Developing Next Standard of Care Therapies for Diabetic ...
Transcript of Developing Next Standard of Care Therapies for Diabetic ...
Developing Next Standard of Care Therapies for Diabetic Eye Disease
Company Presentation Oxurion NV (Euronext : OXUR)
January 2021
Forward looking statement
This document has been prepared by Oxurion NV (the "Company") and is being supplied to you solely for your information and
use by you at the Company presentation. This document and its contents are confidential and may not be further distributed or
passed on to any other person or published or reproduced, in whole or in part, by any medium or in any form for any purpose. All
the numerical data provided in this document are derived from Oxurion consolidated financial statements.
No representation or warranty expressed or implied is or will be made as to, and no reliance should be placed on, the fairness,
accuracy, completeness, or correctness of the information or opinions contained herein. The information set out herein may be
subject to updating, completion, revision, verification, and amendment, and such information may change materially. The
Company is under no obligation to update or keep current the information contained in this document or the presentation to
which it relates, and any opinions expressed in it are subject to change without notice. None of the Company or any of its
affiliates, its advisors, or representatives shall have any liability whatsoever (in negligence or otherwise) for any loss whatsoever
arising from any use of this document or its contents or otherwise arising in connection with this document.
The following information does not constitute investment advice and shall not constitute an offer or invitation for the sale or
purchase of securities or assets of Oxurion in any jurisdiction. No securities of Oxurion may be offered or sold within the United
States without registration under the U.S. Securities Act of 1933, as amended, or in compliance with an exemption therefrom, and
in accordance with any applicable U.S. state securities laws.
2
• Team with proven Track Record : compound developed from the lab bench to the market
• Created new chapter in the treatment of Diabetic Eye Disease – Building DME franchise by providing a full range of therapeutic solutions holding potential for all DME patients
• THR-149 holding potential as optimal therapy for DME patients sub-optimally responding to anti-VEGF therapies (+ 40% of DME patients treated with anti-VEGF)
• THR-687 holding potential as SOC for all DME patients + broader potential DR, wet AMD and RVO
• Near-term value drivers : 2 Phase 2 clinical studies starting in 2020/21 :
• THR-149 in DME - Positive POC Phase 1 data – Phase 2 Study/ Part A RECRUITING – Data by mid 2021
• THR-687 in DME - Positive POC Phase 1 data – Phase 2 Study /Part A start planned by mid 2021 – Data H1 2022
• IP Protected : Composition of Matter protection THR-149 (2034-2039), THR-687 (2039-2044)
• €31.6 million in cash as of September 30, 2020
3Abbreviation(s): DME, diabetic macular edema; HQ; R&D, research & development; VEGF, vascular endothelial growth factor; US, United States
Oxurion Highlights
Oxurion Translating disease knowledge into much better medicines
Developing the next generation of disruptive and transformative diabetic retinal disease therapies
4Abbreviation(s): IP, intellectual property; KU, Katholieke Universiteit (Catholic University); R&D, research & development; VIB, Vlaams Instituut voorBiotechnologies (Flanders institute for biotechnology)
Unique retina disease platform - Understand disease (disease hallmarks), Identify (pathways & targets), Translate (molecules), Develop (medicines)
Two IP-protected lead programs THR-149 & THR-687 designed to deliver much improved treatment outcomes to patients with diabetic macular edema
Academic collaborations with recognized international ophthalmology research groups (Queen’s University Belfast, KU Leuven, VIB) Access disease models
Strategic partnerships with established biopharmaceutical innovators (Bicycle Therapeutics & Galapagos) Access to the “right” molecules
Led by strong specialist team with expertise across R&D
Chief Executive Officer
Oxurion management team
Seasoned leadership team with a solid drug development track record
Chief Medical Officer
Chief Development Officer
Chief Scientific Officer
Patrik De Haes,
M.D.
Grace Chang,
M.D., Ph.D.Andy De Deene,
M.D., M.B.A.
Jean Feyen,
Ph.D.
