Ohr Pharmaceutical, Inc. (OHRP)

Transcription

Initiating Coverage
July 28, 2015
Ohr Pharmaceutical, Inc. (OHRP)
Initiation Report
LifeSci Investment Abstract
Ohr Pharmaceutical Inc. (NasdaqCM: OHRP) is a biotechnology company focused on the
development of novel ophthalmologic therapeutics. The Company is currently preparing for
a Phase III clinical program with OHR-102, a topical treatment for neovascular age-related
macular degeneration (wet AMD). The Phase III program is expected to begin in the second
half of 2015 based on encouraging Phase II results suggesting an improvement in visual acuity
for patients treated with OHR-102 and Lucentis as compared to Lucentis alone.
Key Points of Discussion
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Ohr is Developing OHR-102 for Wet AMD. Ohr Pharmaceutical is developing the firstever topical treatment for the wet form of age-related macular degeneration (wet AMD).
OHR-102, an eye drop formulation of squalamine lactate, recently completed a Phase II
clinical trial. Squalamine inhibits several growth factors to block angiogenesis in the back of
the eye. The wet AMD market is massive, supporting multiple blockbuster therapies such as
Roche/Genentech’s (VTX: ROG.VX) Lucentis (ranibizumab) and Regeneron’s (NasdaqGS:
REGN) Eylea, which are injectable vascular endothelial growth factor (VEGF) inhibitors.
There is potential for new therapies like OHR-102 to act synergistically with VEGF
inhibitors, the current standard of care, to further improve visual outcomes. As a topical
treatment, OHR-102 has the potential to achieve this goal without requiring additional,
inconvenient intraocular injections.
OHR-102 Phase III Program is Set to Begin in the Second Half of 2015. Ohr
completed a Phase II clinical trial demonstrating a numerical improvement in visual acuity
with combination OHR-102 and Lucentis (ranibizumab) treatment compared to Lucentis
alone. The benefit was observed in patients with certain choroidal neovascularization
(CNV) characteristics. Ohr is continuing to analyze the data in order to identify a population
of patients who are most likely to succeed in registration-directed trials.
In earlier discussions with the FDA, Ohr reached an agreement on a 9-month primary
endpoint for Phase III that is based on the proportion of patients who achieve a gain of
3 or more lines in visual acuity. We note that mean visual acuity gain is also an acceptable
endpoint for Phase III wet AMD trial. Patients will be followed for an additional 15 months
for safety. A 3-line visual acuity gain is clinically relevant, corresponding to the ability to see
an object half the size as was possible before treatment. The primary endpoint is 3 months
shorter than the typical timeline for this indication, which should allow Ohr to submit a
regulatory filing faster than usual contingent on positive results for the primary endpoint.
Analysts
Jerry Isaacson, Ph.D. (AC)
(646) 597-6991
[email protected]
Market Data
Price
Market Cap (M)
EV (M)
Shares Outstanding (M)
Fully Diluted Shares (M)
Avg Daily Vol
52-week Range:
Cash (M)
Net Cash/Share
Annualized Cash Burn (M)
Years of Cash Left
Debt (M)
Short Interest (M)
Short Interest (% of Float)
$2.93
$89
$56
30.3
34.9
1,967,800
$2.02 - $12.31
$32.8
$1.08
$15.0
2.2
$0.0
0.95
3.9%
Financials
FY Sep
EPS
Q1
Q2
Q3
Q4
FY
2013A
(0.14)A
(0.02)A
(0.07)A
NA
(0.30)A
2014A
(0.10)A
(0.10)A
(0.09)A
NA
(0.41)A
2015A
(0.18)A
(0.12)A
NA
NA
NA
Expected Upcoming Milestones
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H2 2015 – Launch of Phase III trials with OHR-102 in patients with wet AMD.
H2 2015 – Initiation of Phase I breast cancer trial by DepYmed.
H2 2016 – Data expected from Investigator Sponsored Trial of OHR-102 in
proliferative diabetic retinopathy.
2016 – File IND for the first indication using the SKS Ocular sustained release
platform.
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For analyst certification and disclosures please see page 44
July 28, 2015
 Trend towards Greater Visual Acuity with OHR-102 in Phase II Trial. Ohr conducted a Phase II clinical trial
with OHR-102 in newly diagnosed patients with wet AMD. It was a randomized, double-masked, placebo-controlled
study that enrolled 142 patients at 23 clinical sites in the United States. All patients received an intravitreal injection of
Lucentis at the beginning of the trial and were then randomized to treatment with OHR-102 eye drops or corresponding
placebo twice daily for 9 months. Patients were monitored each month for objective disease activity criteria to
determine the need for additional Lucentis injections. The primary endpoint was the number of additional Lucentis
injections. Additional endpoints pre-specified in this exploratory Phase II program included mean change in bestcorrected visual acuity as well as proportion of patients gaining 3 lines or more of vision from baseline, which are
clinically important measures of disease improvement.
The full trial results were presented at the 2015 Association for Research in Vision and Ophthalmology (ARVO)
conference in May. There was variability in patient response depending on the type of CNV present. In patients with
classic containing CNV or occult CNV of a certain size, there was a numerical improvement in visual acuity when
receiving OHR-102 combination therapy compared to Lucentis monotherapy. A higher percentage of patients in the
OHR-102 arm gained ≥3, ≥4, or ≥5 lines of visual acuity as measured on an eye chart, corresponding to ≥15, ≥20,
or ≥25 letters, respectively. Ohr is designing its Phase III inclusion criteria to enroll patients with the greatest chances
of success in Phase III and to maximize the future market opportunity.
 Recent Investigator Sponsored Trial Results Support Role for OHR-102 in Retinal Disease. Final results from
an open-label investigator-sponsored trial (IST) were presented at the 2015 American Society of Retina Specialists
(ASRS) meeting in Vienna, Austria.1 20 patients with macular edema secondary to branch and central retinal vein
occlusion received twice daily OHR-102 for 10 weeks, accompanied by a Lucentis injection at weeks 2 and 6. Rescue
Lucentis injections were administered every 4 weeks thereafter as needed. After the 10 week loading period, patients
were randomized 1:1 to continue receiving OHR-102 or discontinue the drops for 28 additional weeks. Patients who
continued to receive OHR-102 after 10 weeks experienced a greater numerical improvement in visual acuity compared
to patients who discontinued OHR-102. Patients who continued on OHR-102 gained an average of 7.4 letters from
week 10 to 38, compared to 3.1 letters for the control group. This is the second randomized trial in a back of the eye
disease where OHR-102 combination therapy provided a numerical improvement in visual acuity versus injection of
VEGF inhibitors alone.
 Acquisition of SKS Ocular Expands Pipeline and Adds New Expertise in Ophthalmology to Move Wet AMD
Program Forward. In May 2014, Ohr entered into an agreement to acquire privately held SKS Ocular and its
proprietary sustained release technology for glaucoma, eye allergy, and retinal disease. The platform technology is
versatile and will allow Ohr to develop additional therapeutic candidates using small molecules or proteins for a variety
of ophthalmology indications. The acquisition is consistent with Ohr’s previously stated long-term goal of developing
a pipeline of ophthalmology products led by OHR-102 for wet AMD, and Ohr acquired a research facility to enable
development. Ohr plans to file an IND for one sustained release program based on this platform in 2016.
As part of the SKS Ocular acquisition, Ohr added three members of the SKS leadership to their senior management
team: Dr. Jason S. Slakter, Dr. Glenn L. Stoller, and Dr. Peter K. Kaiser. The new additions are key opinion leaders
(KOLs) in the ophthalmology space and have prior experience with drug development, allowing Ohr to realize the
full value of their clinical-stage OHR-102 program and newly added SKS technology. The Company recently
1
Wroblewski, J.J. & Hu, A.Y.H., 2015. Squalamine lactate ophthalmic solution for the treatment of macular edema secondary to
branch and central retinal vein occlusion. Final data analysis. American Society of Retina Specialists Meeting.
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July 28, 2015
appointed Dr. Avner Ingerman to a newly created position of Chief Clinical Officer. Dr. Ingerman led the Phase III
clinical program for Eylea at Regeneron and brings an extensive clinical experience to Ohr. Having an industry veteran
with such relevant clinical experience should enable the successful execution of Ohr’s Phase III program.
 OHR-102 Could Be Synergistic with Any of the Anti-VEGFs. One of the key advantages of OHR-102 is that
based on its mechanism of action and administration route, it could be synergistic with any anti-VEGF treatment.
OHR-102 is not expected to compete directly with any of the well-established anti-VEGF treatments, but could be
used in combination to enhance efficacy. Achieving this goal without an additional intravitreal injection would allow
physicians to maintain their normal workflow with patients, and continue to use a treat and extend approach without
the added complexity of two intravitreal injection-based drugs. Treat and extend allows the interval between
intravitreal injections to be increased if a patient’s disease is stable. OHR-102 would be administered continuously.
The simplicity of writing a prescription for OHR-102 while treating patients with anti-VEGF therapy is a feature that
is likely to increase the chances of OHR-102 adoption. Ohr is initially seeking approval for use in combination with
Lucentis, although successful trials with the other agents could support label expansion.
 Entry Into Wet AMD Market Could Lead to Indication Expansion. The two FDA-approved treatments for wet
AMD, Lucentis and Eylea, are approved for additional eye diseases that benefit from the action of these growth factor
inhibitors. Both biologics are also approved for diabetic macular edema (DME) and retinal vein occlusion (RVO).
OHR-102 may offer visual acuity gains without the need for additional intravitreal injections in patients with DME
and RVO as well as in wet AMD. The DME market alone exceeds $1 billion and is expected to grow throughout the
decade, representing a significant additional market for Ohr in the future.
 Ohr has a Joint Venture with Cold Spring Harbor Laboratories for Breast Cancer and Additional PartnerReady Program. In 2014, Ohr formed a joint venture with Cold Spring Harbor Laboratory (CSHL) called DepYmed,
Inc. to develop trodusquemine and related analogs. Trodusquemine is an inhibitor of protein tyrosine phosphatase 1B
(PTB1B), a key target for oncology and other indications. The joint venture will be a private entity initially co-owned
by Ohr and CSHL, and both partners will seek funding to pursue the development of trodusquemine-related assets.
CSHL is a leading private, non-profit research institution with substantial funding, and strong support from the NIH.
The institution has participated in the launch of 20 biotechnology start-up companies, including OSI Pharmaceuticals,
which was sold to Astellas Pharma in 2010 for approximately $3.5 billion. The initial focus of DepYmed will be HER2positive breast cancer, and a Phase I trial is expected to begin in the second half of 2015 at North Shore-Long Island
Jewish Hospital.
Financial Discussion
Second Fiscal Quarter 2015 Results and Cash Position. For the second fiscal quarter of 2015 Ohr reported total
operating expenses of $6.5 million, up from $1.9 million for the same period of 2014. Higher expenses were primarily
due to increased corporate overhead, increased hiring, greater stock option expenses, and increased research and
development costs, which rose from $0.6 million in the second fiscal quarter of 2014 to $2.9 million for the second
fiscal quarter of 2015.
On February 11th 2015, Ohr completed a public offering of common stock to raise gross proceeds of $28.8 million.
Ohr sold 4,259,259 shares at a price of $6.75, which included the full exercise of the over-allotment option. The
financing was led by fundamental healthcare institutional investors Broadfin Capital and Deerfield Capital
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July 28, 2015
management, and included additional new investors. As a result of the transaction, the Company had cash and cash
equivalents of $32.8 million at the end of the fiscal quarter, March 31st 2015.
