ARTICLES

ARTICLES New Drug Approvals

Ranibizumab: The First Vascular Endothelial Growth Factor Inhibitor Approved for the Treatment of Diabetic Macular Edema Kirk E Evoy, Steven R Abel

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ithin developed countries, no condition inflicts more vision loss on working-age adults than diabetic retinopathy.1,2 Among patients with diabetic retinopathy, diabetic macular edema (DME) is the leading cause of moderate vision loss.1,2 According to the International Diabetes Foundation, approximately 14% of the 285 million individuals living with diabetes mellitus have DME.3 With the prevalence of diabetes expected to double over the next 20 years, DME will likely become increasingly pervasive.4 DME confers substantial economic burden on the patients affected as well as significant reduction in quality of life.1 This is evidenced by the fact that approximately 50% of patients with clinically significant DME lose at least 2 lines of visual acuity within 2 years, and by 3 years 25% have lost 3 lines (loss of 1 line [or 5

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OBJECTIVE: To review the pharmacology, efficacy, and safety data available for ranibizumab and compare the drug to other therapeutic options for diabetic macular edema (DME) to determine its likely role in therapy.

DATA SOURCES: A PubMed search was initially used to identify all trials pertaining to the use of ranibizumab for DME. This search was conducted in February 2013 without a time frame for exclusion of older trials (all references included were published between January 1987 and February 2013). Following a review of the references of these articles, additional sources were obtained from PubMed, the manufacturer’s website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION:

Trials conducted in animals and those written in a language other than English were excluded. Abstracts of remaining trials were reviewed for determination of relevance to this review. Preference was given to randomized controlled trials. Additional information sources were obtained from a review of references as deemed necessary by the authors. DATA SYNTHESIS:

Six Phase 2 or 3 randomized controlled trials studying the effects of ranibizumab in patients with DME were identified. Within these trials, ranibizumab consistently produced significantly greater gains in mean best corrected visual acuity than focal/grid laser photocoagulation or sham (7.4-12.5 letter improvement with ranibizumab vs 0.5-3 letters following focal/grid laser photocoagulation monotherapy) with a favorable safety and tolerability profile. Ranibizumab was also studied in combination with focal/grid laser photocoagulation, showing no additional gains in vision versus ranibizumab monotherapy. CONCLUSIONS: The identified trials provide support for the safety and efficacy of ranibizumab in the treatment of vision loss due to DME and present a strong case for the shift to first-line treatment with vascular endothelial growth factor inhibitors from focal/grid laser photocoagulation, the standard of care since the Early Treatment Diabetic Retinopathy Study of 1985.

Ann Pharmacother 2013;47:811-8.

Published Online, 8 May 2013, theannals.com, doi: 10.1345/aph.1S013

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letters] of visual acuity refers to loss of the ability to read 1 line previously readable on a standard Early Treatment Diabetic Retinopathy Study [ETDRS] eye chart and a loss of 3 lines represents a doubling of the visual angle).1 Focal/ grid laser photocoagulation (herein referred to as laser), the standard of care for DME since 1985, was shown by the ETDRS to reduce this risk of significant vision loss by 50%, but rarely leads to significant visual improvement and is not a benign treatment in terms of potential harm to the eye.4-7 Thus, the recent discovery that intraocular vascular endothelial growth factor (VEGF) inhibition is well tolerated and reliably provides DME patients substantial gains in visual acuity represents a significant advance in patient care. Currently, 4 anti-VEGF agents are available for intravitreal administration, but due to inferior efficacy (pegaptanib) and the need for more research (aflibercept), 2 agents dominate this market, ranibizumab and bevacizumab.8-10 Ranibizumab, first approved in 2006 for neovascular age-related macular edema (AMD) and later for macular edema secondary to central retinal vein occlusion, recently became the first VEGF inhibitor with a Food and Drug Administration (FDA) indication for the treatment of DME.11 As a number of studies have demonstrated its superior efficacy compared with laser and another recent addition to the DME treatment repertoire, intraocular corticosteroids, anti-VEGF therapy has begun to shift the longstanding paradigm of DME treatment. This article reviews the pharmacology, efficacy, and safety data available for ranibizumab and compares the drug to other therapeutic options for DME to determine its likely role in therapy. Data Sources

A PubMed search of the terms ranibizumab and diabetic macular edema was conducted in February 2013, with no limit for exclusion of older trials, to identify initial literature sources. Animal studies and those written in a language other than English were excluded. Abstracts of remaining studies were reviewed for determination of relevance to this review. Priority was given to randomized controlled trials (RCTs). Additional articles were obtained following a review of references of included studies. All references included were published between January 1987 and February 2013.

