Wednesday, September 23, 2009

Drug News: LX214 successful Phase I completion

Sept 23, 2009 - Business Wire
Lux Biosciences Reports Phase 1 Safety Results and Open Label Efficacy Results for LX214, a Potential Best-in-Class Treatment for Dry Eye

JERSEY CITY, N.J.--(BUSINESS WIRE)--Lux Biosciences, Inc. a privately held biotechnology company focused on the treatment of ophthalmic diseases, today announced results from a Phase 1 human safety and an open-label pilot efficacy study of the company’s potential best-in-class therapy for dry eye, LX214 (topical mixed nanomicellar formulation of voclosporin). Randomized, double-masked, placebo-controlled data from 30 healthy volunteers showed LX214 to be well tolerated at the two doses (0.02% and 0.2%) studied, with safety and tolerability measurements (pain, burning, reddening, photophobia, foreign body sensation and others) indistinguishable from placebo.

An additional cohort of five patients with severe dry eye syndrome was treated with LX214 in both eyes twice a day for 14 days at the target 0.2% concentration. Data from these patients confirmed that systemic exposure to voclosporin was very low and below the threshold level where measurement of voclosporin blood concentrations would be required in future studies. Signs and symptoms of disease were also assessed in this cohort of patients. Despite the small sample size and short duration of treatment, clinically meaningful improvements were noted in both signs (tear production) and symptoms (OSDI index) at both 7 and 14 days, a trend that bodes well for longer term, controlled studies to follow.

“The benign safety and tolerability results in humans demonstrated in both these trials confirm the positive profile exhibited by LX214 in preclinical studies, which showed this drug candidate to establish therapeutic levels in relevant ocular tissues and to be non-irritating when applied topically to the eye,” said Eddy Anglade, M.D., Lux Biosciences’ Chief Medical Officer. “Moreover, even though the 14 day results in severe dry eye patients were based on a small, uncontrolled sample, they presented quite encouraging indicators of efficacy.”

LX214, developed in cooperation with Ashim Mitra, Ph.D., University of Missouri Curator’s Professor of Pharmacy and Director of Translational Research at UMKC School of Medicine School of Pharmacy, University of Missouri-Kansas City, is a proprietary formulation of Lux Biosciences’ next generation calcineurin inhibitor, voclosporin. Utilizing voclosporin and Lux’s proprietary mixed nanomicellar formulation technology, LX214 establishes high levels of drug for 24 hours in relevant ocular tissues following a single administration, including the lacrimal gland and submandibular lymph nodes, suggesting that LX214 may be efficacious and suitable for once daily dosing.

Abstract: Aqueous deficient vs. evaporative dry eye (maybe, maybe not)

This study illustrates quite emphatically (if I understand it correctly) how these terms aqueous deficient dry eye and evaporative dry eye are too frequently used to distinguish between two conditions that really may NOT have any nice simple clear diagnostic distinctions.

Looks like we're graduating from "The tear film has three layers... blah blah blah" and going right back to "Golly the tear film and its diseases sure are complex."

The first thing that jumped out at me when I skimmed this abstract was the absence of any difference in meibomian gland dropout between the two types. What does it mean? That people with ADDE eventually lose their MGs so we're really not looking at ADDE vs EDE but rather ADDE+EDE vs EDE standalone? Or that the criteria for the initial classification was just plain wrong? Or that meibum doesn't really play all that big a role in retarding evaporation? Or, or, or... the possibilities are endless. I found only questions, not answers here.

Tear Physiology of Aqueous Deficiency and Evaporative Dry Eye.
Optom Vis Sci. 2009 Sep 17. [Epub ahead of print]
Khanal S, Tomlinson A, Diaper CJ.
*PhD daggerPhD, DSc, FAAO double daggerFRCS, FRC(Opth) School of Natural Sciences, University of Western Sydney, New South Wales, Australia (SK), Department of Vision Sciences, Glasgow Caledonian University, Glasgow, Scotland, United Kingdom (AT), and Southern General Hospital, South Glasgow University Hospitals NHS Trust, Glasgow, Scotland, United Kingdom (CJMD).

