Tsontcho Sean Ianchulev, MD, MPH

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Piezo-print technology directs a precise stream of micro-droplets to the ocular surface-in less than a blink of an eye.

From my perspective, first as an ophthalmologist and as someone who has brought many innovative technologies into our field, I have come to realize how antiquated and inadequate is the existing paradigm of topical drug delivery.

There is virtually no other situation in medicine where physicians prescribe a therapeutic to patients knowing that, most of the time, they do not receive the correct dose. In the case of pills and injectable drugs, we know that if have prescribed 250 mg of Augmentin or 10 units of insulin, for example, and that is what the patient gets.

When clinicians prescribe one drop of timolol twice a day, however, studies have demonstrated that patients get a drop into their eye only about half the time. When they do manage to get drops in the eye, patients often administer between 2 and 7 drops, or a 100% to 600% overdose.

 Much of this excess goes directly into the blood stream through nasolacrimal drainage, explaining not only the high incidence of ocular side effects, but in the case of cardiotropic drop therapies like beta-blockers, systemic ones as well (eg, slowing heart and respiratory rates).

Another concern patients have about their drops is the frequency with which they run out of their medication because of the overdosing. This concern has been voiced by consumer advocacy groups who say patients are paying too much for wasted medication. They make the case that companies have a responsibility to provide drugs in accurate dosing containers which can deliver smaller drops, precisely as prescribed. This was escalated recently all the way to the Supreme Court which refused to consider industry’s appeal.

Even when a single drop is administered correctly, about half the time, the eye is overdosed by 300%. The eye contains about 6 to 7Î¼L of tear film and yet the legacy eye dropper-the mainstay of topical eye delivery for more than 100 years-dispenses about 30 Î¼L to 50 microliters depending the dropper. Hence, the patient receives more drug, and more preservative, leading to more adverse events. About half of glaucoma patients experience adverse events from their drops,

 and only half are adherent to their therapy.

Not only are the issues associated with drops a barrier to patients’ compliance, they are a stumbling block new drugs must overcome in clinical trials. For example, recent trials have shown adverse events associated with otherwise promising news agents, which can obscure the medication’s potential.

Novel high-precision microtherapeutic delivery technology is being developed to change the way drops are administered to the ocular surface. Previous attempts with sprays have been tried and failed, because aerosols are imprecise and liquid jet sprays are hard on the eye. Instead, this technology uses breakthrough piezoprint technology which creates a micronized droplet stream. Piezo-print technology is how inkjet printers revolutionized the print industry, by using its ability to delivery pixel-sharp fluid stream of droplets to create elaborate images. High-precision piezo-print microdosing technology is leading the way with what we believe can replace the century-year-old legacy eyedropper and dramatically improve the precision of topical drug delivery.

New technology is poised to help usher in next-generation micro-therapeutics that will result in more than an 80% reduction in the eye’s in exposure to the preservative and drug. Piezoprint microdosing delivers drugs in less than 80 milliseconds, beating the eye’s 100-millisecond blink reflex. The technology also integrates smart electronics, allowing for dose monitoring thus enhancing compliance and disease management in a whole new area of smart microtherapeutics.

When considering the best place to go with this technology, glaucoma was the obvious choice: it is a blinding disease, compliance is a major problem, and patients take the drugs for life. It is further realized that there is no FDA approved therapy for chronic angle-closure glaucoma, which accounts for 10% and 50% of all glaucoma diagnoses in the United States and China, respectively.

 This indication is being pursued for an underserved population, and then following with expanded indications in the larger glaucoma market.

There is also interest in progressive myopia, it is recognized as a growing epidemic: about one-third of all American and European adults are myopic.

