Taking a Dermatological Approach to treating Ocular Surface Diseases
MARC GLEESON | CHIEF EXECUTIVE OFFICER
OIS@AAO 2019
for Meibomian Gland Dysfunction, Contact Lens Discomfort & Blepharitis
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Contact Lens Discomfort Blepharitis
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In Office Physician Only Administered Rx Treatment
Patient Administered Rx Chronic Treatment applied to the eyelid
Meibomian Gland Dysfunction
Patient Administered Rx Chronic Treatment applied to the eyelid
Allows continuation of Contact Lens Wear
Patient Administered Rx Treatment applied to the eyelid
New Chemical Entity
Lid Margin Involvement Hyperkeratinization of the Gland Orifice +/- Inflammation
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(MGD)
Modified sebaceous (oil-producing) glands responsible for secreting the outer lipid layer (meibum) of the tear film, which lubricates the ocular surface during blinking and protects against tear evaporation1,2
Reduced secretion of lipids leads to instability of the tear film
and drying of the ocular surface, leading to damage and the
signs and symptoms of dry eye disease (DED).
Obstructive MGD is the most common cause of evaporative
dry DED,1,3 and clinical signs of obstructive MGD are present
in 86% of DED patients4
MGD traditionally regarded as a hypersecretory disorder
associated with bacterial infection and inflammation,1 which
has guided the approach to treatment, often unsuccessfully
1Blackie et al. Cornea. 2010 | 2Knop et al. Invest Ophthalmol Vis Sci. 2011 | 3Baudouin et al. Br J Ophthalmol. 2016 | 4Lemp et al. Ocul Surf. 2009.
Clinical Manifestation
Destabilises the tear film
Results in loss of aqueous
layer by evaporation
Together these result in an
irregular ocular surface and
symptoms of dry eye
Loss of the tear lipid layer
Clinically the Meibomian glands
are blocked, damaged and/or
meibum production in altered
Histopathology: gland
‘blockage” at the orifice and/or
duct, damage and/or functional
alteration to the meibomian
acinar cells, and gland atrophy
Functionally there is reduced
lipid production and/or
secretion
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BLOCKED ORIFICES, THICK LIPIDS AND LIPID DEFICIENCY
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A GUIDING LIGHT FOR THE DEVELOPMENT OF RX TREATMENTS FOR MGD
Meibomian Glands
and Sebaceous Glands
come from the same
embryonic source
Condition – medical use
• Acne
removal of keratin plug
• Seborrheic dermatitis
reduction of hyperkeratosis
• Psoriasis
reduction of hyperkeratosis
• Dandruff
reduction of hyperkeratosis,
keratin breakdown
Keratolytic agents (representative agents)
• Salicylic acid
• Selenium disulfide
• Urea
• Retinoic acid
Acne – Keratin plug
As in diseases of the lid margin, secretory gland hyperkeratinization plays an important role in various skin disorders, and agents that reduce hyperkeratinization of the skin/sebaceous glands are effective in treating these conditions
1Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest
Ophthalmol Vis Sci. 2011 Mar 30;52(4):1938-78. | 2Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf. 2003 Jul;1(3):107-26. | 3Gutgesell
VJ, Stern GA, Hood CI. Histopathology of meibomian gland dysfunction. Am J Ophthalmol. 1982;94:383-387. | 4Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 2004;2:149-165.
