Mono and Combination Therapies for Exudative
BY PETER K.
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
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
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
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
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 email@example.com.
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.
Retinal Physician, Issue: September 2005