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Intravitreal Injection of Liposome-Encapsulated Bromfenac for

Refractory DME

New Sight Pharma is a young company in the process of registration in the United States

The goal of New Sight Pharma is to develop therapeutic alternatives using cutting-edge liposome techonology to treat human ophthalmic diseases

This company arose from pharmaceutical experiences in spontaneous animal models for 5 years

Gustavo A. García-Sánchez, DVM, PhD. Diplomate ACVO and CLOVE. Chief Executive Officer.

Intravitreal Injection of Liposome-Encapsulated Bromfenac for Refractory DME

Our Company

Our Patented biotechnology

Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME

Why liposomes?


Phospholipids in water form closedvesicles, called liposomes, to minimizeexposure of their hydrophobic tails fromto the water.

Hydrophilic molecules can beencapsulated within the internal cavityof the liposome and protected form theexternal environment.

Hydrophobic molecules can beentrapped between the bilayer structureof the liposome and protected from theaqueous external environment.

Possibility of

prolonged release

Reduced toxicity of

encapsulated agents

Vehicle for drugs with

poor solubility/

permeability

Non-toxic by

many routes

Increased therapeutic index and efficacy of

drugs

Protection of drug

breakdown

Why our liposomes?


Industrially Scalable

Non-toxic

Organic solvent free

Preservative Free

First formulation

designed for

prolonged release of

bromfenac by

intravitreal injection

Uniquepatented

proteicstructure in

bilipid membrane

Expertise: Sirolimus liposomes

-25

-15

-29

-22

-40

+1

Overall improvement of OSDI score in pilot study of first 6 human patients with refractory moderated DED.

• Safety was demonstrated after extensive preclinical testing (at OECD recognized entity) by subconjunctival and intravitreal injections.• Significant improvements in spontaneous dog model of DED (dry eye disease) with 10 times higher severity of signs compared with humans.

• Ongoing Phase I and Phase II, controlled clinical trials in human patients with DED . Matching animal results


Dry eye disease

In a canine model

Next Challenge: Bromfenac liposomes


Fast vitreous clearance

NSAID ↑ COX-2

inhibition

Well-

tolerated

Good ocular

tissue

penetration

Bromfenac

Liposomal

Bromfenac

3 to18 times

more potent than

other NSAID’s

Predom

inant

isofo

rm in

RPE

cells

No studies of

IVT use in

humans

Long-lasting effect

Leading cause of

blindness among

working age people

DMEDiabetic Macular

Edema

Global market expected to

grow from $3,710 M in 2017, to over

$4,100 M by 2027

Chronic, non-curable

ocular pathology

8

Why not topical NSAID´s instead of intravitreal application?


1.-William, G., Nepomuceno, A., Messias, K., Barroso, L., Scott, I., Messias, A. and Jorge, R. (2019). Foveal thickness reduction after anti-vascular endothelial growth factor treatment in chronic diabetic macular edema. [ebook] pp.760-764. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28546934 [Accessed 26 Sep. 2019].2.- Li, A., Rieveschl, N., Conti, F., Silva, F., Sears, J., Srivastava, S., Ehlers, J., Schachat, A., Babiuch, A., Kaiser, P., Martin, D. and Singh, R. (2017). Long-Term Assessment of Macular Atrophy in Patients with Age-Related Macular Degeneration Receiving Anti-Vascular Endothelial Growth Factor. [ebook] Cleveland: American Academy of Ophthalmology, pp.1-8. Available at: https://www.ophthalmologyretina.org/article/S2468-6530(17)30405-0/fulltext [Accessed 26 Sep. 2019].3.-Nuyen, B., Weinreb, R. and Robbins, S. (2016). Steroid-induced glaucoma in the pediatric population. [ebook] San Diego: American Association for Pediatric Ophthalmology and Strabismus, pp.1-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28087345 [Accessed 26 Sep. 2019].4.-Razeghinejad, M. and Katz, L. (2010). Steroid-Induced Iatrogenic Glaucoma. [ebook] Ophthalmic Research, pp.66-80. Available at: https://www.karger.com/Article/Abstract/328630 [Accessed 26 Sep. 2019].5.-Zur, D., Iglicki, M. and Loewenstein, A. (2019). The Role of Steroids in the Management of Diabetic Macular Edema. [ebook] Ophthalmic Research, pp.1-6. Available at: https://www.karger.com/Article/Abstract/499540 [Accessed 26 Sep. 2019].

What about chronic use of current gold-standard therapy?

Anti-VEGF Steroids

Cataract 11-15%, glaucoma 12.8%

The risk increases with dose and length of treatment


https://www.ncbi.nlm.nih.gov/pubmed/28546934

https://www.ophthalmologyretina.org/article/S2468-6530(17)30405-0/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/28087345

https://www.karger.com/Article/Abstract/328630

https://www.karger.com/Article/Abstract/499540

The Winning Pitch Challenge @ASRS – Vancouver July 2018


Preclinical Study@ARVO – Vancouver July 2019

Intravitreal bromfenac with liposomes. A toxicology study in rabbit eyes. #2729 - B0260

Idaira Sánchez Santos,Gustavo Adolfo García, Mónica Anayatzin Alba, Vanessa Tirado-González, Elsa Hernández-Piñamora, Jessica Serrano-Aguilar, Luis Daniel García Azarte ,Rodrigo García Santisteban, Abelardo A.Rodriguez Reyes. Roberto González-Salinas , María Lucia Urani, Hugo Quiroz-Mercado, Virgilio Morales-Cantón.