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July 28, 2015
Table of Contents
Company Description .................................................................................................................................................................... 6
OHR-102 (squalamine): Neovascularization Inhibitor ............................................................................................................ 6
Squalamine Background ........................................................................................................................................................... 7
Mechanism of Action ................................................................................................................................................................ 7
Disease Background – Wet Age-Related Macular Degeneration ............................................................................................ 9
AMD Classification ................................................................................................................................................................. 10
Symptoms and Diagnosis ....................................................................................................................................................... 11
Treatment Paradigm ................................................................................................................................................................ 13
Age-Related Macular Degeneration Market Information ...................................................................................................... 14
Currently Approved Treatments for wet AMD ....................................................................................................................... 15
Lucentis – Roche/Genentech .................................................................................................................................................. 16
Eylea – Regeneron and Bayer ................................................................................................................................................. 17
Avastin – Roche/Genentech .................................................................................................................................................. 19
Clinical Trial Discussion .............................................................................................................................................................. 19
IMPACT Phase II Clinical Trial with OHR-102 in Wet AMD Patients ........................................................................ 20
Phase III Clinical Program ..................................................................................................................................................... 24
Investigator Sponsored Trials ................................................................................................................................................ 25
Other Drugs in Development for Wet AMD .......................................................................................................................... 28
Fovista (E10030) – Ophthotech ............................................................................................................................................. 29
DARPin Abicipar Pegol – Allergan/Molecular Partners .................................................................................................. 31
Competitive Landscape ................................................................................................................................................................ 32
Sustained Release Platform ......................................................................................................................................................... 36
Intellectual Property & Licensing ............................................................................................................................................... 39
Management Team ....................................................................................................................................................................... 40
Risk to an Investment .................................................................................................................................................................. 43
Analyst Certification ..................................................................................................................................................................... 44
Disclosures ..................................................................................................................................................................................... 44
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July 28, 2015
Company Description
Ohr Pharmaceutical is a biotechnology company focused on developing novel ophthalmology assets. The Company
is planning to conduct a Phase III program with lead candidate OHR-102 in patients with newly diagnosed neovascular
age-related macular degeneration (wet AMD). Trial launch is expected in the second half of 2015. The Company’s
development pipeline is displayed in Figure 1. Ohr recently acquired SKS Ocular and its sustained delivery technology
that is in preclinical testing for several indications. An IND filing is expected for the first sustained release program in
2016. Ohr recently launched a joint venture with Cold Spring Harbor Laboratories (CSHL) to develop trodusquemine
for HER2-positive breast cancer, and a Phase I trial is expected to launch in the second half of 2015.
Figure 1. Ohr Pharmaceutical Development Pipeline
Preclinical
Phase I
Phase II
Phase III
Partner
OHR-102
Wet Age Related Macular Degeneration
(Phase III program in H2 2015)
Wholly
owned
Retinal Vein Occlusion*
Proliferative Diabetic Retinopathy*
SKS Technology
Glaucoma
Alcon**
Steroid Induced Glaucoma
Wholly
owned
Eye Allergy
Retinal Disease
Trodusquemine
Breast Cancer
CSHL
*Investigator sponsored trials
**Research collaboration
CSHL = Cold Spring Harbor Laboratory
Source: LifeSci Capital
OHR-102 (squalamine): Neovascularization Inhibitor
Squalamine is a small molecule, anti-angiogenic drug that inhibits growth factors such as vascular endothelial growth
factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). These growth
factors are critical for the development of new blood vessels, and their inhibition reduces neovascularization.
Squalamine acts via a unique mechanism to inhibit several growth factors related to angiogenesis, differentiating the
molecule from approved anti-angiogenesis drugs such as Lucentis (ranibizumab), which inhibits only VEGF. Blocking
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July 28, 2015
angiogenesis is critical in diseases such as wet AMD, where abnormal blood vessel development and fluid leakage into
the back of the eye leads to vision loss. The product is formulated as a self-administered eye drop (OHR-102). OHR102 has been tested in a Phase II clinical trial in patients with wet AMD, demonstrating a visual acuity benefit in
combination with Lucentis compared to Lucentis alone. A Phase III program is being finalized and is expected to initiate
in the second half of 2015.
Squalamine Background
Squalamine is an aminosterol originally identified and purified from the dogfish shark Squalus acanthias.2 It was initially
described as an antibiotic and does have antimicrobial properties, although that has not been the focus of development.
Squalamine is a steroidal compound, but it does not interact with the glucocorticoid or minealocorticoid receptors
and has no anti-inflammatory properties. The chemical structure consists of a steroid conjugated to spermidine, as
shown in Figure 2.
Figure 2. Chemical Structure of Squalamine
Mechanism of Action
Squalamine Inhibits Na+/H+ Exchange. One component of squalamine’s mechanism of action is the inhibition
of sodium and hydrogen ion (Na+ and H+) exchange in endothelial cells. Na+/H+ exchange is an important cellular
process that regulates internal pH by increasing or decreasing the amount of free hydrogen ions inside cells.
Downstream signaling of growth factors such as PDGF, hepatocyte growth factor (HGF), and epidermal growth
factor (EGF) acts through Na+/H+ exchange proteins and increases their exchange activity.3,4,5 Increased ion exchange
Moore, K.S. et al., 1993. Squalamine: An aminosterol antibiotic from the shark. Proceedings of the National Academy of Sciences, 90,
pp1354-1358.
3 Di Sario, A. et al., 1999. Intracellular pathways mediating Na+/H+ exchange activation by platelet-derived growth factor in rat
hepatic stellate cells. Gasteroenterology, 116(5), pp1155-1166.
4 Steffan, J.J. et al., 2010. HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity
of Na+-H+ exchangers. Journal of Cell Science, 123 (Pt 7), pp1151-1159.
5 Ghishan, F.K. et al., 1992. Epidermal growth factor up-regulates intestinal Na+/H+ exchange activity. Proceedings of the Society
for Experimental Biology and Medicine, 201(3), pp289-295.
2
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activity is an important component in growth factor signaling, and the inhibition of the exchange process can block
the effects of growth factors. Squalamine specifically inhibits the Na+/H+ exchange protein sodium-hydrogen
antiporter 3 (NHE3), one of three protein isoforms.6
Squalamine Binds and Sequesters Calmodulin. Activation of Na+/H+ exchange is also dependent on the calciumbinding protein calmodulin.7,8 Squalamine binds to calmodulin at a single-digit micromolar concentration to block
activation of Na+/H+ exchange.9 Following squalamine binding, calmodulin is transferred inside the cell and into a
perinuclear membrane compartment, as shown in Figure 3. On the left panel are untreated endothelial cells with
diffuse, fluorescently labeled calmodulin throughout the cell, indicated by green. The right panel shows the
redistribution of calmodulin to a perinuclear compartment after the addition of squalamine. Redistribution of
calmodulin prevents its binding to growth factors and Na+/H+ exchange proteins, blocking downstream signaling to
inhibit the activation of growth factors.
Figure 3. Cellular Distribution of Calmodulin Following Squalamine Treatment
Source: Chen, Q. et al., 1999
The binding of squalamine to calmodulin inhibits Na+/H+ exchange and blocks the activation of growth factor
signaling. Figure 4 is a schematic of the mechanism of growth factor inhibition by squalamine leading to neovascular
inhibition. Growth factors normally bind to receptors and induce capillary formation, and are dependent on Na+/H+
exchange and calmodulin for intracellular signaling. Squalamine treatment inhibits Na+/H+ exchange through
calmodulin binding and blocks the downstream signaling of growth factors to inhibit vessel formation.
Akhter S. et al., 1999. Squalamine, a novel cationic steroid, specifically inhibits the brush-border Na+/H+ exchanger isoform
NHE3. American Journal of Physiology, 276(1 Pt 1), ppC136-144.
7 Turner, J.H. et al., 2007. Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the G i
coupled 5-hydroxytryptamine1a receptor. The Journal of Pharmacology and Experimental Therapeutics. (320)1, pp314-322.
8 Garnovskaya M.N. et al., 2003. Mitogen-induced activation of Na+/H+ exchange in vascular smooth muscle cells involves
janus kinase 2 and Ca2+/calmodulin. Biochemistry, 42(23), pp7178-7187.
9 Chen, Q. et al., 1999. The angiostatic sterol squalamine is a calmodulin chaperone. Clinical Cancer Research, 5(Suppl), pp3768s.
6
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Figure 4. Mechanism of Growth Factor Inhibition by Squalamine
Squalamine’s unique mechanism of action leads to the inhibition of several growth factors, a property of the
compound differentiates it from currently approved therapies. The inhibition of multiple growth factors also facilitates
OHR-102’s ability to enhance visual acuity improvements when used in combination with anti-VEGF agents.
Hypersensitization of Endothelial Cells Via Pericyte Stripping. Blood vessels in the retinal are coated by cells
called pericytes, which help regulate blood flow, clear cellular debris, and perform other important functions. 10,11
Pericytes are recruited to blood vessels via PDGF-β signaling. Inhibition of PDGF-β leads to stripping of the pericytes
and exposure of endothelial cells, making them more susceptible to VEGF inhibitors. This mechanism has been
validated in animal models and is a possible reason for enhanced visual acuity gains observed in Ohr’s IMPACT Phase
II study and Ophthotech’s Phase II study with Fovista.
Disease Background – Wet Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a condition that results in vision loss due to damage of the macula, the
center portion of the retina, and affects an estimated 72 million people in North America and Europe.12 The retina is
Jo, N. et al., 2006. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial
growth factor therapy in multiple models of ocular neovascularization. American Journal of Pathology, 168(6), pp2036-2053.
11 Ribatti, D. et al., 2011. The role of pericytes in angiogenesis. The International Journal of Developmental Biology, 55, pp261-268.
12 Wong, W.L. et al., 2014. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and
2040: a systematic review and meta-analysis. The Lancet. Global health, 2(2), e106-116.
10
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the innermost membrane portion of the back of the eye that contains the photoreceptors responsible for vision. The
central, posterior portion of the retina is called the macula and is responsible for central high-resolution visual acuity.
Figure 5 shows a macroscopic view of the retina and a black circle highlights the macula.
Figure 5. View of Retina and Macula
Source: Jager, R.D. et al., 200813
AMD is one of the leading causes of blindness in elderly individuals. There are two forms of AMD – non-neovascular
(dry) and neovascular (wet). Dry AMD accounts for 90% of all cases of the disease, but only leads to severe vision
loss in 10% of patients. In dry AMD, macular damage occurs via the buildup of drusen, which are extracellular deposits
that accumulate between the retina and the choroid. The choroid is a layer of blood vessels and connective tissue
between the retina and the sclera. In the wet form of AMD, vascularization of the choroid causes fluid buildup behind
the macula that leads to damage of the retina. Many factors can increase the risk of developing AMD, including
advancing age, race, and a history of smoking. There are no drug treatments for dry AMD, while several drugs,
formulated as intravitreal injections, are available to treat patients with wet AMD.
AMD Classification
There are many proposed classification schemes for AMD, with an updated set of criteria published as recently as
April 2013.14 Most schemes use the amount of drusen and pigment abnormalities observed in the retina to classify the
stage of AMD. As people age, drusen begin to accumulate between the retinal pigment epithelium and Bruch’s
membrane of the retina. Excess drusen can lead to inflammation and damage to the photoreceptors. Drusen may also
induce aberrant growth factor expression, leading to neovascularization and the development of wet AMD.
An example of one classification scheme for AMD is shown in Figure 6 with representative images of drusen
accumulation in the macula. In early AMD there are a few medium-sized drusen and some pigment abnormalities. At
least one large druse, numerous medium-sized drusen, and visual signs of atrophy characterize intermediate AMD.
