Purpose: To examine the dose-dependent pharmacokinetics of dexamethasone delivered from a biodegradable hydrogel punctum plug in a canine model.

Methods: Micronized dexamethasone (Dex) was suspended in a multi-arm PEG solution at two different levels (high and low dose) and injected into small bore tubing prior to cross-linking. Fluorescein was conjugated into the hydrogel to aid plug visualization through the tissue using the blue light from a slit lamp. The Dex hydrogel matrix was dried and cut into punctum plugs. The Dex plugs were inserted into the inferior canaliculus of beagles and a subset was removed each week for imaging. Tear fluid samples were collected at weekly intervals and dexamethasone concentration was determined by LC/MS. The high dose was evaluated in a toxicology study and the low dose is a clinically representative dose designed for four weeks of tapered release that was assessed in a PK study.

Results: The Dex plug demonstrated a sustained drug release profile in tear fluid with a tapering effect over the treatment period. Explanted plugs (Figure Two) of the low dose formulation illustrate the drug release over time, with full drug clearance from the plug at four weeks.

Conclusions: Topical corticosteroids, such as dexamethasone, are used to treat inflammation for various ophthalmic conditions including post-operative inflammation. Many therapies require multiple daily administrations (up to hourly for severe conditions) for the first several weeks followed by tapering to a lesser frequency as the inflammation subsides and the condition resolves. A single-dose dexamethasone punctum plug which biodegrades may provide a more convenient option to help eliminate patient compliance with stringent dosing requirements, and help ensure appropriate treatment and resolution of the condition.

Purpose: To evaluate the sustained release of ovalbumin (OVA; 45000 g/mol) and rabbit IgG (rIgG; 150000 g/mol) from preformed hydrogel depots with variable degradation times.

Methods: Fine particles of OVA and IgG were formulated with a selection of PEG hydrogels and were cured, dried and cut to form degradable (a, b, c, d) and non-degradable (e) hydrogel depots. The depots were examined in vitro for sustained release under accelerated conditions. Prior to testing, acceleration rate was calculated using degradation profiles of each hydrogel, absent of OVA and IgG, to compare the relative degradation rate between accelerated and real-time conditions, tris buffer saline (TBS) pH8.5 and phosphate buffer saline (PBS) pH7.4, respectively. Acceleration factor was determined to be 16x in TBS compared to PBS. Accelerated OVA and IgG in vitro release was conducted to determine release profiles as a function of the hydrogel degradation over time. Concentration of OVA and rIgG were determined by HPLC.

Results: Release profiles of OVA and rIgG shown in Figure 1 and 2 show the effect of hydrogel degradation time on sustained release of OVA and rIgG. Slow degrading hydrogels release OVA and rIgG over a longer time period than faster degrading hydrogels. Comparison of OVA and rIgG release using the same hydrogels indicate that rIgG is released slower than OVA due the difference in size and molecular weight. In both cases, hydrogels made using non-degradable SGA linkages used as controls reach a maximum release after diffusion of surface and free particles.

Conclusions: Monoclonal antibody fragments and fusion proteins have been designed to inhibit vascular endothelial growth factors (VEGF) for treatment of posterior segment diseases such as age-related macular degeneration (AMD) and diabetic macular edema (DME). Frequent anti-VEGF intravitreal injections have shown to manage the progression of these diseases to prevent further vision loss and in some cases, gain visual acuity. However, frequent intravitreal injections can increase the risk of infection, retinal detachment, and/or hemorrhage. The ability to tailor the release of OVA and rIgG from hydrogel depots for sustained delivery of proteins could provide a technology platform for use with anti-VEGFs to reduce the number of yearly intravitreal injections and potentially reduce the risk of side effects.

Purpose: To assess the safety and feasibility of a moxifloxacin-loaded punctum plug (MP) in a post-operative cataract surgery group.

