ANTI-VEGF DRUG OUTLOOK

Lucentis: A Small Molecule's Big Impact

Learn how the anti-VEGF treatment breakthrough is changing AMD patient care.

By Rishi P. Singh, M.D.

► Based on its unprecedented effectiveness in Phase 3 clinical trials,^1,2 ranibizumab (Lucentis, Genentech) quickly took its place as the new gold standard of care for neovascular age-related macular degeneration (AMD). What doctors and patients can expect from this anti-vascular endothelial growth factor (VEGF) treatment is significantly different from anything in the past. In clinical trials, monthly injections stabilized vision in more than 90% of patients and improved acuity by at least three lines in nearly 40% of patients.³

Ranibizumab has changed not only treatment expectations, but also nearly every aspect of AMD patient care. Let's take a look at some of the key changes that have occurred and what you can expect in the future.

Shift to Pharmacotherapy

Currently, dosing ranibizumab monthly is the only proven way to achieve the visual acuity results observed in Phase 3 clinical trials. However, for several reasons, vitreoretinal specialists are employing other dosing regimens in clinical practice. First, as with any pharmacotherapy for any medical condition, the effects of ranibizumab aren't the same in every patient with neovascular AMD. While ranibizumab was superior to sham treatment across all subgroups in the trials,⁴ poorer visual acuity outcomes were associated with worse baseline acuity, larger lesion size and increased age. Also, the benefits of treatment were not evident in some patients until later in the 2-year course of therapy.

Furthermore, it's not known whether every patient requires monthly injections to control the disease process and improve visual acuity. Decreasing the number of injections administered whenever possible while still obtaining favorable results is a desirable goal because intravitreal injections aren't without risks, and their long-term effects on the eye aren't known. Finally, monthly injections place a substantial time and cost burden on patients, their families and vitreoretinal practices.

The first alternative dosing regimen to be tested, in the PIER trial,⁵ was three consecutive monthly injections followed by quarterly injections. This approach arrested the growth of choroidal neovascularization (CNV), reduced leakage from CNV, and provided more of a benefit than no treatment at all. However, the PIER regimen isn't ideal because the treatment effect declined during quarterly dosing. On average, by the end of 1 year, patients returned to their baseline visual acuity.

Another approach, tested in the PrONTO study,⁶ involved three consecutive monthly injections followed by individualized dosing guided by optical coherence tomography (OCT) findings. After 2 years, patients experienced visual acuity outcomes similar to the Phase 3 clinical studies and required fewer injections, a mean of 5.6 over 12 months. However, PrONTO was a single-center, open-label study, involving a small number of patients (n=40). A randomized controlled clinical trial is needed to confirm the results.

Given these favorable findings, many vitreoretinal specialists have adopted a PrONTO-type treatment strategy. However, others employ what's known as a "treat and extend" approach. Patients may be treated initially with three consecutive monthly injections or treated monthly until leakage and subretinal fluid has resolved. At the 4-week follow-up after the last injection, if subretinal fluid remains, patients receive another injection and return in 4 weeks. If subretinal fluid has resolved, they receive another injection, but the time until the next follow-up is extended to 5 or 6 weeks or longer.

Another anti-VEGF agent, off-label bevacizumab (Avastin, Genentech), also is used widely today in the treatment of neovascular AMD. Bevacizumab is FDA-approved for the treatment of certain forms of cancer. Based on numerous published case series and a global Internet survey of results,⁷ it appears to be as safe and efficacious as ranibizumab in AMD. Theoretically, its treatment effects may be more durable. However, its ocular use hasn't been evaluated in a randomized controlled clinical trial.

The randomized, controlled, multicenter CATT trial, which is sponsored by the National Eye Institute and currently enrolling patients, is expected to provide valuable information about the use of ranibizumab and bevacizumab. Designed to directly compare the relative safety and effectiveness of the two agents, CATT includes four treatment arms:

• Ranibizumab dosed monthly for 1 year, and then re-randomization to either monthly dosing for a second year or variable dosing based on response to treatment
• Bevacizumab dosed monthly for 1 year, and then re-randomization to either monthly dosing for a second year or variable dosing based on response to treatment
• Ranibizumab on a variable dosing schedule based on signs of lesion activity for 2 years
• Bevacizumab on a variable dosing schedule based on signs of lesion activity for 2 years.