5
Chief Financial Officer
Tom Graney,
C.F.A., M.B.A.
Bringing new MoAs to DME and beyond
A unique wholly-owned R&D pipeline beyond VEGF pathway in the retina field
6
Completed stage Ongoing stage
Abbreviation(s): AMD, age-related macular degeneration; DME, diabetic macular edema; R&D, research & development; MoA, mechanism of action; RCT, randomized controlled trial; RVO, retinal vein occlusion; VEGF, vascular endothelial growth factor
R&D stage
Candidate TargetPotential indication Preclinical Phase I Phase II Phase III Filing
Status at a glance
THR-149Plasma
kallikreinDME
Ongoing Phase II RCT
THR-687Pan-RGD integrins
DMEPlanned Phase II RCT in 2021
THR-687Pan-RGD integrins
Wet AMD - RVO
-
Early research programs
Undisclosed Dry AMD -
Diabetic Retinopathy is a serious chronic complication of diabetes
DR is a chronic, progressive, debilitating, sight-threatening, and life-altering disease and a major public health concern globally
Retina of the eye
Diabetic retinopathyNormal condition
Central retinal veinCentral retinal artery
Retinal venulesRetinal
arterioles
MaculaFovea
Optic discAneurysm
Hard exudates
“Cotton wool” spots
Hemorrhages
Abnormal growth of blood vessels
Patientvision
Blurring & scotomata
7Abbreviation(s): DR, diabetic retinopathy
DME can occur at any stage of DR
Diabetic macular edema is an accumulation of fluid in the macula* due to leaking blood vessels
Courtesy of Heidelberg Engineering Courtesy of Heidelberg Engineering
Diabetic macular edemaNormal eye
RetinaMacula
Macularedema
8* The macula is the part of the retina that controls detailed vision
Abbreviation(s): DR, diabetic retinopathy
DME is a significant AND growing opportunity
9
Abbreviation(s): 7WW, seven major worldwide markets (France, Germany, Italy, Japan, Spain, United Kingdom & United States); DME, diabetic macular edema; DR, diabetic retinopathy; VEGF, vascular endothelial growth factor
Source(s): Datamonitor Healthcare, 2017; Decision Resources Group, 2019; GlobalData, 2020
Urgent and growing need for novel therapies to better treat the underserved DME population
Epidemiology
7WW, 2019
Market
7WW, 2019
Over 37 million people with diabetes (diagnosed)
Over 13 million prevalent DR patients
Between 2.8-5.8 million prevalent DME patients
Growing population due to diabetes epidemic and ageing demographics
+$11.5 billion anti-VEGF therapy market
+$4.5 billion DME/DR market
0.3-0.5 million anti-VEGF-treated DME patients insufficiently responsive
0.7-1.2 million anti-VEGF-treated DME patients
Patients with DME have limited treatment options
Although anti-VEGF therapy is the mainstay of DME therapy, 40% of patients do not achieve clinically meaningful vision gains despite dosing regimens optimized under clinical trial conditions
10
* Based on Protocol T study (Wells et al. Ophthalmology 2016) and proportion of patients BCVA gain 2 lines at 2 years
Abbreviation(s): BCVA, best-corrected visual acuity; DME, diabetic macular edema; DR, diabetic retinopathy; IVT, intravitreal; VEGF, vascular endothelialgrowth factor
Source(s): Bressler at al. JAMA Ophthalmol 2016; Bressler et al. JAMA Ophthalmol 2018; Gonzalez et al. Am J Ophthalmol 2016
Non-drug options based on laser & surgical (vitrectomy) therapies
IVT sustained-release corticosteroids (usually second-line therapy)
IVT anti-VEGF therapy as mainstay treatment (first-line therapy)40% of DME patients treated with anti-VEGF therapies do not achieve clinically meaningful vision gain*
Treatmentmanagement
