Thursday, April 14, 2011

Drug news: One more quickie on RGN-259

Between the good clinical results they're getting on RGN-259 and problems plaguing another unrelated drug they're working on, RGN-259 has been promoted to a real priority for this company which hopefully will translate to good news for US.

RegeneRx Focuses Immediate Clinical Development on Dry Eye Indication with RGN-259, Provides Update on AMI Phase 2 Study Clinical Hold

ROCKVILLE, Md.--(BUSINESS WIRE)--RegeneRx Biopharmaceuticals, Inc. (OTC Bulletin Board: RGRX) (“the Company” or “RegeneRx”) announced today that it has shifted its near-term clinical development focus to RGN-259, its preservative-free topical eye drop, for the treatment of symptomatic dry eye. This reprioritization of the Company’s product pipeline is primarily due to recently announced data supporting the development of RGN-259 for this indication.

In two studies evaluating RGN-259 to treat symptomatic dry eye induced in mice, RGN-259 resulted in statistically significant improvement of corneal healing compared with negative and positive controls. Previous studies in animal models have also shown the ability of RGN-259 to repair the cornea after chemical damage. Following these animal data, and in conjunction with previously reported human clinical data, RegeneRx is expediting its ophthalmic clinical program and is planning a Phase 2 clinical trial in patients with dry eye that will be designed to measure the safety and efficacy of RGN-259 in this indication. This will be in addition to a physician-sponsored clinical trial in patients with dry eye that is currently being supported by RegeneRx in the form of manufacturing and regulatory and clinical guidance.

The Company’s decision to refocus its development efforts on dry eye also results from uncertainty caused by the previously announced clinical hold of the Company’s Phase 2 clinical trial with its RGN-352 product candidate for patients who have experienced an acute myocardial infarction (AMI), commonly known as heart attack. As previously reported, this trial has been placed on clinical hold by the U.S. Food and Drug Administration (FDA) due to current good manufacturing practice (cGMP) compliance issues at one of the Company’s contract manufacturers. While RegeneRx seeks to resolve the compliance issues with the FDA and its manufacturer, the Company cannot predict how long the trial will be on clinical hold. If the FDA were to require re-manufacture of either RGN-352 or placebo for the trial, it would significantly delay enrollment and would require RegeneRx to bear substantial additional cost associated with the trial.

“Because of the new positive data that complement our earlier human and animal ophthalmic data, the relatively short timeframe in which we believe we can generate human dry eye data in a Phase 2 trial, and the significantly reduced cost as compared with the Phase 2 AMI trial, we believe it is in the best interest of the Company and our stockholders to place our highest priority on the clinical development of RGN-259. We are fortunate to have several drug candidates in development and the ability to quickly reprioritize our clinical focus,” stated J.J. Finkelstein, RegeneRx’s president and chief executive officer.

Wednesday, April 13, 2011

Drug news: RGN-259 update

REG BIO : RegeneRx Reports New Statistically Significant Data Confirming Repair of Corneal Damage in Dry Eye Model
April 13, 2011

RegeneRx Biopharmaceuticals, Inc. (OTC Bulletin Board: RGRX) ("the Company" or "RegeneRx") today announced positive new data related to RGN-259, its preservative-free ophthalmic drug candidate. In a second "dry eye" study conducted by Ora, Inc. using their Preclinical CAE? Murine (mouse) Model, four active concentrations of RGN-259 were compared to three control groups, consisting of a negative control (vehicle) and two positive controls (doxycycline and Restasis?). The animals were treated for a total period of nine days following the inducement of moderate, and then severe, dry eye. In the moderate dry eye phase of the study, after six days of treatment, two concentrations of RGN-259 showed a statistically significant reduction in corneal fluorescein staining, a method used to determine the extent of damage to the cornea, which returned to near baseline (normal) levels. After inducement of severe dry eye in the same mice, treatment with RGN-259 for three additional days similarly showed a greater reduction of corneal staining compared to the control groups, although no group achieved statistical significance. This study confirms and expands upon a previous study that also showed a statistically significant reduction of corneal staining back to near baseline levels in a similar animal model. Data from both studies will be presented at the 2011 Association for Research in Vision and Ophthalmology (ARVO) meeting in Ft. Lauderdale on May 3.

