Volume 14, Number 20
Monday, May 19, 2014

In this issue: (click heading to view article)
######### Influence of Vitreomacular Adhesion on Ranibizumab Monotherapy and Combination Therapy for Neovascular AMD
######### RNFL Thickness in Eyes with Hypertensive Uveitis
######### Refractive Changes Following Pharmacologic Resolution of DME
######### Metformin's Effect on Adult-Onset OAG
######### Briefly


Influence of Vitreomacular Adhesion on Ranibizumab Monotherapy and Combination Therapy for Neovascular AMD

The authors of the following post-hoc analysis of prospective randomized 12-month multicenter clinical trial data investigated the influence of vitreomacular adhesion on the efficacy of pro re nata (p.r.n.) ranibizumab mono- and verteporfin photodynamic therapy (PDT) combination therapy for neovascular age-related macular degeneration.

The patient population consisted of 255 treatment-naïve patients with subfoveal choroidal neovascularization. The authors assessed the vitreomacular interface on monthly optical coherence tomography (OCT) with division of patients into the following categories according to continuous one-year grading: posterior vitreous detachment (n=154), dynamic release of vitreomacular adhesion (n=32) and stable vitreomacular adhesion (n=51). Main outcome measures were mean best-corrected visual acuity (BCVA) letter and central retinal thickness changes at month 12 in the vitreomacular interface groups.

Mean BCVA changes at month 12 were +3.5 (posterior vitreous detachment), +4.3 (release of vitreomacular adhesion) and +6.3 (vitreomacular adhesion) in patients receiving monotherapy (p=0.767), and +0.1 (posterior vitreous detachment), +6.6 (release of vitreomacular adhesion) and +9.2 (vitreomacular adhesion) in patients receiving combination therapy (p=0.009). The study authors reported that mean central retinal thickness changes were –113 µm (posterior vitreous detachment), –89 µm (release of vitreomacular adhesion) and –122 µm (vitreomacular adhesion) in monotherapy (p=0.725), and –121 µm (posterior vitreous detachment), –113 µm (release of vitreomacular adhesion) and –113 µm (vitreomacular adhesion) in combination therapy (p=0.924). They also found that mean ranibizumab retreatments during 12 months were 4.9 (posterior vitreous detachment), 6.6 (release of vitreomacular adhesion) and 5.3 (vitreomacular adhesion) in monotherapy (p=0.018), and 4.7 (posterior vitreous detachment), 5.2 (release of vitreomacular adhesion) and 5.8 (vitreomacular adhesion) in combination therapy (p=0.942).

This study adds evidence that the vitreomacular interface status impacts functional outcomes and retreatment requirements, the authors concluded. Patients with posterior vitreous detachment achieve acceptable results with fewer injections in p.r.n. monotherapy, but loose potential vision gain with PDT. Patients with other vitreomacular interface configurations may potentially achieve optimized vision outcomes by combination of anti-angiogenic treatment and vaso-occlusive PDT.

SOURCE: Waldstein SM, Simader C, Mayr-Sponer U, et al. Impact of vitreomacular adhesion on ranibizumab mono- and combination therapy for neovascular age-related macular degeneration. Am J Ophthalmol. 2014;May 1. [Epub ahead of print].



RNFL Thickness in Eyes with Hypertensive Uveitis

Uveitic glaucoma is among the most common causes of irreversible visual loss in uveitis. However, glaucoma detection can be obscured by inflammatory changes. To determine whether retinal nerve fiber layer (RNFL) measurement can be used to detect glaucoma in uveitic eyes with elevated intraocular pressure (IOP), researchers put together a comparative case series of RNFL measurement using optical coherence tomography performed from May 1, 2010, through October 31, 2012, at a tertiary referral center.