• Hyperkeratinization of the orifice and the ductal epithelium results in luminal plugging1
• Orifice Blockage
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BLOCKED GLANDS AT THE GLAND ORIFICE AND THICK LIPIDS
Gla
nd
O
rifi
ce
Normal Glands Blocked Glands
(Gland Orifice Obstruction)1
MGD Pathomechanism• Formation of keratinized epithelial debris (keratin strands
crosslinked linked by strong disulfide bonds)3,4 increases the normal melting point of meibum1
• Basal acinar cells have sparse cytoplasm containing a large number of keratin filament bundles that contribute to meibum1
• Altered Meibum Quality and Thickness
Meib
um
V
isco
sity
Normal Meibum Altered Meibum
(Increased Meibum Keratin)1
MGD Pathomechanism
1 Knop E, Knop N, Millar T, Obata H, Sullivan DA. IOVS, Special Issue 2011. 1938-1978 | 2Korb DR, Henriquez AS.. J Am Optom Assoc. 1980;51:243–251 | 3Tomlinson et al. Invest Ophthalmol Vis Sci. 2011 |4Ong et al. Curr Eye Res. 1991 | 5 Obata et al. 2002;:ARVO E-Abstract 60
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UNBLOCKING GLANDS AND DISRUPTION OF KERATIN PLAQUES WITHIN MEIBUM MATRIX
Keratins are helical
structural proteins
that make up hair,
nails, feathers, horn
and skin
Extremely resilient
and insoluble
Disulfide bond cross
linking hardens
structures to give
strength and
durability
Disulfide bonds are
comparatively strong
and require considerable
thermal energy to
break, >144 ˚C
Readily achieved chemically
For ocular use require mild disulphide bond disrupting agent
Disulfide bond disruption
in hair by ammonium
thioglycolate is the basis
for permanent wave
“perm” hair styling
Bunick and Milstone Journal of Investigative Dermatology 2017, Volume 137, 142-150: The X-Ray Crystal Structure of the Keratin 1-Keratin 10 Helix 2B Heterodimer | Reveals Molecular Surface Properties and
Biochemical Insights into Human Skin Disease | Istrate et al. Macromol. Biosci. 2009, 9, 805–812: Non-Isothermal Kinetics of Hard a-Keratin Thermal Denaturation
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UNIQUE MECHANISM OF ACTION IN MGD
Keratostatic:
Slows down both the rate of keratinocyte
proliferation and keratin production1
Keratolytic:
Softens keratin plug by breaking down
disulfide (S-S) bonds, thereby alleviating
hyperkeratinization that leads to blockage
of Meibomian glands1
AZR-MD-001 is the only known molecule that can target the full scope of dysfunctional Meibomian glands: Hyperkeratosis and Reduced Lipid Production
Lipogenesis
Stimulates lipogenesis to increase the quantity
of lipids produced by the Meibomian glands2
Control of Demodex
Demodex mites on eyelash follicles can
contribute to MGD and blepharitis3,4
Active ingredient in AZR-MD-001 is effective
in treating Demodex folliculitis5,6
1 Data on file, Azura Ophthalmics. Study Report AZRPC003. | 2 Data on file, Azura Ophthalmics. Study Reports AZRPC004, AZRPC005 | 3 Zhang et al. Int J Ophthalmol. 2018 4 Gonzalez-Hinojosa et al. Indian J Ophthalmol. 2018 | 5 Luo et al. Medicine. 2016 | 6 Sanfilippo et al. Cutis. 2005.
Keratinocytes (HaCat Cells)
In Vitro
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IN VITRO/EX VIVO
BrdU – Incorporated into
synthesized DNA of replicating cells
Human Skin
Ex Vivo
Reduction in BrdU = reduction
in cell growth/proliferation
SeS2 reduces growth/proliferation
of keratinocytes
150
125
100
75
50
25
0
Cell proliferation | BrdU, % of control
control 100µM 1mM 10mM
Cell proliferation | BrdU, % of control
vehicle 500µM 1mM 5mM
150
125
100
75
50
25
0
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HUMAN SKIN EX VIVO
Examined the ability of SeS2
to break disulfide bonds in
human keratin
Breakage (chemical reduction)
of disulfide bonds generates
free thiols = keratolytic/skin
softening effect
SeS2 has a keratolytic effect
at high concentration (1% and
2.5% – 2.5-fold and 3.5 fold > free thiol
formation vs. control)
Red
uctio
n
Oxid
atio
n
SH
SH
Free thiols
(S-H)
SS
Disulfide bond
(S-S)
A. 2-h incubation
AZR-MD-001
B. Overnight incubation
AZR-MD-001
Free thiol moieties | % of controlFree thiol moieties | % of control500
400
300
200
100
00 1% 2.5% 0 1% 2.5%
500
400
300
200
100
0
Control 0.01µM 0.10µM
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INCREASES LIPID PRODUCTION
Lipid production
Control SeS2 0.01 µM SeS2 0.1 µM
400%
350%
300%
250%
200%
150%
100%
50%
0%
3D model culture
of Sebocytes
SeS2 or vehicle treatment
for 14 days
Histological staining
with Oil-Red-O
Automated quantification
of surface area
* Arrows point to
lipid staining
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PROOF OF PRINCIPAL CLINICAL ACTIVITY
Remove the
blockage in the
Meibomian Glands
Restore and
enhance lipid
production of
the Glands
Prevent the
process from
recurring
Human
proof of
concept
study
Objective
• Does MGT001C1 improve meibomian gland
function in patients with MGD?
