taking a dermatological approach to treating ocular surface … · 2019. 12. 20. · obstructive...

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

Copyright© Azura Ophthalmics | Confidential

Contact Lens Discomfort Blepharitis


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


(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


BLOCKED ORIFICES, THICK LIPIDS AND LIPID DEFICIENCY


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


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


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


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


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


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


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


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)


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)


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

)


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%


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


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


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


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

THANK YOUMarc Gleeson

[email protected]

+61 422 956 128

taking a dermatological approach to treating ocular surface … · 2019. 12. 20. · obstructive...

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