They assigned 536 eyes with uveitis (309 patients) in the following groups: normal contralateral eyes with unilateral uveitis (n=72), normotensive uveitis (Uv-N) (n=143), raised IOP and normal optic disc and/or visual field (Uv-H) (n=233), and raised IOP and glaucomatous disc and/or visual field (Uv-G) (n=88). Exposures were eyes with uveitis and elevated IOP (>21mm Hg) on at least two occasions. Comparison of RNFL values between groups of eyes and correlation with clinical data; risk factors for raised IOP, glaucoma, and RNFL thinning were the main outcome measures.

According to the researchers, mean (SD) global RNFL was thicker in Uv-N (106.4 [21.4] µm) compared with control (96.0 [9.0] µm; p<0.001) eyes and was thicker in Uv-N eyes with active (119.6 [23.2] µm) compared with quiescent (102.3 [20.8] µm; p=0.001) uveitis, which in turn was not significantly different from control eyes (p=0.07). Compared with Uv-N eyes, they saw significant RNFL thinning in all quadrants except the temporal in Uv-G eyes and significant thinning in the inferior quadrant of Uv-H eyes with no evidence of disc or visual field changes (p=0.03). Risk factors for elevated IOP were male sex and anterior uveitis, they noted. Furthermore, age, higher peak IOP, longer duration of follow-up, and uveitis-induced elevation of IOP were risk factors for glaucoma and RNFL defect.

The researchers concluded that screening for glaucomatous RNFL changes in uveitis must be performed during quiescent periods. Thinning of the inferior quadrant suggests that glaucomatous damage, more than uveitic ocular hypertension, is in fact occurring. Measurement of RNFL may detect signs of damage before disc or visual field changes and therefore identifies a subgroup that should receive more aggressive treatment.

SOURCE: Din NM, Taylor SR, Isa H, et al. Evaluation of retinal nerve fiber layer thickness in eyes with hypertensive uveitis. JAMA Ophthalmol. 2014;May 10. [Epub ahead of print].

Refractive Changes Following Pharmacologic Resolution of DME

Investigators conducted this prospective, randomized study to determine precisely the mean change in refractive power induced by treatment in patients with diabetic macular edema (DME).

Included in the study were 50 eyes of 50 consecutive patients with clinically significant macular edema receiving all three types of current state-of-the-art treatment with intravitreal anti-edematous substances (ranibizumab, bevacizumab or triamcinolone). The study investigators followed up with patients at monthly intervals and treated them following a standardized pro re nata regimen according to protocol. Best-corrected visual acuity (BCVA) was determined by certified visual acuity examiners. Moreover, the refractive power of the treated eyes was determined using a push-plus technique and the change in refraction between baseline and the visit when the macula was completely dry or when the central subfield thickness (CST) measured by optical coherence tomography had reached the thinnest level was analyzed. Main outcome measures were spherical equivalent refraction (SER) and CST.

Fifty eyes of 50 patients received intravitreal therapy using ranibizumab (n=11), bevacizumab (n=20), or triamcinolone (n=19). Mean BCVA was 0.33 ± 0.23 logarithm of the minimum angle of resolution (logMAR) and mean CST was 492 ± 130 µm. The mean SER was 0.41 ± 2.06D at baseline. The BCVA at the time of optimal retinal morphologic features was 0.24 ± 0.2 logMAR, mean CST was 300 ± 78 µm, and mean change in SER was –0.01 ± 0.46 D. Changes is BCVA and CST were statistically significant (p<0.0001), but the SER change was not (p=0.824).

The study investigators concluded that appropriate spectacle correction can be prescribed to patients with DME any time during ongoing therapy using anti-edematous substances because resolution of retinal thickening is not associated with an increased risk of a myopic shift.


SOURCE: Deák GG, Lammer J, Prager S, et al.; Diabetic Retinopathy Research Group Vienna. Refractive changes after pharmacologic resolution of diabetic macular edema. Ophthalmology. 2014;121(5):1054–1058.

