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Review
Therapeutic Topics
ARVO 2012 Gives
Florida Our Best
Highlights from the final Fort Lauderdale meeting of the
Association for Research in Vision and Ophthalmology.
Mark B. Abelson, MD, CM, FRCS, FARVO and Ora staff, Andover, Mass.
T
his year’s ARVO meeting in Fort
Lauderdale marked the end of an
era, as a fixture on the Florida convention calendar begins its nomadic cycle
of west coast to east, beginning with
next year’s meeting in Seattle. As we
bid adieu to the Sunshine State, we
look forward to new adventures across
the country. Before we go though,
here’s a look at some of the best research from this year’s meeting.
Retina Update
Last year saw the release of interim findings from the Comparison
of Age-related macular degeneration
Treatments Trials, the head-to-head
comparison of Avastin and Lucentis for treatment of wet AMD. This
year’s meeting opened with a twin
bill that included both results from
the completed CATT and an interim
analysis of results from the alternative
treatments to Inhibit VEGF in Agerelated choroidal Neovascularization
study.1,2 The latter was a head-to-head
comparison of the two VEGF monoclonal antibody therapies that employed a four-treatment-arm protocol
similar to the one used in the CATT
44 | Review of Ophthalmology | July 2012
study. Monthly injections of each drug
were compared to each other, and to
“as needed” treatments arms. The
p.r.n. criteria in both studies were the
same: Any evidence of fluid, either intraretinal, subretinal or below the retinal pigment epithelium (assessed by
optical coherence tomography) was
an indication for treatment. As with
the interim results from the CATT
study, improvement in best-corrected
vision was the primary endpoint for
the IVAN trial.
Results of the IVAN study mirrored
those from the CATT: Acuity changes
were comparable for Avastin and Lucentis, and while monthly injections
were numerically superior to p.r.n.
therapy, the difference wasn’t significant. The IVAN study group also conducted a meta analysis by including
one-year data from CATT, again with
similar results.
In the second year of the CATT
study, a group of subjects receiving
monthly treatments were randomized to the p.r.n. regimen, allowing
investigators to assess potential effects
of switching patients from one injection schedule to another; this protocol
design demonstrated that the small
benefit accompanying monthly injections is lost when patients transition
to p.r.n. dosing. Analysis of secondary
endpoints reinforced the notion that
there are differences between the two
drugs: While the monthly Lucentis
group showed the highest percentage of patients without retinal fluid as
measured by OCT, this same group
also exhibited the highest rates of geographic atrophy.
Ocular Imaging
As in years past, imaging technologies and their applications were ubiquitous at this year’s ARVO meeting,
with applications that cover the eye
from front to back all on display.
Significant progress has continued
in the development of technologies
and protocols for ocular surface imaging, and these advances were wellrepresented at this year’s meeting.
A major focus was in vivo confocal
microscopy, with several poster sessions focusing particularly on corneal
imaging methods. One study correlated the density of Langerhans’
cells, an indicator of inflammation,
with a course of cyclosporine A in
This article has no commercial sponsorship.
patients with severe keratoconjunctivitis sicca. HRT imaging of the
central cornea showed a significant
decrease in Langerhans’ cell density
following treatment, and this was correlated with tear-film breakup time
increases (but not with tear osmolarity or Schirmer’s tests). (Jacobi C, et
al. IOVS 2012;53:ARVO E-Abstract
2355) Another group described their
use of confocal imaging to assess agerelated changes in normal meibomian glands. They noted two major
changes in the glands over time: a
decrease in gland density and a decrease in homogeneity of acinar structures and secretions. (Canton V, et al.
IOVS 2012;53:ARVO E-Abstract 86)
Studies such as these should be useful in distinguishing the natural aging
process from pathological conditions
associated with meibomian gland dysfunction.
Improvement in imaging technologies has also made its way to the
posterior segment, with the use of
adaptive optics in combination with
other technologies. These technologies are helping us correlate structural
changes with visual function, a key
step in advancing our understanding
of degenerative retinal diseases. New
surrogate endpoints for visual acuity
based on enhanced imaging should
aid in future clinical development
programs. For example, adaptive optics scanning laser ophthalmoscopy
provides high-resolution images for
clear visualization of individual photoreceptor cells, and the high number of retinal imaging abstracts at the
2012 ARVO meeting evidenced the
burgeoning interest in this technology. Imaging the retina in real time,
AOSLO utilizes adaptive optics to remove optical aberrations from images.
