Several groups are working to overcome challenges inherent to drop therapy.
Morgan Fedorchak, PhD
A saying I use often in my lab is “Don’t throw the baby out with the bathwater.” As many know, this idiom refers to the idea of preserving the positive (the baby) while discarding the negative (the bathwater). When it comes to glaucoma eye drops, the aspects to toss include the limited bioavailability, poor patient adherence, and side effects. But what we should try to preserve are the comfort, portability, and familiarity. At Otero Therapeutics, our goal is to maintain these beneficial aspects and improve upon the bad.
THE SOLIDROP TECHNOLOGY
The SoliDrop Technology is a noninvasive one-form eye drop (Figure 1). The drop is administered as a liquid and transitions to a solid, nondegradable gel depot in the fornix. Biodegradable microspheres can be loaded with a wide range of drugs and programmed to release these drugs at a predetermined rate. The gel remains beneath the lower eyelid for the duration of drug release, which is possible for up to 1 month.
Highlights of the SoliDrop are that it is removable and preservative-free. The microsphere release system is predictable and adaptable, and these microspheres are hydrolyzable, which is a well-characterized mechanism for release. We use materials that are low characterized, so they are very safe and effective.
In preclinical studies in rabbit eyes, the SoliDrop technology provided comparable IOP reduction to twice-daily brimonidine drops.1 We saw retention for up to 28 days and no signs of irritation. Interestingly, as expected, we saw a drop in IOP in the control eye, the one that wasn’t treated with the twice-daily standard drops, but we didn’t see that with the single SoliDrop administration. We believe this suggests a decrease of systemic absorption, as we are using a lower administered dose and it is localized at the ocular surface.
Otero has several projects in the works. We started with glaucoma monotherapy and have begun to look at combination therapy. Because the SoliDrop gel and the microspheres are separate, we can take different formulations of the microspheres that have demonstrated in vitro release kinetics and mix them together in predefined ratios.
One ongoing project is our combination with timolol. We saw that, at 10 days, we had not yet exhausted the timolol release. When we combined that with our brimonidine formulation, a few important observations were made. We got the same expected release of brimonidine, and the timolol release did not change. These were mixed in a 2.5:1 ratio, which was maintained over time. This enables off-the-shelf mixing of formulations, as we did not have to change the gel or the individual microsphere formulations to achieve those ratios.
We have conducted in vivo studies with biologics and antiinfectives, and we will be moving toward looking at antiinflammatories as well.
This has been a big year for Otero Therapeutics, as we recently incorporated. In the near future, we will be conducting studies with our glaucoma formulation, which is where the majority of our data lie. We will also be working on in vivo validation of other formulations.
1. Fedorchak MV, Conner IP, Schuman JS, Cugini A, Little SR. Long term glaucoma drug delivery using topically retained gel/microsphere eye drop. Scientific Reports. 2017;7:8639.
Mark S. Humayun, MD, PhD
Whether for the posterior or the anterior segment, the difficulty of any therapy is chronic administration. As a retina specialist, I was involved in the development of the Argus II Retinal Prosthesis System (Second Sight), which is a bioelectronic device that restores sight to patients with retinitis pigmentosa. Through this experience, I began to question the potential role of bioelectronics for glaucoma.
I wondered, could we build a bioelectronic pump for the eye that would deliver medication every hour, day, minute, or whenever we wanted? I envisioned that it would be programmed wirelessly. The reservoir would sit underneath the conjunctiva and sclera, but the cannula could go anywhere—in the anterior or posterior chamber, in the suprachoroidal space, and even to the front of the eye.
The Medtronic pump is the workhorse of the industry. There are other pumps, but they are big, work off pistons, and are not amenable to placement in the eye.
Recognizing the possibility for a smaller, smarter solution, Replenish developed an automated, refillable, implantable ocular drug pump called the Ophthalmic MicroPump System (Figure 2). Designed to be implanted under the skin of the eye, the MicroPump is a “smart device” that is programmable to dispense nanoliter-sized doses of drug at set times. The device can hold up to 12 months of medication and can be replenished using a disposable 31-gauge needle tubing kit.
The MicroPump system is composed of four subsystems: (1) the Anterior MicroPump for glaucoma, (2) the Posterior MicroPump for retina, (3) the Eyelink, and (4) the Drug Refill System. The Anterior MicroPump has a similar cannula system and insertion point to glaucoma drainage devices. The Eyelink is a wireless programmer/charger for bidirectional communication with the MicroPump implants, and the Drug Refill System is a separate console unit used to fill and refill the MicroPump implants with drug.
