Novel therapies abound in pipeline

The importance of novel therapies for ocular disease is a given. However, as most novel therapies are financed by the private sector, it is fortunate that investors find ophthalmology a worthwhile investment.¹

This article provides an overview of new therapies-focusing on U.S. development, while also noting some products from outside the United States.

In 2016, six ophthalmic products with New Drug Applications (NDAs) under consideration at the FDA were not approved based upon matters related to the chemistry, manufacture, and control (CMC). These products included:
 

• A multi-dose, non-preserved formulation cyclosporine ophthalmic emulsion for dry eye disease (Restasis, Allergan);
• A dexamethasone intracanalicular implant for inflammation (Dextenza, Ocular Therapeutix);
• Latanoprostene bunod for glaucoma (Vyzulta,  Bausch + Lomb/Nicox);
• Netarsudil for glaucoma (Rhopressa, Aerie Pharmaceuticals);
• AC-170 (cetirizine) for allergic conjunctivitis (Zerviate, Nicox), and
• A swollen nanocellular microemulsion latanoprost for glaucoma (Sun Pharmaceutical).²

Two products-cyclosporine and cetirizine-were approved this year. The remaining four NDAs are still under consideration.

Recent U.S. approvals, in chronological order starting in early 2016, include:

• A local anesthetic, tetracaine (previously an “unapproved” therapy);³
• A new formulation of the non-steroidal, anti-inflammatory agent, bromfenac (BromSite, Sun Ophthalmics);
• The combination product of riboflavin/ultraviolet radiation for corneal pathology (Photrexa, Avedro);
• An LFA-antagonist for dry eye disease (lifitegrast; Xiidra, Shire), and
• A new antihistamine, cetirizine (Zerviate) for allergic conjunctivitis, as noted above.

Also approved were additional indications for adalimumab for uveitis (Humira, AbbVie); giant cell arteritis for tocilizumab (Actemra, Genentech); additional diabetic retinopathy indications for ranibizumab (Lucentis, Genentech), and as aforementioned, a multidose, non-preserved formulation of cyclosporine (Restasis).

Based upon publicly available information, seven ophthalmic NDAs or Biological License Applications are under FDA review. Some were noted above, as they were initially submitted in 2016. They include: brimonidine 0.025% (redness); dexamethasone insert for intracanalicular use; latanoprostene bunod 0.24%; netarsudil 0.02%; sirolimus 440 μg; an intracameral dexamethasone, and the first ophthalmic gene therapy under review, voretigene neparvovec.

Phase III

Phase III

Several ophthalmic products are in phase III. In glaucoma, these include trabodenoson; an adenosine modulator; a fixed dose of netarsudil and latanoprost; an intracameral erodible drug-delivery system for bimatoprost, and an intracanalicular delivery system for travoprost.

In dry eye disease, products in development include tavilermide (MIM-D3) for dry eye; a new solution formulation of cyclosporine (OTX-101), and RGN 259 (Thymosin beta 4).

Lampalizumab, administered monthly by intravitreal injection, is being evaluated for geographic atrophy (Genentech). Squalamine is being evaluated in the treatment of wet age-related macular degeneration (AMD) (Ohr).

In drug delivery, an erodible anterior chamber implant of bimatoprost is being evaluated for glaucoma (Allergan). Also, a refillable reservoir is being evaluated for ranibizumab for wet AMD; suprachoroidal triamcinolone acetonide for the treatment of macular edema due to uveitis (Clearside Biomedical), and an iontophoretic system for delivery of dexamethasone to treat uveitis. A fixed-dose combination of dexamethasone and povidone-iodine is being evaluated for adenoviral conjunctivitis.

Phase II

In phase II clinical development are a number of anterior chamber drug-delivery systems of prostaglandin analogues (intracanalicular, corneal rings, subconjunctival injection, and intracameral inserts).