In one proof-of-concept study designed to examine whether structural
parameters derived from using AOSLO on AMD patients are related
to the participants’ AMD disease severity, AOSLO was able to produce
In vivo confocal microscopy of the ocular surface is becoming increasingly popular for
following the course of diseases and monitoring treatment. For example, in this image the
normal conjunctival vasculature appears on the left. At right, confocal microscopy shows
infiltrating white cells in the vasculature following allergen exposure.
high-resolution images. In patients
with early to intermediate AMD, the
cone photoreceptors showed reduced
reflectivity and moderately increased
cell spacing, while in patients with
an advanced stage of the disease the
cone mosaic was severely disrupted,
and cone density and reflectivity were
significantly decreased compared to
that of normal subjects. (Zhang Y, et
al. IOVS 2012;53:ARVO E-Abstract
3174) This study opens the door for
future research seeking to examine
the relationship between the statistical structural parameters of the photoreceptors.
AOSLO was also used to characterize hallmark diabetic retinopathy
lesions and then compare the findings
with those from fundus photography
and spectral domain optical coherence tomography. Microaneurysms
were not clearly distinguished from
small dot hemorrhages on ETDRS
photos and SD-OCT, but some were
identified using AOSLO by observing
red blood count flow within feeding
vessels, as well as by observing red
blood count flow within the microaneurysms themselves. AOSLO technology allows for highly detailed in
vivo imaging of diabetic retinopathy
lesions at the cellular level and is useful for discovering new morphological characteristics of various hallmark
pathologies. (Prager G, et al. IOVS
2012;53:ARVO E-Abstract 5654)
Dry Eye
Last year, we noted the growing
interest in osmolarity as a test for dryeye disease, and the continued interest in this measure was reflected in
many poster and slide presentations
at ARVO 2012. Some of these studies were efforts to identify correlations between osmolarity measures
and established dry-eye metrics such
as corneal staining, Schirmer’s testing, tear-film breakup and information from patient questionnaires such
as the Ocular Surface Disease Index
or the five-item Dry Eye Questionnaire (DEQ-5). (Bhosai SJ, et al.
IOVS 2012;53:ARVO E-Abstract 547;
Yang Y, et al. IOVS 2012;53:ARVO
E-Abstract 548; See CW, et al. IOVS
2012;53:ARVO E-Abstract 549; Messmer EM, et al. IOVS 2012; 53:ARVO
E-Abstract 556; Willmann G, et al.
IOVS 2012;53:ARVO E-Abstract
557; Torricelli AA, et al. IOVS
2012;53:ARVO E-Abstract 558) The
goal of these efforts was to identify
a test or combination of tests that
can reliably predict or otherwise be
used to diagnose dry eye. From this
year’s presentations, it doesn’t seem as
though current methods of osmolarity
July 2012 | Revophth.com | 45
Review
Therapeutic
Topics
The results of the 2011 Antibiotic Resistance Monitoring in Ocular Microorganisms study
found fluoroquinolones to be very effective against S. pneumoniae isolates.
measurement can meet that goal at
present. Several presentations reported statistically significant correlations
between these measures, while others
suggest that associations are insignificant, sporadic or both. The take-home
message is a familiar one: As one presenter stated in his conclusion “the
clinical presentation of dry-eye disease is multifactorial, thus correlation
between different tests should not be
expected.” (Sullivan BD, et al. IOVS
2012;53:ARVO E-Abstract 550)
Another study of dry-eye metrics
examined diurnal variation in tear
osmolarity, and showed that tears
are significantly more dilute in the
morning (mean 265 mOsms/L) when
compared to tears from the same
patients measured later in the day
(mean 299 mOsms/L). (Niimi J, et
al. IOVS 2012;53:ARVO E-Abstract
560) Such variations may contribute
to the inability to correlate osmolarity with other dry-eye metrics. Several other presentations examined the
potential impact of hyper-osmolarity
on ocular surface health: One group
reported an effect of hyper-osmolarity
on cytokine production (Jeong S, et
al. IOVS 2012;53:ARVO E-Abstract
563), while others concluded that although increasingly solute concentra46 | Review of Ophthalmology | July 2012
tions may alter frictional forces during blink, they don’t seem to have an
“adverse effect on physical properties
or stability of the tear film,” (Samsom M, et al. IOVS 2012;53:ARVO
E-Abstract 551; Mudgil P, et al. IOVS
2012;53:ARVO E-Abstract 555), this
suggests that hyper-osmolarity itself
isn’t contributing to changes in tearfilm stability of dry-eye patients.
Meanwhile, the search for additional dry-eye therapies continues.
