Lab Report: Products in the Pipeline

Here's a preview of emerging therapies that may play a pivotal role in dry eye management.

BY LESLIE GOLDBERG, ASSOCIATE EDITOR

I have always considered dry eye a conundrum," says Karl Stonecipher, M.D., director of Laser and Refractive Surgery TLC in Greensboro, NC. "It is a multifaceted disease. Some people have evaporative dry eye, some Meibomian gland dysfunction and some simply don't produce enough tears. With dry eye, all three components of the tear film — aqueous, lipid and mucin — can be affected. The only drug that can honestly say that it increases tear production is Restasis (Allergan, Irvine, Calif.) and nothing in our armamentarium at the present time competes with it."

Might that change in the near future? While there is currently no cure for dry eye disease, many investigational drugs in the pipeline may help patients attain a higher degree of comfort. And like Restasis, several aim to go beyond palliative relief by addressing the causes of dry eye. R&D departments around the world have targeted both OTC products, to increase tear volume, and prescription medications, which impact the pathophysiology of dry eye. Below is a preview of several products under investigation that may emerge as marketable dry eye therapies in the coming years.

Phase III Drugs

Acucela Inc. (Tokyo) and Otsuka Pharmaceutical Co., Ltd. (Tokyo) are co-developing rebamipide ophthalmic suspension, Otsuka's proprietary compound for the treatment of dry eye. The company says that rebamipide has a novel mechanism of action that increases the level of mucin in tears covering the conjunctiva and cornea. It is expected to be effective by stabilizing the tear film and leading to improvement of corneal-conjunctival damage associated with dry eye.¹

Diquafosol tetrasodium (Prolacria, Inspire Pharmaceuticals, Durham, N.C.) is another dry eye therapy in development. "Prolacria is designed to stimulate fluid, mucin and lipid secretion by stimulating P2Y2 receptors on the ocular surface," says Kim Brazzell, Ph.D., senior vice president of Ophthalmic Research and Development for Inspire. "It addresses one of the underlying manifestations of dry eye disease — reduced tear production — and works to improve the overall health of the ocular surface."

Dr. Brazzell says that Inspire has a joint development and marketing agreement with Allergan (Irvine, Calif.) for Prolacria and that the two drugs, Prolacria and Restasis, could be synergistic. "Their mechanisms of action suggest that the drugs could be used together," says Dr. Brazzell. "Most experts indicate that dry eye is a multifactoral disease and that many patients may require more than one therapy to adequately manage the disease."

To date, Inspire has completed four Phase 3 clinical trials of Prolacria. In 2003, Inspire filed an NDA with the FDA for Prolacria for the treatment of dry eye disease. Inspire has received two approvable letters from the FDA. In September 2008, Inspire submitted a clinical protocol and request for Special Protocol Assessment (SPA) to the FDA for an additional pivotal Phase 3 environmental trial with Prolacria. The proposed environmental trial focuses on evaluating the effects of Prolacria on the central region of the cornea measured by using fluorescein staining. Once a final SPA agreement is in place, additional details on the trial design will be provided.²

Vismed (Lantibio Inc., Chapel Hill, NC) is currently marketed in Europe under the CE mark as a viscoelastic lubricant eye drop. The proprietary formulation contains a highly purified specific fraction of sodium hyaluronate derived by fermentation from bacteria that the company says gives the product a high viscosity between blinks and a low viscosity during blinking, to ensure efficient coating of the surface of the eye. Sodium hyaluronate also possesses mucoadhesive properties and the ability to entrap water, thus resembling tear mucus glycoprotein. This, together with the coating properties of sodium hyaluronate, results in an increased pre-corneal residence time and tear film breakup time (BUT) and therefore longer lubrication of the eye surface, according to the company. Vismed is preservative free. As a result, it is non-irritating to ocular tissues and can be used frequently and for extended periods without harming the ocular surface (e.g., without causing superficial punctate keratitis).³

Vismed represents a new class of compound in development for the treatment of dry eye in the U.S., offering lubricant properties that can alleviate the discomfort and reverse ocular damage caused by dry eye syndrome.³ Alcon has licensed the U.S. marketing rights from River Plate Biotechnology, Inc., a subsidiary of Lantibio, and TRB Chemedica S.A. River Plate is currently enrolling participants in a Phase III study of Vismed.⁴

