Wednesday, April 22, 2009

New drug news: Lux Biosciences LX214 in Phase I

LX214 has been on the radar for a year or so and I am glad to see it entering clinicals. By description it certainly sounds promising. The idea of a once-a-day dosing drop that doesn't irritate the eyes, well, sure will be appealing if it works.

Lux Biosciences Initiates Phase 1 Study of LX214, a Development Candidate for Dry Eye Syndrome
Feb 17, 2009 article

Lux Biosciences today announced that it has begun treating patients in a Phase 1 study with its third product candidate, LX214, a proprietary topical ophthalmic solution containing the next-generation calcineurin inhibitor voclosporin. The company is developing LX214 as a potential treatment for keratoconjunctivitis sicca, commonly known as dry eye syndrome (DES), and other chronic inflammatory ocular surface diseases.

“We are pleased with the progress of our program for LX214, which we advanced from inception into the clinic in 18 months, in parallel with our LX211 and LX201 phase 3 development programs,” said Ulrich Grau, Lux Biosciences President and Chief Executive Officer.

He noted that LX214 is a unique product that, based on preclinical data, is differentiated from the benchmark therapy by

- much higher drug levels of a 4 fold more potent calcineurin inhibitor in target tissues in the eye,

- the lack of irritation, and

- 24-hour therapeutic drug levels in the eye providing a rationale for once-a-day dosing.

“These features suggest that LX214 may demonstrate advantages over other treatment approaches in the very large dry eye indication,” Dr. Grau commented.

Abstract: Tear cytokine profiles in DTS

Another step in the direction of correlating (or attempting to correlate) tear composition with disease severity. The conclusions all sound kind of "Yeah I think we all know that" at best, so hopefully the details of the findings have helped advance something somewhere.

Tear cytokine profiles in dysfunctional tear syndrome.
Am J Ophthalmol. 2009 Feb;147(2):198-205. e1. Epub 2008 Nov 7.
Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC.
Department of Ophthalmology, Ocular Surface Center, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.

PURPOSE: To compare tear cytokine and chemokine concentrations in asymptomatic control and Dysfunctional Tear syndrome (DTS) patients and determine the correlations between tear inflammatory mediators and clinical severity.

DESIGN: Prospective observational cohort study.

METHODS: Concentrations of epidermal growth factor (EGF), interleukin (IL)-1 alpha (1alpha), 1 beta (1beta), 6, 10, 12, and 13, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and chemokines: IL-8 (CXC); macrophage inflammatory protein-1 alpha (MIP-1alpha) (CCL3); and regulated upon activation, normal T-cell expressed and secreted (RANTES CCL5) were measured by a multiplex immunobead assay in an asymptomatic control group and DTS patients with and without meibomian gland disease (MGD). Spearman correlations between tear cytokines and severity of irritation symptoms and ocular surface signs were calculated.

RESULTS: Tear concentrations of IL-6, IL-8 and TNF-alpha were significantly higher in DTS with and without MGD and EGF was significantly reduced in the DTS without MGD group compared with the control group. MIP-1alpha was greater in entire DTS and DTS without MGD groups than the control group and RANTES was greater in DTS with MGD than the control and DTS without MGD groups. IL-12 was significantly higher in the DTS with MGD than the DTS without MGD subgroup. Significant correlations were observed between IL-6 and irritation symptoms and between a number of cytokines and chemokines and clinical parameters.

CONCLUSIONS: As predicted, patients with DTS have higher levels of inflammatory mediators in their tears that show correlation with clinical disease parameters. Furthermore, different tear cytokine/chemokine profiles were observed in DTS patients with and without MGD groups.

Abstract: Unraveling Sjogrens dry eye

Upbeat article certainly makes the Sjogrens research horizon sound very promising. May it be so!

Unraveling the pathophysiology of Sjogren syndrome-associated dry eye disease.
Ocul Surf. 2009 Jan;7(1):11-27.
Nguyen CQ, Peck AB.
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida 32610, USA.

