New drug news: p.s.

I posted the other day about Alcon's Vexol being in clinical trials with a 2009 NDA expected.

I've been asked why, since this is an already FDA approved corticosteroid which has been on the market for quite some time. The reason for the new clinical trials and new FDA submission is to broaden its indications to specifically include dry eye. As you know topical steroids have been used in dry eye treatment for quite awhile (and Lotemax has been particularly prominent of late) - however, dry eye is an off-label use of topical steroids. Getting FDA approval for a steroid drop specifically for dry eye would mean that the company can market it directly to consumers ala Restasis.

Study: Ocular surgery and dry eye

Minor abstract from a European journal. Nothing earthshattering. The reason I'm posting it is that I find myself increasingly bewildered as to WHY eye surgery patients are not told that they may - and in many cases probably will - experience dry eye either in the short or long term, so that they can be prepared and can learn how to address it before it bushwhacks them with (in some cases) intense pain.

I had a call the other day from a 33-year-old woman who had corneal transplants (advanced keratoconus case) in her 20s. No one ever told her, before OR after her surgeries, how it might affect her tear production; seems I was the first person she had heard say that her current condition did not surprise me given her history. Many of my women readers will be grimacing in sympathy for her increased dry eye susceptibility when they hear she has several young children. For heaven's sake, even LASIK is well known to cause dry eye in a substantial percentage of patients with or without other risk factors - let alone when you cut out a complete corneal button and replace it.

Please doctors, tell patients about dry eye before medically necessary eye surgeries.

The influence of ocular surgery for lacrimal secretion
Samoilă O, Stan C, Vişan O, Crăciun A, Dican L, Mera M
Oftalmologia. 2007;51(3):81-5
Article in Romanian

Dry eye syndrome remains a constant health problem while more and more patients are being involved and final data concerning the etiopathogeny is still missing. This study investigates the hypothesis that ocular surgery inflicts damage on the tear production (regarding quantity, quality or the compositional aspect). Ocular symptomathology was registered with the help of a questionnaire. Lacrimal tests were applied before and after surgery at 6 weeks. Basic and reflex tear secretion was differentiated through Schirmer tests and tear quality was assessed with BUT. Proteomic analysis (global proteins, electrophoresis) and conjunctival biopsy was realized before surgery. Open eye surgery altered tear secretion in 91% of the 22 patients examined.

New drug news: Steroids & stuff

Alcon has Vexol (a corticosteroid) listed on their pipeline as a probably FDA submission for 2009 and it appears in at least one clinical trial database as being in Phase II. I assume this is their answer to the current trend of attacking inflammation (or at least B&L's aggressive Lotemax campaigns).

I haven't heard a PEEP about Rebamipide in ages. Hey Novartis, what gives?

I'm now showing a total of 7 dry eye drugs in Phase III, another 7 in Phase II, and 9 in earlier development. Presumably something somewhere in all this melee is going to turn out really useful.

New drug news: Dehydrex

This is one of those little-known things that manages to fly under the radar. I never would have known about it except that I was digging around for hyperosmotic agents and came across a reference to Dehydrex in a 1985 abstract. I googled it and one thing led to another.

Dehydrex has been around for, oh, 25 years or so and has been considered an orphan drug, used for treatment of recurrent corneal erosions. Some years ago (2001, according to the FDA website) clinical trials were started with FDA support from their Orphan Products Development program. I understand the clinicals were very successful and were recently completed and that an NDA will be filed.

Assuming this gets approved - which based on the clinical trial structure and results seems like a safe assumption - I would not be surprised if it turned out to be useful for a wider indication than RCEs.

Those of you who have followed Dr. Holly's work may be interested to know that Dehydrex was a Dextran-based predecessor of Dwelle, which was Dr. Holly's later development continuing down the "high oncotic pressure" route. Hence its popularity - alas, anecdotally, since no study has ever been completed and published on this specifically, that I know of - in treatment of RCEs.

