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business of retina clinical trials for the retina specialist
Section Editor: Aron Shapiro
Ongoing Trials in AMD
By Aron Shapiro and Ashley Lafond A
lthough there has been much focus and subsequent success generating treatments targeted
at wet age-related macular degeneration
(AMD), minimizing the treatment burden and
enhancing treatment efficacy remain unmet needs in
therapy for this chronic disease.1-3 Additionally, there
are no treatments available for dry AMD.
Fortunately, there is no shortage of ongoing research
for the progressive disease; an initial clinicaltrials.gov
search yielded 360 hits of open AMD studies. In this
column, we will review the status of a few of these
potential therapeutic strategies.
Dry AMD
Reduction of toxic byproducts and extracellular
deposits in the retina has been a targeted treatment
strategy for patients with dry AMD. Amyloid deposits have been found to accumulate in the drusen of
AMD patients, which establishes amyloid beta (Aβ) as
a viable AMD target. RN6G (PF4382923, Pfizer) is an
intravenously administered, humanized monoclonal
antibody that binds with high affinity to the Aβ peptides Aβ40 and Aβ42. Such peptides have been implicated in neurodegenerative disorders, such as Alzheimer,
in which massive neuronal death to due apoptosis is
a common characteristic. It is hoped that treatment
with anti-Aβ antibodies may produce improvements in
retinal function deficits evident in AMD by preventing
the accumulation of Aβ40 and Aβ42. RN6G is currently
under development as a treatment for patients with
geographic atrophy (GA) secondary to dry AMD. Two
phase 1 studies, including a single ascending-dose study
and a multiple ascending-dose study, have been completed.4,5 A phase 2 multicenter, randomized, multidose
study is currently under way.6
Visual cycle modulation programs are also emerging as a treatment approach for dry AMD. Toxic waste
products such lipofuscin and A2E have been shown
to accumulate in the retinal pigment epithelium as
a byproduct of visual cyclying, so modulation of the
cycle seems a logical approach. A phase 2a program
for ACU-4429 (emixustat hydrochloride, Acucela) has
been completed, and a phase 2b/3 study began in
February of this year for the treatment of GA associ24 RETINA Today july/august 2013
The number of active clinical trials
for both wet and dry AMD is evidence of the need for additional
therapies for wet AMD and for a
first-ever FDA-approved treatment
for the dry form of the disease.
ated with dry AMD. This small, nonretinoid visual cycle
modulator specifically targets RPE65, the trans- to
cis-retinal isomerase. A phase 1 dose escalation trial
of ACU-4429 demonstrated linear pharmacokinetics across doses, and the drug was well-tolerated in
healthy subjects.7
Another company also targeting toxic byproducts
is Aldexa, previously know an Neuron Systems Inc.
Aldehydes are toxic mediators known to be elevated
in patients with dry AMD. Aldexa’s lead compound,
NS2, binds to malondialdehyde (MDA), 4-hydroxynonenal (HNE), and retinaldehyde, three common toxic
aldehydes. Therapies targeted at lowering the excessive
levels of these aldehydes in AMD patients represent an
innovative strategy for potential treatment.
Evidence indicating that tetracyclines are active
against many molecular pathways suspected to be
involved in the pathogenesis of dry AMD, and they
may also slow the progression of GA, has prompted
the investigation of doxycycline (Oracea, Galderma
Laboratories LP) for GA treatment. Doxycycline, a
matrix metalloproteinase (MMP) inhibitor, is a broadspectrum antibiotic that is clinically useful due to its
broad antimicrobial properties. Doxycycline is currently
approved for treating the inflammatory lesions of rosacea and appears to be well tolerated. The TOGA trial, a
multicenter phase 2/3 study to assess the efficacy and
safety of daily oral administration of doxycycline compared with placebo on the rate of change in area of GA,
is set to enroll patients in 2013.8
business of retina clinical trials for the retina specialist
New efforts in stem cell replacement therapy are also
creating noise for degenerative diseases of the retina.
