2012: Year for retina approvals

Just about a year ago, the ophthalmic news headlines were buzzing with the approval of aflibercept (Eylea, also known as VEGF Trap-Eye; Regeneron) to treat patients with wet age-related macular degeneration (AMD). The approval was based upon the results of two phase III clinical studies (VIEW 1 and VIEW 2). Other FDA-approved options include verteporfin for injection (Visudyne, QLT Inc.), pegaptanib sodium injection, (Macugen, Eyetech Inc.), and ranibizumab injection (Lucentis, Genentech).

baselineCase example— before and at month 24— of a study patient treated with ranibizumab 0.3 mg (Lucentis, Genentech), including baseline vision, color photo, and optical coherence tomography.

Though the approval of this anti-vascular endothelial growth factor (VEGF) therapy was much anticipated because it offered, among other things, a less-frequent dosing regimen, the complete picture of how the drug may have an effect on the retinal space is still a work in progress. For example, we’ll look forward to additional studies of the drug evaluating specific subgroups or patient populations, as well as alternative dosing regimens.

Since the approval of aflibercept, however, much headway has been made in other treatment avenues as well: ranibizumab received FDA approval for the treatment of diabetic macular edema (DME), and ocriplasmin (Jetrea, ThromboGenics) became the first drug approved to treat symptomatic vitreomacular adhesion (VMA), to name a few.

Ranibizumab approval for DME

In August, the FDA approved ranibizumab for the treatment of DME, a sight-threatening eye disease that occurs in people with diabetes.FDA approves Lucentis to treat diabetic macular edema. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm315130.htm. Accessed Nov. 13, 2012. Ranibizumab was previously approved to treat wet AMD and macular edema following retinal vein occlusion.

According to the Centers for Disease Control and Prevention, diabetes (type 1 and 2) affects upward of 26 million people in the United States, and is the leading cause of new cases of blindness among adults aged 20 to 74 years.National Diabetes Fact Sheet, 2011. http://www.cdc. gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed Nov. 1, 2012. Additionally, from 2005 to 2008, 4.2 million people with diabetes aged 40 years or older had diabetic retinopathy; of these, 655,000 had advanced diabetic retinopathy that could lead to severe vision loss. As the first major development for treating this disease in more than 25 years, the drug is intended to be administered by monthly injection and used along with good diabetic blood sugar control.

The approval of ranibizumab in DME was based on two phase III trials, RIDE and RISE, which were identically designed, parallel, double- masked, sham injection-controlled clinical trials.Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801. A total of 759 patients were randomly assigned to three groups to receive monthly treatment with 0.3 mg ranibizumab (n = 250), 0.5 mg ranibizumab (n = 252) or sham injection (control group, n = 257). The results found that treatment with ranibizumab demonstrated improved clinical outcomes, including substantial visual gain, reduced risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

Second approval for aflibercept

Less than a year after aflibercept was approved for wet AMD, the injection was also approved for the treatment of macular edema following central retinal vein occlusion (CRVO), with a recommended dose of 2 mg every 4 weeks.Regeneron announces FDA approval of EYLEA (aflibercept) injection for macular edema following central retinal vein occlusion. http://investor. regeneron.com/releasedetail.cfm?releaseid=708835. Accessed Nov. 5, 2012. This second U.S. approval for aflibercept was based on data from two phase III, randomized, multicenter, double-masked, shamcontrolled studies: COPERNICUS (Controlled Phase III Evaluation of Repeated intravitreal administration of VEGF Trap-Eye In Central retinal vein occlusion: Utility and Safety) and GALILEO (General Assessment Limiting Infiltration of Exudates in central retinal vein Occlusion with EYLEA).Vascular endothelial growth factor (VEGF) Trap-Eye: Investigation of efficacy and safety in central retinal vein occlusion (CRVO). http://www.clinicaltrials.gov/ ct2/show/NCT00943072?term=COPERNICUS&rank=4. Accessed Nov. 5, 2012.,Vascular endothelial growth factor (VEGF) Trap- Eye: Investigation of efficacy and safety in central retinal vein occlusion (CRVO) (GALILEO). http://www. clinicaltrials.gov/ct2/show/NCT01012973?term=GALIL EO&rank=1. Accessed Nov. 5, 2012.