OPKO Health, Inc. of Miami has acquired exclusive worldwide rights from Winston Labs (Vernon Hills, Ill.) for ophthalmic use of a topical clinical stage compound with potential utility in the treatment of dry eye. The compound, civamide, a proprietary TRPV-1 receptor modulator and neuronal calcium channel blocker, is in Phase III clinical trials in an intranasal formulation to treat various types of pain, including migraine headache. Increased tear production was observed in more than 50% of patients receiving civamide and no systemic side effects were noted.⁵ Preliminary evidence suggests that civamide's effects on tear production result from its ability to modify signal transduction pathways present in the lacrimal gland.⁵

Sirion Therapeutics (Tampa, Fla.) is developing a higher potency formulation of cyclosporine A as an alternative to Restasis. ST-603 includes cyclosporine 0.1%, twice the concentration used in Restasis. At this time there is no firm dosing regimen. Barry Butler, President and CEO of Sirion Therapeutics, says that the company hopes to have ST-603 on the market within the next 24 months.⁶

Phase II Drugs

Alacrity Biosciences (Laguna Hills, Calif.) is developing a proprietary topical formulation of non-antimicrobial doxycycline (ALTY-0501) that has successfully completed a Phase II clinical trial. ALTY-0501 was shown to protect the ocular surface from damage due to desiccating stress in a controlled adverse environment, and to significantly reduce patient symptoms. Phase II trials are completed.⁷

ISTA Pharmaceuticals (Irvine, Calif.) is developing ecabet sodium as a prescription eye drop for the treatment of dry eye syndrome. Ecabet sodium represents a new class of molecules that increases the quantity and quality of mucin produced by conjunctival goblet cells and corneal epithelia. Ecabet sodium is currently marketed in Japan as an oral agent for treatment of gastric ulcers and gastritis. In November 2004, ISTA acquired U.S. marketing rights to ecabet sodium for the treatment of dry eye under a license agreement with Senju Pharmaceutical Co., Ltd. of Osaka, Japan.⁸

In May 2007, ISTA announced positive results from the preliminary analysis of a Phase IIb clinical study of ecabet sodium for dry eye. Patients in the ecabet sodium group achieved a strong trend in the objective sign of blink rate. While ISTA's Phase IIb study was not powered to show statistical significance, patients in the ecabet sodium group did achieve statistical significance in the Ocular Symptom Disease Index (OSDI) assessment and showed a positive trend in the subjective assessment of patients' most bothersome symptom.

Strong and positive trends are used to confirm observations from previous clinical studies and to serve as indicators of potential efficacy endpoints for Phase III studies. There were no reports of serious ocular adverse events compared with placebo. ISTA initiated another Phase II study to confirm the results of its prior studies and expects to complete this trial by the end of 2008. The endpoints in this study are tear production and symptom improvement.⁹

Novagali Pharma (France) has developed Nova22007, a cationic emulsion of cyclosporine A, which the company says should provide "optimal efficacy." Preclinical studies have already demonstrated that Nova22007 can significantly improve the absorption of cyclosporine A in the cornea and conjunctiva. Furthermore, as stated on the company's Web site, a Phase IIa clinical trial conducted in Sjögren's patients with moderate-to-severe keratoconjunctivitis (KCS) has demonstrated good safety and tolerance of the formulation as well as promising preliminary trends toward efficacy to be confirmed in Phase III studies.¹⁰

EyeGate Pharma (Waltham, Mass.) in partnership with Ophthalmic Research Associates (ORA, North Andover, Mass.) has begun enrollment in a Phase II safety and efficacy clinical study of EGP-437, a corticosteroid solution and combination drug/device with a novel delivery system.

The EyeGate II Delivery System works through iontophoresis, which occurs when an applied electric field enhances the mobility of molecules through cells and tissues primarily through electrochemical repulsion. Specifically, a low level of electrical current creates an electrical field that repels like-charged ionized drugs, thus, more effectively delivering drug substances through different tissues to targeted areas in efficacious quantities. These principles can be applied to anionic and cationic molecules.¹¹

"What's interesting and different about the approach with iontophoresis is that the delivery technique allows for penetration of much more drug into the cornea and into the eye itself," says George W. Ousler, director of dry eye research at ORA. "The big advantage is that we are able to load the eye in much higher doses and see if this will treat the underlying symptoms of dry eye. The iontophoresis delivery also helps with compliance and ensuring that the patient is getting the full treatment. Intophoresis drives the chortocosteroid into the eye, and because patients will be given the drug at the doctor's office, compliance is assured."