Anti-VEGFs have multiple unresolved challenges
Current therapy fails to meet the needs of a significant number of patients with DME
Abbreviation(s): BCVA, best-corrected visual acuity; DME, diabetic macular edema; VEGF, vascular endothelial growth factor
Patient needs
Improve treatment outcomes
Improve therapeutic effect in terms of visual function (BCVA) and response rate (proportion of patients)
Extent
of effect
Decrease treatment burden
Enhance convenience by simplifying the dosing regimen
Increase duration of response for longer treatment intervals
Duration
of response
Convenience
11
Speed
of onset
Reduce induction phase by reaching faster optimal therapeutic effect
Oxurion is targeting new biological pathways that could deliver a significant improvement in patient outcomes
* Currently, 2 other plasma kallikrein inhibitors and 2 other integrin antagonists in clinical development
Abbreviation(s): DME, diabetic macular edema; MoA, mechanism of action; VEGF, vascular endothelial growth factor 12
Anti-VEGFlimitations
Improvingextent of effect
Current and upcoming Anti-VEGF-based therapies seem to have reached a plateau in terms of efficacy that they can deliver
Durability is currently targeted by the upcoming anti-VEGF-based therapies, addressing only treatment convenience
Targeting new biological pathways is expected to deliver better patient outcome - overcoming the limitations observed with anti-VEGF-based therapies
THR-149 and THR-687 are both potentially best- or first-in-class drugs with limited competition in these new MoA fields*
13
Creating a new DME therapy paradigm
Durability (convenience)
Exte
nt o
f eff
ect
Effic
acy
(BC
VA im
pro
vem
ent)
Anti-VEGF-based
therapies
Plasma KallikreinInhibitor
THR-149
Pan-RGD integrinantagonist
THR-687
* Currently, 2 other plasma kallikrein inhibitors and 2 other integrin antagonists in clinical development
Abbreviation(s): BCVA, best-corrected visual acuity; DME, diabetic macular edema; MoA, mechanism of action; VEGF, vascular endothelial growth factor
By focusing on new MoAswe are confident we will deliver better treatment options for all DME patients
Limited competition in the field of these new MoAs*
Developing an industry leading DME franchise
Innovative DME franchise will provide a full range of therapeutic solutions to address patient’s individual needs through personalized treatment strategies
Abbreviation(s): DME, diabetic macular edema; MoA, mechanism of action; VEGF, vascular endothelial growth factor 14
DME franchise
THR-687 solutionTHR-149 solution
• Treatment-naïve (new) Treatment initiation
• Treatment-experienced (existing) Switch from anti-VEGFs
Initial target patient group
Market interest & solutions
• DME is an area of high unmet medical need - $ 4.5 billion market p.a.
• Our new drugs with novel differentiated MoAs could deliver a step change in patient outcomes
THR-149Highly potent plasma kallikrein inhibitor targeting a VEGF-independent pathway
Potential to become the SOC for DME patients who respond sub-optimally to anti-VEGF therapy
New generation of DME treatments, beyond VEGF targeting, to answer substantial unmet medical needs
THR-149 Highly potent plasma kallikrein inhibitor for DME
Highly potent, selective and stable peptide targeting Plasma Kallikrein
(Ki PKal = 0.4 nM)
16* Teufel et al. J Med Chem 2018;61(7):2823-2836
Abbreviation(s): BK, bradykinin; DME, diabetic macular edema; FXII, factor XII; KKS, kinin kallikrein system; PK, PreKallikrein; PKal, plasma kallikrein