Positive data surrounding MIM-D3
as a potential dry-eye therapy was
presented by Mimetogen Pharmaceuticals’ Karen Meerovitch, PhD,
and her colleagues. MIM-D3 is a proteolytically stable cyclic peptidomimetic identified as a selective TrkA
receptor agonist. TrkA receptor agonists are a novel pharmacological class
for ocular disease, as nerve growth
factor signaling plays a critical role in
regulating the proliferation, survival
and differentiation of neurons and
many other non-neuronal cell types,
and is mediated via both the TrkA
receptor and the p75NTR receptor.
NGF has multiple activities that may
be beneficial for dry eye, including
neurotrophic effects, corneal healing and mucin secretion. MIM-D3
has demonstrated similar activities
to NGF and is under investigation as
a pharmacologic agent to stimulate
mucin secretion for the treatment of
dry eye. In a multicenter, randomized, double-masked, placebo-controlled study utilizing the Controlled
Adverse Environment model to assess the safety and efficacy of 1% and
5% MIM-D3 compared to placebo
for the treatment of signs and symptoms of dry eye, both doses appeared
safe and well tolerated. The study
achieved significant improvements
in key approvable sign and symptom
endpoints, as MIM-D3 minimized
the exacerbation of staining postCAE exposure compared to placebo,
and significant improvements were
observed for ocular dryness during
the 28-day dosing period. A more
symptomatic subgroup of patients
showed even greater improvements
in symptoms compared to placebo
for both the 1% and 5% dose. Of the
150 subjects in the safety population,
56 reported a total of 87 treatment
emergent adverse events, 26 of which
were ocular TEAs; the majority of the
ocular TEAs were mild to moderate
in severity. (Meerovitch K, et al. IOVS
2012;53:ARVO E-Abstract 578)
Another potential treatment for
dry eye includes the use of Thymosin Beta 4. Recent preclinical evaluations have demonstrated that Tb4
promotes improved corneal epithelial intercellular adhesions following
injury in animal models of dry eye.
(Allan CB, et al. IOVS 2011;52:ARVO
E-Abstract 3782) Given that the results from these studies show that Tb4
reduced corneal staining more than
positive controls and demonstrated
a statistically significant decrease
in staining compared to the vehicle
group, it was anticipated that RegeneRx Biopharmaceuticals’ RGN259 (0.1% Tb4 ophthalmic solution)
would be a novel, safe and effective
therapeutic treatment for dry eye. In
a Phase II study comprising six study
visits and using the CAE to assess the
safety and efficacy of RGN-259 compared to placebo,
subjects receiving the drug saw statistically significant
improvements in both the signs and symptoms. (The
study was conducted by employees of RegeneRx and
other researchers.) There was a statistically significant
reduction in central corneal fluorescein staining at visit
five from baseline compared to placebo and also a greater
reduction in exacerbation of ocular discomfort at visit
four during a 75-minute CAE challenge compared to the
placebo group. (Sosne G, et al. IOVS 2012;53:ARVO EAbstract 577)
Staff and consultants of Novagali Pharma used a post
hoc analysis to evaluate the efficacy of Novagali’s drug Cyclokat (0.1% cyclosporine cationic emulsion) in Sjögren’s
syndrome and non-Sjögren’s syndrome patients with
moderate to severe dry eye. Sjögren’s syndrome is an
autoimmune disorder characterized by lacrimal gland
destruction that leads to prominent clinical features of
dry eye and dry mouth. The researchers administered
the drug q.d. and compared it with its cationic emulsion
vehicle. Of the 379 analyzed patients, the improvement in
dry-eye symptoms in the Cyclokat group compared to vehicle was greater in both the Sjögren’s and non-Sjögren’s
groups and was similar across all levels of dry-eye severity
at baseline as defined by corneal fluorescein staining. That
being said, non-Sjögren’s patients treated with Cyclokat
showed greater improvement in dry-eye symptoms than
those with Sjögren’s, supporting the clinical notion that
dry eye in Sjögren’s patients is more difficult to treat.
(Buggage R, et al. IOVS 2012;53:ARVO E-Abstract 576)
Contact Lenses and Drug Delivery
A topic that’s generating a lot of buzz in ophthalmic
circles is that of drug delivery via contact lens wear. With
continued growth in technologies of polymer chemistry
and manufacture, the contact lens is poised for use in a
host of new therapeutic ways. Studies employing lenses
for therapeutic use in allergy and dry eye are ongoing, but
cutting-edge polymers and other innovations have paved
the way for their use in treatment areas such as glaucoma
and anti-infectives. Combinations of drug delivery and
lenses were a common thread among the presentations
at this year’s meeting, including innovative studies such as
the investigation of hydrogel lenses molecularly imprinted
with hyaluronic acid and timolol maleate. (Guidi G, et al.