PURPOSE.: To determine the differences in tear physiology between aqueous deficiency dry eye (ADDE) and evaporative dry eye (EDE), and evaluate their utility in diagnosis.

METHODS.: Fifty-six dry eye patients were classified into 30 ADDE and 26 EDE according to the recently published Dry Eye Workshop criteria. A range of tear physiology measures comprising of tear evaporation, turnover rate (TTR), distribution, volume and osmolarity, and meibomian gland dropout were measured in these patients. The effectiveness of the tests, singly and in combinations, in differentiating between the dry eye subtypes was evaluated by retrospective allocation into groups and by Receiver Operative Characteristics (ROC) curve analysis.

RESULTS.: Statistically significant differences were seen for TTR and tear evaporation (with lower values for ADDE) between ADDE and EDE, but no significant differences were seen for tear osmolarity, volume, distribution, and meibomian gland dropout scores. Differentiation of ADDE and EDE by a cut-off value of 11%/min for TTR was found to have a sensitivity of 86%, specificity of 75%, positive predictive value 89%, negative predictive value 69%, and overall accuracy 83%. The area under the curve on the ROC curve was 0.83. For tear evaporation, a cut-off of 60 g/mh was found to have a sensitivity of 77%, specificity of 55%, positive predictive value 38%, negative predictive value 80%, and overall accuracy 58% in subtype differentiation. The area under the curve was 0.59 on the ROC curve. The distribution curve of the evaporation rates for ADDE and EDE, showed an overlap coefficient of 0.76 indicating that tear evaporation is within a similar range in these two dry eye subtypes.

CONCLUSIONS.: Tear turnover is significantly lower in ADDE than EDE, but there is considerable overlap of tear evaporation between the two dry eye subtypes. Tear osmolarity and turn over tests can be conducted sequentially to effectively diagnose dry eye and its subtypes.

Abstract: Protein biomarkers in contact lens dry eye

Very interesting.

I would like to better understand what they mean by "contact lens-related dry eye". It doesn't seem as though they're simply distinguishing between CTL wearers with and without dry eye, but at a practical level how could they distinguish those with ctl-related dry eye from dry eye independent of ctls?

Mass Spectrometry-Based Proteomic Analyses in Contact Lens-Related Dry Eye.
Cornea. 2009 Sep 16. [Epub ahead of print]
Nichols JJ, Green-Church KB.
From the Campus Chemical Instrumentation Center Mass Spectrometry and Proteomics Facility, College of Optometry, Ohio State University, Columbus, OH.
PURPOSE:: To identify potential protein biomarkers associated with dry eye in contact lens wearers.

METHODS:: Upon enrollment, current galyfilcon A contact lens wearers completed a previously described questionnaire used to classify dry eye status. Approximately 5 muL of aqueous tears were carefully sampled from the inferior-lateral tear prism of each eye using glass microcapillaries. A variety of proteomic approaches were used to compare samples including quantification by Bradford analyses, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) (alone in varying percentages and with MultiPlex analyses for posttranslational modifications), nano-liquid chromatography tandem mass spectometry (nano-LC-MS/MS), and differential gel electrophoresis.

RESULTS:: Twenty-one subjects were enrolled in the study (age 31.3 +/- 11.6 years). Eleven of the subjects were classified with contact lens-related dry eye, while the remaining 10 were normal contact lens wearers. Across all proteomic approaches, several proteins (including several glycoproteins) were identified as potential biomarkers associated with dry eye disease state. In summary across the approaches used, extracellular proteins identified to be altered included beta-2 microglobulin, proline rich 4, lacritin, and secretoglobin 1D1, which were found to be decreased in the dry eye state. Secretoglobin 2A2, serum albumin, glycoprotein 340, and prolactin-inducible protein were all found to be increased in the dry eye state.

CONCLUSIONS:: Dry eye in contact lens wearers is related to several changes in the tear film protein. While functional studies for these candidate proteins are ongoing, initial insights into the functions of these proteins suggest roles in altered tear secretion, in addition to possible increased susceptibility to infection.