Pharmacology

DME is a manifestation of diabetic retinopathy, a significant microvascular complication of uncontrolled diabetes mellitus. The chronic hyperglycemia experienced by patients with DME harms the blood vessels of the retina. This insult can produce several deleterious effects, includ812

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ing, by multiple mechanisms, potentiation of subsequent retinal hypoxia.2,12 These conditions, along with a number of others not necessarily related to diabetes (eg, inflammation), lead to increased production of VEGF, a factor that plays a major role in the pathogenesis of DME. As a key mediator of angiogenesis, VEGF-A generates many changes within the retinal vasculature when pathologically upregulated, including breakdown of the blood retinal barrier, promotion of vascular leakage, and accumulation of excess extracellular fluid in the macula associated with DME.3,8,1214 Ranibizumab is a 48 kDa recombinant, humanized, IgG1 κ isotype monoclonal antibody fragment that binds to all isoforms of VEGF-A, preventing the growth factor from interacting with its receptors, VEGR-1 and -2, on the endothelial cell surface, reducing the negative effects described above. The result is a decrease in edema and macular density and improved visual acuity.1,8,10,11 Pharmacokinetics

Following intravitreal administration, ranibizumab predominantly localizes to the injected eye, with very little, if any, reaching the fellow eye or systemic circulation.1,10 According to the manufacturer, serum ranibizumab concentrations are approximately 90,000-fold lower than vitreal concentrations, and well below that which is required to systemically inhibit 50% of the biological activity of VEGF, with a predicted steady-state serum concentration of 0.22 ng/mL when administered monthly.11 Extensive study of ranibizumab pharmacokinetics in the human eye is lacking and the pharmacokinetic information provided by the manufacturer is based on predictions from animal models and studies of human serum following intravitreal administration. However, one small-scale (N = 18) trial was recently conducted to explore the intraocular pharmacokinetics following a single intravitreal injection of ranibizumab in patients with macular edema secondary to various underlying disease states (including 6 patients with DME).15 In this study, peak ranibizumab concentrations within the aqueous humor were 36.9-66.1 µg/mL, observed the first day after injection. From that peak, the levels fell monoexponentially. Based on nonlinear regression, the predicted maximum concentration and elimination half-life were 56.1 µg/mL and 7.19 days, respectively. In comparison with its principal competitor, bevacizumab, ranibizumab has a slightly shorter half-life (predicted to be 9.82 days in a methodologically similar study conducted by the same researchers15), likely conferred by its smaller molecular size. However, with a 5- to 20-fold higher biological activity, ranibizumab produces a slightly longer-lasting effect on the eye.10,15 Additionally, while the clinical implications have yet to be fully determined, the smaller sized ranibizumab molecule theoretically could provide slightly greater efficacy because of better penetra-

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tion into the retina and less risk of systemic adverse effects because of quicker elimination.8,10 Clinical Trials

In contrast to its competitor VEGF inhibitors, which currently have little support from high-quality RCTs, ranibizumab has been extensively studied for the treatment of DME in recent years (Table 1).2,4,5,16-19 (Names of the clinical trials are reported in the Appendix.) Among the 6 Phase 2 or 3 RCTs identified, ranibizumab alone or in combination has been studied in more than 2000 eyes. Throughout, it has been safe, well tolerated, and has displayed superior efficacy to sham (placebo-control involving application of pressure to the eye to simulate injection) or laser control in each trial (mean best-corrected visual acuity [BCVA] improvement ranging from 7.4 to 12.5 letters with ranibizumab vs from 0.5 to 3 letters with laser monotherapy). The RESOLVE trial4 (N = 151) and the identically designed, concurrently conducted RISE and RIDE trials19 (N =