• Plasma Kallikrein is a clinically well validated target for edema, inflammation, and the prevention of microhemorrhages*
- PKal and bradykinins are elevated in diabetic eyes- Bradykinins cause retinal edema- PKal inhibition lowers bradykinins and reduce
edema in the retina
• THR-149 was developed in partnership with Bicycle Therapeutics
Rationale for targeting Plasma Kallikrein in DME patients
Two distinct, independent pathways linked to DME
0
500
1,000
1,500
2,000
2,500
3,000
3,500
0
5
15
10
20
PK
al (
fold
incr
ease
)
VEG
F (pg
/mL)
DME patients ID #
PKal levels
VEGF levels
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
17
• PKal is a key driver in DME
• PKal inhibitors have the potential as stand-alone therapy for sub-optimal responders to SOC, or for use in combination
Note: graph adapted from Kita et al. Diabetes 2015;64:3588-3599
Abbreviation(s): DME, diabetic macular edema; PKal, plasma kallikrein; SOC standard of care
THR-149 Preclinical evidence
THR-149 has demonstrated strong anti-inflammatory and anti-edema effects
18
Disease hallmarkin vitro assay/In vivo model
Biological activity
Lead indication
Vessel permeability• Rat paw edema model• Rat STZ model
DR, DME
Inflammation • Rat STZ model DR, DME
Abbreviation(s): DME, diabetic macular edema; DR, diabetic retinopathy; STZ, streptozotocin
THR-149 Diabetic retinal thickness : single vs. repeated injection
19
Repeat administration of THR-149 results in significant reduction (p<0.01) for the inner plexiform layer (IPL), inner nuclear layer (INL), outer nuclear layer (ONL) , and photoreceptor layer (PRL)
Multiple THR-149 IVT injections reduce the thickness of specific retinal layers in the STZ diabetic rat. Single THR-149 IVT injection had no significant impact.
Abbreviation(s): STZ, streptozotocin; IVT, intravitreal; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiformlayer; ONL, outer nuclear layer; PRL, photoreceptor layer
THR-149 Total retinal thickness: single vs. repeated injection
20
Multiple THR-149 IVT injections reduce retinal thickness in the STZ diabetic rat. Single THR-149 IVT injection had no impact.
Mean ± SEM; N=10-14; 1-way ANOVA, * p<0.05 (vs. vehicle)THR-149, 12.5 µg/eye IVT / week; VEGF-Trap, 2mg/kg IP / week
Abbrev.: STZ, streptozotocin; diabetic retinopathy, DR; IVT intravitreal; IV intravenous IP, intraperitoneal , 0
50150
200
250
Reti
na t
hic
kn
ess (
µm
)
* * *
Total retinal thickness @ Week 4
Ret
inal
th
ickn
ess
(
m)
Screening Primary Endpoint
Incidence of DLTs D0-14
THR-149 Clinical evidence Phase 1 study design in DME patients
Open-label, multicenter, 3+3 dose-escalation study to evaluate safety and preliminary efficacy (NCT03511898)
Study treatment
D84D28D0 D1 D14
0.005 mg THR-149
0.025 mg THR-149
0.125 mg THR-149
D7
Total N = 12 patients
Center-involved DME; CST ≥ 320 µm (OCT)
BCVA ≤ 62 and ≥ 23 letters
History of response to prior anti-VEGF / corticosteroid treatment
21Abbreviation(s): BCVA, best-corrected visual acuity; CST, central subfield thickness; D, day; DLT, dose-limiting toxicity; DME, diabetic macular edema; IVT, intravitreal; OCT, optical coherence tomography; VEGF, vascular endothelial growth factor
DLT criteria
Intraocular inflammation: 2+ inflammation on any of intraocular inflammation grading scales
BCVA: 10 ETDRS letter score decrease in BCVA from baseline
D56
22
THR-149 phase 1 Clinical evidence Safe and well-tolerated
All Treated Subjects
E, number of events; n, number of subjects in category; N, number of subjects with data available*Treatment-related