 Multiple randomized controlled Studies from academic collaborative groups have shown that atropine slows the development of myopia by 60% to 70%, and its use is supported by a position paper from the American Academy of Ophthalmology citing level 1 evidence.13 Yet, there is no FDA approved drug because atropine needs to be administered in very low doses to allow for tolerability due to its side effects. This is a perfect candidate for microdosing technology, and we are preparing to initiate a phase III program for FDA registration during the next 12 months. Microdosing and the use of smart technology is a great fit for this savvy patient population who are not receptive to legacy eye drop delivery.

Also being explored is MicroStat for pharmacologic mydriasis; it would be a potential first in-class fixed-combination microformulation of phenylephrine 2.5% and tropicamide 1%.

More than 80 million people a year receive dilated office exams

 and they overwhelmingly complain, finding it very unfriendly, awkward, and uncomfortable. Current preparations essentially “overdose” the eye; MicroStat can deliver the same efficacy as the drop that overdoses by 300%.

Using smart technology to precisely deliver drug to the corneal surface and thereby minimizing adverse events will define a whole new generation of smart microtherapeutics. Microdosing can be applied to many existing ocular drugs that are associated with significant toxicity side effects (e.g., hyperemia, prostaglandin-associated periorbitopathy).

When drugs are delivered precisely, clinicians can improve compliance, which means more treatment effect and better patient outcomes will follow.

Smart technology can make this happen. Drug makers will benefit from better compliance with more prescribers and revenue. Everyone will be happier, including insurers. Drugs are approved for efficacy, but patients and insurers buy effectiveness, after discounting for poor compliance.

There is a huge gap between what is shown in a clinical trial and what happens in the real world. When people run out of their drops, that is not a part of the study.

The aim is to price microdose agents in line with what patients and insurers pay for today’s branded medications-and to have technology adopted as widely as possible and improve as many lives as possible.

Dr. Ianchulev is professor of ophthalmology and director of innovation and technology at New York Eye and Ear Infirmary of Mount Sinai. Dr. Ianchulev reports he is founder of Eyenovia and Iantech Technologies; chairman of the board for Iantech Technologies and on the board of Eyenovia; and the CEO of Eyenovia.

1. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically: the Travatan Dosing Aid Study. Ophthalmology. 2009;116(2):191- 199.

2. Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop instillation in glaucoma patients. Arch Ophthalmol. 2009;127(6):732-736.

3. Hennessy A, Robin AL, Katz J, Covert D. Videotaped evaluation of eye drop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology. In press.

4. Tudor CG. Early Refill Edits on Topical Ophthalmic Products. Baltimore, MD: Centers for Medicare & Medicaid Services, US Department of Health & Human Services; 2010.

5. Geyer O, Bottone EJ, Podos SM, et al. Microbial contamination of medications used to treat glaucoma. Br J Ophthalmol. 1995;79(4):376-379.

6. Leske MC, Heijl A, Hyman L, et al; EMGT Group. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114(11):1965-1972.

7. Tsai T, Robin AL, Smith JP 3rd. An evaluation of how glaucoma patients use topical medications: a pilot study. Trans Am Ophthalmol Soc. 2007;105:29-33; discussion 33-35.

8. Gresko J. Drug companies want Supreme Court to take eye drop dispute. Associated Press. March 31, 2018. https://www.apnews. com/8c76eaec40b740718e32d124301bd701. Accessed June 25, 2018.

9. Parrish RK, Palmberg P, Sheu WP; XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, maskedevaluator multicenter study. Am J Ophthalmol. 2003;135(5):688-703.

10. Aung T, Ang LP, Chan SP, Chew PT. Acute primary angle-closure: long-term intraocular pressure outcome in Asian eyes. Am J Ophthalmol. 2001;131(1):7-12.

11. Vitale S, Ellwein L, Cotch MF, et al. Prevalence of refractive error in the United States, 1999-2004. Arch Ophthalmol. 2008;126:1111-1119.

12. Williams KM, Verhoeven VJ, Cumberland P, et al. Prevalence of refractive error in Europe: the European Eye Epidemiology (E[3]) Consortium. Eur J Epidemiol. 2015;30:305-315.