"Two different concentrations of RGN-259 were observed to be superior to the positive controls and reduced staining essentially to baseline levels in the standard murine dry eye model. The mechanism of action of wound healing and anti-inflammatory properties of T?4, together with the preclinical data from this and the prior animal study indicate a substantial therapeutic potential in dry eye," stated George Ousler III, vice-president of dry eye at Ora, Inc., Andover, MA.

"The results of this latest animal study will have a significant impact on our clinical program and how we view the path toward development of RGN-259. We believe the two dry eye animal studies, along with previous positive results in humans that showed the ability of RGN-259 to repair non-healing corneal ulcers, with no observed adverse safety events, provide a solid foundation to support commercial development. We have already begun planning a Phase 2 clinical trial focused on developing RGN-259 for the treatment of dry eye," stated J.J. Finkelstein, RegeneRx's president and chief executive officer.

Abstract: Psoriasiform blepharitis

This is a little off the beaten path of what I usually report on but it caught my eye because of a long talk I had earlier today with a gal with something that sounded similar. Fairly sudden onset and whammo, massively symptomatic in the lids.

Bilateral Upper and Lower Eyelid Severe Psoriasiform Blepharitis: Case Report and Review of Literature.

The purpose of the present study is to describe a case of severe, psoriasiform blepharitis by means of a case report and literature review. A 44-year-old man developed chronic blepharitis and tearing months after bilateral cataract surgery. Exam showed diffuse quad-eyelid erythema, discharge, edema, madarosis, and scale. He also had insufficient tear drainage due to bilateral upper eyelid cicatricial punctal atresia with bilateral lower eyelid punctal stenosis. Biopsy of the lower eyelids exhibited psoriasiform hyperplasia. Topical 0.1% tacrolimus achieved improvement but caused some subjective eye irritation. Psoriasiform dermatitis manifesting on the eyelids is rare, may be associated with insufficient tear drainage, and may respond favorably to 0.1% tacrolimus.

Ophthal Plast Reconstr Surg. 2011 Apr 1. [Epub ahead of print]
Zhu F, Tao JP.
The Gavin Herbert Eye Institute, University of California, Irvine, California, U.S.A.

Abstract: Primary Sjogrens Syndrome in Chinese patients

This was interesting... apparently Chinese patients have significantly less incidence of dry eyes from Sjogrens than non Chinese. I found the data on age of onset staggering - almost 30% diagnosed by their early thirties? Yowch.

Clinical and prognostic characteristics of 573 cases of primary Sjögren's syndrome.

BACKGROUND: Primary Sjögren's syndrome (pSS) is one of the autoimmune diseases with high incidence. There were several clinical investigations in Caucasian but seldom in Chinese. The aim of this study was to compare the difference of clinical manifestations, immunological features and prognosis of pSS between Caucasian and Chinese pSS patients.

METHODS: Five hundred and seventy-three patients who fulfilled the 2002 international classification (criteria) for pSS from Peking Union Medical College Hospital between 1985 and 2006 were screened retrospectively and compared with other populations.

