It Doesn’t Have To End In Tears

Pharma companies are closely scrutinizing existing products to discover if they have activity for new indications, possibly through new routes of delivery. Repurposing comes with challenges as developers must go back to the drawing board to optimize the product for its new purpose, which may require a new formulation or delivery mechanism. However, repurposing also has many advantages:

• existing drugs are likely to have large portion of their non-clinical packages in place
• regulatory authorities offer simpler submissions (e.g., FDA via 505b(II) submission)
• greater understanding of basic biology in other therapeutic areas is uncovering overlaps in certain pathways and targets, especially in immunology and inflammation
• legislation and social media has made orphan indications more attractive.

Diseases of the eye are one area receiving increased attention from this approach, which is very good news for patients as not all ocular diseases have effective and non-invasive treatments. However, developing drugs for the eye is a significant challenge – the eye is a complex organ with unique anatomy and physiology, and it can be difficult to overcome its natural protective barriers. Repurposing an existing drug for an ophthalmic condition at least gives developers a head start rather than developing a whole new drug from scratch. 

The desired site of action for drug delivery to the eye may be the cornea, conjunctiva, sclera, or other tissues of the anterior segment such as the iris, retina and ciliary body. If the back of the eye is the desired site of action, the blood retinal barrier is an obstacle to systemic delivery so a topical route may offer the best solution. Topical delivery to the eye is the least invasive and most flexible option compared to injection but the formulation has to battle a waterfall of tears induced by the drug’s application and blinking to reach the site of action, which could be on, in or through the surface of the eye. The formulator has to anticipate that any permeation and penetration will be through the cornea, conjunctiva and the sclera. Often, this challenge is too great and developers turn to intravitreal injection (especially if controlled release of the drug could benefit the patient).

Tears are one of the biggest obstacles to overcome when it comes to delivering drugs to the eye, but there are approaches that can significantly improve the chances of success. First, the formulation must be optimized for the desired target site. This may sound obvious but it is amazing how many companies fail to truly optimize their formulations. When repurposing a drug, developers should already have a lot of data about the characteristics of the API – and use these data to decide on whether a topical, systemic or periocular will be the best route of delivery. From there, formulators will need to look at product development with fresh eyes, beginning with pre-formulation work. For ocular delivery, it is imperative to consider how a drug adheres to and penetrates corneal or scleral surfaces whilst in a heavy tear turnover environment. Specific excipients may be required that enhance a drug’s adhesive properties, allowing sufficient time for drug retention and delivery.

Secondly, I strongly recommend identifying effective performance models and using these throughout the product development process to ensure your drug is reaching the correct part of the eye, and is bioavailable. You need to understand the pharmacokinetics and pharmacodynamics of your drug product before significant money is invested in clinical trials. Ex vivo models are developing rapidly for assessing drug permeation and penetration through the cornea/sclera, and can also consider the impact of tear flow. In addition, muco-adhesion models specifically tailored for corneal or sclera drug delivery can demonstrate sufficient retention on the eye surface.

These models are making drug development for the eye much easier and more attractive – and this is exactly what the field needs. Any eye disease can be extremely distressing for patients. If you have an eye disease, you don’t care if it is rare or not – you want the best treatment. Drug development for the eye is challenging, but with new models and growing knowledge around ocular formulations, there is a better chance that more pharma companies will consider repurposing drugs for the eye. I believe the industry has a duty to ensure that patients smile, rather than end up in tears.