IOVS 2012; 53:ARVO E-Abstract 458) Another example
of novel lens use was a pre-clinical study using lenses as a
vehicle for drug delivery of latanoprost for the treatment
of glaucoma. Using this approach, researchers were able
to show that the lens was more effective at delivery of
drug to the anterior chamber over a 14-day period than
Review
Therapeutic
Topics
the control drug, topical latanoprost.
(Ciolino J, et al. IOVS 2012;53:ARVO
E-Abstract 479) Other innovations
in contact lens technology included
a poster that described a new hydrogel lens material that was capable of
providing a continuous, sustained
release of antibiotics. A comparison performed by a researcher and
employees of SEED Co., the lens’s
maker, showed that lens drug delivery
was superior to that of gatifloxacin
0.3% or moxifloxacin 0.5% delivered
by drops. (Kobayakawa S, et al. IOVS
2012;53:ARVO E-Abstract 6102)
with an update from the Antibiotic
Resistance Monitoring in Ocular Microorganisms 2011 surveillance study.
The ARMOR study results displayed
resistance trends among ocular bacterial pathogens such as S. pneumoniae
at 32 sites using antibiotic susceptibility testing. The 2011 results showed
that while almost 46 percent of S.
pneumoniae isolates were resistant to
azithromycin, all isolates were susceptible to fluoroquinolones. Among the
fluoroquinolones, the researchers say
besifloxacin had the lowest MIC90.
(Haas W. IOVS 2012;53: ARVO E-
Anti-Infectives
Another aspect of contact lens use
presented this year was a focus on
the mechanisms underlying the linkage between poor compliance and
the contamination of lenses and lensrelated materials. Classic examples
of this association are the recent outbreaks of ocular infections attributed
to dangerous pathogens such as Acanthamoeba or Fusarium. One study
from AMO determined the comparative rates of Acanthamoeba trophozoite growth on contact lens storage
cases by seeding gram-negative bacteria from contact lens cases and Escherichia coli on non-nutrient agar plates
and inoculating with cysts of A. castellanii or A. polyphaga. Results showed
that contact lens case bacterial contaminants may support the growth of
Acanthamoeba and can provide a food
source for the organism in the development of amoebic keratitis. (Lam
A. IOVS 2012;53:ARVO E-Abstract
6172)
Other highlights from the antiinfective segment included many
posters that discussed the increasing
popularity of fluoroquinolone therapy
due to concerns of antibiotic resistance. A poster presentation by employees of and consultants to Bausch
+ Lomb examined the antibiotic resistance profile of ocular pathogens,
48 | Review of Ophthalmology | July 2012
One study found that
contact lens case
bacterial contaminants
may support the growh
of Acanthamoeba and
can provide a food
source for the organism
in the development of
amoebic keratitis.
Abstract 6195)
In a survey designed to assess ocular
pathogen prevalence and emerging
antibiotic therapy, one study examined
the in vitro activity of a novel isothiazoquinolone (ITQ), ACH-0139586,
against common ocular pathogens (S.
aureus, S. epidermidis, S. pneumoniae, H. influenza, M. catarrhalis and
P. aeruginosa) compared with moxifloxacin and gatifloxacin. ITQs are a
new class in the quinolone family that
has been found to have good in vitro
and in vivo activity against pathogens
such as S. aureus, including MRSA
isolates.3 Fluoroquinolones typically
inhibit both DNA gyrase and topoisomerase IV, which are required for
the DNA replication process, whereas
ITQs add a third mechanism of action
as potent DNA primase inhibitors.3-8
Inhibition of DNA primase increases
efficacy and decreases the chances for
developing resistance compared with
fluoroquinolones. The study demonstrated that ACH-0139586 was more
potent relative to gatifloxacin and
moxifloxacin, regardless of methicillin
and fluoroquinolone resistance, and
that this was most apparent against
evaluated gram-positive pathogens.
(Shapiro A. IOVS 2012;53 ARVO EAbstract 6259)
Though we had to bid a fond farewell to our sunny center of research in
Ft. Lauderdale, we’re looking forward
to greeting friends and colleagues at
ARVO’s new venues, and we can’t
wait to see what study results they’ll
have in store next year. We’ll see you
in Seattle!
Dr. Abelson is a clinical professor
of ophthalmology at Harvard Medical
School and senior clinical scientist at
the Schepens Eye Research Institute.
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