Advanced, non-neovascular AMD patients have drusen and atrophy extending to the center of the macula. Finally, in
13
14
Jager, R.D. et al., 2008. Age-related Macular Degeneration. The New England Journal of Medicine, 358, pp2606-2617.
Ferris III, F.L. et al., 2013. Clinical classification of age-related macular degeneration. Ophthalmology, 120(4), pp844-851.
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advanced wet AMD, neovascularization is present, which may lead to fluid leakage, hemorrhage, or retinal detachment.
The white arrows indicate medium size drusen (panel A), large druse (panel B), geographic atrophy (panel C), and
choroidal neovascularization (panel D). The blue arrow in panel D indicates a subretinal hemorrhage.
Figure 6. Representative Images for Types of AMD
The choroidal neovascularization (CNV) in wet AMD eyes is typically classified as classic or occult. Classic CNV
refers to abnormal blood vessels that grow above the retinal pigment epithelium (RPE) and are associated with rapid
vision loss. Occult CNV refers to blood vessels that are less apparent, typically below the RPE, and with more gradual
leakage leading to slower vision loss. Patients with classic only CNV have no occult involvement. Those with classic
containing CNV may also have occult CNV within the lesion.
Symptoms and Diagnosis
Patients often experience no obvious symptoms from AMD, and that is especially true of dry AMD. Instead, there
are signs and indications of AMD that are detected during ophthalmologic exams. The presence of drusen, pigment
abnormalities, geographic atrophy, and choroidal neovascularization upon ophthalmologic examination are signs of
AMD. Patients eventually experience vision impairment as the disease progresses, and this is the only symptom that
patients will experience and can detect without visiting a clinician. Impairment can manifest as blurred vision,
decreased central vision, visual distortions, rapid worsening of vision, and decreased color intensity.
Diagnosis of AMD involves a patient history and ocular examination. A patient history can identify symptoms
characteristic of AMD. Clinical examination of the eye provides additional evidence for AMD, and there are several
tests that can be performed, including best-corrected visual acuity, an amsler grid test, and stereoscopic fundus analysis.
Best-corrected visual acuity is measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and
an example of the chart is shown in Figure 7. Patients typically stand 20 feet from the chart and read as many letters
as possible. In clinical trials, the number of letters or lines of letters read at baseline relative to follow up evaluations
determines whether visual acuity has increased, stabilized, or decreased over time.
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Figure 7. Chart Used to Determine Patient Visual Acuity
Source: Early Treatment Diabetic Retinopathy Study
The final component to making a diagnosis is a direct examination of the fundus, or the portion of the eye opposite
the lens. The fundus includes the retina, macula, and optic nerve. Stereoscopic examination of the fundus allows for
the identification of drusen, pigment abnormalities, geographic atrophy, and choroidal neovascularization. All of these
features are considered when making a diagnosis of AMD.
While age is the largest risk factor for developing both dry and wet AMD, other factors have also been identified. The
link with AMD and smoking is strong and has been demonstrated in a wide variety of populations, including a
population in Wisconsin,15 a population in Australia,16 and a group of almost 32,000 female nurses.17 The number of
years as a smoker further correlates with the risk of AMD, and is in line with the development of AMD being a longterm process.18 The mechanism by which smoking causes AMD is unknown. Additional risk factors are listed in
Figure 8, and include race, diet, and genetic predisposition.
Klein, R. et al., 1993. The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. American Journal of
Epidemiology, 137(2), pp190-200.
16 McCarty, C.A. et al., 2001. Risk factors for age-related maculopathy. Archives of Ophthalmology, 119, pp1455-1462.
17 Seddon, J.M. et al., 1996. A prospective study of cigarette smoking and age-related macular degeneration in women. The
Journal of the American Medical Association, 276(14), pp1141-1146.
18 Khan, J.C. et al., 2006. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a
major determinant of risk for both geographic atrophy and choroidal neovascularization. British Journal of Ophthalmology, 90(1),
pp75-80.
15
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Figure 8. Risk Factors Associated with AMD
Treatment Paradigm
Several FDA approved treatments are available for patients with wet AMD and most are routinely administered using
intravitreal injections. The first wet AMD treatment approved in 2000 was an intravenous injection of Visudyne
(verteporfin), followed by exposure to nonthermal red light to induce vascular damage in the back of the eye. The
National Institute for Health and Clinical Excellence (NICE) in the United Kingdom (NICE) issues guidelines for
high quality, cost effective treatments for many diseases. NICE recommends treatment with Visudyne as an option if
the best-corrected visual acuity of a patient is 20/200 or better and they have a severe amount of choroid
neovascularization.19
The second treatment approved for patients with wet AMD, Macugen (pegaptanib), is a VEGF inhibitor that is inferior
to recent biological products such as Roche/Genentech’s Lucentis (ranibizumab) and Avastin (bevacizumab). Macugen
is not recommended for any patients by NICE. Lucentis is recommended by NICE in patients that have best-corrected
visual acuity of between 20/40 and 20/315, no permanent structural damage to the central fovea, and evidence of
recent disease progression. Eylea is a recent entrant into the wet AMD treatment space that was recently recommended
as an option by NICE, mostly due to a European Union-specific discount, making the product more competitive with
Lucentis in terms of cost.
Off-label Avastin use has been rising and is now the leading treatment for patients with wet AMD. In fact, more than
50% of ophthalmologists use Avastin as a first-line treatment for wet AMD. Several clinical trials have tested Avastin
and Lucentis head-to-head and demonstrated that Avastin treatment is similar to Lucentis in terms of the benefit to visual
National Institute for Health and Clinical Excellence. Ranibizumab and pegaptanib for the treatment of age-related macular
degeneration. NICE technology appraisal guidance 155, updated May 2012.
19
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acuity.20 The safety profiles of the drugs are also similar.21 Avastin is available at a fraction of the cost of Lucentis or
Eylea, making the drug attractive for cost-conscious patients. Cost coupled with comparable efficacy are the primary
reasons why Avastin is the leading anti-VEGF for wet AMD.
Despite the cost advantages of using Avastin in wet AMD, individual patients in consultation with their eye specialist
must make the ultimate decision regarding its off-label use for this indication, especially when considering the necessity
of pharmaceutical compounding. Avastin is manufactured as single use vials for use in approved indications, and must
be separated into smaller doses for off-label intravitreal injections. The FDA has little regulatory authority over
compounding pharmacies and does not routinely monitor the safety and quality of compounded drugs. It is unclear
how these risks will affect patient decisions going forward, although based on the existing data OHR-102 should be
compatible with any of the back of the eye inhibitors currently being used.
Age-Related Macular Degeneration Market Information
Epidemiology. Wet AMD, the focus of Ohr’s OHR-102 development program, is a common disease that continues
to grow with the increase in average age of people in advanced countries. According to the National Eye Institute, the
prevalence in the US population 50 years and over was estimated at 2.09%, or 2.1 million Americans in 2010, and that
number is expected to increase to 3.7 million by 2030 due to the rapidly aging population. The risk of developing wet
AMD increases dramatically with age, and the prevalence of the disease by age groups is displayed in Figure 9. The
data are consistent with a pooled analysis of three large studies totaling 14,752 subjects found a prevalence of 0.17%
in subjects aged 55-64, which rose to 5.8% in those older than 85.22 A smaller study of Caucasian subjects in Norway
found that 10.9% of patients aged 80 years or more had wet AMD.23
CATT Research Group, et al., 2011. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The
New England Journal of Medicine, 364(20), pp1897-1908.
21 Moja, L. et al., 2014. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.
Cochrane Database of Systematic Reviews, Issue 9.
22 Smith, W. et al., 2001. Risk factors for age-related macular degeneration: Pooled findings from three continents.
Ophthalmology, 108(4), pp697-704.
23 Erke, M.G. et al., 2012. Prevalence of age-related macular degeneration in elderly Caucasians: the Tromsø Eye Study.
Ophthalmology, 119(9), pp1737-1743.
20
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July 28, 2015
Figure 9. 2010 Prevalence of wet AMD by Age in the US
14%
12%
Prevalence
10%
8%
6%
4%
2%
0%
50-54
55-59
60-64
65-69
70-74
75-79
80+
50 and
up
Age
Source: National Eye Institute & LifeSci Capital
Market Size. The wet AMD market is large and growing, since age is the biggest risk factor for developing the disease
and populations in developed countries are aging. Longer lifespans lead to a higher fraction of the population at risk
for wet AMD, and the severe consequences of vision loss makes treatment a necessity for those who can afford and
have access to medical care.
Overall, sales for the current wet AMD treatments are mainly benefiting from the rising incidence and prevalence of
wet AMD, as cost conscious patients use off-label Avastin, and patients seeking relief from intravitreal injections shift
from Lucentis to the less frequently administered Eylea. There is growing attention surrounding Ophthotech’s
development efforts, which aim to enhance visual acuity through a second intravitreal injection of candidate Fovista.
OHR-102 may offer the same benefit to visual acuity without the additional intravitreal injection, saving both time
and money. We believe that payers would be particularly supportive of a treatment regimen that improves visual acuity
since this it is such as important clinical outcome, and OHR-102 has this potential.
Currently Approved Treatments for wet AMD
There are several FDA approved drugs used to treat patients with wet AMD. All treatments limit or reduce the amount
of vascularization in the retina, and all but one treatment does so through inhibition of the pro-angiogenic growth
factor VEGF. All of these treatments are delivered by intravitreal injection except for Visudyne, which is administered
by IV infusion followed by activation with laser light. Figure 10 shows the therapies that are approved or commonly
used to treat wet AMD. Sales of the first approved treatment, Valeant’s Visudyne, are under $20 million per year and
Macugen sales are also declining due to a lack of efficacy compared to newer treatments. Genentech/Roche’s Lucentis
is a monoclonal antibody (mAb) that inhibits VEGF. Due to the cost of Lucentis, which ranges from $13,650 to $23,400
per year depending on the dosing frequency, many doctors administer injections of the cancer mAb Avastin off-label,
with similar visual acuity benefits for patients. Approved by the FDA in November of 2011, Regeneron’s Eylea is the
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July 28, 2015
most recent wet AMD treatment and sales continue to increase rapidly. Eylea has displaced Lucentis in terms of patients
on the treatment due to a reduced dosing frequency and potentially superior efficacy. Approximately 50% of
ophthalmologists believe that Eylea is most effective at decreasing retinal fluid and works best across a broad range of
wet AMD patients.
Figure 10. Wet AMD Treatments
Company/
Approval date
Injection
Interval
2013
Sales
2014
Sales
Indications
Eylea
(aflibercept)
Regeneron/Bayer
(2011)
8 weeks
$1,881 M
$2,775 M
wet AMD; retinal vein occlusion;
diabetic macular edema (DME);
diabetic retinopathy
Lucentis
(ranibizumab)
Genentech/Roche
(2006)
4 weeks*
$4,230 M
$4,302 M
wet AMD; retinal vein occlusion;
diabetic macular edema (DME);
diabetic retinopathy
Avastin
(bevacizumab)
Genentech/Roche
(off label – AMD)
4-6 weeks
$6,841 M
$7,019 M
Colorectal cancer; NSCLC;
glioblastoma; renal cell carcinoma;
cervical cancer, ovarian/fallopian
tube/primary peritoneal cancer
Macugen
(pegaptanib)
Valeant
Pharma/Pfizer
(2004)
6 weeks
-
-
wet AMD
Visudyne
(verteporfin)
Valeant Pharma
(2000)
-
-
-
wet AMD
Drug
*longer duration between intravitreal injections possible with reduced efficacy
Source: Company Reports
Lucentis – Roche/Genentech
In 2006 the FDA approved Lucentis for the treatment of wet AMD. Lucentis binds to the receptor-binding site of
VEGF-A and prevents its interaction with the VEGF receptors. Three clinical trials were conducted to determine the
safety and efficacy of Lucentis, enrolling a total of 1,323 patients. The dosing frequency for Lucentis is every 4 weeks,
although the label has been expanded to allow a less frequent dosing with slightly reduced efficacy. This is consistent
with a dosing frequency of approximately every 6 weeks in routine clinical use.