Metformin's Effect on Adult-Onset OAG

Caloric restriction (CR) and CR-mimetic drugs have geroprotective effects that delay or reduce some risks of aging. This study tested the hypothesis that the CR-mimetic drug metformin can reduce the risk of developing the late-onset trait open-angle glaucoma (OAG).

Nine years of longitudinal data from a large U.S. health claims database (2001 to 2009) were analyzed and diabetics aged 40+ with no pre-existing OAG were monitored for incident OAG. The key predictor was exposure to metformin. A Cox proportional hazard model tested the effect of metformin on the hazard of developing OAG, adjusting for sociodemographic factors, glycemic control (HbA1c level), other diabetes medications, and other ocular and systemic conditions. The University of Michigan Institutional Review Board deemed use of this anonymized database to be exempt.

Of 150,016 diabetics, a total of 5,893 (3.9%) developed incident OAG. Additionally, use of >1,110 cumulative grams of metformin over two years was associated with a 25% reduction in relative risk of developing OAG (HR=0.75; 95% CI=0.59 to 0.95; p=0.017) compared with no metformin use. It was noted that every one-gram increase in metformin was associated with a 0.01% reduced hazard of developing OAG (p=0.001). Thus, someone receiving a normal dose of metformin (2g per day) over two years would show a 13% reduction in absolute risk of OAG relative to someone not taking metformin. When baseline OAG risk and HbA1c level was stratified, the greatest absolute metformin-induced risk reduction was seen for those with the highest baseline risk and the highest HbA1c levels. Although HbA1c levels were associated with increased risk of OAG (HR=1.08; 95% CI=1.03 to 1.13; p=0.003), other hypoglycemic drugs did not reduce risk of OAG, and OAG risk reduction in response to metformin occurred when HbA1c levels were taken into account.

To conclude, metformin use was associated with reduced risk of OAG. This OAG risk reduction was dose-dependent and independent of glycemic control; other diabetes medications did not confer a similar risk reduction. Thus, systems beyond glycemic control, such as neurogenesis, longevity pathways, and/or reduced inflammation, may be involved in metformin-induced OAG risk reduction. If confirmed by prospective clinical trials, these findings would offer novel treatments for this sight-threatening disease and perhaps other diseases of aging as well.

SOURCE: Richards JE, Lin HS, Nan B, et al. Targeting aging: geroprotective drug metformin reduces risk of adult-onset open-angle glaucoma. Association for Research in Vision and Ophthalmology (ARVO) 2014 Annual Meeting: Abstract 1668. Presented May 5, 2014.

  • PHASE II DOSE-RANGING STUDY FOR LOCALLY ACTING ROCK INHIBITOR IN GLAUCOMA INITIATED. In a statement to the press, Amakem Therapeutics reported that the first patients have commenced treatment in a Phase II multicenter, randomized, double-masked, placebo-controlled, dose-ranging study of its lead drug candidate, AMA0076 for the treatment of glaucoma. According to Amakem, AMA0076 is a highly potent, locally acting Rho Kinase (ROCK) inhibitor that has been designed to reduce intraocular pressure (IOP) by acting specifically on the main outflow system in the eye while minimizing side effects such as hyperemia. This study uses an optimized formulation of AMA0076 applied topically as eye drops and aims to enroll approximately 80 patients in the United States. The primary efficacy endpoint will be change in IOP from baseline at the end of 28 days of treatment. Secondary endpoints include IOP assessment at other time points, as well as safety and tolerability assessments. The company expects to report topline results in Q4 2014.

