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Subspecialties Pediatric, Refractive

Fine Print

At a Glance

  • The incidence of myopia is increasing, but so too is the more pathological form of the condition: myopic progression
  • FDA-approved treatments for myopic progression are not yet available, but low-dose atropine drops can have a significant impact on patient outcomes
  • Topical administration of atropine eyedrops may result in either over- or under-dosing of the medication.
  • Eyenovia’s atropine solution (MicroPine) is formulated for administration using the OpteJet microdose dispenser, which is designed to deliver medication as a gentle mist reaching the eye faster than the blink reflex.  The dispenser’s built-in electronic monitoring system also encourages compliance thanks to its in-build electronic monitoring system.

I have spent my career on the front line of retinal therapy and, a decade ago, we introduced Lucentis at Genentech – a biologic for wet AMD which completely transformed AMD management – it was, if you like, a “penicillin moment.” I now believe that we are approaching another step change in patient care, but for an entirely different condition – myopic progression.

Short sight casts a long shadow

The incidence of myopia is increasing at a dramatic rate. Its prevalence in Asia has doubled or tripled over a few decades, and now 80 percent of children in this region are myopic. Unsurprisingly, the condition has attracted attention at a governmental level; China, for example, is examining the link between myopia and mobile device screen use by young adults. But wherever you are, the problem is impossible to ignore; even in the USA, approximately 24 percent to 42 percent percent of adults are myopic (sources: Prevent Blindness America and the National Health and Nutrition Examination Study, CDC), which is double the rate reported 20-40 years ago. These figures would be less of a concern if all myopia was in the mild zone of -1 or -2 diopters – after all, a little bit of short-sightedness doesn’t hurt anybody.

The problem, however, is that the higher grades of myopia have also quadrupled in frequency. And that is a big worry, because the more pathological form of the condition – myopic progression – is associated with significant long-term risks, including retinal detachment, retinal atrophy and blindness. Remember, myopic progression is not simple myopia – it is a back of the eye disease in which the sclero-retina elongates as the eyeball stretches in an unchecked manner, with unfortunate consequences. Kids with myopia of -0.5 or -1 at the age of five may progress to -5 or -6 by age 10 and -10 or -15 within the following decade.

The consequences of progressive myopia range from quality-of-life impact to moderate visual disability to blindness: one of my patients, a 65-year-old who was -18D, is now bilaterally blind due to retinal detachment in both eyes. If we had been able to slow her myopic progression by 70+ percent in childhood, so that she ended up at -6 or -7 instead of -18, she would have a completely different life.

Progression repression

Clearly, simple myopia can be symptomatically addressed with corrective lenses or LASIK surgery – but myopic progression is a back-of-the-eye disease, and such methods do not tackle the underlying cause – just the consequences. What therapeutic options then do we have for this problematic condition? Unfortunately, to-date, pharmaceutical companies have paid little attention to this field, and so any progress has relied on the collaborative efforts of insightful clinicians following hunches... Nevertheless, this non-industry effort has now generated significant data – and it all points in the same surprising direction.

In brief, it is now clear that once-daily drops of atropine can significantly repress myopic progression. Indeed, the effect of topical atropine can be striking: large studies indicate that very low topical doses of atropine eye-drops, by a mechanism that remains unclear, reduce myopic progression by ~60–70 percent. And those are average figures; some children have their progression slowed by 80 or 90 percent.

This level of retinal protection can make a huge difference to the incidence of vision-limiting complications, and the ophthalmological community is increasingly convinced by the atropine data. For example, a couple of years ago the AAO opined that we have level one evidence for inhibition of myopic progression by daily, low-dose atropine. Furthermore, in some parts of Asia – Thailand, for example – about 80 percent of children are now on atropine. That’s almost the kind of uptake you’d expect if the drug were in the water supply!

Figure 1. The Eyenovia Optejet microdosing system.

Dropping the drops

It’s very encouraging that a number of large trials are telling the same story regarding the efficacy of topical atropine. Unfortunately, problems remain with the method of administration, which depends on the clumsy eye-dropper.

As we all know, use of eyedrops can be challenging.  The patient has to tilt the head back, hold the eye open, and squeeze the bottle so that the drop goes into the eye.  About half the time, people miss the eye altogether and the medicine runs down their cheek.  Even when the patient successfully gets the eyedrop in their eye, because a typical eyedropper delivers about 30-50 microliters of solution, there is still a problem with overflow because the entire ocular surface can only retain about 7 microliters of fluid (1/4 the volume of the eyedrop). And, there is the tendency to inadvertently use not just one drop, but two or three drops per eye.  As the result, the eye may be bathed with excess active drug formulation and/or preservatives resulting in topical side effects such as burning and stinging, ocular surface damage, and hyperemia. 