Phase III Trial Data. Trial AMD-2 will be described as a representative example of the three pivotal trials conducted
for the approval of Lucentis. AMD-2 was a Phase III, randomized, active-controlled trial monitoring Lucentis in patients
with choroidal neovascularization (CNV). The term CNV is commonly used when discussing wet AMD patients and
there are two major types, classic and occult. Classic CNV refers to significant leakage of blood and fluid under the
retina and is associated with rapid vision loss. Occult CNV refers to blood vessels that are less apparent with more
gradual leakage leading to slower vision loss. AMD-2 enrolled patients with predominately classic CNV. Visudyne was
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July 28, 2015
used as the active control, which included photodynamic therapy (PDT) or sham PDT. A total of 423 patients were
treated for 24 months after randomization to one of three arms:



0.3 mg of monthly Lucentis injections and sham PDT.
0.5 mg of monthly Lucentis injections and sham PDT.
Sham intravitreal injections and Visudyne plus PDT therapy.
The primary endpoint was the proportion of patients who maintained vision, defined as a loss of 15 letters or fewer
at 12 months compared to baseline. The results from the study demonstrated that Lucentis improved visual acuity in
patients with classic CNV, and 31% of patients receiving Lucentis experienced clinically significant improvements in
visual acuity after 24 months. Figure 11 shows the mean change in visual acuity from baseline to 12 months.24 Patients
receiving 0.5 mg Lucentis gained on average 11.3 letters while those receiving Visudyne lost 9.5 letters. These data clearly
demonstrate the benefits of Lucentis over previous treatments such as Visudyne.
Figure 11. Change in Visual Acuity with Lucentis or Visudyne Treatment
Source: Lucentis Prescribing Information
Eylea – Regeneron and Bayer
Approved in 2011, Eylea is the most recent treatment for wet AMD to reach the market. Eylea is a VEGF inhibitor,
and acts as a decoy receptor that binds both VEGF-A and placental growth factor (PIGF) to limit activation of
endogenous VEGF receptors. The market reception for Eylea has been positive, mostly due to the shorter frequency
of intravitreal injections compared to both Lucentis and Avastin. The safety profile of Eylea is almost identical to Lucentis;
Brown, D.M. et al., 2006. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New England
Journal of Medicine, 355(14), pp1432-1444.
24
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July 28, 2015
the top AEs reported in clinical trials were conjunctival hemorrhage and eye pain. The efficacy profile is also very
similar between the two drugs, as shown in two head-to-head clinical trials. One clinical trial is described below as an
example.
Phase III Trial – VIEW 2. This was the second of two clinical trials comparing Eylea and Lucentis. The trial was a
randomized, multi-center, double-masked, active-controlled study in patients with wet AMD. Patients were treated
for 52 weeks following randomization to one of four treatment arms:




2 mg Eylea every 8 weeks following three initial monthly doses.
2 mg Eylea every 4 weeks.
0.5 mg Eylea every 4 weeks.
0.5 mg Lucentis every 4 weeks.
The primary endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters
at week 52 versus baseline. The results demonstrated that Eylea at a 2 mg dose, either every 4 weeks or 8 weeks, is
clinically equivalent to 0.5 mg of Lucentis every 4 weeks. 95% of patients receiving either drug maintained visually
acuity, and approximately one third of patients gained at least 15 letters. Figure 12 shows the mean change in visual
acuity for patients receiving 2 mg Eylea or 0.5 mg Lucentis. Patients in all treatment arms experienced gains of
approximately 8-9 letters after 52 weeks of therapy. The data from this trial clearly demonstrate the equivalence of
Eylea and Lucentis, despite the decreased frequency of intravitreal injections required with Eylea.
Figure 12. Change in Visual Acuity with Eylea or Lucentis Treatment
Source: Eylea Prescribing Information
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July 28, 2015
Avastin – Roche/Genentech
Off-label Avastin use for wet AMD is rising due to the high cost of FDA approved drugs such as Lucentis. This use
has been moderated recently due to both legal efforts by Roche to keep doctors from using it in this indication and to
fears surrounding compounding pharmacies, since a normal dose of Avastin must be separated into many smaller
doses for use in the eye. Several head-to-head trials have been performed with Avastin and Lucentis to support the use
of Avastin off-label.25,26,27 The Comparison of Age-related Macular Degeneration Treatment Trials (CATT) Research
Group reported 2-year results from their study in July 2012. The trial enrolled over 1,000 subjects and treated wet
AMD patients either monthly or as needed. Both Avastin and Lucentis had similar effects on visual acuity with the same
dosing structure. Switching from monthly to as needed injections, which was permitted at the one-year point, did lead
to a statistically significant decrease in vision during the second year, and is consistent with the Lucentis label describing
an every 8 week dosing regimen with reduced efficacy. The patients that switched to as needed treatment still required
5.0 (Lucentis) or 5.8 (Avastin) intravitreal injections during the second year.
Results from a second 2-year trial were published in July 2013. The Inhibition of VEGF in Age-related choroidal
Neovascularisation (IVAN) trial enrolled and treated over 500 patients with wet-AMD either monthly or as needed,
although all patients received 3 initial monthly injections. The results were similar to those reported by the CATT
group, with Avastin and Lucentis leading to similar benefits to visual acuity. Patients on as needed treatment received
an average of 18 (Lucentis) or 19 (Avastin) intravitreal injections over the 24-month period. These data suggest that
Avastin and Lucentis are similar regarding visual acuity impacts on patients. A recent publication by the Cochrane
Collaboration that analyzed 9 studies found that the safety profiles of the two drugs are largely similar.
Clinical Trial Discussion
Squalamine was previously tested in Phase I and Phase II clinical trials for wet AMD as an intravenous (IV)
formulation in over 250 patients. Biological effects were observed in those trials and most patients had stabilization
or improvement in visual acuity outcomes. However, there were too many challenges associated with maintaining
sufficient levels of squalamine in the back of the eye, and development with the IV formulation was stopped. Since
the reformulation of squalamine as a topical eye drop treatment, Ohr initiated a Phase II clinical trial and announced
encouraging safety and efficacy data. The data suggest that OHR-102 may be used in patients with specific lesion
characteristics to improve visual acuity when used in combination with VEGF inhibitors such as Lucentis. In addition
to the corporate-sponsored Phase II study, initial data have been released from two investigator-sponsored trials.
There are now three studies in back of the eye diseases that suggest OHR-102 has activity as a monotherapy or in
combination with Lucentis. Ohr is in the process of refining its Phase III clinical program based on feedback from
regulatory authorities. The Company plans to initiate Phase III in the second half of 2015 to support a regulatory filing
for wet AMD.
Martin, D.F. et al., 2012. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: 2year results. Ophthalmology, 119(7), pp1388-1398.
26 Chakravarthy, U. et al., 2013. Alternative treatments to inhibit VEGF in age-related choroidal neovascularization: 2-year
findings of the IVAN randomised controlled trial. Lancet, pii: S0140-6736(13)61501-9.
27 Kodjikian, L. et al., 2013. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: Results from
the GEFAL noninferiority randomized trial. Ophthalmology, 120(11), pp2300-2309.
25
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July 28, 2015
IMPACT Phase II Clinical Trial with OHR-102 in Wet AMD Patients
Ohr completed a Phase II, randomized, double-masked, placebo-controlled trial monitoring the safety and efficacy of
OHR-102 (squalamine lactate eye drops) in newly diagnosed, treatment naïve patients with wet AMD. Patients were
randomized 1:1 to one of two trial arms, receiving either twice daily OHR-102 or corresponding placebo drops. The
squalamine formulation is a 0.2% aqueous solution and the placebo is the vehicle solution without squalamine.
Treatment duration was 9 months and the trial enrolled 142 patients at 23 clinical sites.
All patients in the trial received a Lucentis injection prior to randomization and were evaluated monthly for their need
for additional injections based on specific objective diagnostic criteria primarily involving spectral domain optical
coherence tomography (SD-OCT). The primary endpoint for the trial was the number of Lucentis injections in OHR102 treated patients versus placebo. Secondary objectives included mean change in best-corrected visual acuity and
the proportion of patients gaining 3 or more lines of vision, which are a clinically relevant measures of disease
improvement, and the number of adverse events. The design allows for patients to receive standard of care treatment
at the beginning and throughout the trial, and was included to reduce patient apprehension and ethical concerns about
disease progression associated with randomization into the placebo arm.
Study Results. Ohr reported top-line study results on March 27th 2015 and presented additional data at the 2015
Association for Research in Vision and Ophthalmology (ARVO) conference in Denver. There were 65 patients
randomized to the OHR-102 arm and 63 patients in the placebo arm who completed the study. The mean baseline
visual acuity was 59.1 letters, in line with larger studies in this patient population. The visual acuity baseline range was
20/40 to 20/320. Those with 20/40 vision have a limited ability to dramatically improve their vision, and this ceiling
effect should be considered when analyzing the data. Patients with classic and occult choroidal neovascularization
(CNV) were enrolled, and the number of patients in each group was approximately even. The breakdown of types of
CNV is commonly used when discussing wet AMD patients. Classic CNV refers to abnormal blood vessels that grow
above the retinal pigment epithelium (RPE) and are associated with rapid vision loss. Occult CNV refers to blood
vessels that are less apparent, typically below the RPE, and with more gradual leakage leading to slower vision loss.
Patients with classic only CNV have no occult involvement. Those with classic containing CNV also have some occult
lesions.
The trial did not meet the primary endpoint of difference in the number of Lucentis PRN injections in the OHR-102
arm compared to placebo. However, there was a positive trend towards improved visual acuity in patients with certain
CNV characteristics in the OHR-102 arm compared to placebo. Ohr found that patients with classic containing CNV
at baseline responded better to combination therapy than those with large occult only CNV. Figure 13 shows the
mean letter gains for classic containing CNV patients in both arms at baseline, week 4, week 12, week 24, and week
36, which was the end of study. The data represent a modified intent-to-treat (mITT) population of only those patients
who completed 9 months of treatment. A numerical gain in mean letters started at week 4 and extended until the end
of the study, where patients in the squalamine arm gained 11 letters compared to 5 letters in the placebo arm.
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July 28, 2015
Figure 13. Mean Change in Visual Acuity in Patients with Classic Containing CNV (mITT)
Source: Slakter, J.S., 2015 28
In the same population with classic containing CNV, there was a numerically higher percentage of patients in the
OHR-102 arm who gained 3 or more lines from baseline to the end of treatment compared to the placebo arm. Figure
14 shows the proportion of patients gaining 3 or more lines. There was also a trend towards a higher percentage of
OHR-102-treated patients who gained ≥4 or ≥5 lines compared to placebo. By week 36, 44% of patients treated with
OHR-102 gained 3 or more lines in visual acuity versus 28% in the placebo arm. These data are especially important
since Ohr is currently designing its Phase III trials with a primary endpoint based on the proportion of patients
achieving 3 or more lines in visual acuity across 9 months. Observing a numerical difference in this measure from the
Phase II data bodes well for the prospects of successful Phase III studies.