13. Pineles SL, Kraker RT, VanderVeen DK, et al. Atropine for the prevention of myopia progression in children. Ophthalmology. 2017;12(124):1857- 1866. https://www.aaojournal.org/article/S0161- 6420(17)31675-5/fulltext

14. American Optometric Association. State of the Optometric Profession. 2013. Available from: https://www.aoa.org/Documents/news/state_of_ optometry.pdf. Accessed July 3, 2018.

Articles

The piezo-print microdosing delivers drugs in less than 80 milliseconds, beating the eye’s 100-millisecond reflex.

Small drop delivers big advancement

	Take-home message: In this article, Dr Ianchulev discusses MIGS supraciliary microstenting, a compelling new approach for outflow enhancement that results in sustained reduction of IOP and anti-hypertensive topical medication use in OAG patients. 

	Conventional glaucoma surgeries (e.g., trabeculectomy and shunts) have provided us with important treatment modalities for advanced glaucoma for many decades, but safety profiles and postoperative complications limit these approaches to the end-stage of the glaucoma disease spectrum. Even then, the trade-offs are significant.

	On the other hand, medical glaucoma treatment is life-long, expensive, and limited by patient compliance. More than 50% of glaucoma patients fail primary topical therapy and require two or more medications, which compounds adverse effects (AEs) and further diminishes compliance. New micro-invasive glaucoma surgical (MIGS) interventions aim to fill the gap and provide effective long-term IOP control while reducing medication use, without the safety concerns of filtering glaucoma surgery.

	One of the emerging MIGS modalities is supraciliary stenting, which creates a permanent conduit at the sclera - ciliary body interface to direct aqueous outflow to the suprachoroidal space. This separate drainage collateral augments the uveoscleral outflow pathway and makes use of the high resorptive capacity of the choroid and its negative colloidal pressure to provide a strong driving force for aqueous drainage.

 And while earlier surgical approaches to increase supraciliary outflow through an artificial fistula caused bleeding, inflammation, and scarring that limited success,

 the newer, ab-interno micro-invasive method with the CyPass  microstent is able to achieve supraciliary access with minimal tissue trauma and in bleb-less, conjunctiva-sparing approach.

	The CyPass Micro-Stent and implantation procedure

 Micro-Stent (Transcend Medical, Inc., Menlo Park, CA) is a 6-mm-long, biocompatible, polymeric, supraciliary implant that creates a new permanent aqueous outflow channel from the anterior chamber (Figure 1A). The device is a fenestrated tube (300 µm-diameter lumen) that is inserted into the supraciliary space through a small corneal incision such as that used for cataract surgery.

	The CyPass is implanted under topical anesthesia similar to that used for phacoemulsion cataract surgery (phaco). A 1.5-mm clear-corneal incision is performed, acetylcholine is injected to achieve miosis, and the anterior chamber is filled with viscoelastic agent to maintain chamber integrity and expand the angle. The CyPass device is threaded onto the retractable guidewire of its applier, inserted through the corneal incision, and implanted into the supraciliary region via blunt dissection. Gonioscopy is used to guide implantation and to postoperatively confirm correct microstent positioning. Viscoelastic is then evacuated and a self-sealing incision is confirmed prior to completion of surgery.

	In earlier European studies, microstent implantation in combination with phaco normalized ocular hypertension in glaucoma patients by sustainably reducing IOP by 30-35% through at least postoperative 12 months.

 By optical coherence tomography (OCT), an aqueous-filled internal filtration reservoir surrounds the microstent (Figure 1B-C), and early studies by Ahmet et al indicate that cleft size apprears  to correlate with effective drainage.