Characteristic

Ranibizumab for Treatment of Diabetic Macular Edema

759) each demonstrated superiority of ranibizumab versus sham injection. RESOLVE was notable in that it was the only trial to allow investigators to double the initially assigned dose at any point in the trial if prespecified criteria were met.4 As a result, 68.6% of participants undertook the dose-doubling (70-78% of those following month 1). Thus, most patients received a higher dose than that used in the other Phase 2 or 3 trials. Despite this increased dose, efficacy was not significantly improved and a similar safety profile was seen. RISE and RIDE, the trials used as confirmatory evidence for FDA approval for DME (identified as DME-1 and DME-2 in the prescribing information11), were unique in that they were the only trials in which patients received a monthly dose throughout the study, as the others used a set dosing interval initially followed by as-needed administration (Table 1).19 While of similar magnitude to other trials, this aggressive dosing regimen produced the highest BCVA improvement without significantly different safety or tolerability concerns. Both the READ -2 (N = 126)2,16 and RESTORE (N = 345)18 trials compared ranibizumab and laser monotherapy to

Table 1. Summary of Phase 2 and 3 Clinical Trials of Ranibizumab for Diabetic Macular Edema READ-22,16

RESOLVE4

Participants

126

Mean no. of injections

Months 6-24 Pooled ranibizumab: Months 3-11: ranibizumab: 5.3 10.2 ± 2.5 ranibizumab with (maximum 9) Sham: 8.9 ± 3.5 sham: 4.1 FGL: 4.4 (maximum 9) ranibizumab with ranibizumab with FGL: 3.8 FGL: 3.9 sham with FGL: 4.5 (maximum 6)

Design; duration

Intervention

Phase 2; 36 monthsa

Ranibizumab 0.5 mg for 6 months, then prn FGL at baseline, then  prn Ranibizumab with FGL at baseline and 3 months, then prn

Mean BCVA change from baseline (letters)c

Ranibizumab: 7.4 (p < 0.0001) FGL: 0.5 (NS) Ranibizumab with FGL: 3.8 (p = 0.02)

Mean CRT change from baseline (µm)c

Ranibizumab: 340 FGL: 286 Ranibizumab with FGL: 258

151

345

RESTORE18

Phase 2; 12 months Phase 3; 12 months Ranibizumab 0.3 mg/0.6 mg prn Ranibizumab 0.5/1 mg prn Sham

Ranibizumab 0.5 mg prn with sham Ranibizumab 0.5 mg prn with FGL Sham with FGL

Pooled ranibizumab: Ranibizumab with 10.3 ± 9.1 sham: 6.8 ± 8.3 (p < 0.0001) (p < 0.0001) Sham: –1.4 ± 14.2 Ranibizumab with FGL: 6.4 ± 11.8 (p = 0.0004) Sham with FGL: 0.9 ± 11.4

Pooled ranibizumab: Ranibizumab with –194 ± 135.1 sham: –118.7 (p < 0.001) (p < 0.001) Sham: –48.4 ± Ranibizumab with 153.4 FGL: –128.3 (p < 0.001) Sham with FGL: –61.3

DRCR.net5,17

691 (854 eyes)

759

RISE/RIDE19

Phase 3; 60 monthsb

Phase 3; 24 months

Median: 3 fewer injections with prompt FGL vs deferred FGL at 2 years

24 in all groups

Ranibizumab with prompt FGL: 7 ± 15 Ranibizumab with deferred FGL: 9 ± 13 Triamcinolone with prompt FGL: 2 ± 14 Sham with prompt FGL: 3 ± 19

RISE ranibizumab: 11.9-12.5 sham: 2.6 RIDE ranibizumab: 10.9-12 sham: 2.3

Ranibizumab 0.5 mg prn with prompt FGL Ranibizumab 0.5 mg prn with deferred FGL Triamcinolone with prompt FGL Sham with prompt FGL

Ranibizumab with prompt FGL: –138 ± 149 Ranibizumab with deferred FGL: –141 ± 155 Triamcinolone with prompt FGL: –150 ± 143 Sham with prompt FGL: –107 ± 145

Ranibizumab 0.3 mg monthly Ranibizumab 0.5 mg monthly Sham

RISE ranibizumab: –250.6 to –253.1 sham: –133.4 RIDE ranibizumab: –259.8 to –270.7 sham: –125.8

BCVA = best-corrected visual acuity; CRT = central retinal thickness; FGL = focal/grid laser photocoagulation. a Six-month primary data shown because all patients received ranibizumab from months 6 to 36. b Twenty-four month data shown because triamcinolone was not continued beyond 24 months and 60-month results have not been released. c Some p values not included in article text.