  • OHR PHARMACEUTICAL SET TO ACQUIRE ASSETS OF SKS OCULAR. Ohr Pharmaceutical Inc. has entered into a definitive agreement with privately held SKS Ocular LLC and its affiliate SKS Ocular 1 LLC (SKS Ocular) to acquire SKS Ocular's ophthalmology assets. Under the terms of the agreement, in exchange for substantially all the assets of SKS Ocular, Ohr will make an up-front payment of $3.5 million in cash and 1,194,862 shares of Ohr common stock. According to Ohr, the transaction will provide the company with a proprietary, patent-protected, sustained-release technology platform under development as well as a pipeline of preclinical sustained-release drug product candidates that address unmet medical needs in glaucoma, retinal disease and other ophthalmic indications. As part of the agreement, Ohr will also gain a strong research and development team and a state-of-the-art research laboratory in San Diego. The transaction is expected to close by the end of May.

  • SANTEN TO PURCHASE MERCK'S OPHTHALMOLOGY PRODUCTS IN JAPAN AND KEY MARKETS IN EUROPE AND ASIA PACIFIC. Merck has signed an agreement for Santen Pharmaceutical Co., Ltd. to purchase Merck's ophthalmology products (Cosopt, Cosopt PF, Trusopt, Trusopt PF, Timoptic, Timoptic PF, Timoptic XE, Saflutan and Taptiqom) in Japan and key markets in Europe and Asia Pacific. Santen will make an up-front payment of roughly $600 million and additional payments based on defined sales milestones as needed. Santen will also purchase supply of the products covered by this agreement from Merck for a two- to five-year period. The agreement is subject to certain closing conditions and is expected to close in most markets in a few months. Merck divested its U.S. ophthalmology business to Akorn Pharmaceuticals in 2013 and 2014, and will continue to sell its ophthalmology products in Latin America, Canada, Australia, the Middle East, Africa and other markets. Further details can be found here.
  • MANAGEMENTPLUS v.6.0 RECEIVES ONC HIT 2014 EDITION COMPLETE CERTIFICATION. ManagementPlus Inc. recently announced that its ManagementPlus v.6.0 has received ONC HIT 2014 Edition Complete Certification, which designates that the software is capable of supporting eligible providers with meeting the Stage I and Stage II Meaningful Use measures required to qualify for funding under the American Recovery and Reinvestment Act (ARRA). The software was certified by ICSA Labs, an Office of the National Coordinator-Authorized Certification Body (ONC-ACB) and is compliant in accordance with applicable criteria adopted by the Secretary of Health and Human Services (HHS). ONC HIT certification conferred by ICSA Labs does not represent an endorsement of the certified EHR technology by the U.S. Department of HHS. Visit the company's website.

  • ALLERGAN REJECTS VALEANT PROPOSAL; VALEANT RESPONDS. Allergan Inc.'s Board of Directors has unanimously rejected the unsolicited proposal by Valeant Pharmaceuticals International Inc. After a comprehensive review conducted in consultation with its financial and legal advisors, the Allergan Board concluded that the proposal substantially undervalues Allergan, creates significant risks and uncertainties for its stockholders, and is not in the best interests of the company and its stockholders. Valeant chairman and CEO J. Michael Pearson responded to the rejection with a letter to Allergan shareholders, stating that Valeant will “remain resolute in consummating a merger with Allergan,” and plans to improve its offer for the company. According to Mr. Pearson, Valeant is prepared to pay a full and fair price and will not stop its pursuit of this combination until it hears directly from Allergan shareholders that they prefer Allergan's “stay the course plan” to a combination with Valeant. At 8:00 a.m. EDT May 28th, Valeant will hold a webcast to discuss why it believes its offer is substantially superior to an Allergan “go it alone” strategy and will discuss why its proposal offers greater short-, intermediate- and long-term shareholder value by managing Allergan’s assets under Valeant’s operating model.

  • AKORN TO ACQUIRE VERSAPHARM Akorn Inc. has entered into a definitive agreement to acquire VPI Holdings Corp., the parent company of VersaPharm Inc., for $440 million in cash. VersaPharm has a robust pipeline of more than 20 products, and Akorn believes that the company's expertise in developing topical products complements its recently acquired manufacturing platform through its merger with Hi-Tech Pharmacal. Read more here.

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