Slakter, J.S., 2015. Final results from a Phase 2 study of squalamine lactate ophthalmic solution 0.2% (OHR-102) in the
treatment of neovascular age-related macular degeneration (AMD), The IMPACT Study. Association for Research in Vision and
Ophthalmology (ARVO) Conference, Oral Presentation.
28
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July 28, 2015
Figure 14. Gains of 3 or more Lines in Visual Acuity in Patients with Classic Containing CNV
Source: Slakter, J.S., 2015
Visual Acuity in Patients with Smaller Occult Lesions. Ohr performed an exploratory subgroup analysis of
patients with occult lesions of particular sizes to better understand if combination OHR-102 may provide a benefit to
these patients. Many patients with classic containing CNV have some occult component, and the size of the occult
CNV may impact whether OHR-102 in combination with anti-angiogenic therapy is successful. Figure 15 shows
retinal scans and OCT imaging from two patients who both have classic-containing CNV of less than 9 disc areas and
subretinal hyperreflective material. The lesion characteristics of each patient are clearly different, and they are likely to
respond differently to anti-angiogenesis therapy. This highlights the importance of establishing strict CNV criteria in
a clinical trial.
Figure 15. Variability in Lesion Characteristics for Classic Containing Patients
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July 28, 2015
Ohr analyzed patients with an occult CNV area of less than 10 mm2, which could include those with classic and occult
CNV or patients with occult only CNV. 10 mm2 is approximately 4 disc areas. These patients experienced a numerical
improvement in visual acuity when treated with OHR-102 compared to placebo. Figure 16 shows the mean letter
gains in both arms at baseline, week 4, week 12, week 24, and week 36. There was a gain of 11 letters in the combination
arm versus 5.7 letters in the placebo group, which is a difference of 5.3 letters.
Figure 16. Visual Acuity in Patients with Occult CNV Area <10 mm2
The graph in Figure 17 shows the percentage of patients who gained 3 or more lines of vision. 40% of OHR-102treated patients gained 3 or more lines compared to 26% in the Lucentis-monotherapy arm. So, if Ohr decides to
include patients with occult only lesions in its Phase III program, it would substantially increase the number of eligible
study participants relative to a classic-containing population only. This could also translate into an expanded market
opportunity.
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July 28, 2015
Figure 17. Percentage of Patients with Occult CNV Area <10 mm2 with >3 Lines Gained
Safety Results. OHR-102 was well tolerated and there were no serious or systemic treatment-related adverse events
(AEs) reported in the trial. Most ocular AEs were mild. There were two treatment-related study discontinuations, one
due to eye pain and a second due to perceived eye swelling. The safety results are consistent with prior clinical trials
using the IV formulation and preclinical studies.
Data Conclusion. Ohr’s Phase II trial accomplished several goals. The first goal was to provide a signal of activity to
indicate that the OHR-102 drops are actually reaching the back of the eye. The numerical improvement in visual acuity
from the study suggests that OHR-102 is reaching the target location and helping to control neovascularization. The
second goal was to identify patients with the greatest chance of success in Phase III. Ohr has found that patients with
classic containing CNV and/or occult CNV of a certain size are most likely to benefit from OHR-102 combination
therapy. The third goal was to provide sufficient data to initiate discussions with the FDA regarding the next phase of
program development. Ohr discussed interim data with the FDA and reached an agreement for the primary endpoint
for Phase III, and is expected to have additional dialogue with regulators to finalize the Phase III design.
Phase III Clinical Program
Ohr is planning to conduct a Phase III clinical program to support approval of OHR-102 as a combination with
VEGF-inhibition in wet AMD. The Company met with the FDA following interim Phase II data and reached an
agreement for a primary endpoint for Phase III. The endpoint may be the proportion of patients who achieve a gain
of 3 or more lines in visual acuity at 9 months. We note that mean visual acuity gain is also an acceptable endpoint for
wet AMD trials. Ohr is continuing to analyze the Phase II results to determine the most appropriate inclusion criteria
for Phase III, with the goal of including the largest possible percentage of wet AMD patients. At this point, patients
with classic containing CNV appear to respond to OHR-102, and those lesions with occult CNV area of less than 10
mm2 have also been identified as a potential target population.
The total length of the trials will be 2 years to collect sufficient safety data. During the first year patients will be
randomized 1:1 to monthly Lucentis plus twice daily OHR-102 or monthly Lucentis plus placebo. Lucentis will be given
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July 28, 2015
as needed for the remaining year. We expect each trial to enroll approximately 650 patients. Ohr plans to initiate the
Phase III program in the second half of 2015.
Investigator Sponsored Trials
Retinal Vein Occlusion. Dr. John Wroblewski conducted an open-label, proof-of-concept, investigator-sponsored
trial (IST) with OHR-102 in patients with macular edema secondary to branch and central retinal vein occlusion. Initial
results were presented at the 2014 American Society of Retina Specialists (ASRS) meeting, and final data were
presented at the 2015 ASRS meeting.29 A total of 20 treatment naïve patients were enrolled. Nine patients had central
retinal vein occlusion (CRVO), eight had branched retinal vein occlusion (BRVO), and three had hemi-central retinal
vein occlusion (RVO). In part A of the study, patients received twice daily OHR-102 for 10 weeks and an injection of
Lucentis at weeks 2 and 6. Rescue Lucentis injections were administered every 4 weeks thereafter as needed (PRN) based
on visual acuity and retinal imaging. In part B, after the 10-week loading period, patients were randomized 1:1 to
continue receiving OHR-102 or discontinue the drops for 28 additional weeks. The primary and secondary endpoints
included visual acuity, need for rescue therapy, retinal thickness, vascular leakage, and change in area of non-perfusion.
Patients achieved the following average increase in visual acuity at week 10, which was after the loading period where
Lucentis and OHR-102 were both administered:




+20.3 letters across all 20 patients.
+18.2 letters for CRVO.
+18.1 letters for BRVO.
+32.3 letters for hemi-central RVO.
Patients who continued to receive OHR-102 after 10 weeks experienced a greater numerical improvement in visual
acuity compared to patients who discontinued OHR-102. Figure 18 shows the mean visual acuity at week 38 and the
gain in visual acuity from week 10 to 38 for both study arms. Patients who continued on OHR-102 gained an average
of 7.4 letters compared to 3.1 letters for the control group. No patients had decreased visual acuity in the OHR-102
plus Lucentis PRN group whereas 50% of patients receiving Lucentis PRN only lost between 1 and 9 letters of vision.
Those receiving OHR-102 also received fewer Lucentis injections, at a median of 2, compared to those who
discontinued OHR-102, at a median of 3.3.
29
Wroblewski, J.J. & Hu, A.Y., 2015. Squalamine lactate ophthalmic solution for the treatment of macular edema secondary to
branch and central retinal vein occlusion. Final data analysis. American Society of Retina Specialists Meeting.
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July 28, 2015
Figure 18. Efficacy Measure in Patients with RVO
OHR-102 and Lucentis PRN
between weeks 10 to 38 (n=10)
between weeks 10 to 38 (n=10)
+27.8 letters
+23.3 letters
+7.4 letters
+3.1 letters
Loss of any letters
0
50% (1-9 letter loss)
Rescue Lucentis
injections
2
3.3
Mean visual acuity at
week 38
Mean gain in visual
acuity from week 10
to week 38
Lucentis PRN
Source: Wroblewski, J.J. & Hu, A.Y., 2015
At week 38 the central subfield thickness as measure by spectral domain optical coherence tomography (SD-OCT)
was numerically lower in the OHR-102 plus Lucentis group compared to Lucentis alone. 90% (9/10) of OHR-102-plus
Lucentis treated patients had a reduction in the total macular volume whereas 60% (6/10) had a reduction on Lucentis.
The trial results suggest that patients receiving OHR-102 in combination with Lucentis recovered more vision and had
better SD-OCT measurements than patients discontinuing OHR-102. The signal of activity in a back of the eye disease
also adds validations for Ohr’s wet AMD program.
Caution should be taken when comparing results across trials due to inherent differences in the studies. With that in
mind, in the two Phase III trials supporting approval of Lucentis for RVO, CRVO patients gained approximately 12
letters and BRVO patients gained approximately 14 letters after 10 weeks of monthly Lucentis.30,31 In the IST, the
combined improvement for all patients 20.3 letters, as shown in Figure 19. This suggests that adding OHR-102 to
Lucentis may enhance visual acuity relative to the standard of care. The pivotal Lucentis trials were 6 months studies,
and the visual acuity at week 26 was approximately 18.3 letters for CRVO and 14.9 letters for BRVO. In the IST,
patients randomized to OHR-102 gained 27.8 letters by week 38 and those randomized to discontinue OHR-102
gained 23.3 letters. The results were observed despite patients in the IST receiving a PRN dosing schedule and those
in the pivotal trials receiving monthly injections. In previous trials PRN dosing has been known to impact visual acuity
gains. This suggests that OHR-102 may have provided a visual acuity benefit above and beyond what is expected with
Lucentis monotherapy.
30
Campochiaro, P.A. et al., 2010. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary
end point results of a phase III study. Ophthalmology, 117(6), pp1102-1112.
31
Brown, D.M. et al., 2010. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end
point results of a phase III study. Ophthalmology, 1124-1133.
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July 28, 2015
Figure 19. Comparison of IST Data with Pivotal Lucentis Trials
Pivotal CRVO Study
Pivotal BRVO Study
Lucentis + OHR-102
Pivotal CRVO Study
Pivotal BRVO Study
Lucentis + OHR-102 then
Lucentis only (week 10-38)
Lucentis + OHR-102
Injections
Week
Mean Letters Gained
2
2
2
6
6
10
10
10
26
26
12
14
20.3
18.3
14.9
2 + PRN
38
23.3
2 + PRN
38
27.8
Proliferative Diabetic Retinopathy. Dr. Michael Elman is conducting an investigator-sponsored trial (IST) with
OHR-102 in patients with proliferative diabetic retinopathy (PDR).32 The trial is a Phase II, open-label study. Although
the current enrollment status is not known, a total of 5 patients are expected to receive a 0.2% squalamine solution
twice daily unless neovascularization fails to regress at week one or if neovascularization returns during the study,
which will trigger an increase in dose to four times daily. Treatment duration is 20 weeks. The primary endpoint is the
proportion of patients with complete regression of neovascularization as determined by fundus imaging at one month.
Secondary endpoints include the mean change in visual acuity from baseline to 5 months and the proportion of
patients with partial regression of neovascularization.
Dr. Elman presented a positive case report from this trial at the 2014 Macula Society Annual Meeting on February
19th, 2014. The report included a treatment naïve patient who was receiving OHR-102 as a monotherapy. OHR-102
therapy was associated with the regression of neovascularization after two months of treatment, and the regression
remained for the full 6 months of therapy. Neovascularization returned one month after the termination of treatment
and abnormal vessels continued to grow through month 2, which was the furthest recorded time point.
It is interesting to note that PDR involves larger amounts of VEGF protein than wet-AMD, so any activity of OHR102 as a monotherapy is impressive. Dr. Elman is expected to release additional data from the trial in the second half
of 2015.
Investigator-Sponsored Trial Conclusion. The ISTs have the potential to assist in indication expansion efforts by
Ohr through the generation of efficacy data in a variety of new ophthalmology diseases. Diseases like RVO and PDR
involve larger amounts of the protein vascular endothelial growth factor (VEGF), which is one of the targets of OHR102. The expansion of data for OHR-102 to include diseases with different amounts of VEGF will be useful in
determining the efficacy of the drug and which indications to pursue.
