OCULAR DRUG
`DELIVERY SYSTEMS
`
`A rundown of methods for releasing drugs into the eye.
`
`BY RANDALL V. WONG, MD
`
`Prior to the adoption of intravitreal injec-
`tions for the treatment of retinal diseases,
`options were limited. Wet age-related
`macular degeneration (AMD), diabetic
`macular edema (DME), and retinal vein
`occlusions (RVOs) were all treated with laser
`photocoagulation as first-line therapy.
`The Macular Photocoagulation Study
`advocated laser treatment for wet AMD, which results in a
`dense scotoma in the area of the active neovascular tissue.
`The thinking at the time, however, was that it was better to
`cause a finite scotoma than to leave the disease untreated.
`Laser was a difficult treatment to recommend. I had to
`advise patients that wiping out a good portion of their
`central vision was better than not treating their disease and
`allowing it to advance. Most of these patients remember
`only that I caused their vision loss with a laser. Despite the
`treatments, these patients’ vision did not improve.
`Intravitreal injection has supplanted the use of laser
`because it is safe and works better. Before 1999, fewer than
`3000 intravitreal injections were delivered in the United
`States annually.1 By 2008, more than 1 million injections
`were delivered annually, and this number is expected to
`approach 6 million in the next 1 to 2 years.1
`The first generation of intravitreal pharmacologic therapy,
`using direct intravitreal bolus injection, has demonstrated
`that this platform is both highly effective and safe. Now
`the dawning of a new era in intravitreal drug therapy has
`begun: that of controlled delivery of pharmaceuticals, which
`includes sustained-release platforms and implantable eluting
`devices. Still to come are therapies based on nanotechnology
`and other platforms that promise to further improve drug
`delivery to the posterior segment. This article reviews some
`of the methods of delivery currently available that have
`changed the way retina specialists practice.
`
`PHOTODYNAMIC THERAPY
`One of the first alternative methods of drug delivery to the
`retina to become available was photodynamic therapy (PDT).
`Verteporfin for injection (Visudyne, Bausch + Lomb), approved
`by the US Food and Drug Administration (FDA) in 2000, is a
`light-activated drug used in PDT. It is indicated for the treatment
`
`of predominantly classic subfoveal choroidal neovasculariza-
`tion. Once approved, it was quickly recognized as a more viable
`option than traditional laser photocoagulation for treatment of
`wet AMD. Although patients often improve after treatment, the
`preparation and application of the procedure is extremely labor
`intensive, and patients have to avoid sunlight for 3 days after
`treatment. For these reasons, and because of its narrow indica-
`tions and the subsequent advent of intravitreal anti-VEGF injec-
`tions, PDT plays a limited role in AMD therapy today.
`
`INTRAVITREAL INJECTIONS
`Intravitreal injection of a drug better enables the treat-
`ment to reach the retina and reduces systemic toxicities.
`This mode of delivery has also given older drugs, such as ste-
`roids, the potential to treat diseases in new ways.
`For many retina specialists, intravitreal delivery of
`anti-VEGF drugs has become first-line treatment for wet
`AMD, RVO, and DME. Today’s clinicians have multiple
`anti-VEGF options available for intravitreal injection to
`treat a variety of posterior segment diseases. The most
`frequently used of these are ranibizumab (Lucentis,
`Genentech), bevacizumab (Avastin, Genentech), and
`aflibercept (Eylea, Regneron). With experience now in
`millions of injections, treatment with these intravitreal
`anti-VEGF agents has been shown to be safe and effective.
`
`AT A GLANCE
`
`•
`
`Intravitreal injection revolutionized posterior
`segment treatments by delivering drug directly to
`the site of disease.
`
`• Because intravitreal implants release low doses of drug
`directly into the vitreous cavity over an extended period
`of time, they reduce systemic complications.
`
`• Future options in controlled delivery of ocular
`pharmaceuticals will continue to improve patient
`outcomes and reduce treatment burden.
`
`48 RETINA TODAY | JANUARY/FEBRUARY 2016
`
`MEDICAL RETINA FEATURE STORY
`
`Novartis Exhibit 2010.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Pegaptanib
`Pegaptanib sodium injection (Macugen, Bausch + Lomb)
`was the first intravitreal anti-VEGF agent introduced for
`the treatment of wet AMD. It was also essentially the first
`intravitreally injected drug to gain momentum, and it
`demonstrated that this delivery method was more than
`just a theoretic possibility. Approved by the FDA for the
`treatment of AMD in 2004, pegaptanib offered an efficient
`and efficacious way to treat patients with wet AMD. In an
`office setting, patients received an injection directly into the
`vitreous cavity through the pars plana. It was an easy, cost-
`effective, and efficient way to improve patient care, and for
`the first time a therapy was available that could maintain
`visual acuity levels in some patients. Due to manufacturing
`issues, pegaptanib is no longer available in the United States.