Methods: A prospective, single-arm pharmacokinetic study was conducted with 10 patients at the Singapore National Eye Center. The MP was inserted into the punctum of patients following cataract surgery. Study endpoints included ease of insertion, retention and moxifloxacin tear fluid levels at 1h, 24h, and on days 3, 7, 10, 20 and 30. The MP is designed to deliver a bolus followed by extended release encapsulated moxifloxacin; concentrations were targeted to be >250ng/mL through 7 days of treatment.

Results: The average moxifloxacin levels in the tear film by LC-MS/MS ranged from 2,465 to 3,236ng/mL through day 7 as shown in Figure 1. Tear fluid concentrations were below the limit-of-quantification (<LOQ) for days 20 and 30. MP retention was 100% through day 10. Slit lamp examinations most commonly showed aqueous chamber cells and corneal staining/erosion, shown in Table 1. All findings were determined to be related to cataract surgery. Plugs were well tolerated with no adverse events and no ocular complaints or findings other than normal post-cataract symptoms.

Conclusions: The MP delivered and maintained moxifloxacin tear fluid levels above the MIC90s for common susceptible pathogens (250ng/mL) for 7 days in a post-cataract pharmacokinetic study. The MP possessed a favorable safety and tolerability profile over 30 days. Consistent and therapeutic dosing from a punctum plug may be advantageous over patient-administered topical drops to avoid relapse, reduce contagion, and cure the disease.

Purpose: To examine the in vitro release profiles of three nonsteroidal anti-inflammatory drugs (NSAIDs): Bromfenac (BFc), Diclofenac (DFc) and Nepafenac (NFc) from polyethylene glycol (PEG) hydrogel punctum plugs.

Methods: BFc, DFc and NFc were each suspended with equal loading in a multi-arm PEG solution and injected into small diameter silicone tubing prior to cross-linking. The hydrogel NSAID matrix confined within the silicone tubing was cut to 5mm plugs. The NSAID release profile was determined in PBS pH7.4 at 37°C simulating the release from a punctum plug (PP) inserted in the canaliculus. The release media was sampled and exchanged daily. Plugs were removed for photographic imaging to track the release of the drug qualitatively indicated by drug clearance from both ends of the plug. Percent drug release was determined using UV/Vis spectrophotometry.

Results: As shown in Figure 1, each NSAID was released from the plug at a rate relative to their aqueous solubility (BFc, DFc and NFc having a water solubility of 53, 0.6 and 0.006 mg/mL respectively). The most soluble BFc was released in 7 days, DFc was released in 14 days, and the least soluble NFc’s projected release was calculated at approximately 120 days. Images of a DFc-loaded hydrogel plug showing drug clearance over time are included within Figure 2.

Conclusions: BFc, DFc and NFc each showed variable rates of sustained release from a PEG hydrogel plug corresponding to their water solubility. Solubility modifiers and/or modifications to the PEG hydrogel matrix can be employed to tailor the release profile of BFc, DFc and NFc, depending on the drug load and duration of therapy required. Topical NSAIDs, such as BFc, DFc and NFc are used to treat post-surgical inflammation as well as various ophthalmic conditions, and typically require multiple daily dose administrations over extended periods of time. A single dose NSAID punctum plug may provide more consistent dosing while eliminating issues of patient non-compliance.

Purpose: To develop a quantitative method simulating forces an eye may experience during patient manipulation post-clear corneal cataract surgery.

Methods: A Dontrix Gauge (GAC International Inc., Bohemia, NY)(Figure 1a), which is a spring gauge used to apply and measure forces in orthodontics, was modified to have a 3 mm atraumatic tip. The resulting Calibrated Force Gauge (CFG) allows application of calibrated and quantifiable force to the eye in 0.25 ounce increments (Figure 1b). After in-vitro and in-vivo evaluations, an initial clinical study was conducted using the CFG to apply one ounce of force temporal to the limbus in healthy volunteers to examine intraocular pressure (IOP) changes and compare the findings with those in the literature. After confirming the force simulating ocular surface manipulation, the CFG was used to challenge clear corneal incisions (CCIs) which were stromally hydrated (Study 2) or closed with 10-0 Nylon suture (3-1-1 with buried knot)(Study 3); the CFG was placed 0.5 mm temporal to the incision.