In dry eye, there are numerous molecules of various mechanisms of action, including P-321, a phase II topical epithelial sodium channel inhibitor (Shire/Parion Sciences); two natural biologics, lubricin and lacritin; and a non-aqueous, preservative-free formulation of cyclosporine.

Abicipar pegol (an anti-VEGF DARPin) is being developed for the treatment of diabetic macular edema (Allergan). X-82, an oral tyrosine kinase inhibitor, is being developed for the treatment of wet AMD (Tyrogenex).

NS2, an inhibitor of aldehyde formation, is in development for allergic conjunctivitis and also uveitis (Aldeyra Therapeutics).

Emixustat is being evaluated for several retinal disorders, including proliferative diabetic retinopathy and Stargardt disease (Acucela). Numerous molecules and delivery systems are in earlier stage clinical and preclinical development-but beyond the scope of this brief report.

Two approvals from outside the United States are ripasudil (Glanatec, Kowa Co. Ltd.), a rho-kinase inhibitor approved in Japan in 2014 for the treatment of glaucoma,⁴ and an novel formulation of cyclosporine (Ikervis, Santen), approved for the treatment of severe dry eye disease in Europe in 2015.⁵

While ophthalmologists are fortunate to have many novel treatments in development, changes in the American healthcare system continue to raise the hurdles for financial success. For example, in the treatment of glaucoma and ocular hypertension, physicians and patients have generic alternatives in all of the classes.

This is not to say that the generic products are equivalent in all features-however, manufacturers of branded products will have to provide evidence to U.S. insurance companies to support the incremental cost.⁶

References

References

1. Novack GD. Pipeline: Investing in new therapies for ocular surface disease. Ocul Surf. 2015;13:263-267.
2. Novack GD. Chemistry matters! Ocul Surf. 2017;15:264.
3. Novack GD. Unapproved Ophthalmic Drugs. Ocul Surf. 2016;14:317-320.
4. Garnock-Jones KP. Ripasudil: first global approval. Drugs. 2014;74:2211-2215.
5. Leonardi A, Van Setten G, Amrane M, et al. Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial. Eur J Ophthalmol. 2016;26:287-296.
6. Novack GD. What Determines How Much Your Patient Pays for Their Medication in the United States? Am J Ophthalmol. 2016;167:48-51.

Gary D. Novack, PhD, is the founder and president of PharmaLogic Development Inc., a provider of strategic and operational services to the pharmaceutical and biomedical industries through the pharmaceutical, biologic, and device development processes. Founded in the late 1980s, PharmaLogic has contributed to 50 FDA product approvals and clearances.

Over this period, Dr. Novack provided key support in the development and approval of the first pharmacological treatment for macular degeneration, the first site-active corticosteroid, the first and second intravitreal drug delivery systems, and the first neurological indications for botulinum toxin. Through thousands of projects, the company has served more than 500 clients on four continents on and contributed to more than 100 Investigational New Drug (IND) and Device Exemption (IDE) submissions. According to Dr. Novack, PharmaLogic’s consistent success and extensive experience have been the key to becoming a premier services provider to top specialty pharmaceutical and medical device clients.

Dr. Novack is the author of more than 260 peer-reviewed publications, and an active member and frequent presenter in professional ophthalmic organizations. Most recently, he chaired a subcommittee for the Tear Film and Ocular Surface Society Dry Eye Workshop II. He is on the editorial board of The Ocular Surface, the Journal of Ocular Pharmacology and Therapeutics, and Eye & Contact Lens.
He has had a lifelong relationship with the University of California, first, as a student and trainee at UC Santa Cruz, UC Davis and UCLA. He then served in many leadership roles including UC Regent, president of the UC Santa Cruz Alumni Association, and president of the UC Santa Cruz Foundation. He is currently visiting professor of pharmacology and ophthalmology at the University of California, Davis, School of Medicine. He is a consultant for numerous pharmaceutical and medical device firms.