2008 forecast

I'm going to venture a prediction about the dry eye drug scene in the coming year.

I predict that in the US we will see a trend towards filing NDAs (new drug applications) with the FDA for eyedrops well off the beaten path of the new drug model where a small company comes up with something new and promising, gets some capital to put it through some testing, then gets bought by a pharma and proceeds through all the agony of Phase III clinical trials.

I think we'll see 2 to 5, possibly even more, NDAs of this less conventional type. The formulations will not be particularly sexy. They may be substances that are sold over-the-counter everywhere except the US due to the weird way the FDA regulates OTC eyedrops, or they may even be substances currently compliant (more or less) with the OTC regs that actually have considerable therapeutic potential and therefore deserve to be in a different category, though whether they merit the price consumers (or their insurers) will be feverishly (or reluctantly) doling out for them may remain a question. I also predict that one or more of these will be more effective than any other Rx dry eye drug, and that one or more of these will be nothing more than an artificial tear sold at an absurdly high price.

Study: Cooties on the cornea... What to do, what to do

Ocular Pathogen or Commensal: A PCR-Based Study of Surface Bacterial Flora in Normal and Dry Eyes.
Graham JE, Moore JE, Jiru X, Moore JE, Goodall EA, Dooley JS, Hayes VE, Dartt DA, Downes CS, Moore TC.
Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5616-23

PURPOSE: To compare the bacterial population of the ocular surface of normal and dry eye subjects using conventional culture and 16S rDNA PCR.
METHODS: Ninety-one subjects were classified as normal (n = 57) or dry eye (n = 34) by using tear break-up time, McMonnies survey, goblet cell density, and meibomian gland assessment. Conventional bacterial culture and broad-range 16S rDNA PCR, cloning, and DNA sequencing were used for bacterial identification. Repeated sampling was performed in a subset of subjects over a 3-month period. The association between goblet cell loss and bacterial counts in a subgroup of subjects was assessed.
RESULTS: Most of the bacteria identified by culture were coagulase negative staphylococci, whereas molecular methods demonstrated a considerable number of additional bacteria. Atypical ocular surface bacteria including Rhodococcus erythropolis, Klebsiella oxytoca, and Erwinia sp., were identified in cases of overt inflammation and, surprisingly, on the normal ocular surface. The same bacteria remained on the ocular surface after repeated sampling. Increased bacterial flora was associated with reduced goblet cell density.
CONCLUSIONS: Molecular analysis revealed a diverse ocular surface bacterial population. In addition to the normal flora, various potentially pathogenic bacteria were identified. The detection of known pathogens in both normal and dry eyes, with minimal signs of infection, presents a diagnostic dilemma. It remains unknown whether their presence is associated with inflammation and reduced goblet cell density or whether they adversely affect the ocular surface predisposing it to abnormal microbial colonization. In the absence of overt clinical infection, it is unknown whether such results should prompt intervention with therapy.

Study: Another dry eye diagnostic

No comment. I'm permanently jaded and confused after reading about so many new and exciting dry eye diagnostics that I can't keep them straight. Somebody wake me up when one gets adopted for use in a major clinical trial.

Y'all know that one of my hangups is differentiation between aqueous tear deficiency, meibomian gland dysfunction and other ocular surface disease. So from my perspective, how dry your surface is at 2:38pm on December 10th, 2007 does not tell ME a whole heck of a lot except that, if it's awfully dry, it ought to add something to the urgency of finding out WHY in order to treat it appropriately.

On the other hand, a key use of a standardized, reliable dry eye diagnostic would be for what I really, really, really want to see: a really, really good epidemiological study of dry eye. So my first question about these diagnostics is, how long does it take, how much does it cost and how much training does it take to perform reliably?

Automatic dry eye detection.
Yedidya T, Hartley R, Guillon JP, Kanagasingam Y.
Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. 2007;10(Pt 1):792-9.

