risuteganib (luminate ): potential paradigm shift in the ...€¦ · predominant in dme...

Risuteganib (LUMINATE®): Potential Paradigm Shift In the Treatment of

Oxidative Stress-Induced DME

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Allegro is a late stage private biotech company focused on the treatment of retinal diseases

Allegro’s lead investigational drug, Risuteganib (Luminate®), is a broad-spectrum anti-integrin peptide expected to begin phase 3 DME clinical trials 1H 2019

Risuteganib simultaneously inhibits all four oxidative stress-induced pathways in diabetic macular edema (DME)

With a unique MOA, Risuteganib has the potential ability to treat the anti-VEGF inadequate responders

About Allegro

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Anti-VEGFs Are the Current Standard of Care…

Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential

Only 50% of subjects with DME show adequate response to anti-VEGF therapy

Angiogenesis and vascular leakage predominant in DME pathogenesis

Anti-VEGF Responders

50%

Inflammatory or neurodegenerative mechanisms are the other drivers of DME pathogenesis

Anti-VEGF Suboptimal Responders

50%

A broad spectrum approach can synergize with anti-VEGF therapy in the treatment of DME

Singer MA, Kermany DS, Waters J, et al. F1000Res. 2016;5.

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Oxidative Stress in Diabetics Leads to Multi-factorial Changes

Early focal leakage Diffuse leakage Fibrosis Pigmentary

changesLoss of

photoreceptor cells

DME

INFLAMMATION

VEGF-MEDIATED VASCULAR PERMEABILITY

VASCULAR PERMEABILITY

Typical cellular

response to oxidative

stress

Multi-factorial “Switch” will determine efficacy of the treatment

Prasad S, et al. Prev Med. 2012;54(Suppl):S29-37.Acknowledgement: Pravin Dugel, MD.Singer MA, Kermany DS, Waters J, et al. F1000Res. 2016;5.


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Oxidative Stress Underlies DME

Diabetes

Oxidative stress

Cell death + neurodegenerationInflammationAngiogenesisIncreased vascular

permeability

Avastin

Lucentis

Eylea

Ozurdex

Retisert

Iluvien

SteroidsAnti-VEGFs


Diabetes

Oxidative stress

Cell death + neurodegenerationInflammationAngiogenesisIncreased vascular

permeability

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Risuteganib Is an Integrin Inhibitor that Downregulates the Oxidative Stress Response Upstream


Risuteganib is an upstream inhibitor that down regulates all 4 pathways

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Integrins Play a Crucial Role In Oxidative Cell Stress


Luo BH1, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619-47.

Integrins serve as Rheostat by responding to oxidative stress and might enhance sensitivity of the VEGF-receptors/ANG-2 receptors

Active receptor starts initiating different oxidative

stress pathways

When exposed to oxidative stress, receptor activated and

can bind ligands

Ligands and intracellular proteins responsible for signaling:

Cell in homeostasis (no oxidative stress) – integrin

receptor inactive

Fibronectin Actin Talin Kindlin

https://www.ncbi.nlm.nih.gov/pubmed/?term=Luo%20BH%5BAuthor%5D&cauthor=true&cauthor_uid=17201681

https://www.ncbi.nlm.nih.gov/pubmed/?term=Carman%20CV%5BAuthor%5D&cauthor=true&cauthor_uid=17201681

https://www.ncbi.nlm.nih.gov/pubmed/?term=Springer%20TA%5BAuthor%5D&cauthor=true&cauthor_uid=17201681

https://www.ncbi.nlm.nih.gov/pubmed/17201681

Type of disease Medication Targets integrin

isoform Indication

Systemic Tysabri (natalizumab) α4 integrin Multiple sclerosis, Crohn’s disease

Entyvio (vedolizumab) α4β7 integrin Crohn’s disease, ulcerative colitis

ReoPro (abciximab) αIIbβ3 integrin Preventing thrombotic complications after percutaneous coronary intervention

Integrilin (eptifibatide) αIIbβ3 integrin Preventing thrombotic complications after percutaneous coronary intervention

Aggrastat (Tirofiban) αIIbβ3 integrin Preventing thrombotic complications after percutaneous coronary intervention

Ocular Xiidra (lifitegrast) αLβ2 integrin Signs and symptoms of dry eye

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Integrins Are Targets of Medications that Have Already Been Developed for Patients With Systemic and Ocular DiseasesIntegrins have been studied for more than 30 years