Confidential
Adverse event
Low DoseN=3
Middle DoseN=3
High DoseN=6
OverallN=12
n [E] n [E] n [E] n (%) 95% CI
1 subject, 2 events 3 subjects, 6 events 2 subjects, 2 events 6 subjects, 10 events
Anterior chamber inflammation 0 1 [1]* 0 1 (8.3) 0.21, 38.48
Conjunctival haemorrhage 0 1 [1] 0 1 (8.3) 0.21, 38.48
Corneal disorder 0 1 [1] 0 1 (8.3) 0.21, 38.48
Diabetic retinal oedema 1 [1] 1 [1] 1 [1] 3 (25.0) 5.49, 57.19
Eye pain 0 0 1 [1] 1 (8.3) 0.21, 38.48
Macular fibrosis 0 1 [2] 0 1 (8.3) 0.21, 38.48
Vitreous floaters 1 [1] 0 0 1 (8.3) 0.21, 38.48
Positive data
23
THR-149 phase 1 Clinical evidence Safe and well-tolerated
All Treated Subjects
• THR-149 is safe and well-tolerated
• No DLTs, no ocular SAEs
• There was one ocular AE related to study treatment (likely injection procedure) in the middle dose
cohort
• All other ocular AEs were unrelated to study treatment and were likely due to the injection procedure,
underlying disease progression or concomitant diseases
Confidential
Positive data
THR-149 phase 1 Clinical evidence Mean change BCVA from baseline*
BCVA increased rapidly and was maintained for 3 months after a single injection
0
3.9
6.4
7.5
4.8 5.2
6.4
0
5
10
15
Mea
n c
han
ge in
BC
VA
(SE
) fr
om
BLa
(ETD
RS
lett
ers)
Study visit
D14 M1BL D7D1 M2 M3
• A gain in mean BCVA was seen at every visit
• Mean change in BCVA from baseline was the highest at D14 and was maintained at M3
All treated subjects, overall
24
*Value before rescue carried forward
Abbreviation(s): BCVA, best-corrected visual acuity; BL, baseline; CST, central subfield thickness; D, day; DME, diabetic macular edema; ETDRS, early treatment diabetic retinopathy study; M, month
Positive data
0
-18
10.526.4 20.4
30.4 30
-100
-50
0
50
100
Mea
n c
han
ge in
CST
(SE
) fr
om
BLa
(µm
)
Study visit
D14 M1BL D7D1 M2 M3
THR-149 phase 1 Clinical evidence Mean change in CST from baseline*
Marginal impact on mean CST at D1 followed by increase until study end, but mean CST change was minimal and within the variability of measurement
25
*Value before rescue carried forward
Note: Overall mean CST at baseline was 524 µm
Abbreviation(s): BL, baseline; CST, central subfield thickness; D, day; M, month; SE, standard error
All treated subjects, overall
➢ A multicenter, randomized, 2-part study
➢ Target patient number: 122
➢ Target number of sites: 64 (US & EU)
➢ Goal:
➢ Part A: to select the dose of THR-149
➢ Part B: to compare THR-149 to aflibercept
➢ Part A: recruiting
➢ Dose selection: Mid 2021
➢ Part B Topline data: H1 2023
THR-149 Phase 2 in DME Recruiting Anti-VEGF poor responders
Positive data
26Abbreviation(s): BCVA, best-corrected visual acuity; CST, central subfield thickness; DME, diabetic macular edema
Speed of onset
• Rapid onset of action as of D1, with mean 3.9 letters gain
Extent of effect
• Highest BCVA gain at D14, with mean 7.5 letters gain
Duration of response
• BCVA gain maintained post-single injection at M3, with
mean 6.4 letters gain
Phase 1 single dose - results Phase 2 multiple-dose - recruiting
Safety
• Safe and well tolerated, no DLTs or ocular serious AEs
THR-149 Phase 2 study Design RecruitingPrimary Endpoint: BCVA – Secondary Endpoints: CST, AE’s
Screening Dose-level selection for Part B
D1 M1 M2 M3 M4 M5 M6
Part A : Dose level selection THR-149N=18, rando 1:1:1 Results by mid 2021
Part B: Topline data N=104, rando 1:1 Results by H1 2023
0.01 mg 0.04 mg 0.13 mg
Screening Primary EndpointSecondary endpoints