Dry Eye Syndrome is a common disease in the western world, with effects from uncomfortable itchiness to permanent damage to the ocular surface. Nevertheless, there is still no objective test that provides reliable results. We have developed a new method for the automated detection of dry areas in videos taken after instilling fluorescein in the tear film. The method consists of a multi-step algorithm to first locate the iris in each image, then align the images and finally analyze the aligned sequence in order to find the regions of interest. Since the fluorescein spreads on the ocular surface of the eye the edges of the iris are fuzzy making the detection of the iris challenging. We use RANSAC to first detect the upper and lower eyelids and then the iris. Then we align the images by finding differences in intensities at different scales and using a least squares optimization method (Levenberg-Marquardt), to overcome the movement of the iris and the camera. The method has been tested on videos taken from different patients. It is demonstrated to find the dry areas accurately and to provide a measure of the extent of the disease.

Study: Childhood diabetes and dry eye

Not too much to comment on here. Basically... the non-news that kids with Type 1 diabetes are more likely to have dry eyes than kids without.

Dry eye syndrome in diabetic children.
Akinci A, Cetinkaya E, Aycan Z.
Eur J Ophthalmol. 2007 Nov-Dec;17(6):873-8.

PURPOSE. To compare the symptoms, signs, and results of objective tests for dry eye syndrome (DES) in type 1 diabetes mellitus (T1DM) patients and controls.
METHODS. A total of 104 children with T1DM and 104 age- and sex-matched controls were compared in terms of the symptoms, signs, and results of objective tests for DES. Duration of T1DM, presence of diabetic retinopathy, mean hemoglobin A1c level, pubertal status, and a history of accompanying autoimmune disease were noted in T1DM group. Analysis of variance, multivariate regression analysis, Student t, Mann-Whitney U, and chi-square tests were used for statistical analysis.
RESULTS. A total of 15.4% of diabetic children complained of dry eye symptoms, versus 1.9% of the controls (p=0.029). Dry eye signs were detected in 7.7% of diabetic children, versus 0.96% of controls (p=0.034). Tear break-up time (TBUT) and Schirmer test results were significantly lower in T1DM group than controls (p=0.018, p=0.024, respectively). A total of 7.7% of diabetic children had definite and 0.96% had probable diagnosis of DES, versus none of the controls (p=0.03). TBUT and Schirmer test results were significantly lower in patients with more than 10 years duration of T1DM (p<0.001 for both).
CONCLUSIONS. The prevalence of symptoms, signs, and definite diagnosis of DES are higher and basal tear secretion and tear film stability are lower in diabetic children than controls. Duration of T1DM is the only disease-related variable which is associated with basal tear secretion and tear film stability.

Study: BSLPD to treat DES in cGVHD

Anybody know if there are any scientific journals dedicated to the blogosphere yet? If so, remind me to do a search and see whether there are any published studies examining the effect of overuse of acronyms in subject lines on click-through rates in blogs. (And then maybe the impact on reader drop-out rates when five or more prepositional phrases are used in a row in the opening sentence of a blog entry.)

Meanwhile, our good friends at the Boston Foundation for Sight have published another study. About use of sclerals in treating dry eye in chronic graft-versus-host-disease patients.

For those of you skeptics (I'm talking to MDs here, primarily) who stubbornly adhere to the antiquated notion that scleral lenses and dry eye do not belong in the same sentence, and who would perhaps rather condemn these patients to tarsorrhaphy, Lacrilube and chronic misery, this one's for you.

Boston Scleral Lens Prosthetic Device for Treatment of Severe Dry Eye in Chronic Graft-Versus-Host Disease.
Jacobs DS, Rosenthal P.
Cornea. 2007 Dec;26(10):1195-1199

PURPOSE:: To determine if the Boston Scleral Lens Prosthetic Device (BSLPD) reduces symptoms and improves quality of life in patients with severe dry eye from chronic graft-versus-host disease (cGvHD).