In the case of atropine, side effects may also include prolonged pupil dilation resulting in photosensitivity and blurred vision. These have obvious consequences for patient safety, comfort and compliance.  Furthermore, half the time the drop doesn’t even make it into the eye – people just miss the target altogether! And that miss-rate is for adults, so you can imagine what it would be for children. What does make it into the eye is often an over-delivery to the patient: bathing the entire eye resulting in drug and/or preservative-related topical and potentially systemic side effects, such as ocular surface damage, hyperemia and potential non-ocular problems. These have obvious consequences for patient safety, comfort and compliance. In summary, the eye-dropper really is a very poor technology in general and even more problematic with kids.

If children give up on the medication before the age of eighteen or twenty, when their eyes are still developing, the disease may recur.

But conventional eye-dropper formulations, with all their delivery problems, represent opportunities for Eyenovia – in fact, the low-dose atropine clinical trial results from ATOM1 and ATOM2 were perfectly timed for us. We had already started development of our novel microdosing delivery system (see box Shooting Ahead) for other ocular indications – and when we saw what was happening with atropine and myopia, we immediately realized this was the perfect indication for a microdose drug.

We moved quickly to develop MicroPine – a proprietary piezo formulation of atropine – and have now initiated the CHAPERONE Phase 3 clinical trial. The intent is to show that atropine microdosing with piezo-printing technology can achieve the same or better levels of efficacy reported in trials such as ATOM1 and ATOM2. Given that critical aspects of the design of our trial are already validated through the multiple RCTs conducted by the collaborative academic groups (ATOM1, ATOM2, LAMP), we are very confident of our therapeutic approach!

There is, however, far more to Optejet than a convenient means of precisely delivering microdosed medication. A particularly important aspect of the Optejet is its electronic monitoring capability, which encourages compliance. Good adherence to the prescribed drug regime is hugely important in the control of myopia progression; consistent delivery over the long-term is essential for efficacy in this condition. If children give up on the medication before the age of eighteen or twenty, when their eyes are still developing, the disease may recur.

I believe that compliance may also be assisted by the intrinsic attributes of Optejet: our high-tech, high-precision, communicative system is exactly what today’s kids are used to. Finally, Optejet doesn’t give kids any reason to avoid drug administration: the system is designed for no discomfort, just a sensation of wetness. The system really is unique (see Box Shooting Ahead); true, one or two other companies are developing low-dose atropine eye-drop products, and conventional eye-dropper formulations are better than having no atropine at all, but these approaches only solve part of the problem.

Shooting Ahead

The Eyenovia Optejet microdosing system (see Figure 1) is based on inkjet printer technology. In brief, microdoses of drug are piezo-printed onto the cornea in the same way that an inkjet machine delivers pixels of ink to a piece of paper. Advantages over the eye-dropper include:

  • Similar efficacy with enhanced safety and tolerability.  With 20 percent of the actual active drug load of traditional eye drops targeted directly at the cornea, there is a high likelihood of lower systemic exposure and a better local tolerability profile
  • Easy and reliable for use by children.  Horizontal delivery of a gentle mist of medication that beats the blink reflex means kids don’t have to hold their heads back fighting to keep their eyes open when drops are administered. Microdosing spray delivery is also more comfortable than bathing the eye in a low pH traditional eye drop.  
  • Built in treatment adherence capabilities.  With the ability to communicate with smart devices, the Optejet dispenser is designed to provide audio and video cues and updates to the patient, parent and/or prescriber.

Watch the video here.

Small doses do big things

We are in a very fortunate position with microdosed atropine: the collaborative study group has generated such robust data that we likely will need to conduct only a single registration study - the ongoing CHAPERONE trial – for approval. This study, which includes children with myopia as mild as – 1.0, in an age-range of three to 12 years at the time of enrollment, will randomize them to one of three groups of once-daily administrations: placebo, 0.1 percent microdosed atropine and 0.01 percent microdosed atropine.

The end point is change in refractive error at three years; we chose this time point because, as the treatment is intended to be chronic, we wanted enough time for longer-term effects to become apparent. But as I said, we are pretty confident about what the outcome will be – three large, randomized control studies of the same design have already been done, and the data already analyzed. That’s why, instead of going through Phase I and II trials, we can jump straight to Phase III with a good sense of what results will be.

