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Risuteganib (LUMINATE®): Potential Paradigm Shift In the Treatment of
Oxidative Stress-Induced DME
2
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
3
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.
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
5
Oxidative Stress Underlies DME
Diabetes
Oxidative stress
Cell death + neurodegenerationInflammationAngiogenesisIncreased vascular
permeability
Avastin
Lucentis
Eylea
Ozurdex
Retisert
Iluvien
SteroidsAnti-VEGFs
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
Diabetes
Oxidative stress
Cell death + neurodegenerationInflammationAngiogenesisIncreased vascular
permeability
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Risuteganib Is an Integrin Inhibitor that Downregulates the Oxidative Stress Response Upstream
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
Risuteganib is an upstream inhibitor that down regulates all 4 pathways
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Integrins Play a Crucial Role In Oxidative Cell Stress
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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
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
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
9
RGD Class Integrins Are Sensors That Mediate Oxidative Stress In Retinal Disease
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
11
DEL MAR Phase 2b With Risuteganib
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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)
Risuteganib 2.0 mg (n=26)
Risuteganib 3.0 mg (n=32)
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
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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Risuteganib: Novel MOA to Treat the Upstream Oxidative Stress in DME
Copyright 2018, All Rights Reserved, Allegro Ophthalmics, LLC. – Confidential
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