The MicroPump features a one-way check valve to prevent backflow leakages, a fluidic flow sensor, a directional telemetry system for wireless programming and battery recharges, and a programmable microcontroller with a calendar to “wake up” when time to deliver medication. An optional cannula with a pars plana clip can direct medication in the same location as intravitreal injections.
The Replenish MicroPump system is incredibly accurate for both large and small molecules. It is easy to access the refill port because it can be transilluminated. This device has a lot of potential, with multiple chambers for different drug delivery.
We coupled the MicroPump with a closed-loop IOP-monitoring system that measures data every 5 seconds. The system stores the data, which the user can download when he or she charges the pump.
Overall, the MicroPump is a safe and reliable system that can deliver the appropriate amount of drug at determined intervals and therefore address patients’ adherence issues.1,2
1. Guiterrez-Hernandez JC, Caffey S, Abdallah W, et al. One-year feasibility study of Replenish MicroPump for intravitreal drug delivery. Trans Vis Sci Technol. 2014;3(4):8.
2. Humayun MS, Santos A, Altamirano JC, et al. Implantable MicroPump for drug delivery in patients with diabetic macular edema. Trans Vis Sci Technol. 2014;3(6):5.
Molly M. Walsh, MD, MPH
Glaucoma specialists are acutely aware of the issues inherent to topical glaucoma therapy. Due to the challenges in eye drop administration and compliance, many patients do not get the appropriate therapy they need, and, as a result, their vision continues to worsen. We must acknowledge the pressing need to improve our drug delivery strategies.
Technologies are certainly advancing. Although exciting, there are setbacks to any new methods developed. Among the topical and the subconjunctival extended-release delivery modalities, there are issues with topical irritation and the requirement that the drug pass through the cornea. In addition, intracameral extended-release modalities still require the use of a 26- or 27-gauge needle to penetrate the cornea. Not only do patients typically dislike having a needle passed through the cornea, but there is also evidence that continued intracameral injections may cause corneal endothelial damage.
Several years ago, I began working on a project with our late chairman, David Epstein, MD, and my colleauge Stuart McKinnon, MD, PhD, aiming to deliver drugs directly to the anterior segment using the aqueous outflow system. Our Retroject device provides general compression of episcleral venous outflow for the eye while simultaneously allowing access to the episcleral veins. Any drug that we inject into the superficial episcleral veins will therefore move in a retrograde direction into Schlemm canal, the trabecular meshwork, and finally the anterior chamber.
HOW IT WORKS
With this technology, we place a plastic ring around the eye. The ring has a soft cuff that seals on the eye, and a gentle vacuum is applied in the ring that compresses the outflow vasculature of the anterior segment. This transiently impedes blood flow from the episcleral veins. We can then access a superficial vein using only a 30- or 32-gauge needle. Any drug that we inject into that vein will move in a retrograde direction into Schlemm canal and the trabecular meshwork. Because this vein is so superficial, patients don’t feel this injection after using only topical anesthetic drops.
AREAS OF FOCUS
We have obtained robust data in a mouse model. We have also completed an IRB-approved pilot safety study in glaucoma patients at the Duke University Eye Center. In addition, we have collaborated with Jennifer West, PhD, a biomedical engineer at Duke, as well as several other third parties, to access liposome and nanoparticle versions of many drugs of interest in glaucoma.
RESULTS AND OBSERVATIONS
In our investigations with the Retroject device, we first injected liposomes of latanoprost in a C57-black mouse population. We were encouraged by the IOP-lowering effect. However, we were disappointed to find that it was only clinically significant for approximately 6 weeks after a single injection. We then moved to a nitric oxide-and-latanoprost combination nanoparticle. When we injected these nanoparticles into the same C57-black mouse population, we found an extended IOP-lowering effect that lasted 9 weeks. Although 9 weeks is not ideal, we are working on ways to modify the nanoparticles for a longer duration of effect.
We completed a pilot study using the Retroject device in eight human subjects at the Duke University Eye Center. This was a proof-of-concept study to show that patients tolerated the device being placed on the eye. We found no safety issues with either placement of the Retroject device or with episcleral vein injection.
We are continuing to develop our in-house extended-release formulations for the treatment of glaucoma. We are also pursuing external collaborations to improve drug delivery to the trabecular meshwork and Schlemm canal for the treatment of glaucoma and to enhance other therapeutic modalities targeting the anterior segment.
How It Works: PRINT Technology
By Casey Kopczynski, PhD
- A proprietary polymer (green) is added to the surface of a micropatterned master template (grey).