METHODS:: This is a noncomparative interventional case series reporting 33 consecutive patients with severe dry eye from cGvHD, unresponsive to conventional therapy, who were fitted with the BSLPD. A patient survey was undertaken after lenses were dispensed and worn regarding the effect of scleral lens wear on their symptoms, quality of life, and activities of daily living. The patient population was characterized from a retrospective chart review. Survey data were tabulated.

RESULTS:: BSLPD wear resulted in improvement in pain, photophobia, and general quality of life in nearly all patients, with more than half reporting the highest improvement level for pain (52%) and photophobia (63%), and more than two thirds (73%) reporting the highest improvement level for quality of life. There was improvement in reading and driving in >90% of those who reported previous compromise, with >60% reporting the highest improvement level for each of these activities.

CONCLUSIONS:: The BSLPD mitigates symptoms and improves quality of life in patients with severe dry eye from cGHvD.

To "Anonymous" who complained about the "grey on blue"

This blog is not grey on blue, it's dark grey on white. I saw what you were talking about briefly tonight - I think it's blogger.com running really slow or something so at times it was not loading the proper color background.

By the way, it never hurts to be POLITE when you're complaining or making a suggestion.

Study: Gel-to-drop, for Rx or OTC

Hm. Is this basically a souped-up version of the Lacriserts concept, or more? Sounds interesting anyway.

It seems as though there are always some kind of technologies in the works to reduce or eliminate the need for eyedrop application. Several I've read about or been talked at about by excited inventors in the past year or so include a punctal plug that secretes drops, contact lenses used to deliver drugs, special glasses with a microchip and tiny jets aiming a stream of tiny drops at the eyes, and now this gel-to-drop drug delivery system. It will be interesting to see if any of these types of things ever really comes to fruition.

Sustained Ocular Drug Delivery from a Temperature and pH Triggered Novel In Situ Gel System.
Gupta H, Jain S, Mathur R, Mishra P, Mishra AK, Velpandian T.
Drug Deliv. 2007 Nov;14(8):507-15.

Various ocular diseases like glaucoma, conjunctivitis, and dry eye syndrome require frequent drug administration. Poor ocular bioavailability of drugs (< 1%) from conventional eye drops is due mainly to the precorneal loss factors that include rapid tear turnover, nonproductive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the drugs to corneal epithelial membrane. These problems may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ocular delivery system of timolol maleate based on the concept of both temperature and pH-triggered in situ gelation. Pluronic F-127 (a thermosensitive polymer) in combination with chitosan (pH-sensitive polymer also acts as permeation enhancer) was used as gelling agent. The developed formulation was characterized for various in vitro parameters e.g., clarity, gelation temperature and pH, isotonicity, sterility, rheological behavior, drug release profile, transcorneal permeation profile, and ocular irritation. Developed formulation was clear, isotonic solution, that converted into gel at temperatures above 35 degrees C and pH 6.9-7.0. A significant higher drug transport across corneal membrane and increased ocular retention time was observed using the developed formulation. The developed system is a viable alternative to conventional eye drops for the treatment of glaucoma and various other ocular diseases.

Study: Where da numbers?

Right on boys. The acid test: IS LIFE BETTER with this drug? Let's see some numbers please. It's not new anymore - it's been around long enough to figure this out.

Pharmacoeconomics of new medications for common chronic ophthalmic diseases
Hirsch JD, Morello C, Singh R, Robbins SL.
Surv Ophthalmol. 2007 Nov-Dec;52(6):618-33

There is increasing pressure for medical care reimbursement to be linked to outcomes. New medications approved for glaucoma, age-related macular degeneration (AMD), and dry eye disease may offer improved outcomes, but they have higher acquisition costs. This article reviews published pharmacoeconomic studies assessing the incremental change in outcomes achieved vs. the increased medication costs incurred....Notably missing in all analyses are the effects of improved treatment on patient productivity. Although the diversity and small number of studies limit conclusions, there is some evidence that the newer glaucoma medications, as a group, produce economic offsets such as reduced glaucoma surgeries and fewer physician visits. Photodynamic therapy for AMD may be cost-effective when used early in patients with better visual acuity allowing cost-offsets over longer periods of time to be considered. The single pharmacoeconomic analysis of topical cyclosporine for dry eye disease was only hypothesis-generating. Comprehensive studies that investigate clinical, economic, and humanistic outcomes for the patient and society are needed to adequately assess the comparative value of current and future ophthalmic medications.