All the eye-dropper problems – drug wastage, low delivery efficiency, impossibility of reliable microdosing, local and systemic side-effects due to over-application – can all be lessened by high-precision microdosing.

Commercially, the impact of microdosed atropine product – MicroPine – will be huge. We estimate that its market could be as large as those of wet AMD and glaucoma together; that is, about $10 billion annually in the US and Europe combined, assuming a price of about $200 per month. Note that the health economics argument for the product is strong: after all, the consequence of untreated progressive myopia is many years of poorer quality-of-live, and potentially significant visual disability with its related social and economic impact! Moreover, the drug could prevent a range of conditions such as retinal atrophy, myopia-related vascularization and pathological myopia, thereby improving vision and quality of life for a variety of patients over their lifetime. The argument for third-party reimbursement for MicroPine is likely as strong as that for glaucoma.

The penicillin moment

Our hope is that, after CHAPERONE is completed, MicroPine will be broadly accepted as the first-line treatment for myopic progression. And just as the introduction of a biologic drug completely transformed the AMD standard of care, so MicroPine will, we believe, turn out to be a pivot point in the management of myopic progression. No longer must we contemplate a future in which children with myopic progression end up with a poorer quality of life, visual disability or more severe problems such as bilateral detachment. This really could be myopia’s “penicillin moment” – it is an exciting time to be involved!

And it’s an exciting period for Eyenovia on other fronts too: the company is about to initiate a Phase III glaucoma/ocular hypertension trial for its microdosed prostaglandin product (MicroProst), and has completed Phase III mydriasis trials for a fixed combination of phenylephrine and tropicamide (MicroStat). Basically, our contention is that anybody taking a drug in eye-drop form will benefit from a microdose formulation, so we are taking the technology forward in multiple indications. We truly believe that the OpteJet microdose delivery approach is a step-change in ocular drug-delivery.

The Practitioner’s Perspective

Pamela Gallin is Clinical Professor of Ophthalmology (Pediatrics), Department of Ophthalmology, Columbia University, New York.

Eye-drop side effects are nearly always a consequence of an excessive volume of drug formulation being delivered to the eye. This in turn contributes to the well-known problem of eye-drop compliance; indeed, my experience is that 95 percent of my pediatric patients will refuse the eye-dropper, even when it provides rapid allergy relief. But, having used the Optejet microdose system, I can say that it is easier and less unpleasant to administer, and therefore likely to result in better drug regimen adherence. Eyenovia’s system of administering precisely controlled microdoses is therefore of paramount importance, and should be transformational for the field of topically-delivered ocular drugs.

Optejet microdosing could have an equally profound effect in the specific context of myopia progression. Consider brain development: if the retina does not form and send a clear image to the occipital lobe in early childhood, the cells of the visual processing center will not organize themselves correctly. You must correct the image before age 7 to 9 if the brain itself is to self-correct. Glasses can do this, but – particularly at higher prescriptions – produce a kind of tunnel vision in that the corrected field becomes narrower. We need an alternative.

Encouragingly, it is now clear that atropine eyedrops will inhibit changes in axial length: the only question concerns optimal dose. Hence, the ATOM1 study, in 2006, tested 1 percent atropine; ATOM2, from 2012, used 0.5, 0.1 and 0.01 percent concentrations; and the 2019 LAMP study tried 0.05 percent, 0.025 percent and 0.01 percent solutions. And now the Eyenovia CHAPERONE trial is testing 0.1 and 0.01 percent doses. Results from the completed trials show that the local side effects seen with 1 percent atropine – light sensitivity and reading difficulty related to pupil dilation – are not seen with lower doses. This is very promising, but as a practitioner I would remain concerned about atropine’s systemic effects; in particular, if I had a child with a cardiac condition, I would check with a cardiologist before prescribing atropine drops. The much-reduced systemic exposure associated with Optejet microdosing should help address this kind of concern.

In summary, from a practitioner’s perspective, myopic progression is a common problem, and its long-term consequences should not be underestimated. In the past, we just had to live with it, but it is now clear that the future does not have to be that way; topical atropine, particularly in a microdose formulation, could turn out to be a great gift to patients and physicians alike.

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About the Author
Sean Ianchulev

Sean Ianchulev is Professor of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, USA; Founder of Eyenovia, Iantech, Iantrek, KYS Vision, PME ventures.

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