The U.S. Phase II safety and efficacy study utilizing the EyeGate II Delivery System will administer the company's lead clinical compound, EGP-437, with the objective of assessing safety and efficacy in dry eye patients.

Great Expectations

Other products are earlier in the pipeline but nevertheless hold promise for future applications.

Alcon recently entered into a licensing agreement with GlaxoSmithKline for global ophthalmic rights to cilomilast, a phosphodiesterase IV inhibitor that exerts multiple pharmacological effects, including pro-secretory and anti-inflammatory effects, in contrast to the immunosuppressive mechanism of action used by topical cyclosporine A.¹²

"While we are in the early stages of development, we believe that cilomilast has the potential to have an effect on one or more of the aspects of the dry eye disease continuum, including the reduction of inflammation," says Doug MacHatton, vice president of strategic corporate communications and investor relations at Alcon. "We are hopeful that our clinical studies will support the efficacy and safety of the compound in treating both the signs and the symptoms of dry eye."

Lux Biosciences (Jersey City, N.J.) is developing LX214, a clear, mixed micellar formulation of voclosporin for the treatment of dry eye syndrome and potentially other chronic inflammatory ocular diseases. LX214 is currently in late stages of preclinical development and is expected to reach the clinic beginning 2009.¹³

Resolvyx Pharmaceuticals is developing a new class of medicines called resolvins, naturally-occurring, small molecule lipid mediators with the potential to treat a wide range of inflammatory diseases. Resolvins work by activating the body's own mechanisms for shutting off inflammation. The company's drug, RX-10045, is a synthetic resolvin analog formulated for topical application to treat eye disease. In pre-clinical models, RX-10045 has demonstrated potent efficacy in models of dry eye and neovascular retinopathy.¹⁴

SARcode Corporation (San Francisco, Calif.), a private company focused on small molecule LFA-1 inhibitors to treat inflammatory diseases, and Sunesis Pharmaceuticals, Inc. have announced a Phase 1 clinical trial of a small molecule LFA-1 product candidate for T-cell mediated ophthalmic diseases. "LFA-1 antagonists mediate both migration and adhesion of the white blood cells to sites of inflammation as part of the body's immune response," said Tom Gadek, Ph.D., chief executive officer of SARcode. "Lead indications for LFA-1 include dry eye and allergic conjunctivitis, both large indications with unmet medical needs. The results of this study will inform dose selection for several Phase 2 studies to commence in the first half of 2009."¹⁵

While the above represent only a few of the drugs under development, each is designed to increase ophthalmologists' ability to better treat dry eye sufferers. Time will tell. OM

References

1. Helzner G. At Press Time. Ophthalmol Mgmt. 2008;10:10-14.
2. www.inspirepharm.com/pipeline.html. Accessed Nov. 3, 2008.
3. www.lantibio.com/newsroom5.htm. Accessed Nov. 13, 2008.
4. clinicaltrials.gov/ct2/show/NCT00599716?term=vismed+dry+ eye&rank=1. Accessed Nov. 20, 2008.
5. http://74.125.47.132/search?q=cache:ghGBA9xe8ogJ:files.shareholder.com/downloads/OPKO/0x0x136410/8af2ba88-c756-4f39-90d4-d364da27059f/268407.pdf+opko+civamide&hl=en&ct=clnk&cd=6&gl=us. Accessed Nov. 13, 2008.
6. www.siriontherapeutics.com. Accessed Nov. 5, 2008.
7. www.alacritybio.com/research/index.php. Accessed Nov. 13, 2008.
8. www.istavision.com/research/products_ecabetsodium.asp. Accessed Nov. 13, 2008.
9. www.drugs.com/clinical_trials/ista-pharmaceuticals-announces-positive-preliminary-results-ecabet-sodium-phase-iib-study-1087.html. Accessed Nov. 13, 2008.
10. www.novagali.com/en/eye-therapy/severe-dry-eye/. Accessed Nov. 13, 2008.
11. www.pipelinereview.com/content/view/23289/115. Accessed Nov. 19, 2008.
12. Alcon announces two agreements designed to expand its future drug portfolio. View the press release at http://invest.alconinc.com/phoenix.zhtml?c=130946&p=irol-newsArticle&ID =1209666&highlight=. Last accessed Nov. 20, 2008.
13. www.luxbio.com/dryeye.htm. Accessed Nov. 20, 2008.
14. www.resolvyx.com/about-us/index.asp. Accessed Nov. 20, 2008.
15. www.sarcode.com/news.html. Accessed Nov. 20, 2008.