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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?
Intravitreal Injection of Liposome-Encapsulated Bromfenac for Refractory DME
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?
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
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
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
Dry eye disease
In a canine model
Next Challenge: Bromfenac liposomes
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
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?
Intravitreal Injection of Liposome-Encapsulated Bromfenac for Refractory DME
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
Intravitreal Injection of Liposome-Encapsulated Bromfenac for Refractory DME
The Winning Pitch Challenge @ASRS – Vancouver July 2018
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
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.
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
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
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
Intravitreal Injection of Liposome-Encapsulated Bromfenac for Refractory DME
CF 20/400
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
The road so far…
2 Patients
BRVO/CRVO
12 Patients
DME1
PatientnAMD
90% improvement inBCVA ETDRS
30%improvement in
SD-OCT thickness map
Intravitreal Inyection of Liposome-Encapsulated Bromfenac for Refractory DME
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