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vestigators recommend an as-needed regimen in which the combination of the treatments. In each case, ranibizumab ranibizumab is initially administered monthly, but upon alone and combined with laser was superior to laser achieving stable visual acuity for 3 consecutive visits, disconmonotherapy in terms of BCVA gain. Comparing the 2 treattinuation is warranted as long as the patient is monitored ments, ranibizumab monotherapy provided a nonsignificantmonthly or bimonthly, such that treatment can be resumed ly greater mean BCVA change than when given concomiwhen a decrease in vision is noted.1,2,4,5,7,16-18 While some patantly with laser, but required more injections and resulttients may need continuous monthly dosing for maximum ed in slightly greater residual edema. Additionally, only BCVA gains, as-needed regimens have shown similar efficaRESTORE evaluated health-related quality of life outcy and substantially decrease the economic burden to the pacomes.18 Measured through periodic questionnaires, both the tient and the health care system.2,4,5,16-19 ranibizumab and combination arm were shown to signifiNo dose adjustments are required for elderly patients or cantly improve quality of life compared to laser monotherathose with renal or hepatic dysfunction. Ranibizumab has py. not been studied in pediatric patients or pregnant or nursFinally, the DRCR.net trial (691 participants; 854 eyes) ing women and is pregnancy category C. compared 4 interventions: ranibizumab plus prompt (within 7 days of initial injection) or deferred (at least 24 weeks after initial injection) laser, triamcinolone plus prompt laser, or Adverse Effects laser alone.5,17 Both ranibizumab arms were superior to either Safety results shown in RISE and RIDE are summarized laser alone or triamcinolone plus laser; however, ranibizumab in Table 2.11,19 Enophthalmitis, a known potential serious adplus deferred laser showed the greatest increase in visual acuverse event of intravitreal injections, has been observed folity and was significantly greater than ranibizumab plus lowing administration of ranibizumab.7 Key safety concerns prompt laser treatment. However, once again the use of conassociated with systemic VEGF inhibition include procomitant laser therapy decreased the number of injections nounced hypertension and increased risk of arterial thromneeded. In the subset of pseudophakic eyes, triamcinolone boembolic events (ATEs). For a better perspective as to the plus laser showed efficacy similar to that of the ranibizumab extent of this risk, a pooled analysis of 3 randomized trials (N arms. If this is proven reliable in future studies, the use of tri= 490) of the oncologic VEGF inhibitor bevacizumab adminamcinolone instead of ranibizumab in this population would istered intravenously (ie, systemic VEGF inhibition) with adprovide significant cost savings. ditional chemotherapy medications showed the rate of grade From these trials as a whole, several conclusions can be III hypertension and ATEs to be 16% and 5%, respectively, drawn. It is clear that, with the possible exception of pseuin patients receiving bevacizumab versus 3% for both grade dophakic eyes, ranibizumab provides improvement in vision III hypertension and ATEs in those not receiving bevacizusuperior to that of laser monotherapy or the combination of laser and triamcinolone.2,4,5,16-19 This recovery also occurs more rapidly, as laser generally produces results delayed over months whereas significant Table 2. Adverse Events Occurring in at Least 3% of Patients in improvement was observed upon the first followRISE and RIDE Trials11,19 up after ranibizumab injection (as early as week Sham, Ranibizumab Ranibizumab 1).1,19 Typically, these visual gains are recognized Adverse Event % 0.3 mg, % 0.5 mg, % within the initial year of therapy and for many Conjunctival hemorrhage 32 47 51 patients can be maintained long-term (at least 3 Cataract 32 28 18 years) with less frequent dosing.2,5,16,17 AdditionIntraocular pressure increased 7 18 16 ally, ranibizumab appears efficacious in a wide Eye pain 13 17 17 variety of patients with DME, as evidenced Vitreous detachment 15 11 12 through several subgroup analyses that failed to Foreign body sensation in eyes 5 10 5 show a patient population in which ranibizumab Vitreous floaters 4 10 11 Ocular hyperemia 9 9 7 was not more efficacious than sham or laser.4,5,17-19 Dosage Recommendations

The FDA-approved dose of ranibizumab for DME is 0.3 mg administered by intravitreal injection once a month.11 However, of the 6 major clinical trials conducted, only RISE and RIDE followed a monthly dosing regimen for the entire course of the trial.2,4,5,16-19 Instead, many in814

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