`
`Ranibizumab
`The FDA approved ranibizumab for the treatment of wet
`AMD in 2006, RVOs in 2010, DME in 2012, and diabetic
`retinopathy in the presence of DME in 2015.
`
`Bevacizumab
`In 2004, the FDA approved bevacizumab for the treat-
`ment of colorectal cancer. It is currently used off label in the
`treatment of neovascular eye diseases.
`
`Aflibercept
`The most recent anti-VEGF agent available commercially,
`aflibercept was approved by the FDA for the treatment of
`wet AMD in 2011, DME in 2014, and diabetic retinopathy
`in the presence of DME in 2015.
`
`SUSTAINED-RELEASE DRUGS
`Parallel with the acceptance of intravitreal bolus injection
`as a safe and effective way of delivering drugs into the eye,
`several intravitreal implants have also found success. These
`devices are surgically implanted or injected directly into the
`vitreous, thereby allowing drugs to cross the blood-brain
`barrier and delivering direct, targeted treatment to the reti-
`na. Clinical results with these devices have been positive.
`Sustained-release therapy has significant clinical and eco-
`nomic implications. It enables continuous treatment with
`excellent outcomes, fewer office visits, reduced treatment
`burden, socioeconomic savings, improved access to health
`care, and improvement in compliance.
`
`Ganciclovir Implant
`The first intravitreal implant, the ganciclovir implant
`(Vitrasert, Bausch + Lomb), was approved by the FDA for the
`treatment of cytomegalovirus (CMV) retinitis in AIDS patients
`in 1996. It consisted of a 4.5-mg pellet of ganciclovir coated in
`a laminated system of biocompatible polymers. This mode of
`delivery reduced morbidity from systemic use of ganciclovir
`
`and immunosuppressive drugs (eg, steroids) while alleviating the
`patient’s eye disease. The implant has recently been discontinued.
`
`Dexamethasone Intravitreal Implant
`The dexamethasone intravitreal implant 0.7 mg (Ozurdex,
`Allergan) is indicated for the treatment of macular edema
`secondary to RVO, noninfectious posterior uveitis, and DME.
`Each implant releases dexamethasone for roughly 4 months.
`
`Fluocinolone Acetonide Implants
`In 2005, the FDA approved the fluocinolone acetonide
`implant 0.59 mg (Retisert, Bausch + Lomb) for the treatment of
`chronic noninfectious posterior uveitis. According to the com-
`pany, it delivers corticosteroid therapy for roughly 2.5 years.
`The fluocinolone acetonide implant 0.19 mg (Iluvien, Alimera
`Sciences) was approved in 2014 for the treatment of DME in
`patients who are not steroid responders (ie, those who did
`not experience a significant elevation of intraocular pressure in
`response to a previous course of steroid treatment). It releases
`fluocinolone acetonide for up to 36 months.
`These implants are among the first intravitreal devices to
`carry and release a drug over an extended period of time.
`Because they directly target the vitreous cavity and retina, sys-
`temic complications may be avoided. In the case of posterior
`uveitis, patients can avoid systemic immunosuppression and
`the morbidity of related infections. In the case of CMV retinitis,
`not only were more frequent intraocular injections avoided, but
`hematologic and systemic side effects were minimized as well.
`Intravitreal implants have shown that crossing the
`blood-brain barrier with a drug is possible, while at the
`same time reducing systemic toxicity and enabling treat-
`ments to better reach the retina.
`
`CONCLUSION
`The availability of intravitreal modes of drug therapy has
`allowed us to improve treatments for many posterior seg-
`ment diseases. Their adoption into our treatment protocols
`has allowed us to realize the advantages of crossing the
`blood-brain barrier. In the past 10 years alone, we have made
`huge strides in the ways we treat retinal diseases.
`The new era of controlled delivery of ocular pharmaceuti-
`cals will expand on these improved patient outcomes, further
`reducing treatment burdens and creating the potential for
`huge cost savings. What is to come promises to involve true
`nanotechnology, as proteins, particles, and even DNA may be
`continuously delivered to the posterior segment. n
`1. Campbell RJ, Bronskill SE, Bell CM, et al. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a
`population-based analysis. Arch Ophthalmol. 2010;128(3):359-362.
`
`Randall V. Wong, MD
`n retina specialist at Dressler Ophthalmology Associates PLC in Fairfax, Va.
`n financial interest: none acknowledged
`n randall.v.wong@gmail.com
`
`JANUARY/FEBRUARY 2016 | RETINA TODAY 49
`
`M E D I C A L R E T I N A F E A T U R E S T O R Y
`
`Novartis Exhibit 2010.002
`Regeneron v. Novartis, IPR2020-01317
`
`