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Shire to Acquire SARcode Bioscience
Shire announced that it will acquire SARcode Bioscience Inc., a privately held biopharmaceutical company based in Brisbane, California. This acquisition continues to build Shire's presence in the ophthalmology therapeutic category and brings a new phase 3 compound, lifitegrast, currently under development for the signs and symptoms of dry eye disease, into Shire's portfolio. Shire anticipates launching lifitegrast in the United States as early as 2016 pending a positive outcome of the phase 3 clinical development program and regulatory approvals. Shire is acquiring the global rights to lifitegrast and will evaluate an appropriate regulatory filing strategy for markets outside of the United States.
Under the terms of agreement, Shire will make an upfront payment of $160 million and SARcode shareholders will be eligible to receive additional undisclosed payments upon achievement of certain clinical, regulatory, and/or commercial milestones. The transaction is expected to close in the second quarter, subject to regulatory approval in the United States, and other customary closing conditions.
Lifitegrast, a small-molecule integrin antagonist, is believed to work by reducing inflammation through binding inhibition of the proteins lymphocyte function - associated antigen 1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), influencing T-cell activation and cytokine (protein) release. The interaction between these two proteins plays a key role in the chronic inflammation associated with dry eye. T-cells are important components of the immune system that help control the body's response to a foreign or harmful substance or stimuli. lifitegrast is administered via a preservative-free topical eye solution.
The ongoing lifitegrast clinical development program includes two pivotal Phase 3 studies, called OPUS-1 and OPUS-2. According to the company, the 700-patient OPUS-2 study, which commenced earlier this year, will aim to build on the positive sign and symptom data resulting from OPUS-1. The results from these two studies, along with data from an ongoing year-long safety study called SONATA, will support a planned New Drug Application.
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R-Tech Ueno Receives FDA IND Approval for Clinical Trial of RU-101 for Severe Dry Eye
R-Tech Ueno, a bio venture company based in Japan, received IND (Investigational New Drug) approval from the U.S. Food and Drug Administration (FDA) to initiate Phase I/II clinical trials for RU-101 ophthalmic solution which is being developed for treatment of severe dry eye.
RU-101 is a recombinant human serum albumin-containing ophthalmic solution project that is focused on the treatment of corneal epithelial diseases including dry eye. R-Tech Ueno has confirmed that serum albumin enhances the production of mucin, one of the components of tears, in an experiment in conjunctival epithelial cells, and also has intellectual property rights concerning the treatment of dry eye with albumin.
The trial consists of two stages. At the first stage, the safety will be mainly assessed using placebo (without the active ingredient) as control to evaluate maximum dosage of RU-101 ophthalmic solution for treatment of patients with severe dry eye. In the next stage, RU-101 ophthalmic solution of maximum dosage, the safety of which will have been confirmed at the first stage, will be instilled for 12 weeks, and the safety and effectiveness will be evaluated using placebo as control.
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Eleven Biotherapeutics Presents Data on EBI-005 for the Treatment of Dry Eye Disease at ARVO 2013
Eleven Biotherapeutics, a biopharmaceutical company creating novel and differentiated protein-based biotherapeutics for the treatment of ocular diseases, announced the presentation of data for EBI-005 at the Association for Research in Vision and Ophthalmology (ARVO) 2013 Annual Meeting. Three poster presentations1-3 highlighted EBI-005 as a new approach to optimize topically applied proteins on the surface of the eye and as the first rationally-designed topically administered IL-1 (Interleukin-1) protein for the treatment of ocular diseases, including dry eye disease.
In the posters Eleven Biotherapeutics researchers presented data demonstrating that EBI-005 was safe and well-tolerated in both preclinical testing and in a clinical Phase 1a study in healthy volunteers.1-3 These data led to Eleven's Phase 1b clinical study of EBI-005 in subjects with dry eye disease, with top-line data from the Phase 1b study expected in the second half of 2013. According to the company, these data also support Eleven's new plans to evaluate the potential of EBI-005 in additional ocular surface inflammatory diseases, including severe allergic conjunctivitis.
1. Goldstein MH, Eleven Biotherapeutics. Early Clinical Development of EBI-005, a Potent Interleukin-1 (IL-1) Receptor-1 (R1) Blocker for Topical Ocular Treatment of Dry Eye Disease (DED). Poster #C0057
2. Furfine ES, Eleven Biotherapeutics. Preclinical Development of EBI-005: a Potent Interleukin-1 (IL-1) Receptor-1 (R1) Blocker for Topical Ocular Administration was Safe in GLP Toxicology Studies and Active in a Mouse Model of Dry Eye Disease (DED). Poster #C0058.
3. Barnes T, Eleven Biotherapeutics. Use of Galectin-3 Fusions to Extend the Surface Residence Time of Proteins Topically Applied to the Eye. Poster #0067.
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B+L Signs Exclusive License Agreement with Paragon BioTeck for Phenylephrine
Bausch + Lomb (B+L) and Paragon BioTeck, Inc. announced that the companies have entered into a license agreement for B+L to commercialize and distribute Paragon's phenylephrine in the United States on an exclusive basis beginning this month.
Phenylephrine Hydrochloride Ophthalmic Solution, USP 2.5 percent and 10 percent, is an alpha-1 adrenergic receptor agonist used for dilation of the pupil due to its vasoconstrictor and mydriatic action. Phenylephrine possesses predominantly alpha-adrenergic effects. In the eye, phenylephrine acts locally as a potent vasoconstrictor and mydriatic by constricting ophthalmic blood vessels and the radial muscle of the iris.