	In a prospective, multicentre, single-arm clinical trial (DUETTE study, ClinicalTrials.gov Identifier NCT01166659),

we evaluated the safety and effectiveness of CyPass Micro-Stent implantation for reducing IOP and medication use in POAG patients who had failed ≥1 class of topical medical therapy. Of 65 eyes all achieved successful implantation. All subjects met inclusion criteria and had the diagnosis of POAG which had failed topical medication therapy with at least one IOP lowering medication and the entry medicated IOP was over 21 mmHg. At baseline, mean medicated IOP was 24.5 +/-2.8 mmHg and mean number of topical medications was 2.2 +/- 1.1.  Consistent with the MIGS profile of the CyPass device, there were no vision-threatening serious ocular adverse events, and the most frequent ones were transient intraoperative blood reflux (6%), transient IOP elevation (11%), cataract progression (7%), PAS (3%). More than 80% of subjects were controlled with the CyPass procedure and avoided filtration surgery, which was indicated for nearly all subjects at baseline. At the 12-month visit, 47 eyes were available for efficacy evaluation. In a paired analysis, IOP was reduced by a mean of 32% as compared with baseline to a mean value of 16.7 ± 5.5 mmHg (p<0.0001) and the mean number of IOP-lowering medications was 1.5 ± 1.3 (p=0.008), with an average reduction of 0.5 medications per subject.

	A smaller single-center study in Poland followed 23 POAG patients that received a CyPass device during concurrent phaco.

 Baseline medicated IOP 16.9±5.0 mmHg was reduced at 1 and 2 years to 14.2±3.0 mmHg (n=19) and 15.1±1.8 mmHg (n=18), respectively. The number of glaucoma medications was reduced from 2.3±0.9 at baseline to 0.3±0.7 medicines at 2 years.

	A similar trial in Germany tracked 24 POAG patients with uncontrolled IOP that underwent microstent implantation during phaco.

 Baseline IOP of 22.3±6.6 mmHg was reduced and maintained at 15.0±3.4 mmHg at 12 months (n=17), representing a paired 21% reduction. Subjects that had been taking a mean 1.8±1.2 IOP-lowering medications at baseline had this number reduced by more than half, to 0.7±1.0 at 12 months.

	The aforementioned study sites are participants in a much larger, ongoing, multicentre study, the CyPass Clinical Experience Study (CyCLE; ClinicalTrials.gov Identifier NCT01097174), that has enrolled and treated 555 POAG patients with microstent implantation. One included sub-study is detailed as follows. A prospective European trial

 evaluated microstenting in combination with phaco for 2 years in a POAG patient pool that was divided into medicated subjects with either uncontrolled IOP (≥21 mmHg, Cohort 1, n=51) or controlled IOP (<21 mmHg, Cohort 2, n=85). No sight-threatening AEs occurred. The most common AEs were transient hypotony (15%) and microstent obstruction (9â%), typically due to iris tissue overgrowth. Fifteen subjects (11â%) required secondary incisional glaucoma surgery. Of 82 subjects remaining in the study at 24 months, mean IOP in Cohort 1 (n=23) was15.8 ± 3.8 mmHg, reflecting a 37â±19â% decrease from baseline (P <0.0001). Although Cohort 2 (n=59) IOP was significantly decreased at 6 and 12 months vs. baseline, the mean 24-month IOP, 16.1±3.2 mmHg, was unchanged from baseline. At 24 months, the mean ± SD number of medications was 1.0 ± 1.1 in Cohort 1 and 1.1 ± 1.1 in Cohort 2. Mean decrease from baseline medication use was statistically significant at months 6 (P <0.001), 12 (P <0.001), and 24 (P = 0.0265) in Cohort 1, and at months 6, 12, and 24 (all P <0.0001) in Cohort 2.

	The Next Wave of CyPass Clinical Studies

	There are a wave of robust RCTs on the horizon that together will provide level-1 clinical evidence in the field of glaucoma.