Study design
• Controlled contra-lateral eye comparison
• Outcome measure: Lipid Quality and Tear Film
Stability (Tear Break-Up Time - TBUT)
Methods
• MGT001C1 treatment for 3-4 weeks (2x a week)
• One eye treated and fellow eye control
• Main outcome measures: Mean change
from baseline
-20%
-10%
0%
10%
20%
30%
40%
1 3 11 22
Mean
±SEM
(%
)
Evaluation visits (days)
Treated Control
Lipid quality (n=14)
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NON OPHTHALMIC FORMULATION
-2
-1
0
1
2
3
4
5
6
7
1 3 11 22
Mean
±SEM
TB
UT (
seco
nd
s)
Evaluation visits (days)
Treated Control
Tear stability (n=14)
At day 22, TBUT improved from ~9sec to ~15sec (~65% increase) in
the treatment group with no change in the control group (p=0.0008)
At day 22, Lipid quality improved by ~35% (3.27 to 2.12) in the
treatment group with no change in the control group (p=0.002)
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PILOT STUDY IN MGD PATIENTS | RESULTS
Treatments period Stopped Treatment
base
lin
e
Outcomes:
At day 22 study group
TBUT improved from ~9sec
to ~15sec (~65% increase)
No change was observed
in the control
group (p=0.0008)
Following treatment
cessation treatment group
returned to baseline levels
Treated Control
-3
-2
-1
0
1
2
3
4
5
6
7
8
day 1 day 3 day 11 day 22 day 44 day 62 day 105
evaluation visits (days)
Seco
nd
s (±
SEM
)
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PILOT STUDY IN MGD PATIENTS | RESULTS
Treatments period Stopped Treatment
base
lin
e
Treated Control
evaluation visits (days)
Outcomes:
At day 22 the study group
improved Meibum quality
by ~35% (3.27 to 2.12 )
No change was observed
in the control
group (p=0.002)
Following treatment
cessation treatment group
returned to baseline levels day 1 day 3 day 11 day 22 day 44 day 62 day 105
Seco
nd
s (±
SEM
)
20%
-10%
0%
10%
20%
30%
40%
50%
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INNOVATIVE OPHTHALMIC FEATURES
Stabilisation
• SeS2 stabilised by anhydrous
semi-solid composition that
prevents formation of
particle aggregates
Surfactant-free
• Ocular formulation with
homogeneous dispersion
of SeS2 particles
Adhesion
• Good spread ability and
adhesiveness on eyelid
Optimal melting
• Specific composition with
optimal melting point and
viscosity range suitable for
softening and fluidisation
of meibum lipids
Applicator
• Combination of
formulation and applicator
in single, ready-to-use
ocular product
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MASKED VEHICLE CONTROLLED DOSE RANGING - ADAPTIVE DESIGN
Dose
concentration
• 0.1%, 0.5%,
1.0% & 2.5%
Dose
frequency
• Twice weekly
or daily
Study adapts to:
Screening
(D-14)
Baseline
(D 0) D 14 M 1 M 1.5 M 3
SeS2 0.1%: Bi-weekly,
N=8
SeS2 0.1%: Bi-weekly,
N=4; QPM, N=4
Vehicle: Bi-weekly, N=2Vehicle: Bi-weekly, N=1;
QPM, N=1
SeS2 X%*: Bi-weekly or
QPM, N=16
Vehicle: Bi-weekly or
QPM, N=4
SeS2 High* dose (N=32)
SeS2 Low* dose (N=32)
Vehicle (N=32)
M 1 M 3
Cohort 1 (Group 1-4) Expansion cohort
SeS2 0.5%: Bi-weekly,
N=8
SeS2 0.5: Bi-weekly, N=4;
QPM, N=4
Vehicle: Bi-weekly, N=2Vehicle: Bi-weekly, N=1;
QPM, N=1
DRC, safety/tolerability to select/inform dose range for expansion
PI decision: Escalation, de-escalation or stop (evaluation conducted by
patient/PI can consult DRC medical team for masked advice)
Primary efficacy endpoint
* Informed by the DRC (available doses: 0.1%, 0.5%, 1.0% or 2.5%)
Group 1
Group 2
Group 3&4*
*Replicate Groups 1 & 2