The primary efficacy endpoint in both was the proportion of patients who gained at least 15 letters of best-corrected visual acuity at 24 weeks compared with baseline as measured by ETDRS; 56% to 60% of patients who received aflibercept gained at least 3 lines of vision compared with 12% to 22% of patients who received a sham injection.

Ocriplasmin for VMA

Approved in October for the treatment of symptomatic VMA, ocriplasmin is the first drug approval of its kind.FDA approves Jetrea for symptomatic vitreomacular adhesion in the eyes. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm324369.htm. Accessed Nov. 13, 2012. VMA is observed after partial posterior vitreous attachment, when a portion of the vitreous remains attached to the macula, which can cause a pulling action/ traction to occur and adversely affect a patient’s vision.

 

EyleaLess than a year after aflibercept (Eylea) was approved for wet AMD, the injection was also approved for macular edema following CRVO.

Protein bonds in vitreomacular interface responsible for VMATop: Protein bonds in vitreomacular interface responsible for VMA. Bottom: Ocriplasmin breaks protein bonds to resolve VMA.

Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretina interface (e.g., laminin, fibronectin, and collagen), which are responsible for VMA.JETREA (ocriplasmin) Intravitreal Injection, 2.5 mg/ mL. http://jetrea.com/JETREAPrescribingInformation. pdf. Accessed Nov. 2, 2012. The breakdown of these proteins allows a better separation between the vitreous and macula and can reduce the chances that tugging will occur.

 

Prior to the approval, there were no pharmacologic treatments for symptomatic VMA. Treatment may allow for earlier invention, faster recovery time, and reduce necessary follow-up appointments compared with the surgical alternative.

The safety and efficacy of ocriplasmin was demonstrated in two multicenter, randomized, double-masked, vehicle-controlled, phase III clinical trials to compare a single intravitreal injection of ocriplasmin with a placebo injection in patients with symptomatic VMA.Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012; 367:606-615. A total of 652 patients were treated: 464 with ocriplasmin and 188 with placebo. VMA resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes, and nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes as compared with 10.6% of placebo-injected eyes.

Fluocinolone acetonide for DME

 

The push for supplementary information and additional clinical trials must continue to accelerate therapeutic options.

While not yet approved in the United States, a sustained-release intravitreal implant that delivers submicrogram levels of fluocinolone acetonide (Iluvien, Alimera) is finding success abroad. In 2010, Alimera submitted a marketing authorization application (MAA) to seven European countries via the Decentralized Procedure, with the Medicines and Healthcare products Regulatory Agency of the United Kingdom (MHRA) serving as the Reference Member State.Alimera Sciences’ Iluvien receives marketing authorization in Germany for the treatment of chronic diabetic macular edema. http:// investor.alimerasciences.com/releasedetail. cfm?ReleaseID=695624. Accessed July 26, 2012.

 

The MAA included data from two phase III pivotal clinical trials (FAME [Fluocinolone Acetonide in Diabetic Macular Edema] Study) to assess the efficacy and safety of fluocinolone acetonide for the treatment of DME. The FAME study consisted of two masked, randomized, multicenter trials that involved 956 patients in sites across the United States, Canada, Europe, and India. On July 26, 2012, Alimera Sciences announced that Germany represented the fifth national approval in the European Union, preceded by Austria, Portugal, the United Kingdom, and France.

Last year, the FDA stated that it was unable to approve the new drug application because the company did not provide sufficient data to support that the drug is safe and effective. The FDA also indicated two additional clinical trials would need to be conducted to demonstrate that the product is safe and effective for the proposed indication.Alimera Sciences receives complete response letter from FDA for Iluvien. http://investor.alimerasciences. com/releasedetail.cfm?ReleaseID=623128. Accessed July 12, 2012. However, on Aug. 1, pSivida Corp. reported that its licensee, Alimera Sciences Inc., is resubmitting its application to the FDA for approval to treat DME. Alimera intends to use data from its two previously completed phase III clinical trials.pSivida Corp. reports Alimera’s intention to resubmit application to FDA for Iluvien in DME using data from completed trials. http://psdv.client.shareholder.com/ releases.cfm. Accessed Aug. 2, 2012.