Sjogren syndrome (SS) is one of the most common autoimmune diseases. Early clinical manifestations of SS are primarily decreased tear and saliva secretion, leading to dry eye and dry mouth syndromes, but in its later stages, it can become systemic, even resulting in B cell lymphomas. The use of new animal models, coupled with new technologies, is providing exciting insights into the pathogenesis, genetic predisposition, and, possibly, early diagnosis of SS. This article reviews newly described features of SS identified in experimental animal models and their relationship to human disease. New technologies, such as genomics and proteomics, may permit identification of potential candidate genes and biomarkers for disease diagnosis. Current studies using appropriate animal models in parallel with studies of human subjects are rapidly establishing a foundation for new intervention strategies that go beyond merely treating symptoms.

Abstract: Corneal pain without stain

The title of this study says it all. I know a lot of you out there can relate to it and it's wonderful to see a really in-depth study of the severe pain some patients experience without classic visible symptoms of dry eye.

Corneal pain without stain: is it real?
Ocul Surf. 2009 Jan;7(1):28-40.
Rosenthal P, Baran I, Jacobs DS.
Boston Foundation for Sight, Needham, MA 02494, USA.

Clinicians often encounter patients who report corneal pain suggestive of dry eye disease, yet lack equivalent signs. These patients represent a diagnostic and therapeutic challenge that is more easily dismissed than addressed. We review the physiology of pain and the pathophysiological mechanisms of neuropathic corneal pain and speculate on the mechanisms of certain etiopathogenic triggers, such as LASIK, severe dry eye disease, and Sjogren syndrome. Recognizing corneal neuropathic pain as a disease in its own right is the first step toward developing more effective treatments for these severely disabled and presently inadequately served patients.

Abstract: Thyroid eye disease and dry eye

Very interesting study of patients whose dry eye symptoms led to the discovery that they had thyroid eye disease. 21 of 539 dry eye patients is quite a noticeable number. Something for doctors and patients both to keep in mind as a possibility.

Occult thyroid eye disease in patients presenting with dry eye symptoms.
Am J Ophthalmol. 2009 May;147(5):919-23. Epub 2009 Feb 10.
Gupta A, Sadeghi PB, Akpek EK.
Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland 21287, USA.

PURPOSE: To describe the clinical presentation, laboratory features, and treatment outcomes in a series of patients with occult thyroid eye disease (TED). DESIGN: Retrospective observational case series.

METHODS: Among 539 patients who were referred for dry eye evaluation over 2 years, 21 were diagnosed with occult TED, based on typical findings in orbital echography. Medical records of these patients were reviewed to collect information on demographics, clinical findings, laboratory studies, and treatment response.

RESULTS: All patients presented with symptoms of dry eye. Median age of patients was 57 years (range, 24 to 78 years), with the majority female (86%). No patients carried prior diagnosis of TED or had typical findings of TED such as proptosis, dysmotility, or diplopia. Suspicion of TED was based on conjunctival hyperemia with or without chemosis localized to extraocular muscles (100%), and subtle widening of interpalpebral fissure (48%). Clinical findings included corneal fluorescein staining (57%), rapid tear break-up time (31%), and abnormal Schirmer test (19%). Nineteen percent of patients had other rheumatologic disorders commonly associated with dry eye: Sjögren syndrome (n = 3), and rheumatoid arthritis (n = 1). Patients were treated topically using cyclosporine 0.05% 2 to 4 times a day, with or without steroid. Other treatments were also employed as necessary including warm compresses, artificial tears, and puntal plugs. Majority of patients (76%) had improvement of their symptoms.

CONCLUSION: Occult TED is a potential cause of inflammatory ocular surface disease with dry eye symptomatology and should be considered in the differential diagnosis when evaluating dry eye patients.

Abstract: Economics of Restasis

Seems to be a strong argument for insurers to cover Restasis.

Value-based medicine, comparative effectiveness, and cost-effectiveness analysis of topical cyclosporine for the treatment of dry eye syndrome.
Arch Ophthalmol. 2009 Feb;127(2):146-52.
Brown MM, Brown GC, Brown HC, Peet J, Roth Z.
Center for Value-Based Medicine, Box 335, Flourtown, PA 19031, USA.