- This is crosslinked to generate a precise mold with microscale cavities.
- This mold is then filled with drug and polymer, generating an implant array.
- The implants can be removed from the array and inserted into a needle for injection. PRINT implants maintain the dimensions of features on the master template.
1. Sandahl M, Melton D, Tully J, et al. Evaluation of reproducibility and uniformity of PRINT implant manufacturing. Poster presented at: ARVO 2018; April 29 to May 3, 2018; Honolulu, Hawaii.
Casey Kopczynski, PhD
• Chief Scientific Officer, Aerie Pharmaceuticals, Durham, North Carolina
• Financial disclosure: Employee (Aerie Pharmaceuticals)
By Tejal Desai, PhD
Despite advances in ophthalmic medications, patients and practitioners are still limited in terms of drug delivery technologies. Formed in response to this limitation, Zordera is a company focused on developing engineered polymer film technology for ocular drug delivery.
When it comes to glaucoma, barriers to successful medical therapy include not only patient compliance but also the physiology of the eye, in getting drugs across the cornea. As we at Zordera started to think about this, we realized that we wanted to develop a drug delivery system that could provide not just controlled or sustained delivery, but what we call zero-order delivery.
With zero-order delivery, we can dial in the exact amount of drug to be administered, per day, over an extended period of time. To that end, we are hopeful that this approach will not only improve patient compliance but also enhance medication efficacy, lower side effects, and potentially reduce costs.
The Zordera technology is based on the concept of an engineered biopolymer thin film. The platform is amenable not only to small molecules but also to biologics—from antibodies, to peptides, to small–molecular-weight entities. It is a bioerodible device that allows for controlled release of drug but then falls apart at the end of that release. This allows us to decouple our kinetics with the actual platform or polymer technology.
We have demonstrated sustained zero-order delivery over 4 to 6 months and even longer with small molecules.1 This translates to release rates within 0.5 to 1.0 µg per day, and we can dial that up or down based on the molecule of interest. What that allows us to do is show that we can control the IOP effect over that same time period. There is no ramp-up or ramp-down in the beginning or at the end of delivery because of the zero-order feature.
We have developed an intracameral implant, which allows us to bypass the physiological barriers and get the drug exactly where we want. We can also use these films to deliver combination therapy and dial in two delivery rates, depending on what is needed therapeutically.
The safety of the Zordera technology has been demonstrated in rabbits and nonhuman primates. The device is made from materials that have a long history of being implanted in the body, and they were all tolerated in different form factors, be it films or multilayer films. We have shown that they result in no choroidal, intracameral, or anterior chamber toxicity and have found no alterations or deleterious effects.
In addition to glaucoma, we have done work in the biological space for age-related macular degeneration. We have shown that we can achieve zero-order delivery with large biologics, including antibodies, and that these antibodies are not only delivered over a sustained period of time but are also stable and biologically active for multiple months.
Zordera has shown feasibility for multiple targets, both small molecules and larger biologics. With this technology, we can get linear, zero-order kinetics for at least 6 months and possibly even longer. The beauty of this is that we can tune those release rates to the molecule without having to alter the formulation. n
1. Kim J, Kudisch M, Mudumba S, et al. Biocompatibility and pharmacokinetic analysis of an intracameral polycaprolactone drug delivery implant for glaucoma. Invest Ophthalmol Vis Sci. 2016;57(10):4341-4316.
Tejal Desai, PhD
• Chair of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California San Francisco
• Cofounder, Zordera
• Financial disclosure: Employee (Zordera)
Morgan Fedorchak, PhD
• Assistant Professor of Ophthalmology, Chemical Engineering, and Clinical & Translational Sciences, and Director of the Ophthalmic Biomaterials Laboratory, University of Pittsburgh
• President and Chief Technology Officer, Otero Therapeutics
• Financial disclosure: Employee (Otero Therapeutics)
Mark S. Humayun, MD, PhD
• Cornelius J. Pings Chair in Biomedical Sciences; Professor of Ophthalmology, Biomedical Engineering, and Integrative Anatomical Sciences; Director of the Institute for Biomedical Therapeutics; and Director of the University of Southern California Roski Eye Institute, Los Angeles
• Cofounder, Replenish
• Financial disclosure: Consultant, Equity Owner, Patent Owner (Second Sight Medical Products); Employee (Replenish)
Molly M. Walsh, MD, MPH
• Glaucoma specialist, Duke University Eye Center, Durham, North Carolina
• Cofounder and Chief Executive Officer, Retroject
• Financial disclosure: Employee (Retroject)