[email protected]

Introduction

Based on basic pathogenic mechanisms, there are

several therapeutic strategies in DR

1. anti-VEGF therapy:

About half of the patients do not respond.

Targeting inflammation for the treatment of DME

• NSAIDs inhibit the cyclooxygenase (COX) enzymes and

the synthesis of pro-inflammatory prostaglandins (PGs).

• COX-2 is the predominate isoform in RPE cells. It has

an impo rtant ro le in i n f lammat io n and angiogenesis and has been implicated in CNV and

PDR.

• COX-2 inhibition has favorable effects on intraocular

inflammation and DME.

• Bromfenac may be 3x to 18x more potent of an inhibitor of COX-2 than diclofenac, ketorolac and amfenac.

• There are no studies that currently evaluate the

toxicity and efficacy of intravitreal bromfenac for treatment of DME.

Innovation in DME drugs

2. Corticosteroids

The risk of complications are high: Intraocular pressure elevation and cataract formation.

Methodology Preclinical toxicology study in rabbit eyes.

A) Objectives

1.To prove the safety of intravitreal bromophenac (100 µg / 0.1 ml) encapsulated in liposomes.

2.To demonstrate the drug is non-toxic in rabbit eyes.

B) Liposomes

• Can trap both hydrophilic and lipophilic drugs. • Non toxic and biodegradables

• Protecting them from degradation and providing slow

release, which can help to decrease the number of injections needed.

Kalepu, S., et al (2013). Int J

Bromfe

C) Ocular examination • Basal ERG • OCT • Fundus photography

E) Evaluation at: • 1 week • 6 weeks • 3 months

Enucleation for histological study

No decrease in responseD) Intravitreal injection

RGI RetinoGraphics, Inc.9 Dock Road, Norwalk, CT 06854-4704

O.S.

Owner: Hugo Quiroz Mercado Patient: Conejo Bromfenaco 1

Breed: I.D.: Age (mo):

CURSORS

Implicit Time (ms):

Amplitude (µV):

1 2 <2-1> 3 4 <4-3>

0.25

48.47

9.75

64.72

9.50

16.25

11.50

64.86

38.50

-33.19

27.00

-98.06

COMMENTS: DARK-ADAPT15m

Test:ERG

Date:

Apr.

02

201909:50:57

Ave.

of

ITT:

5ms/Div. Filter: None Flash: Single 0dB White LED Bgnd: None

10µ

V/D

iv.

Sm

oo

thed (

6)

--

4

2s

0

1

23

4

No evidence of toxicity in retina layers.

Preservation of the number of layers, without changes in cytotoxicity.

RGI RetinoGraphics, Inc.9 Dock Road, Norwalk, CT 06854-4704

O.S.

Owner: LIPOSOMAS 2 Patient: CONEJO 1 OS

Breed: I.D.: Age (mo):

CURSORS

Implicit Time (ms):

Amplitude (µV):

1 2 <2-1> 3 4 <4-3>

0.00

130.14

2.75

129.44

2.75

-0.69

6.00

126.53

34.00

220.56

28.00

94.03

COMMENTS: DARK-ADAPT15m

Test:ERG

Date:

Mar.

12

201911:24:55

Ave.

of

ITT:

5ms/Div. Filter: None Flash: Single 0dB White LED Bgnd: None

10µ

V/D

iv.

Sm

ooth

ed

(6

)

--

4

2s 0

123

4

D I S C L O S U R E S : S a n g a r t L a b o r a t o r y

E) Conclusions 1. Bromophenac (100 µg / 0.1 ml) encapsulated in liposomes is not toxic in

rabbit eyes model

2. We will continue with a pilot study in humans to evaluate the effectiveness

and the toxicity of the drug.

Normal retinal structure and function after 100µg/0.1ml IVT injection in New Zealand rabbits.

A BHistological sections of rabbit retinas after 100µg/0.1ml bromfenac liposomes IVT injection . Hematoxylin/eosin 10x. A) Left eye of rabbit #10; B) Left eye of rabbit #20.

Before

After 3 months

SafetyIntravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME

Proof of conceptOS measurements of 62 y/o female patient with DME, 7 Wetlia applications and 1 Avastin application (Anti-VEGF

treatments, last application of Wetlia 3 months prior). Visual acuity prior injection 20/200, 2 weeks follow up 20/150.

Baseline

2 weeks after treatmentwith bromfenac

liposomes

676

377


VA: 20/200

VA: 20/150

13

OS measurements of 85 y/o female patient with DME. History of >10 applications of different anti-VEGF therapies + 2 Ozurdex applications (intraocular dexametasone).

Baseline

5 weeks after treatment

213241


CF 20/400


The road so far…

2 Patients

BRVO/CRVO

12 Patients

DME1

PatientnAMD

90% improvement inBCVA ETDRS

30%improvement in

SD-OCT thickness map


Conclusion

Our results in end stages of non-responsive macular edema have a potential additive effect to the use of gold-standard therapy

The positive biological effect observed in our trial will be evaluated in further studies to determine availability, efficacy and therapy on other pathologies

Liposome engineering with bromfenac has the potential to rescue eyes non responders to anti-VEGF and steroids

Future studies will include eyes with less severe pathology

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