RESULTS: (1) The study consisted of 524 (91%) female and 49 (9%) male patients (female: male = 10.7:1). Mean age at the onset of the disease was (39.0 ± 13.7) years and in 169 (29.5%) patients the disease onset occurred before the age of 30 years. The average duration from disease onset to pSS diagnosis was 48 months (range, 1 - 552 months). It had been shortened during the recent five years. (2) Dry mouth (84.5%) and dry eyes (70.0%) were the most common symptoms, significantly lower than foreign patients (P = 0.000). Two hundred and seventy-two (47.5%) patients presented with rampant caries, 160 (27.9%) with parotidomegaly. The positivity of xerostomia, xerophthalmia and salivary gland biopsy were 91.9%, 94.8% and 90.7%, respectively. (3) Systemic involvement occurred in 91.4% patients. Compared with studies done outside China, higher prevalence of fever 41.0%, myositis 4.9%, pericardial effusion 14.8%, pulmonary involvement 42.3%, renal involvement 33.5%, thyroid involvement 32.7%, pancrease involvement 5.6% (P < 0.01) and lower prevalence of fatigue, lymphadenectasis and Raynaud's phenomenon (P < 0.01) were seen. (4) Risk factors of death include pulmonary artery hypertension, liver damage and interstitial lung disease.

CONCLUSIONS: Chinese pSS differs significantly from the non-Chinese cases in terms of the age of onset, systemic involvement, autoantibodies and proportional mortality rate. Lung and liver damage were found to be the highest risk factors of the disease prognosis.

Chin Med J (Engl). 2010 Nov;123(22):3252-7.
Lin DF, Yan SM, Zhao Y, Zhang W, Li MT, Zeng XF, Zhang FC, Dong Y.
Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China.

Abstract: Dry eye severity after bone marrow transplant - does donor gender matter?

This was rather interesting....

Donor-recipient gender difference affects severity of dry eye after hematopoietic stem cell transplantation.

To determine whether the incidence rate and severity of dry eye after hematopoietic stem cell transplantation varies with donor vsrecipient gender.

We limited this study to patients received bone marrow transplantation (BMT). In all, 172 patients received BMT at Keio University School of Medicine between January 2000 and May 2007. Of them, 136 recipients who survived at least 70 days were studied prospectively. We classified the 136 patients according to the gender of the donor and the recipient (group I: female to female; group II: male to male; group III: male to female; group IV: female to male). The incidence and severity of chronic graft-vs-host disease-associated dry eye were determined for each group. The donor gender was masked when we assessed dry eye and calculate the incidence.

The incidence of dry eye was 47.4% for group I, 37.5% for group II, 58.6% for group III, and 42.9% for group IV. The percentage of patients with severe dry eye was 44.4, 50.0, 35.3, and 77.8% respectively. There was a significant difference between the percent severe dry eye/total dry eye incidences in groups III and IV (P=0.0375) (odds ratio, 7.6; 95% confidence interval, 1.00-101.01).

Close attention must be paid to the development of dry eye in cases of female to male BMTs, because the ratio of severe/total dry eye is more common in cases of female to male BMTs than in other gender combination.

Eye (Lond). 2011 Apr 8. [Epub ahead of print]
Kamoi M, Ogawa Y, Uchino M, Tatematsu Y, Mori T, Okamoto S, Tsubota K.
Department of Ophthalmology Keio University School of Medicine, Tokyo, Japan.

Drug news: MIM-D3 - Phase II enrollment completed

Medwell Capital Announces that Mimetogen Pharmaceutical Inc. Completes Patient Recruitment in Phase II Clinical Trial for Dry Eye Disease

EDMONTON, April 8 /CNW/ - Medwell Capital Corp. ("Medwell") (TSXV: MWC) today announced that Mimetogen Pharmaceuticals ("Mimetogen") completed patient recruitment in its phase II clinical trial of MIM-D3 for dry eye disease. A total of 150 patients have been enrolled in the trial with results expected in the second half of 2011. Under the terms of the agreement announced on February 25, 2011, Medwell will advance a second tranche of funds pursuant to its $2,000,000 financing commitment....

Mimetogen's lead drug candidate for the treatment of dry eye disease, MIM-D3, is a small molecule mimetic of nerve growth factor (NGF). NGF is a naturally occurring protein in the eyes that is responsible for the maintenance of corneal nerves and epithelium, mucin and tear production. In contrast to most other products in development or on the market, MIM-D3 is designed to quickly and directly improve the quality of the tears produced by the eyes whilst reducing symptoms of chronic burning and stinging. Dry eye disease is estimated to be a $1 billion US market for which there is currently only one FDA-approved treatment.