OBJECTIVE: To assess the comparative effectiveness and cost-effectiveness (cost-utility) of a 0.05% emulsion of topical cyclosporine (Restasis; Allergan Inc, Irvine, California) for the treatment of moderate to severe dry eye syndrome that is unresponsive to conventional therapy.

METHODS: Data from 2 multicenter, randomized, clinical trials and Food and Drug Administration files for topical cyclosporine, 0.05%, emulsion were used in Center for Value-Based Medicine analyses. Analyses included value-based medicine as a comparative effectiveness analysis and average cost-utility analysis using societal and third-party insurer cost perspectives.

MAIN OUTCOME MEASURES: Outcome measures of comparative effectiveness were quality-adjusted life-year (QALY) gain and percentage of improvement in quality of life, and for cost-effectiveness were cost-utility ratio (CUR) using dollars per QALY.

RESULTS: Topical cyclosporine, 0.05%, confers a value gain (comparative effectiveness) of 0.0319 QALY per year compared with topical lubricant therapy, a 4.3% improvement in quality of life for the average patient with moderate to severe dry eye syndrome that is unresponsive to conventional lubricant therapy. The societal perspective incremental CUR for cyclosporine over vehicle therapy is $34,953 per QALY and the societal perspective average CUR is $11,199 per QALY. The third-party-insurer incremental CUR is $37,179 per QALY, while the third-party-insurer perspective average CUR is $34,343 per QALY.

CONCLUSIONS: Topical cyclosporine emulsion, 0.05%, confers considerable patient value and is a cost-effective therapy for moderate to severe dry eye syndrome that is unresponsive to conventional therapy.

Free books (again)

Once again, courtesy of the Sjogrens Syndrome Foundation (thank you SSF!) we have copies of "The Dry Eye Remedy" by Dr. Latkany available free of charge in The Dry Eye Shop.

Limit of 2 per customer. Already read it? Consider getting another copy for a friend or for your eye doctor. And let your doctor know which topics you found particularly helpful!

Shipping is not free, but it's only $2.58 via Media Mail. Please note that books always ship separately so if you order other items they will arrive first.

If you want to get the book and also browse other items, click on this link:
The Dry Eye Remedy free book offer

If you want to get the book only and check out in record time, click on this direct checkout link:
The Dry Eye Remedy quick checkout

Tuesday, April 21, 2009



2.5 months with no updates or Dry Eye Bulletin. Tsk, tsk.

And now, to reward myself for finally tackling the growing mountain of news I need to write about, I'll indulge in a single post about anything except eyeballs.

So, what's been going on with the Petrises lately?

First... our little 'homestead'. I think I wrote about this a little after we first moved in. We're renting an old farmhouse on 10 lush acres in Poulsbo, Washington. I am thrilled right down to my toes to be living in a place like this and learning a new and much wanted life in the slow lane (at least part time). The first few months were rough due to minor problems with the house like heat and plumbing, but things are sorting themselves out and the weather is FINALLY warming up after an unbelievably long winter here. It's not supposed to snow in Puget Sound. But it's really not supposed to snow in December, January, February, March and April in Puget Sound. I was soooo glad to see the mercury (or do I mean the digital weatherstation?) climb up to 70-something even if the weatherman is threatening to set us back a month tomorrow.

We have our chickens! I mail-ordered them (don't do that... find them locally if you can) because I was looking for a breed that is not too common around here, Australorps. The adults are that beautiful greeny-black color, large, and excellent layers. Our "chicks" are 6 weeks and 1 day old today. We have 19. I ordered a straight run, where you don't get to pick the gender, and we're not quite sure yet but there seem to be at least 6 boys. I'm going to try to identify the nicest rooster of the bunch to keep for breeding, along with 7 or 8 of the hens, and everybody else goes in the freezer. Not without some interesting preliminaries of course. I haven't made up my mind 100% about how to do it. There is an organic meat processing place in Tacoma that reportedly will do chickens for around ~$3 but given that part of the point was to get really good food at a reasonable price I'm kind of begrudging the cost. More likely, I'll take them up to my sister's place in Sequim, where they have a sizeable organic free range poultry operation, and ask my brother-in-law to 'do the deed' while I do the plucking & eviscerating, which I was fascinated to learn during a visit a few weeks ago.