Embryonic stems cells may provide a potential therapy
to replace damaged RPE cells and to sustain visual function for suffering patients. Advanced Cell Technology
(ACT) has initiated 2 separate phase 1/2 trials to test
the safety of the human embryonic stem cell (hESC)derived RPE cellular therapy for dry AMD and for
Stargardt macular dystrophy.9,10 Each patient will
receive a single uniocular subretinal infusion of MA09hRPE cells in 1 of 4 dose levels. A phase 1/2a study to
evaluate the safety and tolerability of MA09-hRPE cellular therapy in patients with advanced dry AMD is also
being conducted with CHA Biotech, a Korean-based
biotechnology company that entered into a licensing
agreement with ACT in 2009.11 ACT confirmed in a
press release that the vision of a patient enrolled in 1
of the clinical trials involving the company’s RPE cells
derived from hESCs has improved from 20/400 to 20/40
following treatment.12
iScience Interventional and Johnson & Johnson have
partnered for site-specific subretinal drug delivery. A
phase 1/2a multicenter, randomized study is evaluating
the safety and clinical response of a single, subretinal
administration of human umbilical tissue derived cells
(CNTO2476) using the iTrack Model 275 microcatheter in patients with visual impairment associated with
GA.13
MC-1101 (MacuCLEAR) is a topically administered
eye drop that works by increasing ocular blood flow in
the choroidal vessels, preventing the rupture of Bruch
membrane. A successful phase 1b/proof of concept
human clinical trial demonstrated that MC-1101 was
safe and well tolerated. A phase 2/3 vehicle-controlled,
double-masked, single-center study is currently being
conducted over the course of 2 years.14
The fluocinolone acetonide implant (Iluvien, Alimera
Sciences) is being investigated as a possible treatment
for patients with bilateral GA, and a second trial, the
MAP study, is evaluating the implant for wet AMD.15,16
Alimera is also considering nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase inhibitors to
treat dry AMD, particularly GA.
Wet AMD
The current standard of care for wet AMD works to
bind and inhibit preexisting VEGF that causes bleeding and fluid leakage into the eye. Allegro’s integrin
peptide therapy, ALG-1001, collectively turns off the
production of aberrant blood vessels, reduces the leakage of aberrant blood vessels, and inhibits the growth
of aberrant blood vessels. ALG-1001, a small molecule
oligopeptide that targets multiple integrin receptor
sites that play a key role in cell signaling and regulating
cellular shape, motility, and the cell cycle, is being investigated for treatment of several vascular eye diseases
including wet AMD, diabetic macular edema (DME),
and symptomatic vitreomacular adhesion. In a phase 1
study in 2011 including 15 end-stage DME patients, 8 of
the 15 patients had 3 to 5 lines of best corrected visual
acuity (BCVA) improvement as well as a 30% to 80%
reduction in central retinal thickness. Interim data on
a phase 1b/2a dose-ranging, monotherapy study in wet
AMD was presented this year.17,18 In this first-in-human
6-month wet AMD study, the drug appeared safe and
well tolerated, and a treatment effect was seen to last
more than 4 months off-treatment. There was also a
robust response in the 3.2 mg dose group of at least 3
months off-treatment in all subjects. A demonstrated
mean BCVA improvement of +8 ETDRS letters as measured by in this group corresponded to a 30% decrease
in central macular thickness and improvement in retinal architecture. ALG-1001 has the potential to serve
as a standalone therapy or as combination therapy. In
May, Allegro and Senju Pharamaceutical announced a
collaboration and license agreement to develop and
market integrin peptide therapy in Japan.19
Allergan, together with Molecular Partners, is seeking
alternative options for wet AMD with AGN-150998, an
anti-VEGF DARPin. The phase 2 REACH study is currently examining this small target-binding protein in
two stages: first, in a dose-escalation assessment of the
safety of AGN-150998 administered as an intravitreal
agent, and second in a comparison of the safety and
treatment effects between the drug and ranibizumab.20
Midstage trial results showed some product differentiation over ranibizumab but not enough to support
moving the product directly into a phase 3 program.
The current study results are slotted to be presented at
the American Academy of Ophthalmology meeting in
November; meanwhile, Allergan plans to further evaluate its DARPin treatment by adding another arm to the
existing trial.21
Last year, Ophthotech Corp. announced positive
results with its Fovista anti-PDGF therapy (1.5 mg)
administered in combination with ranibizumab compared with ranibizumab monotherapy. Formerly known
as E10030, Fovista is an aptamer targeted against
PDGF-B, which regulates neovascular pericytes. The
prospective, randomized, controlled phase 2b trial evaluated 449 patients who were randomized to receive 1
of the following treatment regimens administered every
4 weeks for 24 weeks: Fovista 0.3 mg/ranibizumab;
Fovista 1.5 mg/ranibizumab; or sham/ranibizumab.
july/august 2013 RETINA Today 25
business of retina clinical trials for the retina specialist
Patients receiving the combination of Fovista 1.5 with
anti-VEGF therapy gained a mean of 10.6 letters of
vision on the ETDRS chart compared with 6.5 letters for
those receiving anti-VEGF monotherapy.22 Additional
studies examining this anti-PDGF therapy are anticipated to begin in the near future.
