It’s All in the Small Print

Patients dislike glaucoma eye drops; the delivery mode is inconvenient and imprecise – in fact, unlike no other medical field, in ophthalmology we deliver the wrong dose more often than we do the prescribed one – with many studies now demonstrating that only one third to a half of all patients are able to successfully deliver the indicated topical dose to their eye (1). Most of the time they miss the eye altogether or deliver 200-500 percent overdose causing side effects, waste and missed compliance.  Ophthalmic formulations cause a range of unwanted side effects from discoloration to periorbital dermatitis. Hence the famously high non-adherence levels associated with topically-applied glaucoma medication. But given that the standard eye-dropper method dates from before the 20th century, should we really be surprised that it’s problematic? Ianchulev certainly takes this view, and is indignant that the subject isn’t more broadly discussed. “Physicians are using a 150-year-old device to deliver 50 microlitres of drug into a seven microlitre tear film volume – no wonder eye drops are poorly tolerated!” But now Ianchulev’s company, Eyenovia, is bringing 21st century engineering to ocular drug delivery. “By marrying piezo-printing technology with smart drug delivery, we’re completely disrupting the eye-drop technology,” he says. In fact, the implications of the Eyenovia technology go far beyond issues of drug tolerability: some of the off-target effects associated with eye drops are life-threatening, and include cardiotoxicity symptoms, such as arrhythmia and bradycardia. So, by reducing off-target tissue exposure, Ianchulev’s microdosing approach may improve not just patient comfort, but patient safety – good news for patients, physicians and healthcare systems alike.

What’s new about the Eyenovia approach? Discarding the ancient eyedropper, Ianchulev’s team has turned to piezo-electric ink delivery systems – well known for precise delivery of suitable amounts of ink onto paper – by modifying such technology to administer 6–8 µL drug doses that are more compatible with natural physiology; in other words, the volume delivered does not overload the eye with fluid in the same way as an eyedropper. Louis Pasquale, Ianchulev’s clinical collaborator, makes another important point: “Keeping the administration volume to 8 µL or less is important; larger quantities cause a lachrymal reflex that washes much of the dose out of the eye,” he says. “When you think about it, it’s amazing that glaucoma eye drops work at all – much of the administrated dose is washed out by the lachrymal reflex.” Avoiding this wash-out is not only more efficient in terms of drug use, but also more pleasant for the patient.

When and where

But it’s not just about how much drug is delivered. Piezo-electric technology is also precise (imagine if your inkjet printer was not!). Eyenovia’s device aims to accurately and uniformly coat the small volume of drug onto the corneal surface (where intraocular drug penetration occurs) (2). Could such efficient drug delivery also lead to less frequent administration? Time will tell.

In any case, microdosing intuitively indicates less drug-associated toxicity. And if the side effects are reduced, patients should hopefully be less reluctant to adhere to treatment regimens; hence, one of the first indications being explored by Eyenovia is glaucoma medication (Box 1), where satisfactory regime compliance is a long way off. In this context, it’s interesting that Eyenovia has taken compliance one step further by coupling an app that reminds patients when their dose should be taken with Bluetooth-enabled monitoring of device actuation. According to the Eyenovia website, its “intelligent electronic system is one of the first smart technologies to enter FDA clinical trials for ophthalmic use.”

Finally, as well as assuring physicians that their patients will be safer and more compliant when taking existing drugs, Eyenovia’s approach could open the door to products that – because of toxicity issues – are currently not approved in eyedrop form. “There is Level 1 evidence for atropine slowing the progression of myopia in children by 60 percent (3). However, we haven’t been able to prescribe atropine eye drops because of their side effects. The option of accurate microdosing completely changes this situation,” says Ianchulev. “Small, precise doses may eliminate eye-drop toxicities and turn an unacceptable drug into a tolerable product.”

Room to grow

However innovative the technology, for a company to survive, the objective must also make commercial sense – a point not lost on Eyenovia. Potential markets for the technology are large, and include not only adult glaucoma and pediatric myopia patients, but also the 80 million patients in the US alone per year who undergo dilation in the doctor’s office – and suffer stinging or burning eyes from the preservative and the dual overdose, since doctors often use two agents simultaneously to dilate the pupil (tropicamide and phenylephrine) (4). “Eyenovia microdosing delivers the same therapeutic benefit as eye drops, but much more mildly – in a high-precision single microdose of a fixed co-formulation of the two drugs,” says Ianchulev. He adds that the improved safety associated with controlled microdoses suggests that GPs could start administering drugs that previously were only provided by specialist ophthalmologists, making patient management more straightforward and cost-effective. Ultimately, however, Ianchulev sees the technology as far more than just a means of enabling delivery of third-party drugs; the company is building a pipeline of proprietary formulations, including three products in Phase III – for mydriasis, myopia and chronic angle closure glaucoma – and one in Phase I for dry eye. 

And the longer-term aim? Ianchulev has set his sights high: nothing short of resolving the world’s myopia problem… In the meantime, he’ll settle for lower side effects and a transformation in adherence monitoring. If Eyenovia’s tech does end up being disruptive, what of the loser? Well, when compared with piezo-electric Bluetooth-enabled microdose delivery, the humble eyedropper starts to look like something not just from a previous century, but from the dark ages!