Results: In the first study, mean baseline IOP was 17.5 mmHg and rose to 43.4 mmHg upon applying 1.0 ounce of force using the CFG. Literature states that application of light and firm digital forces on the eye equate to IOP of 27 and 58 mmHg respectively. As a result, 1.0 ounce of force appeared adequate to simulate eye touching, rubbing, or forced blinking. When the CFG was used to challenge CCIs closed with stromal hydration in Study 2 (n=30), 66.7% of wounds leaked with ≤ 1.0 ounces of force. In the suture group (Study 3), wounds were challenged prior to and after application of the suture. Only CCIs which leaked on the initial challenge were sutured and challenged with the CFG a second time. Out of these wounds, 23.7% leaked with application of ≤ 1.0 ounces of force (Figure 2).

Conclusions: Applying one ounce of force proximal to a CCI appears to be a clinically relevant assessment of wound integrity and propensity to leak under patient manipulation. Reports in the literature suggest that wounds which leak have a 44-fold increased risk for endophthalmitis. This risk is hypothesized to be related to wound gape allowing fluids to travel between the ocular surface and anterior chamber. If a wound leaks under CFG manipulation after cataract surgery, it may be an indication that the incision architecture is not adequate and closure is necessary to prevent postoperative wound leaks.

Purpose: To formulate 1, 2 and 3-month sustained release travoprost from biodegradable hydrogel punctum plugs for the treatment of glaucoma.

Methods: Travoprost was encapsulated in various formulations of polylactide microparticles (PM), which were dry blended and suspended in a multi-arm polyethylene glycol (PEG) precursor solution conjugated with fluorescein and injected into small bore tubing prior to cross-linking. The travoprost in the PM/hydrogel matrix was dried in tubing and cut into plugs. Drug release rate from the respective formulations was assessed in PBS at pH 7.4 at 37 C until complete dissolution. The 3-month formulation was evaluated for plug visualization through the tissue in a canine model under illumination with a blue light and yellow filter.

Results: Sustained release of travoprost via PEG hydrogel punctum plugs was confirmed in vitro for each of the three formulations tested (Figure 1). Additionally, each formulation released a daily dose (based on in vitro release data) exceeding that administered by commercially available travoprost eye drops. Visualization and retention of the plug was confirmed in vivo (Figure 2).

Conclusions: 1, 2 and 3-month sustained release of travoprost from biodegradable punctum plugs is feasible, and can deliver travoprost into the tear fluid at therapeutic levels. Plug retention is a key attribute to achieve clinical success, and confirmation of plug presence can be done by physicians and patients for monitoring. In recent clinical trials, the 1- and 2-month formulations demonstrated a reduction of intraocular pressure (IOP) in patients with glaucoma and ocular hypertension comparable to commercially available topical prostaglandin analogs.

ReSure Sealant was evaluated in a prospective, randomized, parallel arm, controlled, subject-masked U.S. Pivotal Clinical Trial in which 488 subjects were enrolled at 24 sites throughout the United States. The study compared the ReSure hydrogel sealant with sutures for safety and effectiveness within the first 7 days following cataract surgery. The proposed indication for ReSure Sealant is intraoperative management of clear corneal incisions with a wound leak as demonstrated by a Seidel test, and for prevention of postoperative fluid egress following cataract or intraocular lens placement surgery.