Oraya Therapeutics is bringing about novel techniques for wet AMD therapy by using radiation, which
has been used medically, most notably for cancer, for
its antiangiogenic, antiinflammatory, and antifibrotic
effects. In March, results of the INTREPID study, which
evaluated stereotactic radiotherapy in conjunction
with as-needed anti-VEGF therapy, met its primary
endpoints demonstrating that a single dose of Oraya
therapy significantly reduced the need for injections
in wet AMD patients, with a favorable safety profile
1 year post administration.23 A second phase 2 study
(ENDEAVOUR) has been initiated to confirm these
results with respect to the number of anti-VEGF injections and frequency of visits during the first year after
treatment.24
All eyes are also on Ohr Pharma’s wet AMD study
featuring a topical formulation of squalamine targeted
for wet AMD. Squalamine, a small molecule inhibitor of multiple growth factors (VEGF, PDGF), was
acquired in 2009 from Genaera, which had previously
conducted studies using an intravenous formulation
of the drug and has reformulated it into a twice-daily,
self-administered eye drop. The eye drop solves several
of the issues associated with intravenous delivery such
as suboptimal dosing, patient compliance, and the
commercial challenges of a weekly intravitreal infusion
for the intended patient population. Preclinical data
presented recently highlighted the potential therapeutic value of the program by demonstrating that
the eye drop formulation was safe and well tolerated.
Additionally, squalamine concentrations in the posterior sclera/choroid were well above the target therapeutic levels. In May 2012, the squalamine eye drop
program was granted fast track designation by the US
Food and Drug Administration (FDA), and a phase 2,
double-masked, placebo-controlled clinical trial is currently enrolling patients.25
The number of active clinical trials for both wet and
dry AMD is evidence of the need for additional therapies for wet AMD and for a first-ever FDA-approved
treatment for the dry form of the disease. n
Aron Shapiro is Vice President of Retina at
Ora Inc., in Andover, MA.
Ashley Lafond is a medical writer at
Ora Inc.
26 RETINA Today july/august 2013
1. Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004;291(15):19001901.
2. Age-Related Eye Disease Study Research G. A randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision
loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
3. NIH study provides clarity on supplements for protection against blinding eye disease. https://web.emmes.com/
study/areds2/resources/areds2_press_release_050513.pdf. Accessed May 22, 2013.
4. Safety and tolerability study of RN6Gin patients with dry, age-related macular degeneration. http://www.
clinicaltrials.gov/ct2/show/NCT00877032?term=RN6G&rank=2. Accessed April 30, 2013.
5. Safety and tolerability study of RN6G in subjects with advanced dry, age-related macular degeneration including
geographic atrophy. http://www.clinicaltrials.gov/ct2/show/NCT01003691?term=RN6G&rank=3. Accessed
April 30, 2013.
6. Efficacy, safety and tolerability study of RN6G in subjects with geographic atrophy secondary to age-related
macular degeneration. http://www.clinicaltrials.gov/ct2/show/NCT01577381?term=RN6G&rank=1. Accessed
April 30, 2013.
7. Kubota R, Boman NL, David R, Mallikaarjun S, Patil S, Birch D. Safety and effect on rod function of ACU-4429, a
novel small-molecule visual cycle modulator. Retina;32(1):183-188.
8. Clinical study to evaluate treatment with ORACEA® for geographic atrophy (TOGA). http://clinicaltrials.gov/ct2/
show/NCT01782989. Accessed April 30, 2013.
9. Safety and tolerability of sub-retinal transplantation of hESC derived RPE (MA09-hRPE) cells in patients
with advanced dry age related macular degeneration (Dry AMD). http://clinicaltrials.gov/ct2/show/
NCT01344993?term=MA09-hRPE&rank=4. Accessed April 30, 2013.
10. Sub-retinal Transplantation of hESC Derived RPE(MA09-hRPE)Cells in Patients With Stargardt’s Macular Dystrophy. http://clinicaltrials.gov/ct2/show/NCT01345006?term=MA09-hRPE&rank=3. Accessed April 30, 2013.