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RGD Class Integrins Are Sensors That Mediate Oxidative Stress In Retinal Disease


RisuteganibRisuteganib

Integrinisoform

Downstream stress pathways Disease association

αVβ3Angiogenesis and vascular leakage

Observed in CNV associated with neovascular (wet) AMD

αVβ5Angiogenesis and vascular leakage

Associated with proliferative diabetic retinopathy (PDR)

α5β1Angiogenesis and vascular leakage

Expressed in both neovascular AMD and diabetic retinopathy

αMβ2 Inflammation Associated with Complement 3 and Leukocyte attachment

Risuteganib (small molecule – 750 dalton)

Ris

uteg

anib

5umRPE

Photoreceptor

ChoroidSclera

Gonzalez VH. The promise of integrin receptors for treatment of vitreoretinal disorders. Retina Today. July/August 2016.

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Phase 2 DME Clinical Update


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DEL MAR Phase 2b With Risuteganib


Phase 2b – Stage 1: Monotherapy vs Bevacizumab with 6-month follow-up (n=136)

Phase 2b – Stage 2: Bevacizumab pretreatment vs combination therapy with 5-month follow-up (n=80)

Drug Safety Dose Ranging DurabilityEfficacy vs anti-VEGF

Goal

More Dose Ranging (0.5 to 1.0 mg)Increase efficacy by clearing out pre-existing VEGF load

Goal

Study Design Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24

Bevacizumab (n=19)

Risuteganib 1.0 mg (n=26)



Bevacizumab

Risuteganib

Final Risuteganib dose Primary endpoint assessed 12 w post Risuteganib

Study Design Baseline Week 1 Week 4 Week 8 Week 12 Week 16 Week 20

Bevacizumab (n=13) Sham

Risuteganib 0.5 mg + Bevacizumab sequential (n=15)

Risuteganib 1.0 mg + Bevacizumab sequential (n=16)

Risuteganib 0.5 mg + Bevacizumab combination (n=12)

Sham

Risuteganib 1.0 mg + Bevacizumab combination (n=9)

Sham

Bevacizumab

Risuteganib

Primary endpoint assessed 12 w post Risuteganib

Final Risuteganib dose

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Depending on Where the DME Patient Is on the Spectrum Determines Which Treatment Is More Appropriate


Early focal leakage Diffuse leakage Fibrosis Pigmentary

changesLoss of

photoreceptor cells

DME

INFLAMMATION

VEGF-MEDIATED VASCULAR PERMEABILITY

VASCULAR PERMEABILITY

Typical cellular

response to oxidative

stress

Prasad S, et al. Prev Med. 2012;54(Suppl):S29-37.Acknowledgement: Pravin Dugel, MD.Singer MA, Kermany DS, Waters J, et al. F1000Res. 2016;5.

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Phase 2b DEL MAR Stage 1 & 2 Combined Datasets – Best Response to Risuteganib in Inadequate Anti-VEGF Responders


6.9

9.3

5.26.0

4.1

7.5

0

1

2

3

4

5

6

7

8

9

10

11

12

BC

VA c

hang

e fr

om b

asel

ine

(lette

rs)

n=19n=32 n=42 n=13 n=19 n=23

All subjects Treatment-naïve Inadequate anti-VEGF responders

Avastin 1.0 mg Risuteganib

Stages 1 & 2: Average BCVA Change From Baseline at Week 20

Anti-VEGF inadequate responders: VA: 20/60 – 20/70CRT: 490 micron~ 12 anti- VEGF pre-treatment

Allegro Ophthalmics [data on file].

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Preliminary Phase 3 DME plan:§ Overall very similar to Phase 2s

� Same target population � Similar design� Same endpoints

Ongoing US Phase 2a study in dry AMD§ Top line results mid 2019

Allegro Is Gearing Up to Start Phase 3 In 1H 2019


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Risuteganib: Novel MOA to Treat the Upstream Oxidative Stress in DME


Risuteganib’s Profile:

Broad spectrum treatment due to its unique MOAAbility to treat anti-VEGF inadequate respondersGenerally proven safe§ ≈ 1,150 injections in over 370 patients

Phase 3s in DME 1H 2019

risuteganib (luminate ): potential paradigm shift in the ...€¦ · predominant in dme...

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