Sustained-Release Drugs: Heralds of the Future
BY JERRY HELZNER, SENIOR EDITOR
On a spring night in 1974, Rolling Stone music critic Jon Landau sat in a theatre in Cambridge, Mass., listening to an opening-act band that had attracted a local following among college students. Later that night, he wrote: “I have seen the future of rock and roll and its name is Bruce Springsteen.”
In the late-winter chill of early 2010, retina specialists and drug researchers are saying to anyone who will listen: “I have seen the future of medical ophthalmology and its name is sustained-release drug delivery.”
The real promise of sustained-release ophthalmic drug delivery lies in the form of more durable, patient-friendly and cost-effective therapies leading to less crowded practice waiting rooms. Especially in the area of retinal disease, sustained-release drugs could largely replace the frequent intravitreal injections that are now the norm for many patients.
“What we are looking for are safe, effective and easy-to-use drugs,” says retina specialist Michael Singer, MD, of San Antonio. “Ophthalmologists and patients don't want every-month injections.”
Future applications for sustained-release delivery will not be limited to the back of the eye. For the anterior segment, sustained-release systems are currently being studied for treatment of glaucoma and dry eye, and for administering antibiotics following ocular surgery. And in the future, sustained-release systems could potentially come in the form of implants, inserts, gels, microspheres, polymers, sealants or even incorporated into an existing visual system such as a contact lens or IOL.
Pioneers Led the Way
The history of sustained-release drug delivery in ophthalmology dates back only to the 1990s. Credit goes to pioneers Bausch & Lomb and its partner Control Delivery Systems (now pSivida), the company that designed the drug-releasing implant first used in the product known as Vitrasert. Vitrasert was approved in 1996 to treat cytomegalovirus retinitis, a condition associated with late-stage AIDS that often leads to blindness. Vitrasert releases ganciclovir (Cytovene) directly to the diseased area of the eye over a period of six to eight months and has been a successful treatment for thousands of patients over the past 14 years.
From that small start, more recent ideas for sustained-release delivery systems for both the back and front of the eye have mushroomed into numerous and varied efforts, ranging from the conceptual to the investigational to FDA-approved products now being used routinely in everyday practice. However, with so many companies entering the sustained-release arena, expect that there will some hits and some misses. This is an area of innovation where the risks of picking the wrong disease or being outflanked by a newer, more effective therapy are very real.
This article will touch on a wide range of sustained-delivery initiatives and explain why ophthalmologists and patients alike are hoping that sustained-release represents the wave of the future in drug delivery.
The Approved: Retisert and Ozurdex
• Retisert. Following up quickly on its Vitrasert success, Bausch & Lomb again teamed with Control Delivery Systems to begin clinical trials for Retisert, a sustained-release implant for chronic noninfectious posterior uveitis, a sight-robbing condition that affects an estimated 175,000 people in the United States. This type of uveitis is extremely damaging because it tends to strike people in their prime working years and its repeated bouts of inflammation — unless controlled — can lead to tissue destruction and vision loss.
Despite being about the size of a grain of rice, the Retisert implant is capable of delivering the potent anti-inflammatory corticosteroid fluocinolone acetonide over a period of approximately 30 months with minimal or no systemic exposure. Retisert was approved by the FDA in 2005. Implantation is done in the OR, using a procedure that most retinal specialists can master with little difficulty, though wound healing issues can occasionally arise. B&L offers both written and video instructional material on Retisert implantation, with opportunities to practice the procedure in a wet-lab environment.
Quan Dong Nguyen, MD, of the Wilmer Eye Institute at Johns Hopkins, specializes in uveitis and has broad experience treating a disease that he characterizes as “very complex.”
Dr. Nguyen says that the first task of the retina specialist in treating uveitis is making the correct diagnosis. Uveitis can present anteriorly in the iris, intermediately in the ciliary body or in the posterior, where it tends to be more severe and chronic.
The Retisert implant is about the size of a grain of rice.
“Anterior uveitis would not normally require a Retisert implant as it is typically managed medically,” he notes. “Use of a Retisert becomes more of a consideration when there is intermediate/posterior involvement. But before you even think about using Retisert, you must determine that the uveitis is noninfectious and that it is not associated with a systemic condition with multi-organ involvement such as sarcoid. Using Retisert in those cases would only cause big problems.”
Dr. Nguyen will usually start the treatment of uveitis patients with a course of oral steroids, primarily prednisone. “By using prednisone, I can confirm if the uveitis is non-infectious,” he asserts. “It is a lot easier to stop the prednisone than to remove a Retisert implant if a case turns out to be infectious.”