32
http://clinicaltrials.gov/ct2/show/NCT01769183
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July 28, 2015
Other Drugs in Development for Wet AMD
Wet AMD is an active area of development due to the large number of patients and the need for alternative therapies.
Candidates fall into one of four categories:




PDGF inhibitors as single agents or developed in combination with VEGF inhibitors.
Novel VEGF inhibitors.
Gene therapy or other methods to deliver prolonged VEGF inhibition.
Novel targets.
Figure 20 shows many of the programs in development. Ophthotech’s intravitreal injection Fovista is the most
advanced program and it is being evaluated in three large Phase III studies. Molecular Partners/Allergan’s abicipar
pegol program is a novel anti-VEGF that entered Phase III trials in June 2015, and Alcon launched a Phase III
program in December 2014. The remaining programs are earlier stage with no concrete plans for pivotal studies. All
agents are administered by intravitreal injection except for Avalanche’s AVA-101, which involves delivery as a
subretinal injection. Below we describe Ophthotech’s and Molecular Partners’ programs in more detail.
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July 28, 2015
Figure 20. Programs in Development for Wet AMD
Company
Ophthotech
(NasdaqGS: OPHT)
Regeneron
(NasdaqGS: REGN)
Santen, Inc. (SNPHY)
Alcon (Novartis,
NYSE: NVS)
Molecular Partners
(Swiss: MOLN.SW)/
Allergan (NYSE:
ACT)
Avalanche Biotech
(NasdaqGM: AAVL)
Genzyme/Applied
Genetic Technologies
(NasdaqGM: AGTC)
Allegro Ophthalmics
(private)
Lpath (NasdaqCM:
LPTN)/
Pfizer (NYSE: PFE)
Candidate
Mechanism/
Target
Status
Fovista (E10030)
PDGF inhibitor
Three Phase III trials ongoing33,34,35;
data expected in 2016
REGN2176-3
PDGF inhibitor; coformulated with Eylea
Phase II ongoing36
DE-120
VEGF/PDGF inhibitor
Phase I/IIa ongoing37
RTH258
VEGF inhibitor
Phase III ongoing38
DARPin abicipar
pegol
VEGF inhibitor
Two Phase III trials ongoing39,40
AVA-101
Gene therapy to deliver
VEGF inhibitor
Phase IIb planned
AAV2-sFLT01
Gene therapy to deliver
VEGF inhibitor
Phase I ongoing41
Alg-1001
Anti-integrin
Phase Ib complete
iSONEP
Anti-S1P
Phase II complete
Fovista (E10030) – Ophthotech
Fovista is a short DNA-based oligonucleotide aptamer, which binds with high affinity to PDGF to inhibit activation
of the PDGF-β receptor. As described in the mechanism of action section, activating PDGF-β is a critical step in the
recruitment and maturation of pericytes, and these cells are important regulators of anti-VEGF treatment resistance
in neovascular tissue. Inhibition of PDGF-β by Fovista removes the pericytes from new blood vessels, making them
vulnerable to an anti-VEGF insult. In a Phase I study, Fovista in combination with Lucentis yielded a significant visual
acuity gain of 15 letters and dramatically reduced choroidal neovascularization by 85%. Ophthotech has also
completed a randomized Phase IIb trial and recently launched a pivotal Phase III program.
35 http://clinicaltrials.gov/ct2/show/NCT01940887
39
40
33
34
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July 28, 2015
REGRESS Phase IIb Trial. Ophthotech completed a large randomized, double-masked, controlled, Phase IIb study
(REGRESS). A total of 446 newly diagnosed wet AMD patients were randomized to receive intravitreal injections of
0.5 mg Lucentis alone, Lucentis plus 0.3 mg Fovista, or Lucentis plus 1.5 mg Fovista. Lucentis and Fovista are not coformulated and patients received two independent injections. The primary endpoint was the change in mean visual
acuity from baseline to 24 weeks for the combination therapy compared to Lucentis monotherapy. Secondary endpoints
included additional visual acuity measures, mean change in area of choroidal neovascularization, and safety.
There was a significant improvement in visual acuity for patients receiving the 1.5 mg dose of Fovista in combination
with Lucentis compared to Lucentis monotherapy from baseline to 24 weeks (p=0.019). The mean change in visual
acuity is displayed in Figure 21. At week 24, patients in the combination arm achieved a +10.6 letter gain compared
to +6.5 for the monotherapy arm (p=0.019). This corresponded to a 62% comparative benefit from baseline.
Figure 21. Mean Change in Visual Acuity from Baseline to Week 24
Source: Ophthotech 2014 10-K
The percentage of patients gaining more than 3 lines at week 24 was 36.4% in the 1.5 mg Fovista combination arm
compared to 28.6% in the Lucentis monotherapy arm. Fovista was well tolerated and there were no cases of infection
inside the eye or any difference in the incidence of adverse events between the Fovista combination and Lucentis
monotherapy arms.
Ophthotech has a royalty agreement in place with Novo A/S, the holding company of the Novo Nordisk Foundation,
and has received $83.3 million out of a total $150 million expected. Novo A/S will receive low to mid-digit royalties
on worldwide sales of Fovista. In May 2014, Ophthotech signed a deal potentially worth more than $1 billion with
Novartis for ex-US rights to Fovista. Ophthotech received a $200 million upfront payment and is eligible for $130 in
clinical milestones, $50 million of which has already been received. The company is eligible for an additional $700
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July 28, 2015
million in potential regulatory and sales milestones, and will receive a royalty in the mid-thirties percentage on any
sales of Fovista in Novartis’s territories.
Ophthotech has initiated three Phase III studies to support a regulatory filing for Fovista in wet AMD. A total of 1,866
patients are expected to enroll in the studies. Two of the Phase III trials will evaluate the safety and efficacy of Fovista
in combination with Lucentis. One trial is fully enrolled and the second study is expected to complete enrollment by
the end of the third quarter of 2015. The third is enrolling patients and will examine Fovista in combination with Avastin
or Eylea. The primary endpoint for the studies will be the mean change in visual acuity from baseline to 12 months.
Data from the two trials in combination with Lucentis are expected in 2016, 1 year after the last patient is enrolled in
the second study.
One potential drawback to this treatment paradigm is that Fovista and Lucentis are not co-formulated, thereby
necessitating dual intravitreal injections on a monthly basis with a likely 30-minute wait time between injections.
Ophthotech has reported that co-formulation is possible.
DARPin Abicipar Pegol – Allergan/Molecular Partners
Allergan and Molecular Partners have teamed up to produce designed ankyrin repeat proteins (DARPins) aimed at
treating wet-AMD. Ankyrins are important for mediating protein-protein interactions. DARPins are essentially
genetically engineered proteins made of repeated ankyrins that mimic the actions of antibodies. They have a small
molecular weight (14 kDa), specific binding, high (picomolar) affinity, high thermal stability, do not contain T-cell
epitopes, and can be expressed easily in E. coli cultures. 42 DARPin-based abicipar pegol inhibits VEGF-A and is
delivered by intravitreal injection.
Molecular Partners has conducted a Phase II study with abicipar. A total of 64 patients were randomized to receive 1
mg abicipar, 2 mg abicipar, or 0.5 mg Lucentis. All patients received 3 doses of therapy at weeks 0, 4, and 8. Lucentis
was administered monthly thereafter and patients in the abicipar groups received sham injections. There was a
numerical mean improvement in visual acuity from baseline to week 16 in the abicipar groups compared to Lucentis.
The mean letter gain for each group is shown below:



1 mg abicipar: +6.3 letters.
2 mg abicipar: +8.2 letters.
0.5 mg Lucentis: +5.3 letters.
The data were collected 4 weeks after the last Lucentis injection and 8 weeks after the last abicipar injection. There were
no serious adverse events reported in the study although two patients treated with 2 mg abicipar and 3 patients treated
with 1 mg abicipar developed ocular inflammation. These episodes were resolved with anti-inflammatory drops.
On June 30th 2015, Molecular Partners and Allergan announced the launch of a Phase III program. The program
consists of two randomized, double-masked, placebo-controlled trials, CEDAR and SEQUOIA, that are expected to
enroll 900 patients each. Patients will be enrolled into the 1 of 3 arms:
Sennhauser, G. et al., 2007. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biology,
5(1), e7.
42
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July 28, 2015



2 mg abicipar on day 1, week 4, and week 8 followed by injections every 8 weeks out to week 96.
2 mg abicipar on day 1, week 4, and week 12 followed by injections every 12 weeks out to week 96.
0.5 mg Lucentis every 4 weeks from day 1 to week 96.
The initiation of the trials triggered a $15 million milestone payment from Allergan to Molecular Partners. The
companies formed a deal in 2011 worth up to $375 million in upfront, developmental, and regulatory, and sales
milestones.
Competitive Landscape
OHR-102 Could be Synergistic with Any of the Anti-VEGFs. The general consensus among ophthalmologists is
that Eylea is the most effective anti-VEGF used for the treatment of wet AMD patients. However, the other two antiVEGFs, Lucentis and Avastin, are widely used in practice. Lucentis was the first FDA approved anti-VEGF for wet
AMD and still captures approximately 20% of the market. Avastin is substantially cheaper than Lucentis and Eylea, and
head to head studies have found Avastin and Lucentis to be similar regarding safety and efficacy. The significant cost
advantages of using compounded Avastin have made it the most widely used anti-VEGF by physicians despite not
having a label for wet AMD. It is important to note that all anti-VEGF treatments are delivered via an intravitreal
injection and act on a common molecular pathway. For this reason, it is expected that if OHR-102 is successful at
improving visual acuity in Phase III trials in combination with Lucentis, it will also be successful with Eylea and Avastin.
Therefore, OHR-102 will not be directly competing with these well-established wet AMD treatments, and could
instead by used to further enhance their efficacy. This treatment paradigm also allows physicians to keep patients on
the current standard of care, a feature that is likely to increase the chances of OHR-102 adoption.
Visual Acuity Gains for OHR-102 Compared to Historical Data. Although caution must be taken when
comparing any two studies, when analyzing data from a larger trial testing Lucentis and Avastin versus Ohr’s IMPACT
Phase II study, there is clearly potential for visual acuity benefit from OHR-102. Data from a study conducted by the
Comparison of AMD Treatment Trials (CATT) Research Group is presented below.43 The trial was a multi-center,
single-masked, non-inferiority study where 1,208 patients were randomized to receive Lucentis or Avastin
(bevacizumab) on a monthly or PRN schedule. The primary endpoint was the mean change in visual acuity at 12
months.
The mean baseline visual acuity was similar between patients in Ohr’s Phase II trial and the CATT study, which
averaged approximately 60 letters. Figure 22 shows the number of patients who gained 3 or more lines of visual
acuity, which is the Phase III endpoint for Ohr’s upcoming pivotal clinical program. 40% or more of the patients
treated with OHR-102 gained 3 or more lines. In comparison, the percentage of patients gaining 3 or more lines was
less than 30% for the placebo group and for all treatment arms in the CATT study.
CATT Research Group, 2011. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. New England
Journal of Medicine, 364(20), pp1897-1908.
43
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Figure 22. Percentage of Patients Gaining 3 or More Lines in CATT and IMPACT Studies
Source: Company Reports, CATT Research Group et al., 2011, & LifeSci Capital
Comparisons between Ohr’s IMPACT and Ophthotech’s REGRESS Trials. Although we must remind caution
when comparing results from different trials, we have examined Ohr’s Phase II trial compared to Ophthotech’s Phase
IIb REGRESS study. Figure 23 shows the percentage of patients gaining 3 or more lines of vision in each trial. Ohr’s
trial was 12 weeks longer, which should be considered when looking at the data. It is also important to note that Ohr
enrolled patients with occult lesions up to 12 disc areas, whereas Ophthotech enrolled patients with occult lesions of
5 disc areas of less. Treating large occult lesions may not benefit visual acuity as expected with classic lesions.