Advances in imaging

Ultra-wide-angle fluorescein angiography has had a huge effect on the assessment and management of retinal diseases because the periphery and the posterior pole can be visualized at the same time.

While standard fluorescein angiography is only able to capture an image 30° across, a more panoramic technique provides high-resolution retinal images, as well as identification of peripheral pathology without the need for several images. For example, an ultra-wide- field retinal imaging system (Optos, Optos PLC) is capable of producing wide-field fundus images of up to 200° in breadth.Kaines A, Oliver S, Reddy S, Schwartz SD. Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthalmol Clin. 2009;49:53-59. The model uses a green (532 nm) laser to image the retina and inner retinal pigment epithelium (RPE) and a red (633 nm) laser to image the outer RPE and choroid.

Pipeline prospects

Fovista: This anti-platelet-derived growth factor (PDGF) agent is showing potential to be an additional treatment for wet AMD when used in combination with an anti-VEGF drug. In a prospective, randomized, controlled phase IIb clinical trial including 449 patients with wet AMD, Fovista anti-PDGF therapy administered in combination with ranibizumab anti-VEGF therapy showed statistically significant superior efficacy over ranibizumab monotherapy.

The primary efficacy endpoint in the study was the mean change in visual acuity from baseline at the week 24 visit. Patients receiving the combination of Fovista (1.5 mg) and ranibizumab gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared with 6.5 letters for patients receiving ranibizumab monotherapy (p = 0.019).

AKB-9778: AKB-9778 is a small-molecule, Tie-2 activating agent that effectively blocks vascular leak and pathologic angiogenesis in multiple disease conditions and is currently being developed for the treatment of DME. In September, Aerpio Therapeutics announced that it had treated the first patient in a phase Ib/IIa trial of AKB-9778 designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and pilot efficacy of multiple ascending dose levels of the drug given as subcutaneous injections daily for 28 days in patients with DME.Aerpio Therapeutics initiates phase 1b/2a trial of AKB-9778 in diabetic macular edema. http://www. aerpio.com/news/Aerpio-Phase-2-9778-Initiation.pdf. Accessed Nov. 5, 2012.,Safety and pilot efficacy of AKB-9778 in subjects with diabetic macular edema. http://www.clinicaltrials.gov/ct2/show/ NCT01702441?term=aerpio&rank=1. Accessed Nov. 5, 2012.

ALG-1001: This small-molecule, synthetic anti-integrin oligopeptide interferes with several pathways of the angiogenic cascade by binding to multiple integrin-receptor sites that have been associated with different forms of neovascularization. It is believed that integrin peptide therapy is effective in treating diabetic macular edema and wet AMD. A phase I proofof- concept study on DME has been completed with positive results presented at ARVO (Boyer D. IOVS. 2012;53: ARVO E-Abstract 1337), and a phase Ib/IIa study to evaluate the safety and efficacy of ALG-1001 in subjects with DME is listed at www.clinicaltrials.gov.Safety study of ALG- 1001 to treat diabetic macular edema. http://www.clinicaltrials.gov/ct2/show/NCT0 1482871?term=Allegro&rank=21. Accessed Nov. 13, 2012.

MP0260: MP0260 is a DARPin-based, small therapeutic protein with dual activity, inhibiting VEGF-A and PDGF-B, and is currently being explored for its use in wet AMD.Allergan and Molecular Partners enter into exclusive alliance: Global partnership will develop novel products for eye diseases. http://www.molecularpartners.com/ public/files/pdfs/20120820_agnmp_press_release_ final.pdf?PHPSESSID=e15eec359af12aea4fa408aff546 1fa8. Accessed Nov. 13, 2012. In August, Allergan Inc. and Molecular Partners AG announced that they had expanded their existing relationship by entering into two separate agreements to discover, develop, and commercialize DARPin products for the treatment of ophthalmic diseases. The first agreement is an exclusive license for the design, development, and commercialization of MP0260.

Conclusion

The retinal arena is seeing more therapeutic breakthroughs than ever, offering additional —and sometimes even first-ever—treatment options for a variety of diseases. The push for supplementary information and additional clinical trials must continue to keep up the pace. We look forward to and anticipate seeing these advancements through 2013.