Extended release anti-VEGF systems: a strategy whose time has come? Or already gone?

KEYWORDS:

• Age-related macular degeneration
• anti-VEGF
• degeneration
• vision loss
• diabetic macular edema
• anti-VEGF drugs

The widespread use of drugs that inhibit the actions of vascular endothelial growth factor (VEGF) has helped millions of patients throughout the world by significantly decreasing vision loss due to neovascular age-related macular degeneration (nAMD) [1–3], diabetic macular edema (DME) [4–6], and edema due to retinal vein occlusion (RVO) [7,8]. Monthly injections of anti-VEGF drugs as given in the phase III registration trials not only prevent significant vision loss (≥15 Early Treatment Diabetic Retinopathy Study letters) in 95% of eyes, but they produce 1-year mean improvements in best corrected visual acuity (BCVA) of +7 to +12 letters in eyes with nAMD and DME, and +16 to +18 letters in eyes with RVO.

Trials that extend beyond 1 year show that maintaining the initial gains can be difficult, and these success rates often vary according to the underlying disease and the frequency of injections. Eyes with DME generally experience stable visual acuity (VA) through 3–5 years despite transitioning from monthly injections that initially ranged from 4 months to 3 years, to as-needed (PRN) regimens [4,5]. The phase III registration trials for the treatment of RVOs all transitioned to PRN injections at only 6 months, after which eyes lost several letters of VA. The HORIZON (Extended Follow-up of Patients With Macular Edema Due to bRanch rETinal Vein Occlusion [BRVO] or centrAl Retinal veIn occlusioN [CRVO] Previously Treated With Intravitreal Ranibizumab) extension trial found that vision continued to deteriorate when examination intervals were extended to bimonthly [9].

The long-term prognosis for eyes with nAMD is less clear as studies with follow-ups through 7 years report highly variable VA results [10–12]. These results are confounded by several study variables: different follow-up and treatment intervals; high drop-out rates for a variety of reasons; and the development of retinal pigment epithelial atrophy. There appears to be a trend toward better long-term BCVA with more anti-VEGF injections but more data are needed before firm conclusions can be drawn.

1. The need for more durable therapy

Long periods of monthly injections may produce the best VA results for eyes with BRVO and nAMD but many ophthalmologists believe that complying with such regimens is beyond the ability of most patients [13]. Early in the anti-VEGF era, physicians recognized that monthly injections may not be necessary for all patients with nAMD, so extended interval (PIER [A Phase IIIb, Multicenter, Randomized, Double Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects With Subfoveal Choroidal Neovascularization (CNV) With or Without Classic CNV Secondary to Age Related Macular Degeneration], EXCITE [A Randomized, Double-masked, Active-controlled, Multi-center Study Comparing the Efficacy and Safety of Ranibizumab Administered as Two Dosing Regimens in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration], VIEW [A Randomized, Double Masked, Active Controlled Phase III Study of the Efficacy, Safety, and Tolerability of Repeated Doses of Intravitreal VEGF Trap in Subjects With Neovascular Age-Related Macular Degeneration]) and PRN (PrONTO [Prospective Optical Coherence Tomography (OCT) Imaging of Patients With Neovascular Age-Related Macular Degeneration (AMD) Treated With Intra-Ocular Lucentis™ (Ranibizumab): PrONTO Study], EXTEND-1 [Open-label Multicenter, Phase I/II Study Assessing the Safety and Efficacy of Ranibizumab (RFB002) in Japanese Patients With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular Degeneration (AMD)]) regimens were studied. Only patients in the VIEW trials could be successfully treated at intervals beyond 1 month, probably because of aflibercept’s [slightly] extended duration of action [3]. All ranibizumab trials failed to stabilize patients with regularly scheduled, extended-interval dosing so this strategy was abandoned.

PRN injections with monthly exams in PrONTO produced BCVA results comparable to those from the phase III registration trials while using fewer injections [14]. Unfortunately, PrONTO did not include a monthly injection control arm and patients still required monthly visits to the physicians’ office. PrONTO showed that drug costs could be reduced, but physicians’ offices were still inundated with a large number of patients, and indirect costs of therapy were unaffected. American Society of Retinal Specialists Preferences and Trends surveys indicate that most physicians have adopted a treat-and-extend (T&E) strategy to minimize both the numbers of injections and clinic visits. Neither registration trials nor their extensions include T&E options but physicians will undoubtedly use newer injections in this manner.

Some healthcare systems have difficulty performing the large number of required intravitreal treatments so physicians have organized injection clinics run by specially trained nurses. Complication rates from these clinics appear favorable and though the use of non-physician extenders remains controversial among many physicians, future use of this model will probably increase.

To decrease direct and indirect costs incurred by anti-VEGF therapy, improve patient compliance, and decrease injection-related complications, patients and physicians need a more durable therapy that does not require frequent office visits.

2. Extended release strategies in development

Extended release corticosteroid inserts that elute drug for 3 months or 3 years have been approved by the US FDA for the treatment of DME, but the development of antibody containing devices has trailed for a couple of reasons. First, developing a polymer that is compatible with proteins has proven more difficult. Second, the large molecular weight of the proteins, 48–149 kDa (120–360 times that of corticosteroids), makes it difficult to create a reservoir that contains sufficient drug to meaningfully extend its duration of clinical action.