For those uveitis cases that are deemed appropriate for Retisert, Dr. Nguyen finds that the implant is an excellent therapy that provides good long-term control of the disease while limiting cumulative damage. He also uses Retisert off-label for the treatment of diabetic macular edema.
The benefits from Retisert can be quite significant. In quantifying these benefits, two pivotal clinical studies demonstrated that implantation of Retisert reduced disease recurrence after 34 weeks from the 40% to 54% range to the 2% to 13% range. In addition, the clinical studies showed that 19% to 21% of Retisert recipients had improved visual acuity of more than three lines after 34 weeks and 15% to 17% of these individuals maintained that improvement after one year. Retisert also reduced the percentage of patients requiring systemic corticosteroid therapy after 34 weeks from the 47% to 63% range to the 5% to 10% range.
The tradeoff for these important benefits comes in the form of a high incidence of side effects, primarily cataract and increased intraocular pressure. These side effects are tolerable because they are actually less serious than the effects of the disease itself and the side effects caused by alternative therapies.
In the pivotal trials, the therapy provided by Retisert resulted in nearly all phakic study eyes developing cataracts (which were extracted) and about 77% of patients displaying high IOP, which was generally managed by topical medications and/or filtering procedures. A much smaller percentage of patients developed glaucoma. These complications were anticipated given the nature of the disease and the type of drug used.
“Because the Retisert implant is placed in the pars plana, which is close to the lens, you are going to have these types of side effects, says Henry Hudson, MD, of Tucson, Ariz. Dr. Hudson, who has extensive experience using Retisert, contrasts the manageable side effects of Retisert with the more serious potential side effects of other interventions.
“Corticosteroid treatments, administered either systemically or via periocular injections of Kenalog every two to four months, have proven effective in managing the disease, but because of their toxicity they often lead to a myriad of side effects that are both debilitating and detrimental to patients' quality of life,” says Dr. Hudson.
The most common side effects of these corticosteroid treatments are diabetes, hypertension, osteoporosis, weight gain and changes in appetite. In addition, repeated periocular injections can result in perforation of the globe, orbital fibrosis and ptosis. (Haupert CL, Jaffe GJ. New and emerging treatments for patients with uveitis. Int Ophthalmol Clin 2000;40:205-220.)
Dr. Hudson notes that it is difficult to quantify the current use of Retisert by retina specialists because the disease is relatively uncommon and each case must be handled on an individual basis.
“In a typical case, I will begin treatment with oral steroids such as prednisone with or without Cellcept,” he notes, “but I will tend to go to Retisert rather than using [the systemic immunosuppressive] cyclosporine. Retisert is a great tool when a maximum medical regimen fails.”
Dr. Hudson says that some physicians, patients and insurance companies are still taken aback by Retisert's $18,000 price tag. There has been resistance by some insurance carriers to reimbursing the full cost but education regarding the even higher cumulative cost of alternative treatments has helped in obtaining reimbursement. Dr. Hudson's perception is that many retina specialists are using the Retisert implant “sooner than they used to.”
Bausch & Lomb says demand for Retisert “is consistent and proportional with the disease for which it is indicated.” B&L says there are no near-term plans to make any changes in the implant or the implantation procedure.
• Ozurdex. This biodegradable implant, comprised of dexamethasone at a dose of 0.7 mg, has been approved for the treatment of macular edema associated with retinal vein occlusion, with approval for additional indications anticipated.
The implant is placed in the vitreous cavity through an office-based injection. It can deliver medicine for up to six months with a relatively mild side effect profile. Maximum effectiveness, as measured in pivotal clinical trials, occurs between 60 and 90 days.
According to Julia A. Haller, MD, ophthalmologist-in-chief at Wills Eye Hospital and an Ozurdex investigator, in the pivotal clinical trials the mean change in visual acuity peaked at 60 days and tapered thereafter out to 180 days in all Ozurdex dosage groups, at which time a cumulative 41% of treated patients had gained three or more lines of vision, compared with 23% of patients receiving sham treatment.
Ozurdex, which was initially called Posurdex, has a history dating back almost a decade. Allergan partnered in 2001 with the original developer of the implant, Oculex, and then purchased Oculex in 2003.
Ozurdex was approved for the macular edema indication in June of last year. Late in 2009, Allergan filed a supplemental new drug application with the FDA for the approval of Ozurdex to treat non-infectious intermediate and posterior uveitis. In addition, Ozurdex is currently in a phase 3 trial for the treatment of diabetic macular edema.
