Thursday, September 9, 2010

Drug news: Cyclokat Phase III complete

Thanks to an eagle-eyed reader for noticing this... According to the clinicaltrials.gov page for Cyclocat, Phase III is completed, so we are now awaiting results.

Cyclokat is a high-concentration (0.1%, vs. Restasis which is 0.05%) Cyclosporine drug.

Go to my clinical trial roster to see other drugs in Phase II or Phase III.

Abstract: Mapracorat

Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells.
Mol Vis. 2010 Sep 2;16:1791-800.
Cavet ME, Harrington KL, Ward KW, Zhang JZ.
Pharmaceutical R&D, Bausch & Lomb, Inc., Rochester, NY.

PURPOSE: Increasing evidence suggests that tear hyperosmolarity is a central mechanism causing ocular surface inflammation and damage in dry eye disease. Mapracorat (BOL-303242-X) is a novel glucocorticoid receptor agonist currently under clinical evaluation for use in the treatment of dry eye disease. This study assessed the anti-inflammatory effects of mapracorat in an in vitro osmotic stress model which mimics some of the pathophysiological changes seen in dry eye.

METHODS: Human corneal epithelial cells were cultured in normal osmolar media (317 mOsM) or 440 mOsM hyperosmolar media for 24 h. Luminex technology was used to determine the effect of mapracorat on hyperosmolar-induced cytokine release. Effects of mapracorat on mitogen-activated protein kinase (MAPK) phosphorylation were determined by cell based ELISA. Effects of mapracorat on nuclear factor kappa B (NFkappaB) and activator protein-1 (AP-1) transcriptional activity were assessed by reporter gene assay. Dexamethasone was used as a control.

RESULTS: Hyperosmolar conditions induced release of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) from cultured human corneal epithelial cells, and altered the phosphorylation state of p38 and c-Jun N-terminal kinase (JNK) and transcriptional activity of NFkappaB and AP-1. Incubation of cells with mapracorat inhibited hyperosmolar-induced cytokine release with comparable activity and potency as dexamethasone. This inhibition was reversed by the glucocorticoid receptor antagonist mifepristone (RU-486). Increased phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat. Mapracorat also significantly decreased the hyperosmolar-induced increase in NFkappaB and AP-1 transcriptional activity.

CONCLUSIONS: Mapracorat acts as a potent anti-inflammatory agent in corneal epithelial cells challenged with osmotic stress, with comparable activity to the traditional steroid dexamethasone. These in vitro data suggest that mapracorat may be efficacious in the treatment of dry eye disease.

Abstract: Punctal occlusion

Punctal occlusion for dry eye syndrome.
Cochrane Database Syst Rev. 2010 Sep 8;9:CD006775.
Ervin AM, Wojciechowski R, Schein O.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, W5010, Baltimore, Maryland, USA, 21205.

BACKGROUND: Dry eye syndrome is a disorder of the tear film and is associated with symptoms of ocular discomfort. Punctal occlusion is a mechanical treatment in which the tear drainage system is blocked in order to aid in the preservation of natural tears on the ocular surface.

OBJECTIVES: The objective of this review was to assess the safety and efficacy of punctal plugs for the management of dry eye.

SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 6), MEDLINE (January 1950 to June 2010), EMBASE (January 1980 to June 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (http://clinicaltrials.gov). We also searched the Science Citation Index-Expanded database and reference lists of included studies. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 21 June 2010.

SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of collagen or silicone punctal plugs in symptomatic participants diagnosed with aqueous tear deficiency or dry eye syndrome.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study investigators for additional information.

MAIN RESULTS: Seven randomized controlled trials including 305 participants (601 eyes) met the inclusion criteria and are summarized in this review. We did not perform meta-analysis due to appreciable variability in interventions and follow-up intervals. Although punctal plugs provided symptomatic improvement and clinical outcomes also improved from baseline measures, few studies demonstrated a benefit of punctal plugs over the comparison intervention. Reported adverse effects included epiphora (overflow of tears), foreign body sensation, eye irritation, and spontaneous plug loss.

AUTHORS' CONCLUSIONS: This systematic review shows a relative scarcity of controlled clinical trials assessing the efficacy of punctal occlusion therapy in dry eye. Although the evidence is very limited, the data suggest that silicone plugs can provide symptomatic relief in severe dry eye. Moreover, temporary collagen plugs appear similarly effective to silicone plugs on a short-term basis.

Tuesday, September 7, 2010

Drug news: Can-Fite CF101 to enter Phase III

Can-Fite wins FDA nod for Phase III trial
Globes
5 September 10 12:27, Hillel Koren

CEO Prof. Pnina Fishman: The treatment positions the company in the forefront of drug development for dry-eye syndrome.

Can-Fite BioPharma Ltd. (TASE:CFBI) has obtained US Food and Drug Administration (FDA) approval for the Phase III clinical trial of its CF101 anti-inflammatory drug for the treatment of dry-eye syndrome. The trial will last for six months, and include 300 patients in the US, Europe and Israel.