For these reasons, drug and device developers have been forced to use other strategies to create longer duration anti-VEGF therapies. ForSight4 and Genentech have developed a refillable ranibizumab reservoir that bridges the sclera after being surgically implanted beneath the conjunctiva. Patients receive a 0.5-mg ranibizumab bolus at the time of implantation with an additional 0.25 mg in the reservoir; refills are performed as needed. A phase I trial with 20 eyes reported 1-year BCVA improvements that were comparable to those achieved in monthly treatment trials [15]. Patients required a mean of 4.8 refills, which was fewer than those receiving PRN ranibizumab in year 1 of CATT (6.6) [16] but more than during year 2 of the VIEW trials (4.7) [3]. Given the relatively high frequency of refills, which will be more difficult and time consuming to perform than intravitreal injections, this device does not appear to provide a significant advantage over standard intravitreal injections.

Encapsulated cell technology consists of a semi-permeable, implanted cylinder that is populated with immortalized retinal pigment epithelium cells programmed to over-produce a single molecule. A cylinder that produced ciliary neurotrophic factor was tested in patients with retinitis pigmentosa and atrophic AMD [17], and demonstrated an impressive half-life, as measured by the rate of CNT production, of 54 months. A two-site, phase I nAMD study evaluated a cylinder that produced an aflibercept-like molecule with a high binding affinity for VEGF. A third-generation reservoir that produces more of the anti-VEGF molecule is now entering phase II nAMD trials. This technology is compelling, but questions persist over patient selection and its future role when combination therapy is introduced.

An adenovirus vector (AAV) that inserts a VEGF-blocking gene into the retinal pigment epithelium is being studied in patients with nAMD [18]. Results from a recently reported phase II trial were disappointing as the AAV arm performed poorly compared to the arm receiving anti-VEGF injections. Questions regarding both the efficacy and safety of this technology persist.

3. The changing treatment of chorioretinal vascular conditions

Given our current understanding of angiogenesis, anti-VEGF therapy will likely remain an important part of most patients’ treatment regimens. But since we have hit a therapeutic ceiling of +10 letters in nAMD trials, the need for additional therapies becomes obvious. Considerable variability in treatment responses exist among patients with the same chorioretinal diagnoses, suggesting that drugs that target different biochemical pathways may be of value as alternative therapies or in combination with anti-VEGF drugs. Experts have long predicted that we would treat nAMD with combination therapy, similar to how oncologists treat neoplasms. Early combination therapy regimens paired verteporfin photodynamic therapy with corticosteroids and anti-VEGF drugs, but improvements in efficacy were not realized.

Several drugs that block different molecular targets are being developed and platelet derived growth factor (PDGF) inhibition appears to be the most promising strategy. In a phase II trial, monthly intravitreal fovista (Ophthotech, New York, NY) combined with ranibizumab produced VA gains at 6 months that were superior to those achieved with ranibizumab monotherapy (+10.6 letters vs. +6.2 letters). Multicenter, phase III trials with fovista are currently underway [19]. Other PDGF blocking strategies that include a co-formulation with aflibercept and a dual binding VEGF/PDGF DARPin molecule are being developed.

4. Future state

Patients who require long-term, frequent anti-VEGF injections stand to benefit most from extended-duration strategies. Successful extended release technologies might decrease the number of visits and interventions to only 1–2 per year in these patients. Drugs such as RTH258 and abicipar, which are currently being injected every 3 months in phase III nAMD trials, could potentially extend T&E intervals to 4 months or more. Extended duration of action, particularly if it helps improve patient compliance, could halt the decline in visual acuity that is seen in many long-term nAMD studies.

Several factors, however, may limit the widespread adoption of the extended release technologies. For the minority of patients with nAMD who do not require long-term anti-VEGF therapy and the majority of patients with DME who require an average of only 3–4 yearly injections after year 1, extended release of an anti-VEGF drug would constitute over-treatment and would incur an unnecessary expense. Combination therapy with both PDGF and VEGF blockade may be available for selected patients with nAMD as soon as 2018, and may require an ongoing series of anti-PDGF injections in addition to anti-VEGF therapy, or regular injections of either a co-formulation or dual binding drug. We do not yet know what an anti-PDGF regimen will resemble after the initial 6 months, but if monthly injections and/or visits are required for a longer period, then having an extended duration anti-VEGF device will do little to ease treatment burden on patients and physicians. The encapsulated cell chamber can be configured to provide dual therapy, such as anti-VEGF and anti-PDGF, but the development of such a device would be more than a decade away.

Because of its efficacy and low cost, bevacizumab has been favored by many physicians in both industrialized and developing countries. Conbercept has been approved for the treatment of nAMD in China [20] and off-label intraocular injections of ziv-aflibercept [21] are being increasingly used as low-cost alternatives to ranibizumab and aflibercept. Cost is an increasingly important element in health care, and as more low-cost drugs are being successfully tested, the use of expensive, extended release devices may be limited for economic reasons.

Ongoing pharmaceutical development will provide patients and physicians with an expanding menu of treatment options, which will require that regimens be tailored to each patient. Extended release strategies will be an attractive option but I believe that they will constitute a niche market, appropriate for a relatively small proportion of carefully selected patients.

Declaration of interests

M.W. Stewart is on the advisory board for Allergan and Regeneron, is a consultant for Boehringer-Ingelheim and Momenta Pharmaceuticals and has received institutional research support from Allergan and Regeneron. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.