Scott Whitcup, MD, executive vice president for R&D at Allergan, points out several features that should appeal to both ophthalmologists and patients.
“First, Ozurdex is bio-erodable, meaning that when the medicine is used up, all you have is water and carbon dioxide, so there is nothing left in the eye. Second, the procedure can be done in the office, which is a huge plus for both ophthalmologists and patients. Third, the side effect profile using dexamethasone is relatively well tolerated. We do see some increases in pressure, usually peaking around day 60, but the IOP does return to baseline by month six.”
In the pivotal clinical trials, about 7% of the patients receiving the 0.7 mg implant developed cataract.
By having the Ozurdex implant technology in-house rather than farming out the drug-delivery system to a third party (pSvivida and SurModics are leaders in this area), Allergan believes it now has a “platform” for future applications of its sustained-release technology.
“We now have a trial under way using our implant technology to deliver brimonidine tartrate for the treatment of geographic atrophy associated with dry AMD,” notes Dr. Whitcup. “We foresee many more indications that would be applicable to our sustained-release technology in the future.”
Despite its many appealing features, Ozurdex has its detractors. The criticism has come in two areas: the relatively short duration of drug delivery and the stellar results recently demonstrated by Lucentis in treating both branch and central retinal vein occlusion in both the BRAVO and CRUISE trials.
Ozurdex's biodegradable matrix three weeks after implantation.
Dr. Singer is a strong believer in Ozurdex. He likes the fact that it can be administered in the office. He praises its mild side effects. He says that Ozurdex is particularly effective in vitrectomized eyes, where traditional intravitreal injections clear too quickly to be of much use. However, Dr. Singer prefers to use Ozurdex in combination with anti-VEGF therapy in treating macular edema.
“There are both benefits and challenges in using Ozurdex for macular edema,” says Dr. Singer. “It starts strong and then peters out after about three months. However, when I use it in combination with Avastin, I find that I am maximizing the effectiveness of both drugs.”
Dr. Singer believes that, once approved, Ozurdex will be a valuable option for the uveitis indication.
“The clinical data for uveitis is stellar,” he says. “The Retisert implant is good for 30 months but if Ozurdex delivers medicine for six months, I could see using it three or four times in a patient.”
• Iluvien. Of the implants currently classified as investigational, Iluvien (see graphic at the beginning) is one of the furthest along in the clinical trial process. Developed by Alimera Sciences with a sustained-release Medidur implant designed by pSivida, Iluvien is a treatment for diabetic macular edema that can deliver fluocinolone acetonide for 24 to 36 months. Based on positive 24-month efficacy and safety data from a pivotal phase 3 trial, Alimera has indicated that it will file an NDA with the FDA for Iluvien sometime in the second quarter of 2010.
Iluvien is inserted into the patient's eye in an office-based procedure using a proprietary inserter with a 25-gauge needle, which allows for a self-sealing wound. The method of administration is similar to an intravitreal injection.
For patients treated with the lower 23 μg dose of Iluvien, 26.8% to 30.6% demonstrated improvement in best corrected visual acuity of 15 letters from baseline, and for patients receiving the higher 45 μg dose of Iluvien, 26.0% to 31.2% demonstrated improvement of 15 or more letters in BCVA from baseline, both at two years.
Safety was assessed for all patients treated in the study. IOP increases of 30 mmHg or greater at any time point, a key adverse event studied in the trial, were seen in 16.3% of the low dose patients and 21.6% of the high dose patients. Over the 24-month period, 2.1% of patients receiving the low dose and 5.1% of the patients receiving the high dose had undergone a trabeculectomy to reduce their eye pressure.
Alimera says that, with either dose, Iluvien will be releasing the smallest daily amount of drug among products currently undergoing clinical trials for treating DME.
• Lucentis. In the area of wet AMD, Genentech recently signed an agreement with SurModics for that company to develop a microsphere implant that will deliver Lucentis for approximately four to six months. According to Genentech, development of the implant is progressing rapidly and a clinical trial could be initiated late this year.
• Latanoprost-covered punctal plugs. An interesting study is under way by QLT, Inc. to develop latanoprost-treated punctal plugs for sustained-release treatment of open-angle glaucoma or ocular hypertension.