The primary outcome measure is change in visual acuity, but important secondary outcome measures include number of treatments, anatomical changes, adverse events and cost.

New imaging technologies, such as spectral domain OCT and scanning laser ophthalmoscopy (SLO) angiography, also may yield new information about how best to use anti-VEGF therapy and how individuals can be expected to respond.

Discussing Anti-VEGF Therapy with Patients

In this new anti-VEGF era, it's crucial that patients have a realistic understanding of what they can expect from treatment. Some may think AMD inevitably leads to blindness, and others may expect to be cured. Therefore, it's imperative that ophthalmologists revisit how they discuss AMD and its treatment with patients.

Doctors must convey several key points about anti-VEGF therapy. First, while outcomes are better than in the past, the realistic outcome for the majority of patients is stabilization of vision or a slower decline in vision than that experienced in the natural course of the disease. Second, monthly injections are the surest way to potentially gain three or more lines of vision, which may be less likely to occur with less frequent dosing.

Doctors must explain that because AMD is a chronic disease, it requires long-term therapy and monitoring. From the outset, patients must understand that frequent injections for an indefinite period of time may be required. In addition, seeing the doctor as recommended, even if the disease is in remission, is the only way to preserve the most vision possible. In some cases, doctors and their patients must decide together whether committing to a lifetime of treatment for what may be a modest vision gain is worthwhile.

In the future, anti-VEGF agents also may be routinely used in the treatment of retinal vascular diseases, such as vein occlusion and diabetic macular edema. This, of course, would necessitate similar changes in how to educate these groups of patients.

Transformation of the Vitreoretinal Practice

Anti-VEGF therapy has changed how vitreoretinal practices operate in fundamental ways. With frequent dosing, the number of patient visits each practice must handle has increased exponentially. Each visit may be twice as long as in the past because OCT and/or angiographic imaging and injections must be performed. Furthermore, for monthly injections, doctors must be in the same office within a 30-day window all of the time.

More of a physical infrastructure, such as extra rooms for injections, is required. Many practices also must hire additional staff members, in particular technicians and billing personnel. The higher cost of ranibizumab compared with previous AMD treatments and the volume of insurance transactions that need to be processed and tracked also present challenges. It's difficult, for example, for some practices to underwrite the cost of treatment when third-party reimbursement can take 90 to 120 days.

The introduction of the HCPCS J Code J2778 for injection of ranibizumab has alleviated reimbursement delays and payment denials to a certain extent, and practices continue to find ways to handle patient care and billing efficiently. Many report success with such strategies as scheduling injections in blocks, obtaining OCT scans before each patient sees the doctor, stepping up efforts to collect copays at the time of the visit, and being more proactive in obtaining insurance preauthorization to administer ranibizumab for returning AMD patients.

Outlook for The Future

Anti-VEGF therapy will play a dominant role in AMD care in the foreseeable future. A primary focus will continue to be achieving visual outcomes equivalent or superior to those achieved in the Phase 3 clinical trials of ranibizumab, while decreasing the number of treatments required. This may come in the form of alternative modes of administration, such as sustained drug delivery implants. Or, it may be accomplished by taking advantage of potential synergies between anti-VEGF agents and other types of treatments.

Building on a large set of case series, several ongoing clinical trials will be instrumental in confirming which treatment combinations may be effective. For example, results from the DENALI trial comparing ranibizumab monotherapy with full fluence and reduced fluence photodynamic therapy (PDT) are expected soon. Other potentially effective combinations, such as ranibizumab plus focal radiation and ranibizumab plus PDT and a steroid, are also progressing through clinical trials.

Many other monotherapies, such as VEGF Trap, which target VEGF in various ways, have reached pivotal trials. Finally, hundreds of compounds are currently being evaluated preclinically and clinically for their ability to affect other pathways involved in the neovascular AMD disease process. By addressing inflammation, oxidative stress, hypoxia or genetics, one or more of these compounds may become the next breakthrough in AMD care. To be successful, however, any therapy first will need to match the efficacy of ranibizumab. nMD