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).
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.
In August, the FDA approved ranibizumab for the treatment of DME, a sight-threatening eye disease that occurs in people with diabetes.
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.
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.
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.
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.
Approved in October for the treatment of symptomatic VMA, ocriplasmin is the first drug approval of its kind.
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.
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.
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.
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.
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.
■ 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.
■ 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.
■ 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.
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.