11. A phase I/IIa, open-label, single-center, prospective study to determine the safety and tolerability of Subretinal transplantation of human embryonic stem cell derived retinal pigmented epithelial(MA09-hRPE) Cells
in patients with advanced dry age-related macular degeneration(AMD). http://clinicaltrials.gov/ct2/show/
NCT01674829?term=MA09-hRPE&rank=1. Accessed April 30, 2013.
12. ACT confirms clinical trial participant showed improvement in vision from 20/400 to
20/40 following treatment. http://advancedcell.com/news-and-media/press-releases/act-confirms-clinical-trialparticipant-showed-improvement-in-vision-from-20-400-to-20-40-following-treatment/index.asp. Accessed
May 22, 2013.
13. A safety study of CNTO 2476 in patients with age-related macular degeneration. http://clinicaltrials.gov/ct2/
show/NCT01226628?term=CNTO2476&rank=1. Accessed May 22, 2013.
14. Efficacy and Safety Study of MC-1101 1% TID in the Treatment of Nonexudative Age-Related Macular Degeneration. http://clinicaltrials.gov/ct2/show/NCT01601483?term=MC1101&rank=1. Accessed May 15, 2013.
15. The MAP Study: Fluocinolone Acetonide (FA)/Medidur (TM) for Age Related Macular Degeneration (AMD) Pilot.
http://clinicaltrials.gov/ct2/show/NCT00605423?term=fluocinolone+acetonide+AND+AM D&rank=1. Accessed
May 15, 2013.
16. Fluocinolone acetonide intravitreal inserts in geographic atrophy. http://clinicaltrials.gov/ct2/show/NCT00695
318?term=fluocinolone+acetonide+AND+AMD&rank=3. Accessed May 15, 2013.
17. A Safety And Efficacy Study Of ALG-1001 In Human Subjects With Wet Age-Related Macular Degeneration.
http://clinicaltrials.gov/ct2/show/NCT01749891?term=ALG-1001&rank=1. Accessed May 15, 2013.
18. Kaiser P. Integrin peptide therapy: The first wet AMD experience. Paper presented at the Association for
Research and Vision in Ophthalmology annual meeting; May 2013; Seattle, Washington.
19. Allegro Ophthalmics and Senju Pharamceutical announce collaboration in Japan to develop integrin peptide
therapy as first in-class treatment of vascular eye disease. http://www.allegroeye.com/press-release/allegroophthalmics-and-senju-pharmaceutical-announce-collaboration-in-japan-to-develop-integrin-peptide-therapyas-first-in-class-treatment-of-vascular-eye-diseases/ Accessed May 22, 2013.
20. Evaluation of AGN-150998 in exudative age-relatedmacular degeneration (AMD). http://clinicaltrials.gov/ct2/
show/NCT01397409?term=AGN-150998&rank=1. Accessed May 22, 2013.
21. Allergan Shares Fall After CEO Says Two Studies Delayed. http://www.bloomberg.com/news/2013-05-01/
allergan-shares-fall-after-ceo-says-drug-trial-will-be-delayed.html. Accessed May 22, 2013.
22. Ophthotech’s novel anti-PDGF combination agent Fovista™ demonstrated superior efficacy over lucentis®
monotherapy in large controlled wet AMD trial. http://www.ophthotech.com/ophthotechs-anti-pdgf-fovistasuperior-efficacy-phase2b/Accessed May 22, 2013.
23. Jackson TL, Chakravarthy U, Kaiser PK, et al. Stereotactic radiotherapy for neovascular age-related macular
degeneration: 52-Week safety and efficacy results of the INTREPID study. Ophthalmology. Mar 12.
24. An open-label study to evaluate the clinical and economic benefits of I-Ray in patients with choroidal neovascularization secondary to age-related maculardegeneration (ENDEAVOUR). http://clinicaltrials.gov/ct2/show/
NCT01521065?term=IRay&rank=6. Accessed May 15, 2013.
25. Efficacy and safety of squalamine lactateeEye drops in subjects with neovascular (wet) age-related macular
degeneration (AMD). http://clinicaltrials.gov/ct2/show/NCT01678963?term=squalamine&rank=3. Accessed
May 15, 2013.
26. Taraporewala IB, Elman MJ, Hirschman SZ, Backenroth SI. A novel eye drop formulation of squalamine for
exudative AMD: evaluation of ocular distribution and ocular safety in rabbits. Paper presented at the Association for
Research and Vision in Ophthalmology annual meeting; May 2013; Seattle, WA.
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