	The COMPASS study (ClinicalTrials.gov Identifier: NCT02448875) is one of the largest MIGS trials to date  - sample size 505 subjects randomized to either the cataract surgery (control group) vs cataract surgery with concurrent CyPass Micro-Stent implantation (active treatment). It is the first FDA study with 2-year efficacy and safety primary endpoints, and the first MIGS trial to control for medication confounding by using 1- and 2-year terminal washout as well as diurnal IOP measurements. The COMPASS study was just completed and the company announced that the trial met all primary and secondary endpoints at both 12 and 24 months. Data were recently submitted to the FDA and are pending publication.

	In a new randomized, international trial (ClinicalTrials.gov Identifier: NCT02448875), we are currently evaluating whether a new MIGS approach to increase the size of the supraciliary peri-stent aqueous reservoir additionally reduces IOP and glaucoma medication use in microstented POAG eyes. To date, 63 eyes of 63 POAG patients (mean age 68 years, range 45â86) were randomized to  receive either the supraciliary microstent alone, or microstenting with supplemental viscoexpansion using 30 or 60 µl of viscoelastic agent (Healon® 5; Abbott Medical Optics, Inc., Abbott Park, IL).

	Adaptive viscoelastic spacer is injected through the device applier during microstent implantation, to enlarge the supraciliary space and increase outflow capacity. The 60 µl injected amount of viscoelastic represents a volume that is 40-fold greater than that of the microstent alone.

	Although size attenuation occurred over time, viscoexpansion significantly and dose-dependently enlarged the cross-sectional area of the peri-stent aqueous reservoir (Table 1). At 6 months, the mean reservoir area was 4.7-fold larger in the Visco-60 group vs the Stent-only group. Preliminary data analysis indicates that viscoelastic expansion maintains persistent reservoir enlargement beyond 12 months and is associated with reduced IOP and glaucoma medication use.

	Table 1. Viscoexpansion enlarges the peri-stent, supraciliary, aqueous drainage reservoir

	Data are mean (SD); n=21 subjects/group. Cross-sectional area measured immediately posterior to the microstent by quantitative analysis of OCT images. Two-tailed Student’s t-test.

	There were no serious  vision-threatening AEs and we are monitoring all subjects through 12 months of follow-up. The safety profile of the CyPass Vx  procedure appears similar to Cypass alone implantation and are consistent with what we see from MIGS interventions.

	Growing experience and evidence with ab-interno stenting of the supraciliary space using the CyPass Micro-Stent, alone or in combination with phacoemulsification cataract surgery or viscoexpansion, demonstrates a MIGS-like safety profile with sustained treatment effect through 24 months of follow-up. With the results of the COMPASS study demonstrating positive 2-year efficacy in an FDA randomized clinical investigation, this will eliminate some of the concerns with trabecular by-pass stenting where the effect was not sustained at 2 years with statistical significance in the FDA trial. And with the advent of adapting visco-expansion to augment microstent-mediated supraciliary drainage, we may soon have a minimally invasive solution for patient care over the broad spectrum of glaucoma severity.

	Dr Tsontcho Ianchulev is a Clinical Associate Professor at the Department of Ophthalmology, University of California at San Francisco, and Chief Medical Officer of Transcend Medical, Inc., Menlo Park, California, USA.

	Disclosure: Dr. Ianchulev has following disclosures: Financial interest and patent holder in Transcend Medical; Inventor of the technology for Intraoperative Aberrometry and financial interest / patent holder in Wavetec, Inc/Alcon; Venture Partner in PME & Tullis Health Ventures with interests in portfolio companies; previously Head of Clinical Development, Genentech;

In this article, Dr Ianchulev discusses MIGS supraciliary microstenting, a compelling new approach for outflow enhancement that results in sustained reduction of IOP and anti-hypertensive topical medication use in OAG patients.

Tsontcho Sean Ianchulev, MD, MPH

Articles

Small drop delivers big advancement

Supraciliary microstenting: advancing glaucoma treatment in the age of MIGS