Glaucoma is a condition that frequently requires complicated long-term therapy to achieve IOP-lowering goals. According to the Glaucoma Research Foundation, 3 million Americans have glaucoma and 120,000 are blind from the disease.1 Akin to other chronic conditions such as hypertension and diabetes, patients with glaucoma struggle to adhere to their treatment regimens. In a recently published study,2 as many as 27% of patients self-reported poor compliance, citing difficulty with drop instillation and forgetfulness as the two most common reasons for missed medications. A large percentage of these patients may benefit from a sustained medication delivery system. Multiple designs are currently undergoing investigation and offer great promise in mitigating the limitations of traditional topical therapeutic agents.
Ocular Therapeutix is developing OTX-TP, a sustained-release polyethylene glycol hydrogel punctal plug, which degrades over 3 months, releasing preservative-free travoprost. The design of the plug allows for optimal physiologic placement, and patients are even able to visualize the device using an externally held modified blue light.
Recent results from the phase 2b trials demonstrate not only impressive IOP lowering in both the travoprost and timolol arms but also an improved retention rate of 88% at day 75 and 48% at day 90, when the hydrogel is expected to be largely resorbed.3 Notably, no ocular hyperemia has been reported to date, although the full safety and efficacy data will be released upon study completion.
The major advantages of a punctal plug system over other options include ease of insertion, low risk of serious complications, and simple visualization of the device. As phase 3 trials ensue with design modifications not only to the implant but also to the medication itself, OTX-TP may offer many glaucoma patients a very promising solution.
Amorphex Therapuetics has developed the Topical Ophthalmic Drug Delivery Device, or TODDD, a polymer lens insert that can incorporate multiple classes of medications. Preliminary clinical data in human patients demonstrate good tolerability of the device and the ability to successfully deliver medications in a sustained fashion (data on file).
The results of the phase 1 and subsequent trials will be of particular interest, given the variety of ophthalmic indications the TODDD could potentially serve. A major advantage of the TODDD over other options is the fact that the device does not need to be placed by health care professionals, obviating the need for superfluous office visits. The relative ease of removal compared with other sustained-release platforms is an additional advantage in the case of an adverse reaction.
A variety of sustained-release injectables are currently in development and fall into a slightly more invasive category than the aforementioned technologies. Ohr Pharmaceuticals has developed a hydrogel template, known as its SKS sustained release technology, which potentially allows for sustained release of microparticles to ocular tissues. Preclinical results released in early December 2015 demonstrated positive results with suprathreshold delivery of medications via the SKS in an animal model (data on file). This versatile technology is particularly promising, as the dissolvable hydrogel template allows the sustained release of a whole spectrum of agents and biologics with a variety of biochemical properties.
Durasert by pSivida is currently in phase 1/2 clinical trials in collaboration with Pfizer. Durasert is a bioerodable insert designed to be injected into the subconjunctival space via a specialized 27-gauge system with the goal of delivering latanoprost for 6 to 12 months. This is a modification of the recently approved Iluvien system, which successfully delivers steroid to the posterior segment for up to 3 years. Of particular interest is the possibility of injecting sustained-release neuroprotective agents utilizing the same injector system, a prospect that has thus far remained elusive in glaucoma management.
ENV515 (travoprost XR) is a similar product by Envisia that is designed to inject a depot of medication via the Particle Replication in Nonwetting Templates, or PRINT, platform. In October 2015, the company reported the initial phase 2a results of sustained IOP reduction by -6.7 mm Hg (P<.001) over 25 days.4 The results are similar to once-daily travoprost dosing, and the main reported side effect is early hyperemia. Longer-term studies are ensuing to confirm preclinical results, which demonstrated an impressive 8-month IOP-lowering effect.
Bimatoprost SR by Allergan is an intracameral implant designed to last 4 to 6 months. In the phase 1/2 paired-eye controlled trial,5 a single dose of bimatoprost SR reduced IOP in 92% (n=69) of patients at 4 months and 71% (n=53) of patients at 6 months. The implant has entered phase 3 trials, and the results are highly anticipated. The theoretical advantages of placing the depot of medication closer to its therapeutic target not only has ramifications in terms of efficacy but furthermore may mitigate myriad adverse effects to the ocular surface that may be associated with other external platforms.
The Ophthalmic MicroPump System by Replenish is a programmable device designed to deliver nanoliters of drug directly into the anterior chamber or pars plana. The platform is surgically implanted similar to a glaucoma drainage device and can be refilled with a 31-gauge needle in the clinic. Current studies have demonstrated a good safety profile in canine models without excess inflammation or scarring at 12 months.6
Although the MicroPump is a more invasive procedure, there is additional potential for this device to aid in the chronic treatment of retinal pathology with sustained-release therapeutic agents, obviating the need for repeat intravitreal injections.
As trials continue, we look forward to having a spectrum of new options to offer patients to better manage both acute and chronic eye disease. Improved compliance and focused delivery of medications will likely not only solve many of the logistical hurdles of traditional topical therapy but also may functionally reduce disease progression.
1. Congdon N, O’Colmain B, Klaver CC, et al; for the Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477-485.
3. Ocular Therapeutix reports on topline results of phase 2b glaucoma clinical trial. October 22, 2015. https://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2100516. Accessed December 9, 2015.
4. Envisia Therapeutics’ lead product candidate, ENV515 (travoprostXR), achieves primary efficacy endpoint in phase 2a glaucoma clinical trial. October 6, 2015. https://www.envisiatherapeutics.com/wp-content/uploads/sites/3/2015/10/ENV515-Ph2a-Cohort-Release.pdf. Accessed December 9, 2015.
5. Positive phase I/II interim data of bimatoprost sustained-release implant for IOP therapy in glaucoma. November 16, 2015. Available at: https://www.allergan.com/news/news/thomson-reuters/positive-phase-i-ii-interim-data-of-bimatoprost-su. Accessed December 9, 2015.