays a role
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in ischemic diabetic maculopathy [33]. There have been reports of ischemic events following bevacizumab and ranibizumab, including non-arteritic ischemic neuropathy, retinal venous circulation, retinal artery occlusion, hemorrhagic macular infarction and ocular ischemic syndrome [33]. It is hypothesized that these side-effects would not be seen with pegaptanib, which avoids complete VEGF blockade.
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6.
Expert opinion
DME is the most common cause of visual loss in working-age people. Thus it is important to identify treatments that will allow prompt improvement of visual function. Pegaptanib has the potential to improve visual acuity quickly with an excellent long-term risk-to-benefit ratio. Phase III data support the beneficial effect of pegaptanib on visual acuity and central macular thickness. Systemic adverse effects of pegaptanib are potentially minimized compared with those of pan-VEGF-A blockers such as ranibizumab and bevacizumab. Patients with diabetes are more likely to have an underlying increased risk for systemic vascular events such as stroke and myocardial infarction. As patients with DME may require long-term treatment with intravitreal injections, it is important to consider potential systemic effects in a population prone to vascular events when deciding between agents with varying levels of VEGF-blockage. In addition, deleterious local adverse effects may occur from complete blockage of VEGF after intravitreal injection. In patients with DR, excessive VEGF blockage may increase the risk of adverse effects such as macular ischemia, retinal vascular occlusion, geographic atrophy and/or systemic vascular events. It will be particularly important to contrast the adverse effect profiles of pegaptanib and ranibizumab in their Phase III trials. Although this is no substitute for a direct comparative controlled trial, it is unlikely that such a trial would be designed. In terms of efficacy, ranibizumab appears to have slightly better visual outcome, however, 37% of patients treated with pegaptanib had over 10-letter gain in the Phase III study. Unlike in neovascular age-related macular degeneration, a short delay in receiving ranibizumab is unlikely to have
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long-term deleterious effect. In the RESTORE extension study, the patients in the laser-treated group were given ranibizumab after 12 months, and the final visual acuity at 36 months was not significantly different from that of the two groups who had ranibizumab from the beginning [34,35], suggesting that a 12-month wait is acceptable. One can propose that physicians can use pegaptanib as an initial therapy and if it has not achieved the desired result, one can then convert to a pan-VEGF blocker, as pegaptanib is potentially safer. However, as pegaptanib is not approved for DME, it can potentially create a regulatory hurdle. On the other hand, bevacizumab is unlicensed for intraocular use, but it is often used in practice; so the use of pegaptanib in DME should not be prohibited, particularly in places where bevacizumab use is widespread. A long-acting version of pegaptanib is currently under development. Pegaptanib is an aptamer, they are more stable with temperature changes, which is commonly required in compacting them into drug delivery medium. Biologics such as ranibizumab can be denatured by the increased temperature and slow delivery might be more difficult to achieve. Furthermore, a long-term pan-VEGF blockade might also be harmful. In summary, VEGF is an important molecule in the pathophysiology of DME, and VEGF blockade is an effective treatment for DME. It is possible to block either the VEGF-165 isoform alone or to block all isoforms of VEGF, depending on the agent used. Selective blockade has the advantage of less potential risk as normal VEGF-mediated physiological functions are more preserved.
Declaration of interest V Chong is a consultant for Allergan, Bayer, Novartis and Quantel Medical. His department has received grant support from Allergan, Novartis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Drug Metab. Toxicol. (2014) 10(8)
Pegaptanib octasodium
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VEGF blockade on the vascular status, and pegatanib may be safer as a firstline treatment.
Affiliation
Rupal Morjaria1,2 & Ngai Victor Chong†1,3,4 † Author for correspondence 1 Oxford University NHS Trust, Division of Ophthalmology, Healey Way, Oxford, OX3 9DY, UK Tel: +01865 234736, +0845 556 1253, +0207 467 5470, +01865 234 987; E-mail: [email protected], [email protected], [email protected] 2 Sandwell and West Birmingham NHS Trust, Division of Ophthalmology, City Road, Birmingham, B18 7QH, UK 3 Visiting Professor of Ophthalmology, University of Aston, Birmingham, UK 4 Visiting Professor of Ophthalmology, University of Hong Kong, Hong Kong, UK
