Therapeutic focus – Plenty of dry eyes in the house

Analysis

Ever since Novartis’s acquisition of Alcon ophthalmology has provided fertile ground for deal making, and within this a hitherto poorly characterised condition – dry eye disease – could be the latest vision disorder to seize the limelight.

While EvaluatePharma identifies numerous industry projects that have at some point been tested for dry eye, the current pipeline is fairly narrow (see tables below). But it is well worth watching a handful of projects that target the underlying cause of the condition, especially those from Shire and Mimetogen, which face imminent readouts from pivotal trials.

Although dry eye disease might seem a vague indication much recent work has taken place to characterise it. Moreover, it accounts for a market worth over $1bn, of which three products account for the lion’s share: Restasis and Refresh from Allergan, and Santen Pharmaceuticals’ Hyalein.

Disclosed sales of top five dry eye drugs ($m)
Product Company Pharmacology class 2011 2012 2013e 2014e 2015e 2016e 2017e 2018e
Restasis Allergan Tear secretion enhancer 697 792 895 873 859 736 630 595
Refresh Allergan Eye preparation 395 411 419 432 450 470 490 512
Hyalein Santen Pharmaceutical Hyaluronan 282 256 199 188 183 171 166 161
Diquas Santen Pharmaceutical P2Y2 receptor agonist 36 67 79 92 106 115 125 136
TheraTears Nutrition Akorn Omega-3 fatty acid - 13 25 29 34 39 44 50

The gold standard is Restasis – a near blockbuster and the only one of the three to act pharmacologically rather than being an artificial tear-based product aimed at mild disease. Restasis is a cyclosporine immunomodulator.

Immunosuppression is one of two main pharmacological approaches to treatment, the other being the stimulation of tear secretion. The disease is believed to have multiple underlying mechanisms and is thought by some to be the final manifestation of several separate conditions, but can broadly be caused by an inflammatory mechanism or by excessive tear evaporation.

The Shire project, lifitegrast, disrupts the immune cascade by inhibiting lymphocyte function-associated antigen-1. Although its first phase III trial failed, it is quite possible that the FDA might accept a positive result from a second as part of an approval application (Event – Shire faces unusual binary outcome, December 2, 2013).

Shire’s biggest threat will be Mimetogen’s MIM-D3, given this project’s positive 150-patient phase II readout showing statistically significant improvement in signs and symptoms of disease. To underline its potential, Bausch + Lomb, now owned by Valeant Pharmaceuticals, acquired opt-in rights in July.

Should MIM-D3’s 400-patient phase III study turn out equally positive – results are due by the end of next year – it would be logical to expect the opt-in to be exercised, challenging Shire and the established products alike.

Clinical trial requirements

Two other phase III projects – Acucela’s rebamipide and OphthaliX’s CF101 – also offer interesting mechanistic approaches, and pivotal readouts for both are expected by the end of this year.

But these might pose less of a threat given their pivotal study designs, which involve measuring only disease signs (via corneal staining) and not symptoms; no phase II data are available for CF101, and formally the US FDA requires improvements in signs and symptoms to be shown.

True, the agency is aware of the difficulty of demonstrating the latter, and Restasis was approved having missed some pivotal endpoints. But a drug that does demonstrate improvements in both endpoints should prove formidable, which is why such importance is placed on lifitegrast and MIM-D3 – whatever the risk of coming up short might be.

Key industry projects targeting dry eye disease
Project Type Company Pharmacology class Status Note
rebamipide NME Acucela Mucin secretagogue Phase III 4 phase III studies completed – data expected by end of 2013.
lifitegrast NME Shire LFA-1 antagonist Phase III NCT01743729
MIM-D3 NME Mimetogen Tyrosine kinase receptor agonist Phase III NCT01960010 – data expected in 2014. Valeant has opt-in rights.
CF101 NME OphthaliX/Can-Fite BioPharma Adenosine A3 Receptor Agonist Phase III NCT01235234 – data expected by end of 2013.
Cyclokat (ciclosporin) Drug delivery Santen Pharmaceutical Immunosuppressant Phase III NCT01751126
Bromday (bromfenac) Drug delivery Valeant Pharmaceuticals NSAID Phase III NCT01212471 completed in 2013. Already sold for cataract surgery.
PRO-148 NME (ex-US) Laboratorios Sophia Artificial tear Phase III-ready NCT01657253 not yet recruiting.
DA-6034 NME Dong-A ST Flavonoid Phase II NCT01670357 completed in 2013.
R348 NME Rigel Pharmaceuticals Janus kinase (JAK)-3 inhibitor Phase II NCT01900249 – data expected in 2014.
RX-10045 NME Auven Therapeutics Anti-inflammatory agent Phase II NCT01675570 completed in 2012. Synthetic resolvin analogue.
ISV-101 (bromfenac) Drug delivery InSite Vision NSAID Phase II NCT01478555
Chitosan-N-acetylcysteine OTC Croma-Pharma Eye preparation Phase II NCT01753752 completed in 2013.

The remaining late-stage projects are reformulations. Santen’s Cyclokat is, like Restasis, a cyclosporine, while Valeant’s Bromday is a formulation of the non-steroidal anti-inflammatory drug bromfenac. A bromfenac formulation is also in phase II development by InSite Vision.

Among the phase II projects is Rigel’s JAK-3 inhibitor R348. Dry eye could prove to be an interesting new indication for the JAK mechanism, although it should be borne in mind that Pfizer’s own JAK-3 inhibitor, Xeljanz, was also to undergo a phase II study in dry eye, but this was withdrawn before recruitment, according to clinicaltrials.gov.

It is also worth pointing out that the Alcon portfolio acquired by Novartis contained numerous projects targeting dry eye disease. However, while there has been no official word about their discontinuation, no further trials have been initiated since the last studies were completed two years ago or more.

Such notes of caution support the experience of many industry players who have found it difficult to demonstrate a clear clinical trial benefit in a disease whose symptoms wax and wane. Upcoming readouts of MIM-D3 and lifitegrast should provide far greater clarity.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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