At the 2009 of the American Glaucoma Society, Richard Lewis, MD, presented new data on the phase 2 CORE study to deliver glaucoma medication via latanoprost-coated punctal plugs. Dr. Lewis reported that early results were positive but not as robust as hoped. He said patients demonstrated an average IOP reduction of 20%. The target range was a 30% to 35% reduction. He also noted that researchers used three different concentrations and did not witness a dose response. Researchers concluded that the concentrations used may have been too low. There are now ongoing efforts that seek to improve upon the design of the initial study.
One issue that arose during the phase 2 study was a problem with some plugs not remaining in the eye for the full 12-week trial. That issues is being addressed.
Studies for the I-vation implant for DME have been suspended.
• Encapsulated cell technology. Neurotech's lead investigational implant, NT-501, is an ECT-ciliary neurotrophic factor (CNTF) product that consists of encapsulated cells that secrete recombinant human CNTF. Following implantation, CNTF is released from the cells into the vitreous gel in a sustained manner for approximately 12 months. NT-501 is designed to be sterile, nonpyrogenic and retrievable. The current device is about 6 mm in length, including a titanium loop, and is placed well outside the visual axis in the human eye. CNTF therapy is designed to reduce or stop the progressive loss of photoreceptors. Photoreceptor loss is characteristic of retinitis pigmentosa, AMD and related retinopathies.
A phase 2 human trial of CNTF sponsored by Neurotech focused on the treatment of geographic atrophy. Last year, the company announced that its CNTF implant stabilized vision in more than 96% of 51 patients at 12 months.
• I-vation, a helical-shaped metallic implant for the treatment of diabetic macular edema, developed by Merck and implant partner SurModics, is an example of the risks attendant to the development of sustained-release therapies. The I-vation implant was designed to deliver triamcinolone acetonide over a period of up to two years. However, when study data released in 2008 favored focal/grid photocoagulation over preservative-free intra vitreal triamcinolone acetonide as a treatment for DME, Merck suspended the phase 2b I-vation trial.
• Cyclosporine A Implant. Lux Biosciences completed enrollment last year in the 493-patient phase 3 LUCIDA clinical trial program for Lumitect (LX201), a silicone matrix ocular (episcleral) implant designed to provide the continuous release for one year of therapeutic levels of cyclosporine A locally to the eye to prevent corneal transplant rejection.
Conceptual Implant Ideas
One of the more interesting potential applications for sustained-release drug delivery is the possibility of placing ophthalmic drugs in contact lenses.
Cambridge Eyenovations is a Boston-area team of researchers that won the MIT Life Sciences competition with a concept for contact lenses that can deliver drugs to the eye for up to 100 days. If commercialized, the technology would help glaucoma patients who now must rely on frequent administration of eye drops, creating compliance issues. The team says the drug-eluting lenses could also be used for treating eye conditions such as dry eye and for delivering antibiotics following ocular surgery.
Along similar lines, there have been early discussions of delivering sustained-release medications through IOLs or glaucoma shunts.
Additionally, efforts are also underway at places such as Emory University to study the possibility of placing retina drugs in areas of the eye where side effects could be minimized, such as transscleral delivery via gels, polymers, sealants and/or inserts. One of the primary obstacles that has to be overcome in this type of delivery would be assuring that the medicine could reach the back of the eye in sufficient quantity to be therapeutic. This is an issue that will require further research.
The Future of Sustained-Release
Experts say that the potential of sustained-release ophthalmic implants is considerable. The number of recent investigational efforts in this area bears out the enthusiasm relating to this type of drug delivery.
However, companies that invest in sustained-release concepts should be aware of several risk factors.
As the suspension of the I-vation trial indicates, if you pick a disease where a simpler, safer and more effective treatment is available, your sustained-release drug will likely be the loser.
If the price of a sustained-release implant causes raised eyebrows at insurance companies, reimbursement could be an issue. This has at times been the case with Retisert, though ophthalmologists have largely succeeded in making the case to insurers for reimbursement.
As Dr. Nguyen points out, Retisert can be a very cost-effective therapy in the appropriate cases, as it stays in the eye for 30 months, eliminating the need for such drugs as monthly cyclosporine, which can cost approximately $12,000 a year, combined with additional associated tests every three or four months.
If an implant requires a complicated procedure to be placed in the eye, ophthalmologists with already crowded schedules may look to simpler therapies. In regard to implantation procedures, a simple office-based implantation that is similar to an intravitreal injection, such as Ozurdex or Iluvien, offers advantages to implantations that must be performed in the OR.
Members of the ophthalmology community would be well advised to follow developments in the sustained-release area, as new approvals are on the horizon and innovative initiatives will continue to sprout. OM