Mono and Combination Therapies for Exudative AMD
BY PETER K. KAISER, MD
In the last few years, the development of therapies to combat choroidal neovascularization (CNV) has come to the forefront. Retinal specialists are studying these therapies hoping to widen the small treatment armamentarium that is available today, and also increase the efficacy of both FDA-approved therapies and those in late phases of clinical trials.
Mono and combination therapies are offering promising results and researchers are moving forward with new clinical trials. Here is a look at some results of studies and a glimpse at the criteria and goals of the upcoming Verteporfin (Visudyne, QLT/Novartis) intravitreal Triamcinolone Acetonide (Kenalog, Bristol Meyers Squibb) Study (VeriTAS) trial.
There is mounting evidence to suggest that angiogenic factors, such as vascular endothelial growth factor (VEGF), play a role in the pathogenesis of age-related macular degeneration (AMD). The effect of VEGF on the retinal vasculature is multifaceted in that it stimulates vascular endothelial cell proliferation, induces vascular permeability, and enhances angiogenesis. Additionally, VEGF is a survival factor, and is pro-inflammatory. Agents that block VEGF activity, including ranibizumab (Lucentis, Genentech/Novartis), an anti-VEGF antibody fragment, and pegaptanib sodium (Macugen, Eyetech/Pfizer), a VEGF aptamer, have been shown to benefit patients with neovascular AMD.
Pegaptanib's clinical efficacy and safety have been demonstrated in the VEGF Inhibition Study In Ocular Neovascularization (VISION) trial. This trial involved 2 multicenter, double-masked, randomized, controlled clinical studies, and investigated patients with all CNV lesion subtypes up to 12 disc areas in size. At the 12-month time point in the VISION study, 70% of the 0.3 mg pegaptanib-treated patients vs. 55% of the placebo-treated patients lost fewer than 15 letters of best-corrected visual acuity from baseline (P<.001).1 Ocular severe adverse events, including endophthalmitis, iatrogenic traumatic cataract, and retinal detachment were rare.
The phase 3 studies for ranibizumab are ongoing, but a press release of the Minimally classic/occult trial of the Anti-VEGF antibody RhuFab V2 In the treatment of Neovascular AMD (MARINA) study indicated that at the 12-month time point, approximately 95% of ranibizumab-treated patients vs. 62% of the placebo-treated patients lost fewer than 15 letters of best-corrected visual acuity from baseline (P<.0001).2 While the phase 3 studies for ranibizumab are ongoing, in a completed multidose phase 2 study (FVF2128g), 40 of 41 patients (98%) had either stable or improved visual acuity (VA) at day 210; 18 (45%) had a greater than or equal to 15-letter increase, while 22 (54%) remained stable.
These are exciting results indeed and the use of anti-VEGF therapy adds another treatment modality to the small but growing list of AMD-related management strategies. Along with anti-VEGF treatments, other promising therapies, especially combining available treatments, are being studied.
Occlusion of CNV is presumed to be the major mechanism of the beneficial effect of verteporfin therapy. Occlusion can occur through free radical damage to the endothelial cells, causing subsequent platelet adhesion, degranulation, and thrombus formation.
A reduction in blood flow from the new vessels may lead to a confinement in the growth of the fibrovascular portion of the CNV, with subsequent reduced risk of further vision loss compared with no treatment. Thus, verteporfin therapy reduces the area of the macula affected by CNV and spares viable photoreceptors from destruction caused by fibrovascular disorganization of the outer retina. In general, multiple treatments are required due to regrowth or recannulization of the CNV after therapy.
The source of lesion regrowth seems to be stimulated by the relative ischemia of the retinal pigment epithelium (RPE) and photoreceptors within the photodynamic therapy (PDT)-affected choriocapillaris. This leads to an increase in VEGF secretion as well as inflammation hours to days after PDT. In fact, histologic evaluation of PDT treated retinas found an increased expression of VEGF in the choriocapillaris 7 days after PDT. Thus, it seems plausible that the suppression of VEGF in combination with PDT may prevent the angiogenic cascade reaction, and improve results.