Can-Fite added, however, that to register the drug for use, two Phase III trials, with 500 patients altogether, will be needed.
Can-Fite noted that it had successfully completed a Phase II clinical trial of CF101 for dry-eye syndrome, which demonstrated with statistical significance that the drug was effective and safe.

Can-Fite CEO Prof. Pnina Fishman said, "Can-Fite today took another important step forward in the development of its first innovative drug. The FDA's approval strengthens recognition of the company and the potential of CF101. The treatment positions the company in the forefront of drug development for dry-eye syndrome. Assuming that the Phase III trial succeeds as did the previous trial, CF101 will be an effective treatment for a disease with a currently estimated market of $2 billion."
Can-Fite's updated estimates said that more than 30 million people in the US alone suffer from dry-eye syndrome.
Can-Fite's share price rose 6.1% in morning trading to NIS 0.53, giving a market cap of NIS 110 million.

Abstract: Preservatives - the good, the bad, and the ugly

Yes, that's actually the title of the study!

Bottom line: DON'T USE BAK in medications that have to be taken for a long time.

Preservatives in eyedrops: the good, the bad and the ugly.
Prog Retin Eye Res. 2010 Jul;29(4):312-34. Epub 2010 Mar 17.
Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F.
Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, INSERM, U968, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, CNRS, UMR_7210, Paris F-75012, France. baudouin@quinze-vingts.fr

There is a large body of evidence from experimental and clinical studies showing that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, corneal surface impairment, and the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been described in patients receiving antiglaucoma treatments for long periods of time. However, the mechanisms involved, i.e., allergic, toxic, or inflammatory, as well as the respective roles of the active compound and the preservative in inducing the toxic and/or proinflammatory effects of ophthalmic solutions, is still being debated. The most frequently used preservative, benzalkonium chloride (BAK), has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies. As a quaternary ammonium, this compound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, and damage to deeper ocular tissues. The mechanisms causing these effects have not been fully elucidated, although the involvement of immunoinflammatory reactions with the release of proinflammatory cytokines, apoptosis, oxidative stress, as well as direct interactions with the lipid components of the tear film and cell membranes have been well established. Preservative-induced adverse effects are therefore far from being restricted to only allergic reactions, and side effects are often very difficult to identify because they mostly occur in a delayed or poorly specific manner. Care should therefore be taken to avoid the long-term use of preservatives, otherwise a less toxic alternative to BAK should be developed, as this weakly allergenic but highly toxic compound exerts dose- and time-dependent effects. On the basis of all these experimental and clinical reports, it would be advisable to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those suffering from preexisting or concomitant ocular surface diseases, and those experiencing side effects related to the ocular surface. Indeed, mild symptoms should not be underestimated, neglected, or denied, because they may very well be the apparent manifestations of more severe, potentially threatening subclinical reactions that may later cause major concerns.

Abstract: Comorbitities of dry eye

...in other words, what other diseases are most commonly shared by people who have dry eye?

Only a couple of these (RA and lupus) are directly related to dry eye; some others are probably related through medication. But overall many of the conditions on this list are many things which like dry eye are just more common in an elderly population.

Comorbidities of dry eye disease: a nationwide population-based study.
Acta Ophthalmol. 2010 Aug 31. [Epub ahead of print]
Wang TJ, Wang IJ, Hu CC, Lin HC.
Department of Ophthalmology, Taipei Medical University Hospital, Taipei, Taiwan.


Purpose:
To investigate the comorbidities of dry eye disease in a nationwide population-based data in Taiwan.

Methods:
This study features a study group and a comparison group. The study group comprised 12 007 patients who sought ambulatory care for treatment of dry eye in 2005 and 2006. In total, 36 021 randomly selected patients were in the comparison group. Conditional logistic regression analyses conditioned on gender, age, monthly income and level of urbanization of the community in which the patient resided were conducted to calculate the odds ratio (OR) for each of 33 comorbidities among patients with and without dry eye disease.

Results:
The regression analyses revealed that compared to patients without dry eye disease, patients with dry eye disease were more likely to have comorbidities of ischaemic heart disease (OR = 1.36), hyperlipidaemia (OR = 1.68), cardiac arrhythmias (OR = 1.55), peripheral vascular disorders (OR = 1.57), stroke (OR = 1.31), migraines (OR = 1.76), myasthenia gravis (OR = 2.85), RA (OR = 2.86), systemic lupus erythematosus (OR = 3.98), asthma (OR = 1.25), pulmonary circulation disorders (OR = 1.37), diabetes with complications (OR = 1.31), hypothyroidism (OR = 1.94), liver diseases (OR = 1.71), peptic ulcers (OR = 1.76), hepatitis B (OR = 1.64), deficiency anaemias (OR = 1.31), depression (OR = 2.11), psychoses (OR = 1.87) and solid tumours without metastasis (OR = 1.41).

Conclusions:
This study demonstrates significantly higher prevalence of medical comorbidities in patients with dry eye disease in Taiwan