The chicks are great fun. There are stages where you swear you can actually see them growing. And no wonder. We discovered a few days ago that my sister had accidentally given me the 24% protein Turkey starter mash instead of the regular poultry mash which I think is 20% protein. Superturbo chicks. - I wish we could free range them... but there are dogs in the neighborhood and we are not 100% fenced. So I do the next best thing, pasturing them in moveable coops & runs that get shifted around to different spots.

Meantime, my other projects have included land clearing, some greenhouse gardening and gearing up for real gardening. This place is blackberries galore. It was not till two months after we moved in that I discovered the greenhouse behind the shed - buried under several years worth of blackberries. I hacked all that stuff out by hand and am now starting on digging up the roots. You wouldn't BELIEVE how big these roots get. There have been a couple that we've been tempted to hang on the wall as a trophy in place of antlers or something. I'm talking 5 inches in diameter.

The greenhouse is cute as a button and we're getting lettuce & spinach that I planted back in February, plus there are a ton of starts from herbs to tomatoes to eggplants that are ready to go outside. - My brother-in-law loaned us his rototiller so we've plowed up a good bit of land for the veggie garden. I'm hoping to do some grains as well.

Once I finished up with the worst of the blackberries around the greenhouse, I started taking a closer look at other blackberry patches. Hmmmmm. It seems blackberries like to grow ON things. Every patch became a possible new treasure. I'm not letting myself go after them all until I've got the roots dealt with around the greenhouse but I'm salivating over some of these patches wanting to know what's under them. The only other one I've cleared revealed a sawmill. Seriously. A long track sort of thing with a trolley on it that carries logs along to be sawn into planks. The blade was still there... and still sharp. This place seems like it was set up to be the perfect self-sufficient sustainable farm.

Chaidie and I finally planted the potatoes the other day and carrots this morning. We figure we'll try to plant one new thing every day till they're all done.

Other news... my dearest friend, who I haven't seen in nearly 15 years, visited me from Australia with her husband recently and was able to stay for a month. We all came down with an awful virus which they both took home with them and Chaidie and I are still getting over. But it was a wonderful time.

The fruit trees are putting out leaves and some of them are flowering. We saw the buds day after day, week after week, looking like they just needed a few hours or moderate temperatures to open. But right up till late last week we were still sometimes dipping into the 20s at night. Warmer now, and Chaidie is so thrilled to be able to go around barefoot and in shorts in our "dandelion field".

The birds are a real delight. We have two very popular hummingbird feeders out front where the Rufous hummingbirds actually line up for drinks. There are a couple dozen types of birds that we see regularly in the orchard including pileated woodpeckers, stellars jays of course and lots of little ones that I can't see well enough to identify without binoculars.

And our latest "wildlife" visitor?

A peacock.

Yup, he just showed up in our front yard one day. Those birds make the most appalling noises. We just about jumped out of our skins, then rushed to the door and had a look. He strolled all the way around the house, checking us out, and eventually went back home. He's been back several times, and once with a friend. I wish I had some video footage of Chaidie following him around trying to get a feather. The two of them walked around and around and around a little clump of filberts for about 10 minutes with Chaidie's hand poised just so above the tail of an apparently supremely indifferent peacock. Just as well she never got a grip. If I were a bird I don't think I'd like having a big feather pulled out, and those birds are more than big enough to do some damage.

I eventually asked the Acknowledged Source of All Wisdom, our postal deliverer Michelle, who told me there's a place not far away that breeds them. Apparently they, er, free range them.

Alright, I guess it really is time to get back to eyeballs!