Proof of concept for this hypothesis comes from preclinical work with ranibizumab in combination with verteporfin PDT, where a greater reduction in angiographic leakage than PDT or intravitreal vehicle injection alone was seen in experimental CNV. In addition, phase 1 and 2 studies with pegaptanib sodium and ranibizumab in combination with PDT appear promising. The 12-month results of the phase 1 and 2 randomized RhuFab V2 Ocular Treatment Combining the Use of Visudyne Evaluate Safety (FOCUS) trial reported that more than 90% of patients maintained or improved vision (defined as a loss of less than 15 letters in VA) when treated with the combination of ranibizumab and verteporfin, compared to approximately 68% of those treated in the verteporfin-only control arm (P=.0003).3 Given that only predominantly classic lesions were included in this study, this is a very good outcome. These observations further suggest the combination of PDT with verteporfin and an anti-VEGF treatment may be a promising strategy with potential to further increase the efficacy results of photodynamic or anti-VEGF monotherapy.
Because we now have more than one way of attacking CNV, we also have the opportunity to test combinations of treatments, similar to the successful approaches used for various cancers. The VeriTAS will evaluate different combinations of available treatments to attempt to improve outcomes in exudative AMD. Specifically, the study will examine patients with subfoveal CNV secondary to AMD and use verteporfin plus 2 different dose regimens of intravitreal triamcinolone acetonide (1 mg and 4 mg) and compare it to verteporfin plus intravitreal pegaptanib. PDT causes inflammation, so by using verteporfin plus corticosteroids, the latter agents possess anti-VEGF effects that decrease permeability and inflammation.
The VeriTAS Study will enroll patients with any lesion composition up to 9 disc areas in size with visual acuity between 20/40 and 20/320. For occult with no classic CNV, the lesion must have presumed recent disease progression defined as having at least 1 of the following criteria: blood associated with the lesion at baseline, loss of vision in the previous 3 months, or a greater than or equal to 10% increase in the greatest linear dimension (GLD) as assessed by fluorescein angiography (FA) in the previous 3 months. Patients will be randomized in a 1:1:1 scheme to either PDT with either 1 mg or 4 mg intravitreal triamcinolone (where triamcinolone is administered with PDT at 3-month intervals based on leakage from the CNV on FA); or PDT (administered at 3-month intervals based on leakage from the CNV on FA) and intravitreal pegaptanib given every 6 weeks for 10.5 months (regardless of fluorescein leakage). The patients will be actively treated for 12 months with the primary outcome being the proportion of patients who lose less than 15 letters in VA score at 12 months. The second year of the study will be a safety follow-up where patients can be treated with any standard of care treatment at the investigator's opinion if they experience a loss of 2 or more lines of vision.
With many new treatments for exudative AMD on the horizon, differentiating between the various treatments by simply comparing study results will be problematic. Trials such as the VeriTAS will become important to help retinal physicians determine the best treatment for their patients. While case series are compelling, only through these randomized trials can we really determine which tools to use from our armamentarium against exudative AMD.
Peter K. Kaiser, MD, is director of the Clinical Research Center and Digital OCT Reading Center of the Cole Eye Institute at the Cleveland Clinic Foundation. Dr. Kaiser currently is study chairman of the VeriTAS trial, and principal investigator in multiple national, multicenter clinical trials. He can be e-mailed at firstname.lastname@example.org.
1. Gragoudas ES, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
2. Phase III Study Shows Lucentis Improved Vision In Patients With Wet Age-Related Macular Degeneration [press release]. Montreal: Genentech, Inc.; July 18, 2005.
3. Heier J. Intravitreal ranibizumab with verteporfin photodynamic therapy for neovascular age-related macular degeneration: year one results. Presented at the Meeting of the American Society of Retina Specialists; Montreal, Canada, July 18, 2005.