The Phase II randomized, double-masked, multi-center, placebo-controlled trial designed to evaluate the safety, tolerability and efficacy of MIM-D3 in improving the signs and symptoms of dry eye....

Pharma news: Merck to acquire Inspire

Merck to acquire Inspire Pharma for $430 million

April 5, 2011

(Reuters) - Merck & Co (MRK.N) said on Tuesday it would acquire eye treatment maker Inspire Pharmaceuticals Inc (ISPH.O) for about $430 million to expand its ophthalmology business.

Inspire's key product is Azasite, a treatment for bacterial conjunctivitis, sometimes referred to as "pink eye." It also receives royalties on sales of Allergan Inc's (AGN.N) dry-eye drug Restasis.

With Inspire, Merck adds to an eye-care portfolio that includes the proposed glaucoma treatment Saflutan, now being reviewed by the U.S. Food and Drug Administration.

The $5-per-share cash offer for Inspire represents a 26 percent premium to Inspire's closing stock price on Monday.

Wedbush Securities analyst Liana Moussatos, who had valued Inspire at $7 a share, said Merck is snapping up Inspire after the Raleigh, North Carolina-based company suffered a blow to its pipeline when its cystic fibrosis drug denufosol failed in a late-stage study in January.

Another product, the prescription eye drop Elestat, is facing generic competition, Moussatos said.

"Because they had the bad news with the pulmonary franchise, and Elestat now has generic competition and they will lose that royalty stream, that's why they were taken out at a discount in my opinion," she said.

The transaction has been unanimously approved by the boards of both companies. In addition, private equity firm Warburg Pincus WP.UL, which owns about 28 percent of Inspire's outstanding shares, has agreed to tender all of its shares into Merck's offer.

Shares of Inspire rose 97 cents, or 24.5 percent, to $4.95 on Nasdaq. Merck shares fell 16 cents, or 0.48 percent, to $33.11 on the New York Stock Exchange.

Abstract: SS dry eye, literature review

Ho hum. This is one of those studies that I sort of feel obliged to post since they happened, but which don't actually add anything of value whatsoever. Yes, we all know about Restasis and artificial tears and that Salagen and Evoxac are not remarkable for helping the eyes. Next please.

Treatment of Sjögren's Syndrome-Associated Dry Eye An Evidence-Based Review.

BACKGROUND: Outcomes-based review of reported treatment options for patients with dry eye secondary to Sjögren's syndrome (SS).

CLINICAL RELEVANCE: Dry eye affects many individuals worldwide. Significant proportion of patients with dry eye has underlying SS, a progressive autoimmune condition. The few suggested guidelines for the treatment of dry eye are mostly based on severity of symptoms and/or clinical findings rather than on outcomes analysis, and do not differentiate SS from other causes of dry eye. METHODS AND

LITERATURE REVIEW: A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by ≥4 review authors.

RESULTS: The searches identified 3559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review.

CONCLUSIONS: In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The efficacy of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye.

FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Ophthalmology. 2011 Apr 2. [Epub ahead of print]
Akpek EK, Lindsley KB, Adyanthaya RS, Swamy R, Baer AN, McDonnell PJ.
The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Tuesday, April 12, 2011

Abstract: Looking at the MGs in vivo with a confocal

Bless IOVS... they publish the neatest stuff. This study (scroll down) apparently came out in February, but I just now saw it. I think PubMed's email alert system is experiencing some constipation lately because that's happened to me several times.

I don't have a subscription but I couldn't help shelling out the $15 to get the full text of this study. If you want to see it all, look for it on this page of the IOVS site under Cornea. It was a very interesting read. MGD patients, while this may not have a practical application for you right now - confocal microscopes are expensive and your local doc probably doesn't have one - it's still fascinating info. And you can always ask.