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CLINICIAN'S CORNER
Amber Gaume Giannoni, OD, FAAO
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Managing Mild-to-Moderate OSD
Case 1: A 61 year-old Asian female with a long-term history of dry eye and filamentary keratitis (see image), presented for a follow up reporting increasing discomfort in her left eye despite compliant use of Restasis bid, lotepredenol gel qhs, warm compresses, omega supplements, and artificial tears qid. Her vision in that eye was reduced to 20/80, mostly due to a prior retinal detachment, and her meibomian glands were obstructed with some dropout.
What do you do when all regular options have been exhausted? In this case, the patient was fit with Prokera (Biotissue), an FDA-approved medical device consisting of a thin piece of amniotic membrane tissue held by a clear, plastic ring. It is applied to the eye much like a large diameter rigid contact lens and assists in the restoration of corneal integrity. Prokera should remain in place until full healing is observed, or the membrane dissolves (anywhere from a few days to a few weeks). Topical medication can be instilled over the device, and a decline in visual acuity is expected with wear as the membrane is slightly hazy.
In this patient's case, device application was straightforward and no discomfort was experienced during or after the procedure. Following three days in Prokera, corneal filaments were completely resolved, staining was significantly reduced, and the patient was much less symptomatic. It is too early to know how long the effect will last for this patient as her underlying dry eye condition is still at play, yet in theory, "resetting" her cornea could aid in maintaining results and may positively impact her long-term progression.
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RESEARCH UPDATE
Sruthi Srinivasan, PhD, BS Optom, FAAO
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In 2003 Restasis, topical ophthalmic cyclosporine, was approved for use in patients with decreased aqueous production and is used to treat chronic dry eye that may be caused by inflammation. It is hard to believe that it has been 10 years since we have had any additional topical dry eye therapeutic agents approved by the FDA. That isn't for lack of trying—some industry reports hint that over 15 compounds have initiated the FDA process and have failed somewhere along the way. Indeed, analysts report that the typical "drug" can take on average 12 years from bench to market, and can cost hundreds of millions for a drug that gains approval.
Where does that put dry eye today? The industry, including large companies and small start-ups, is moving forward with research protocols of new and repurposed compounds for the treatment of ocular surface disease, and this issue's abstract (seen below), Topical Interleukin 1 Receptor Antagonist for Treatment of Dry Eye Disease, is one such example. Kineret (anakinra) is approved for injection subcutaneously for the treatment of Rheumatoid Arthritis (RA) and Cryopyrin-Associated Periodic Syndromes (CAPS). Interleukin-1 receptor agonists block the activity of IL-1, a proinflammatory cytokine, and thus can reduce the destructive inflammatory processes that can occur in autoimmune conditions like RA and on the ocular surface in dry eye disease. This study demonstrated that symptoms were significantly reduced when compared between groups and to baseline; however, only bilateral corneal clearance demonstrated both between group and against baseline significant differences relative to the staining outcomes. This study is relatively small, so it is possible that more robust differences will be observed when larger samples are evaluated, as likely will be done in the future. Early stage studies such as this are promising, and are intended to test different concentrations of the compound, as well as "try out" outcomes to be used in future studies. We shouldn't be quick to judge—if this was so easy it would have been done within the last 10 years, so stay tuned.
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Topical Interleukin 1 Receptor Antagonist for Treatment of Dry Eye Disease: A Randomized Clinical Trial.
IMPORTANCE: The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy. OBJECTIVE: To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction. METHODS: Seventy-five participants were randomized to receive treatment with topical anakinra, 2.5% (n = 30), anakinra, 5% (n = 15), or vehicle (1% carboxymethylcellulose) (n = 30) 3 times daily for 12 weeks. MAIN OUTCOMES AND MEASURES: Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye-related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality. RESULTS: Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P = .12 compared with vehicle and P ≤ .001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P = .88 compared with vehicle and P = .33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P = .11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2of 29 patients (7%) treated with vehicle (P = .03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P = .02 and P = .01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms. CONCLUSIONS: Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681109.
Amparo F, Dastjerdi MH, Okanobo A, Ferrari G, Smaga L, Hamrah P, Jurkunas U, Schaumberg DA, Dana R. JAMA Ophthalmol. 2013 Apr 18:1-9. doi: 10.1001/jamaophthalmol.2013.195. [Epub ahead of print]
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Dry Eye 101: Nuts and Bolts
Jillian Meadows, OD, MS
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Question: I want to start a dry eye clinic in my practice. What is the best way to grade fluorescein and lissamine green staining?
Answer: Recording a wealth of information in a concise way can help you better track changes over time or with treatment. The DEWS diagnostic template for staining recommends dividing the cornea into 5 regions (superior, inferior, nasal, temporal, and central) and the interpalpebral conjunctiva into six regions (far nasal, far lateral, superonasal/lateral, and inferonasal/lateral). This method is frequently used in clinical trials, and the regions, each graded on a 0 – 3 scale (0=none, 3=worst ever), are commonly summed. Clinically, if your EMR system allows a template, the grades for each region can be entered quickly.
The question is whether you want that detailed of information. At minimum, you should record a different grade for the inferior and central cornea—inferior being the most common location of staining and central being a hallmark of more severe disease. Most clinicians will grade only nasal and temporal lissamine green (LG) staining, rather than dividing them into smaller regions. The important thing is to be consistent between patients and visits. If you prefer a 0 – 4 scale, it can help to "dot count" to gauge the grade. A grade 3 is usually too many dots to count but not full coverage of the area.
Clinical pearl: Wait 1-2 minutes after dye instillation to grade staining patterns, and be sure to grade fluorescein staining before instilling LG. The wait time can be used to ask about symptoms, previous treatment successes and failures, or changes since the last visit. What would you grade the cornea seen in this newsletter in Clinician's Corner? (A: I=4, N=4, T=4, C=4, S=3)
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