Study: "Osmoprotection"

Sorry but... my tolerance for hyperosmotalk wore out somewhere in the years of "complete dry eye relief for everyone" marketing which so far as I can tell has not yet completely relieved everyone.

Osmoprotection as a new therapeutic principle
Messmer EM, Ophthalmologe. 2007 Nov;104(11):987-990.

Dry eye syndrome is one of the most common disorders encountered in daily ophthalmological practice. New pathophysiological concepts have been developed over the last few years. Hyperosmolarity of the tear film is one of the key pathogenetic factors in the development of a - commonly subclinical - inflammation of the ocular surface, the lacrimal gland and the tear film in dry eye syndrome. Osmoprotective agents act through compatible solutes to prevent - at least in theory -a hyperosmolar tear film from damaging the ocular surface.

Another update on my BSLs (one more entry on a very long list for Thanksgiving this year....)

Well, last Monday I think I pretty much gave my BSLs the acid test, and they passed with flying colors.

First, I stayed up past midnight on Sunday. Had to take out my lenses around 10pm, so my eyes had two whole hours during which to dry out nicely before bed.

Next, I got up at quarter to three, showered, finished packing, and drove 1.5 hours through a wet windstorm to make an early flight. Managed to time the drive just right... on Monday mornings, if you don't make it to SeaTac at just the right time, you're screwed. I'm glad I took the time to print out my boarding pass, and wasn't checking luggage. Even so, within 5 minutes of my joining the 100+ line at security, it had doubled - at least.

Next, 2.5 hour flight to Orange County. Took out my lenses so I could doze.

Later, a 1-hour drive up towards UCLA in an air conditioned rental.

After dinner (i.e. long after sunset), a hasty drive to LAX.

Next, hanging out in another lovely dry fluorescent-lit airport waiting for a delayed inbound aircraft. Then, another 2.5-hour flight, arrival late at night, and last, I drove myself home in the middle of the night, arriving about 24 hours after I'd gotten up.

NOW, all that sounds just like business as usual to any normal business traveler. By my own travel standards of years ago, that's a light day. But for the past 6 years - in wintertime, at least - THIS IS A BIG DEAL for me. I could not have driven myself to the airport at 4 in the morning with or without rain and wind and debris, I could not have driven down a 10 lane LA freeway (that's an awful lot of starburst-and-halo-generating headlights and taillights) freeway after dark, and I most certainly could not have driven myself home in the middle of the night under any circumstances, let alone after spending an entire day in some kind of rigid contact lens.

With my current pair of T6 BSLs, I can do all that. It's amazing, and I am so grateful. Thank you Dr. Rosenthal, and Mark. :-)

Travel tip for road warriors:

I discovered on this trip that Ocusoft lidscrub foam 50mLs are exempt from the liquids restrictions BUT they trigger a search and an interesting conversation with the security folks, so, um, next time if I'm not checking luggage I'll leave them at home....

Newsblurb: Dry as a desert

Nothing special about the news item per se but there's kind of a cute photo of some fake eyeballs in the sand. (Wee bit of time on our hands today, have we???)

Ozarks Health
Dry As A Desert

The women's health group released a report this summer naming office jobs, many requiring prolonged computer use, as the work most likely to contribute to dry eye. Next are construction and manufacturing jobs, which expose workers to dust, allergens and wind.

Contact-lens users are especially vulnerable to dry eye, Esposito says, because the lenses draw moisture off the eyes.

The condition is more common in Hispanic and Asian women and in people with autoimmune diseases such as Sjogren's syndrome, lupus and rheumatoid arthritis. People who take antihistamines, diuretics, antidepressants and other medications are at higher risk, too.