To me, anything taking a really serious look at the MGs of significantly different dry eye groups is going to be worth reading - they just don't come along often enough. This one ran the gamut, from the classic signs (BUT, Schirmer, staining, etc) to meibography and confocal microscopy.

I find the MG differences between Sjogrens and MGD patients interesting. Clearly the Sjogrens patients are taking a big hit in the MGs - yet their oil is staying clearer and coming out much more easily. But in this study, they hurt a LOT more than the MGD patients.

So, what's still missing from this picture as far as I'm concerned is why SOME patients with MGD experience pain levels rivaling the Sjogrens crowd. On DryEyeTalk, this always seems to be the predominant theme, whether they've been diagnosed with ocular rosacea or classic bleph or demodex or whatever the MG diagnosis du jour in their locale happens to be. These people and the ones I get phone calls from are - from an OSDI score standpoint - completely unlike those represented in studies such as Dr. Villani's. WHY? What are all these outliers? They've got a ton of pain; some have really annoying eyelids and some don't; most don't have really dramatic clinical findings. Many, maybe most get widely varying diagnoses from different doctors.

I find myself more and more frequently wondering if MGD isn't a sort of red herring in many of these cases. On the other hand I don't buy the corneal neuralgia explanation for all of them either (some, just not all). Way back in the day, there were a lot of studies going on that had me thinking that the mucin layer really was key to the differences in pain levels. I don't see too much happening in that world lately. And that may be the wrong tree to bark up. But if so, I'd sure like to know what is. This MGD or pseudo MGD stuff is striking younger and younger people and we need to make more progress in tackling it. What are we going to do in another ten years when there's a whole bunch more kids who have grown up on soda, antidepressants and computers and were fitted with contacts at age 8? They're already showing up in the pediatric docs' offices with MGD. Sigh.

In vivo confocal microscopy of meibomian glands in Sjögren's syndrome.

PURPOSE: To evaluate morphologic changes in meibomian glands (MGs) and the status of periglandular inflammation in patients with primary and secondary Sjögren's Syndrome (SS) using in vivo confocal laser microscopy (LSCM).

METHODS: Twenty patients with primary SS (SSI), 25 with secondary SS (SSII), 20 with MG dysfunction (MGD), and 25 age- and gender-matched control subjects were enrolled consecutively. Each participant completed an Ocular Surface Disease Index questionnaire and underwent a full eye examination, including tear film break-up time (BUT), fluorescein and lissamine green staining, Schirmer test, and an LSCM examination of the MGs, the last to determine acinar unit density and diameter, glandular orifice diameters, meibum secretion reflectivity, inhomogeneous appearance of glandular interstice, and acinar wall.

RESULTS: All parameters indicated statistically significant differences among groups (P < 0.001, Kruskal-Wallis test). LSCM demonstrated no differences between SSI and SSII (Mann-Whitney U test). Compared with control subjects, SS subjects' MGs showed more periglandular inflammation and higher secretion reflectivity (P < 0.001, Mann-Whitney U test). Compared with MGD patients, SS patients' MGs had higher acinar density, smaller diameters, greater density of periglandular inflammatory cells, and lower secretion reflectivity (P < 0.001, Mann-Whitney U test). In SS patients, the two measured confocal signs of inflammation were significantly interrelated and correlated with corneal fluorescein staining (P ≤ 0.01, Spearman correlation coefficient). Acinar density and diameters were strongly correlated among themselves (P < 0.001) and with BUT (P < 0.05).

CONCLUSIONS: LSCM is capable of effectively revealing morphologic and inflammatory changes in MGs and showed discernible patterns of MG abnormalities in SS and MGD not easily distinguishable by the usual clinical exams.

Invest Ophthalmol Vis Sci. 2011 Feb 16;52(2):933-9. Print 2011 Feb.
Villani E, Beretta S, De Capitani M, Galimberti D, Viola F, Ratiglia R.
Università degli Studi di Milano, UO Oculistica Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.