Abstract: High frequency use of Restasis

High-frequency Topical Cyclosporine 0.05% in the Treatment of Severe Dry Eye Refractory to Twice-daily Regimen.
Cornea. 2009 Sep 15. [Epub ahead of print]
Dastjerdi MH, Hamrah P, Dana R.
From the Cornea and Refractive Surgery Service, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA.

PURPOSE:: The purpose of this study was to report the efficacy of topical cyclosporine 0.05% at a frequency of 3 to 4 times daily in severe dry eye disease.

METHODS:: We retrospectively identified a cohort of patients with severe dry eye disease who had shown inadequate response to at least a 4-month course of treatment with twice-daily use of topical cyclosporine 0.05% but who showed significant improvement to more frequent dosing.

RESULTS:: Twenty-two patients, including 13 patients with ocular graft-versus-host disease and 9 patients with primary or secondary Sjögren's syndrome, were included. After a minimum of a 2-month course of treatment with more frequent dosing of cyclosporine 0.05% (3 times a day in 7 patients and 4 times a day in 15 patients), overall dry eye symptoms were improved in 15 (68.2%) patients (9 patients with ocular graft-versus-host disease and 6 patients with Sjögren's syndrome). Mean corneal fluorescein staining scores (National Eye Institute scale of 0-15) improved (decreased) from the baseline (precyclosporine use) by -3.5 (range, 0 to -7) in patients with ocular graft-versus-host disease (P < / = 0.0008) and -2.8 (range, 0 to -5) in patients with Sjögren's syndrome (P < / = 0.001). After treatment with high-frequency use of cyclosporine 0.05%, the global physician assessment of dry eye status was favorable (improved) in 16 (72.7%) patients. Three (13.6%) patients reported new-onset symptoms of burning or irritation with the use of high-frequency dosing of topical cyclosporine. No other associated adverse effect was reported.

CONCLUSION:: These data suggest that patients with severe dry eye may require more frequent dosing of topical cyclosporine 0.05% than twice daily.

Monday, September 21, 2009

Abstract: VisMed and Tears Again liposomal spray

Interesting study comparing a sodium hyaluronate drop with a popular eyelid spray, both for evaporative dry eye.

Klin Monatsbl Augenheilkd. 2009 Sep 15. [Epub ahead of print]
Comparative Investigation of Treatments for Evaporative Dry Eye.
Khaireddin R, Schmidt KG.
Klinik und Poliklinik für Augenheilkunde, Universitätsklinik Hamburg Eppendorf.

BACKGROUND: Evaporative dry eye is the most common form of tear film dysfunction. The present trial aims to evaluate the efficacy of two established treatment options with different modes of action by comparison.

PATIENTS/MATERIAL AND METHODS: 216 patients suffering from evaporative dry eye were included in this prospective, randomised two-centre trial. Divided into two treatment groups, patients either received treatment with hyaluronate artificial tears (Vismed light) or a phospholipid-liposome eye spray (Tears Again), each for three months. Tests (lid-parallel conjunctival folds [LIPCOF], non-invasive break-up time [NIBUT], Schirmer's test, inspection of lids and subjective assessment) were performed before as well as 4 and 12 weeks after initiation of this study.

RESULTS: In the patients of the eye spray group there was a significantly greater reduction of the LIPCOF grade (p < 0.02) and the grade of inflammation of the lid margin (p < 0.002). With respect to the tear film break-up time (NIBUT) there was a significant difference between the results of both groups (p < 0.003). The improvement of the break-up time in patients of the eye spray group turned out to be more than twice as high as that in the artificial tears group.

CONCLUSIONS: Both therapies improved evaporative dry eye, but patients on phospholipid-liposomal eye spray demonstrated greater clinical benefit from their therapy, particularly regarding the degree of inflammation of the lid margins as well as the grade of LIPCOF. When compared to hyaluronate artificial tears, NIBUT more than doubled in the phospholipid-liposome eye spray group. Clinical severity of dry eye is more pronounced when evaporative dry eye and aqueous tear deficiency coincide. A combination of the phospholipid-liposome eye spray and artificial tears appears to represent a considerable advancement in tear replacement therapy for severe cases of dry eye.