Clear corneal wounds are often closed by hydrating the stroma of the cornea, which transiently inflates the tissue to more closely oppose the wound edges. However, evidence suggests these incisions may not be, and/or do not remain, watertight. Wound leaks are widely believed to increase the risk of various post-operative complications. “This trial demonstrated that clear corneal incisions may be more vulnerable than previously thought, with zero to minimal touch pressure required to produce a wound leak in 76% of cases,” stated Terry Kim, M.D., Professor of Ophthalmology, Duke University Eye Center. “More protection may be necessary to safeguard these incisions, and ReSure Sealant has demonstrated to be a valuable adjunct to clear corneal cataract surgery in this trial.”

Cataract surgery is the most commonly performed surgery in the United States, with well over 3 million procedures conducted annually.1 Pending FDA approval, ReSure Sealant would be the first and only sealant approved for ophthalmic use. “We are very pleased with the results of the trial and believe our data set is strong,” stated Amar Sawhney, President and CEO of Ocular Therapeutix. “Should FDA view our trial results favorably, we hope to have the opportunity to offer ReSure Sealant to U.S. clinicians later this year.”

About Ocular Therapeutix, Inc.:
Ocular Therapeutix, Inc. is a privately held company based in Bedford, MA, focused on the development and commercialization of ophthalmic therapeutic products using its proprietary hydrogel technology. Ocular Therapeutix is focusing on development of drug-eluting punctum plugs for treatment of glaucoma and post-operative inflammation and pain, injectable depots for back-of-the-eye diseases, and ReSure Sealant for sealing clear corneal incisions following lens implantation surgery.

¹ The Global Cataract Surgery Devices Market is forecast to exceed $3.8 Billion by 2017. ASDR Reports, February 22, 2012. https://www.asdreports.com/news.asp?pr_id=261.

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Ocular Therapeutix will use the funds to further advance development activities and implementation of clinical trials for its sustained release drug programs, including travoprost for the treatment of glaucoma, and dexamethasone for the resolution of post-operative inflammation and pain. The funds will also be used to support U.S. commercial launch efforts and to develop sustained release therapies for retinal diseases in collaboration with pharma partners.

Sustained release drugs offer advantages over current topical ophthalmic medications by improving patient compliance and eliminating the peaks and valleys associated with topically-administered drugs, which may improve disease control and the safety profile of certain drugs.

About Ocular Therapeutix, Inc.:
Ocular Therapeutix, Inc. is a privately held company based in Bedford, MA, focused on the development and commercialization of ophthalmic therapeutic products using its proprietary hydrogel technology. Ocular Therapeutix is focusing on development of drug-eluting punctum plugs for treatment of glaucoma and post-operative inflammation and pain, injectable depots for back-of-the-eye diseases, and ReSure® Sealant for sealing clear corneal incisions following lens implantation surgery.

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Dr. Lindstrom is a board-certified surgeon and recognized leader in ophthalmic pharmaceuticals and cataract, corneal, and refractive surgery. He is the founder and an attending surgeon of Minnesota Eye Consultants, Adjunct Professor Emeritus at the University of Minnesota Department of Ophthalmology, and advisor to numerous ophthalmic companies throughout the world. He holds over 30 patents in ophthalmology, and has been at the forefront of the industry’s evolutionary changes throughout his career.

“We are incredibly fortunate to have Dr. Lindstrom join our Board of Directors” stated Amar Sawhney, President and CEO of Ocular Therapeutix, Inc. “As one of the top thought leaders in the industry, Dr. Lindstrom’s input and guidance will be invaluable as we advance our sustained release drugs through clinical trials.”

Ocular Therapeutix’s sustained release drug technology encapsulates proven and approved drugs within the company’s proprietary polyethylene glycol (PEG) hydrogel and releases them in a sustained fashion over a predetermined period of time.

“Ocular Therapeutix’s sustained release technology is an exciting prospect for the world of ophthalmology,” stated Richard Lindstrom, MD. “These drugs have the potential to significantly advance the ophthalmic pharmaceutical industry by eliminating patient compliance issues and putting drug dosing in the hands of the physician.”