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July 28, 2015
Figure 23. Percentage of Patients Gaining 3 or More Lines in REGRESS and IMPACT Studies
Source: Company Reports & LifeSci Capital
Figure 24 shows the mean visual acuity gains for patients in the REGRESS and IMPACT studies. Patients in the
IMPACT trial experienced a similar visual acuity gain when compared to Lucentis monotherapy as those in the
REGRESS trial despite receiving PRN therapy and the trial enrollment criteria allowing larger areas of CNV that may
negatively impact treatment activity. Note that in the graphs below the REGRESS data is for 24 weeks while the
IMPACT study shows treatment up to 36 weeks. Keep in mind that the control arm in the IMPACT trial was similar
to that in the REGRESS trial, but patients taking Lucentis PRN in the IMPACT trial didn’t perform as well as those
taking monthly injections, which is in line with expectations. Then, the key thing to note here is that the OHR-102
plus Lucentis as needed (right graph, blue line) performed similarly to Fovista 1.5 mg plus Lucentis (left graph, top grey
line).
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July 28, 2015
Figure 24. Mean Visual Acuity Gain in REGRESS and IMPACT Studies
Source: Company Reports & LifeSci Capital
Squalamine Offers Potential for Visual Acuity Gains without Additional Intravitreal Injections. Ophthotech’s
Fovista is an intravitreal injection that is administered to patients during their regular treatment visit, meaning that
patients receive two intravitreal injections within a short time period. Data from the REGRESS Phase IIb trial indicate
that Fovista plus Lucentis significantly increases the mean visual acuity of patients compared to Lucentis alone (p=0.019).
The data validate the use of a PDGF inhibitor to improve visual acuity alongside a VEGF inhibitor such as Lucentis.
Ohr’s Phase II data suggest that OHR-102 may also provide a visual acuity enhancement, which is consistent with the
multi-growth factor inhibition mechanism of OHR-102, but without additional intravitreal injections.
At the end of the REGRESS trial, which was 24 weeks, patients received 12 injections compared to an average of 6.4
across 9 months of the IMPACT study. Note that in the Phase III program with OHR-102, patients will receive
monthly Lucentis injections for the first year, and so they will receive 6 injections over 24 weeks. This would still be
half the number of injections required with Ophthotech’s injectable Fovista to achieve a benefit in visual acuity over
the standard of care.
Competitive Advantages of Squalamine Could Translate to Additional Indications. Other ophthalmic
indications can benefit from the intravitreal injection of VEGF inhibitors, and drugs like Lucentis and Eylea are
becoming the choice of patients for many eye diseases. They are FDA approved for wet AMD, retinal vein occlusion,
diabetic macular edema (DME), and diabetic retinopathy. DME represents a greater than $1 billion market opportunity
alone. Following potential approval of OHR-102 for wet AMD, Ohr would be in a position to work for expansion to
DME and RVO. The competitive advantages of OHR-102 described above should translate to these other indications,
opening up significant additional markets.
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July 28, 2015
Sustained Release Platform
In May 2014 Ohr entered into an agreement to acquire SKS Ocular and its proprietary sustained release technology
being developed for glaucoma, eye allergy, and retinal disease. The platform technology is versatile and should allow
Ohr to develop additional candidates using small molecules or proteins for a variety of ophthalmology indications. As
a testament to the potential for the technology, Ohr has a research collaboration for the glaucoma program with
Alcon, a leading ophthalmology player wholly owned by Novartis. The acquisition is consistent with Ohr’s previously
stated long-term goal of developing a pipeline of ophthalmology products led by squalamine for wet AMD, and Ohr
acquired a research facility to enable development. The acquisition also brought several key opinion leaders onto the
Ohr management team to help lead efforts with OHR-102 and the newly acquired sustained release programs.
Target Indications. SKS technology is in preclinical development for several ophthalmology indications. There are
two glaucoma programs, one in collaboration Alcon, and a second for steroid induced glaucoma. Glaucoma is a
relevant indication for a sustained release technology, as patients typically experience few symptoms until permanent
damage develops, and the lack of major symptoms contributes to a low rate of compliance with existing treatments.
Even when patients have been diagnosed with glaucoma and begin receiving eye drop treatment they may fail to
comply due to a lack of noticeable symptoms. Using SKS technology, treatment would be administered by a physician
and have the potential to increase compliance to 100%. The two additional preclinical programs in retinal disease and
allergy are also relevant indications based on the capabilities of the SKS technology. Ohr plans to file an IND for its
leading sustained release program in 2016.
Sustained Release Technology. Ohr has a proprietary platform technology (SKS) to facilitate the delivery of
therapeutic molecules to the eye in a sustained manner and with great flexibility. The technology allows manufacture
of well-defined particles that contain small molecules or biologics, which are released in a controlled fashion to deliver
an initial bolus followed by sustained drug delivery for up to 6 months. The manufacturing process is patented and
designed for large-scale batch production, facilitating cost effective production and commercial feasibility.
Unlike many other sustained release technologies, Ohr’s manufacturing process yields particles with a consistent size.
Uniform particles translate into a reproducible and predictable drug release profile. The microparticle size is controlled
using a dissolvable hydrogel template during the manufacturing process, which is depicted in Figure 25. In steps 1 to
3, the hydrogel template is produced from a silicon wafer. In step 4, polymer and drug are added to the predefined
wells. Once the polymer solidifies, the hydrogel template is gently dissolved to yield microparticles of a defined size,
as shown in steps 5 and 6.
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July 28, 2015
Figure 25. Microparticle Manufacturing
Advantages of Ohr’s Sustained Release Technology. There are distinct potential advantages of the SKS
technology over alternative sustained delivery systems. Figure 26 lists some of the features of SKS versus alternatives.
SKS provides a level of versatility and patient convenience that is unmatched by other methods, including the ability
to control the degree of initial drug release and load multiple drugs into the same particle.
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July 28, 2015
Figure 26. Features of SKS Versus Sustained Delivery Systems
Preclinical Data. Ohr presented preclinical data from the sustained release platform at the 2015 Association for
Research in Vision and Ophthalmology (ARVO) meeting.44 Data were presented supporting use of the platform in
glaucoma, steroid-induced glaucoma, inflammation, and retinal disease. For glaucoma, Ohr demonstrated the ability
to fine-tune drug release. Particles were created that release drug over 1, 3, or 4 months. Cumulative drug release
profiles are shown in Figure 27. In the 1 month formulation indicated by the blue line, 100% of the drug was released
within the target timeframe. Similar release profiles are shown for the 3 and 4 month formulations. Ohr has also used
a layering process to minimize rapid drug release during the first several days of administration. The amount of drug
released without layering is displayed on the right of the figure.
44
Malavia, N. et al., 2015. Biodegradable sustained release drug delivery systems fabricated using dissolvable hydrogel template
technology for the treatment of ocular indications. The Association for Research in Vision and Ophthalmology Meeting.
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July 28, 2015
Figure 27. Drug Release of Hydrophilic Molecule for Glaucoma Indication
Source: Malavia, N. et al., 2015
The following results were presented for the remaining indications:



Steroid-induced glaucoma – sustained release was achieved using a hydrophobic drug molecule.
Inflammation – tunable release was observed using two different biodegradable polymers or a mixture of the
two.
Retinal disease – sustained released was accomplished with a biologic of approximately 150 kilodaltons (kDa).
For reference, Lucentis is 48 kDa and Avastin is 149 kDa.
The data suggest that Ohr can control and tune the release of several types of drugs including small molecules and
biologics. The versatility of the platform positions Ohr well as the Company expects to file an IND for 1 sustained
release program in 2016.
Intellectual Property & Licensing
Ohr maintains a portfolio of over 100 US and foreign patents and patent applications protecting its pipeline products.
These patents cover composition of matter, syntheses, methods of use and drug product formulations, and the
Company continues build on and augment its intellectual property portfolio. The issued squalamine lactate active
pharmaceutical ingredient (API) composition of matter patents extend to 2029, and those on eye drop formulations
extend to 2030, exclusive of Hatch-Waxman extensions.
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July 28, 2015
Management Team
Irach Taraporewala, Ph.D.
Chief Executive Officer and President
Dr. Taraporewala has over 30 years in drug development and regulatory affairs experience. He was formerly the Vice
President of Regulatory Affairs and Clinical Research at Austin, TX-based Mystic Pharmaceuticals Inc. where he led
the regulatory strategy for the company's ophthalmic and intranasal drug products and drug delivery systems. Prior to
that, Dr. Taraporewala served as Senior Consultant in the Drug Development Consulting division of Boston-based
PAREXEL International Corp., a leading global pharmaceutical services provider, where he provided technical
expertise and regulatory advice to small and large biotechnology and pharmaceutical company clients worldwide, and
also conducted due diligence for companies and venture capital firms on technology and portfolio evaluation and
product acquisitions. From 1998 to 2004, Dr. Taraporewala was Director of Chemistry and Quality Control at
Yonkers, NY-based Advanced Viral Research Corporation where he helped take OHR/AVR118, an
immunomodulator drug, into clinical trials for AIDS, cancer cachexia and rheumatoid arthritis, working closely with
Shalom Hirschman, M.D., Ohr's Chief Scientific Advisor. Prior to that, Dr. Taraporewala worked in research and
development at CIBA-Geigy, which later merged with Sandoz to become Novartis. He has also served as principal
investigator on four National Institute of Health and U.S. Department of Defense funded biomedical research grants
on antiviral drugs, DNA-based cancer diagnostics and on antimalarial compound development. Dr. Taraporewala
earned bachelors' and masters' degrees in chemistry and microbiology from the University of Bombay, India and a
Ph.D. in medicinal chemistry from the Philadelphia College of Pharmacy. He conducted postdoctoral research at the
University of Texas at Austin, the University of Minnesota and the Southwest Foundation for Biomedical Research.
Dr. Taraporewala has multiple scientific publications and patents to his credit, and has lectured extensively.
Sam Backenroth
Chief Financial Officer and Vice President of Business Development
Mr. Backenroth has executive experience in advising and financing biotechnology companies. He previously worked
as an Investment Banker with The Benchmark Company LLC, an Investment Banking firm specializing in micro-cap
biotechnology transactions. While at Benchmark, Sam helped fund numerous small biotechnology companies raise
equity growth capital through a variety of structures. Mr. Backenroth also acted as an advisor to multiple public and
private biotechnology and pharmaceutical companies in assisting with business development activities, joint ventures,
licensing, strategic partnerships, and mergers & acquisitions. He graduated with honors from Touro College with a
Bachelor's degree in finance.
Jason Slakter, M.D.