About Ocular Therapeutix, Inc.:

Founded in November 2006, Ocular Therapeutix, Inc. is a privately held company based in Bedford, MA, focused on the development and commercialization of ophthalmic therapeutic products using its proprietary hydrogel technology. Ocular Therapeutix is focusing on development of drug-eluting intracanalicular plugs for treatment of glaucoma and post-operative pain and inflammation, injectable depots for back-of-the-eye diseases, and an ocular sealant.

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The pilot Phase II study enrolled twenty patients (36 eyes) at the Umhlanga Hospital Medical Centre and Netcare Alberlito Hospital in South Africa.  Patients with documented open-angle glaucoma or ocular hypertension (intraocular pressure (IOP) ≥ 24 mmHg and ≤ 34 mmHg) were enrolled in the study, with a mean IOP at baseline of 28.7 mmHg.   A single plug was administered in each enrolled eye.  Analysis showed a decrease in IOP of 6.8 mmHg over two months of treatment.  No excessive tearing or other unanticipated adverse events occurred.

Results are comparable to topical brand name ophthalmic solutions, Travatan® (Alcon Laboratories, Inc.), Lumigan® (Allergan, Inc.), and Xalatan® (Pfizer, Inc.).¹ However, current topical administrations are plagued with issues of non-compliance, which can lead to costly and invasive surgeries, vision impairment, and even blindness.  It has been reported that up to 60% of patients do not administer ophthalmic drops as directed, even though patients’ perception is that they are compliant with 97% of their dosing.2  Sustained release travoprost may help to circumvent these issues of patient non-compliance by eliminating the need for daily dosing.

“Not only did the plug deliver therapeutic amounts of drug over two months, reduction in intraocular pressure remained consistent and significant throughout the entire treatment period” stated Pierre Wassermann, Principal Investigator at the Umhlanga Hospital Medical Centre in South Africa.  “This product has the potential to revolutionize management of the disease by putting drug dosing in the hands of the physician rather than the patient.”

Glaucoma is a chronic disease that must be monitored and treated for life, impacting more than 2 million Americans, and is the leading cause of blindness in the United States.  “Achieving clinically meaningful IOP reduction over a two-month period with single-dose administration is a tremendous achievement” stated Amar Sawhney, President and CEO of Ocular Therapeutix, Inc.  “We are optimistic about recent advances in extending delivery, visualization, and persistence of our formulations to longer durations.”

About Ocular Therapeutix’s Drug Products:

Ocular Therapeutix uses the company’s proprietary polyethylene glycol hydrogel intracanalicular plug technology to release proven and approved drugs in a sustained fashion over a specified period of time.  At the end of the treatment period, the plug begins to absorb, and exits the nasolacrimal system without need for removal by the physician. The plugs contain a visualization agent for retention monitoring throughout the treatment period.

 About Ocular Therapeutix, Inc.:

Founded in November 2006, Ocular Therapeutix, Inc. is a privately held company based in Bedford, MA, focused on the development and commercialization of ophthalmic therapeutic products using its proprietary hydrogel technology. Ocular Therapeutix is using its hydrogel technology for development of a variety of ophthalmic applications including hydrogel sealants for ocular surface protection, drug-eluting punctum plugs for treatment of various anterior segment diseases, and with therapeutic agents for back-of-the-eye diseases.

¹Package Inserts: Xalatan® 0.005% latanoprost ophthalmic solution, Pfizer, Woodstock, IL, USA. 2011; Lumigan® 0.01% and 0.03% bimatoprost ophthalmic solution, Allergan, Irvine, CA, USA. 2012; Travatan Z® 0.004% travoprost ophthalmic solution, Alcon, Fort Worth, Texas, USA. 2010.

²Goldberg I. Compliance with Medical Management in Glaucoma. Asian J of Ophthalmol 2000;2(4):3-6.

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