Chief Medical Officer
Dr. Jason S. Slakter is an internationally recognized retinal and macular disease specialist. He was previously Chief
Executive Officer and cofounder of SKS Ocular LLC. He is also is the Founder and Director of the Digital
Angiography Reading Center (DARC) in New York, which is the largest center for ocular image evaluation for clinical
trials of posterior segment disease with over 700 certified clinical sites in over 40 countries worldwide. The DARC
model for digital imaging, electronic image management and assessment has become the industry standard for
ophthalmic clinical trials. Dr. Slakter has been involved extensively in the design and application of new diagnostic
and treatment modalities for ophthalmic diseases. As Director of DARC, a principal investigator of many clinical
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July 28, 2015
trials, and a pharmaceutical industry consultant, Dr. Slakter has played a major role in the discovery, development and
commercialization of treatments for age-related macular degeneration, diabetic retinopathy, retinal vascular disease,
central serous chorioretinopathy and other retinal diseases. He has provided critical assistance in the design of clinical
trials at all stages of development, and has participated in numerous meetings with the FDA. In addition, Dr. Slakter
served as Chief Medical Officer for Potentia Pharmaceuticals from its inception through its acquisition by Alcon
Laboratories, Inc. (Novartis). Dr. Slakter is a member of The American Ophthalmological Socieity, The Macula
Society, The Retina Society, and The American Society of Retina Specialists. He was the founding Editor-in-Chief of
Retinal Physician journal. He has been the recipient of many awards including The Macula Society’s Richard and
Hinda Rosenthal Award for outstanding contribution to the treatment of ocular disease by an individual under the age
of 45, and the 2003 Helen Keller Manhattan League Award. Dr. Slakter is a Clinical Professor of Ophthalmology at
New York University School of Medicine and practices at the Vitreous-Retina-Macula Consultants of New York.
Glenn L. Stoller, M.D.
Chief Scientific Officer
Dr. Glenn L. Stoller is a nationally recognized retina specialist, medical scientist and innovator. He was previously
Chief Scientific Officer and cofounder of SKS Ocular LLC. He has participated in all stages of preclinical and clinical
development for therapeutics and devices as well as and post-approval sales and marketing. As a principal investigator,
pharmaceutical industry consultant, and scientific advisory board member, he has participated in over 40 clinical trials
for ocular diseases including wet age-related macular degeneration, dry age-related macular degeneration, diabetic
retinopathy, and retinal venous occlusive disease. Dr. Stoller led Lpath Ocular and oversaw the preclinical and clinical
development of iSONEP, from inception through a development and commercialization partnership with Pfizer. He
led the non-GLP and IND enabling studies for iSONEP leveraging relationships with biotech companies, contract
research organizations, and academia. He was actively involved in all aspects of the iSONEP ocular program, including
formulation, toxicology and CMC. He played a key role in the design and development of clinical protocols and
presentation of the program to the FDA. Dr. Stoller currently serves as a member of the Pfizer-Lpath Joint
Development Committee. He played a key role in establishing that bioactive lipids are mediators of human retinal
disease. He is a member of the major medical organizations in his field including The Retina Society and The American
Society of Retina Specialists. He is currently a Steering Committee Member of the American Academy of
Ophthalmology’s Ophthalmic Registry Work Group where he serves as the sole representative for The Macula Society,
The Retina Society and The American Society of Retina Specialists. He has served as Editorial Board Member of The
American Academy Of Ophthalmology.
Avner Ingerman, M.D.
Chief Clinical Officer
Dr. Ingerman is an ophthalmologist, with more than 15 years of pharmaceutical industry product development
experience. Dr. Ingerman's previous roles included serving as Vice President of Ophthalmology at Regeneron
Pharmaceuticals, where he was responsible for the Eylea® development program, which was conducted in
collaboration with Bayer Healthcare. At Johnson & Johnson, he was research and development director in Israel and
the UK, and clinical leader for the Lastacaft® development program in the U.S. Dr. Ingerman additionally served as an
ophthalmology development consultant to numerous companies. Dr. Ingerman received his MD degree from the TelAviv University Sackler School of Medicine and completed his ophthalmology residency at the Rabin Medical Center
in Israel.
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July 28, 2015
Peter K. Kaiser, M.D.
Senior Vice President of Product Development
Dr. Peter K. Kaiser is an internationally recognized vitreoretinal specialist and a leader in ophthalmic pharmaceutical
development. He was previously Chief Medical Officer and cofounder of SKS Ocular LLC. Dr. Kaiser has been a
principal investigator in over 50 trials evaluating new treatments for AMD, DR, and other retinal disorders, and Study
Chairman of 7 major, multi-center, international clinical trials. He has participated in the preparation of regulatory
filings and presentations to the FDA for Regeneron, and Thrombogenics. Dr. Kaiser is the founder and director of
the Digital Optical Coherence Tomography Reading Center (DOCTR), which is the OCT coordinating center for
numerous multicenter clinical trials. He serves on the scientific advisory boards of Bayer, Novartis, Digisight,
Genentech, GlaxoSmithKline, Allegro, Alcon, Allergan, Regeneron, Bausch and Lomb, Thrombogenics, Alimera,
Oraya, Ophthotech, and Kanghong. He is a National Institute of Health RO1 funded investigator and leads a team
involved in the evaluation of vascular biology in age-related macular degeneration and diabetic retinopathy. He has
authored six ophthalmology textbooks, and more than 200 peer-reviewed papers. He is Editor-in-Chief of Retinal
Physician, Associate Editor of International Ophthalmology Clinics, and serves on the editorial boards of American
Journal of Ophthalmology, Retina, Retina Today, and Ocular Surgery News. Dr. Kaiser has been recognized by the
American Academy of Ophthalmology and American Society of Retina Specialists with both Achievement and Senior
Achievement Awards.
Barbara Wirostko, MD
Vice President of Clinical Development
Dr. Barbara Wirostko serves as Vice President of Clinical Development at Ohr Pharmaceutical, Inc. Dr. Wirostko
maintains an academic research and clinical practice with the Moran Eye Center, as a Clinical Adjunct Associate
Professor in Ophthalmology as well as a Adjunct Associate position with the Department of Engineering at the
University of Utah. She has served and been recognized for her leadership roles both in small biotech and in large
Pharmaceutical companies. As the Principle Investigator and co founder for Jade Therapeutics, Inc., she has received
Phase I & II SBIR grants from the National Science Foundation as well as the Department of Defense to develop
Hyaluronic acid polymers as an on-eye drug delivery system. She serves on various editorial boards, and is a member
of the Glaucoma Research Foundation Science Committee and The Glaucoma Foundation scientific advisory board,
as well as a grant reviewer for California Institute of Regenerative Medicine for the past 4 years Dr Wirostko as the PI
has received Phase I & II SBIR grants from the National Science Foundation as well as the Department of Defense
to develop polymers as an on-eye drug delivery system. Dr Wirostko as the PI has received Phase I & II SBIR grants
from the National Science Foundation as well as the Department of Defense to develop polymers as an on-eye drug
delivery system.. She chaired the yearly GTC Ocular Diseases and Drug Development Conference from 2009-2012.
As Senior Medical Director within the Specialty division at Pfizer in NY from 2006-2010, she oversaw the
development of pipeline glaucoma strategy and originated the Sustained Release Xalatan program now in clinical. She
completed her glaucoma fellowship at Cornell University, NY and received her Ophthalmology training as well as her
MD at Columbia University, College of Physicians and Surgeons in NY. Her BA with distinction was from Cornell
University, Ithaca, NY. She is an active member and fellow of the American Academy of Ophthalmology, ARVO,
Women in Ophthalmology, and local state societies.
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July 28, 2015
Marlene Modi, Ph.D.
Vice President, Preclinical Development and Regulatory Affairs
Marlene Modi serves as Vice President of Preclinical Development and Regulatory Affairs at Ohr Pharmaceutical, Inc.
She has more than 25 years of experience in the pharmaceutical industry. Previously, she was Vice President of
Preclinical Development at Optherion, Inc. and Senior Director of Clinical Pharmacology at Eyetech Pharmaceuticals,
Inc with responsibilities for assessing the pharmacology and toxicology of compounds in development. For 15 years,
Dr. Modi worked at Hoffmann-La Roche in key management positions, including Site Head and Director of Clinical
Pharmacology. Dr. Modi has extensive expertise in the areas of preclinical and clinical development of large molecules
(e.g., proteins, monoclonal antibodies, aptamers and pegylated compounds). She has facilitated the IND submission
of more than 14 compounds within the last 5 years. She has played a key role in the submissions of
NDAs/BLAs/MAAs and sNDAs including Pegasys®, CoPegasus® and Macugen®. Her work has included the
therapeutic areas of ophthalmology, virology, infectious disease, neurology, oncology, diabetes and asthma. Her areas
of expertise include drug-drug interactions, pharmacokinetic-pharmacodynamic relationships, ocular and intraocular
formulation development, and dose- and exposure-response relationships in special populations. She received a B.S.
in Pharmacy from the University of Houston and a Ph.D. in Pharmaceutics from the State University of New York
at Buffalo.
Risk to an Investment
We consider an investment in Ohr to be a high-risk investment. Ohr is a developmental stage company with no history
of taking a treatment to market, and currently has no FDA approved drugs in its portfolio. The neovascular agerelated macular degeneration market is especially crowded with existing competitors, which could make a successful
entry into this market challenging. Ohr’s lead program has not yet entered Phase III trials and has limited clinical data
to date in the current formulation. Furthermore, early indications of efficacy do not necessarily translate into positive
late-stage results. As with any company, Ohr may be unable to obtain sufficient capital to fund planned development
programs. There are regulatory risks associated with the development of any drug and Ohr may not receive FDA
approval for its candidates despite significant time and financial investments. Regulatory approval to market and sell
a drug does not guarantee that the drug will penetrate the market, and sales may not meet the expectations of investors.
Page 43
July 28, 2015
Analyst Certification
The research analyst denoted by an “AC” on the cover of this report certifies (or, where multiple research analysts are primarily responsible
for this report, the research analyst denoted by an “AC” on the cover or within the document individually certifies), with respect to each
security or subject company that the research analyst covers in this research, that: (1) all of the views expressed in this report accurately
reflect his or her personal views about any and all of the subject securities or subject companies, and (2) no part of any of the research
analyst's compensation was, is, or will be directly or indirectly related to the specific recommendations or views expressed by the research
analyst(s) in this report.
DISCLOSURES
This research contains the views, opinions and recommendations of LifeSci Capital LLC (“LSC”) research analysts. LSC (or an affiliate)
has received compensation from the subject company for producing this research report. Additionally, LSC provides investment banking
services to the subject company and has received compensation from the subject company for such services within the past 12 months.
LSC expects to receive or intends to seek compensation for investment banking services from the subject company in the next 3 months.
An affiliate of LSC has also provided non-investment banking securities-related services, non-securities services, and other products or
services other than investment banking services to the subject company and received compensation for such services within the past 12
months. LSC does not make a market in the securities of the subject company.
Neither the research analyst(s), a member of the research analyst’s household, nor any individual directly involved in the preparation of
this report has a financial interest in the securities of the subject company. Neither LSC nor any of its affiliates beneficially own 1% or
more of any class of common equity securities of the subject company.
LSC is a member of FINRA and SIPC. Information used in the preparation of this report has been obtained from sources believed to be
reliable, but LSC does not warrant its completeness or accuracy except with respect to any disclosures relative to LSC and/or its affiliates
and the analyst's involvement with the company that is the subject of the research. Any pricing is as of the close of market for the securities
discussed, unless otherwise stated. Opinions and estimates constitute LSC’s judgment as of the date of this report and are subject to change
without notice. Past performance is not indicative of future results. This material is not intended as an offer or solicitation for the purchase
or sale of any financial instrument. The opinions and recommendations herein do not take into account individual client circumstances,
objectives, or needs and are not intended as recommendations of particular securities, companies, financial instruments or strategies to
particular clients. The recipient of this report must make his/her/its own independent decisions regarding any securities or financial
instruments mentioned herein. Periodic updates may be provided on companies/industries based on company specific developments or
announcements, market conditions or any other publicly available information. Additional information is available upon request.
No part of this report may be reproduced in any form without the express written permission of LSC. Copyright 2015.
Page 44

Ohr Pharmaceutical, Inc. (OHRP)

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