D1 M1 M2 M3 M4 M5 M6
Selected dose THR-149 Part A Aflibercept 2 mg
Anti-VEGF suboptimal responders:
Center-involved DME; CST ≥ 320 µm (OCT)
BCVA ≤ 73 and ≥ 39 letters
≥ 5 anti-VEGF injections
6
6
6
52
52
Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; CST, central subfield thickness; D, day; DME, diabetic macular edema; M, month; N, number; OCT, optical coherence tomography; Rando, randomization; VEGF, vascular endothelial growth factor
N
N
USUK
ES
FRIT
DE CZSK Slovakia:
4 sites (1 activated)
Czech Republic:2 sites (1 activated)
Germany:6 sites
Italy:4 sites e.g., Dr. Bandello
UK:9 sites
France:5 sitese.g., Dr. Tadayoni
Spain:11 sites
US:23 sites (13 activated)e.g., Dr. Khanani
THR-149 Phase 2 : 64 Study Sites & Locations in US and EUPart A target: 35-40
THR-687Pan-RGD integrin antagonist with the potential to become the SOC for all DME patients, based on its broader biological effect than anti-VEGF therapy
New generation of DME treatments, beyond VEGF targeting, to answer substantial unmet medical needs
Abbreviation: DME, diabetic macular edema; SOC, standard of care; VEGF, vascular endothelial growth factor
THR-687 Pan-RGD integrin antagonist with a broad MoA
Potential to become the SOC for all DME patients based on its broad MoA, targeting receptors involved in multiple disease hallmarks
* Hu TT et al. Exp Eye Res 2019;180:43-52
Abbreviation(s): AMD, age-related macular degeneration; DME, diabetic macular edema; DR, diabetic retinopathy; MoA, mechanism of action; RGD, arginylglycylaspartic acid; VEGF, vascular endothelial growth factor
• THR-687 is a novel, potent RGD integrin antagonist*, licensed from Galapagos
• Inhibition of integrins targets multiple processes involved in pathological angiogenesis and vascular leakage
• Integrin antagonists work both upstream and downstream of VEGF, hence have broader potential efficacy
• THR-687 has a broad therapeutic potential:
- DR with and without DME
- Wet (neovascular) AMD
- RVO
Diabetic retinopathy
Inflammation
Leakage
Neo-vascularization
Fibrosis
Diabetes mellitus Growth factors
CytokinesOther mediatorsVEGF
Integrin antagonistAnti-VEGF
30
THR-687 Highly potent pan-RGD integrin antagonist
Characteristics & integrin receptor profiling
31
Integrin Integrin Receptor ClassTHR-687
IC50 ± SD (nM)
αvβ3
RGD binding
4.4 ± 2.7
αvβ5 1.3 ± 0.5
α5β1 6.8 ± 3.2
αvβ6 9.0 ± 5.3
αvβ8 1.5 ± 0.7
αvβ1 3.2 ± 1.3
αIIbβ3* 2,000 ± 1,500*
α4β1 Leukocyte-specific 3,800 ± 1,700
α2β1 Collagen binding 121,000 ± 25,000
α3β1 Laminin binding > 5,000,000
β1
β6
β8
β5
β3
IIb
5
V
8
RG
D In
tegr
in r
ece
pto
rs
* THR-687 did not affect platelet aggregation up to 100 µM (fibrinogen as ligand)
Note(s): full ovals represent integrin receptors involved in DR disease hallmarks
Abbreviation(s): DR, diabetic retinopathy; IC50, half maximal inhibitory concentration; RGD, arginylglycylaspartic acid; SD, standard deviation
Hu TT et al. Exp Eye Res 2019;180:43-52
THR-687 Preclinical evidence
THR-687 targets multiple disease hallmarks, supporting broad therapeutic potential
Disease hallmarkin vitro assay/In vivo model
Biological activity
Lead indication
Other indication(s)
Neovascularization
• Endothelial cell migration• Ex-vivo choroidal explant
• Monkey CNV model
DR Wet AMD
Vessel permeability
• Mouse VEGF-induced leakage model• Rat STZ model
• Monkey CNV model
DR, DME Wet AMD
Inflammation • Rat STZ model DR, DME Wet AMD
Fibrosis
• Alpha-smooth muscle actin expression• Collagen gel contraction
• Monkey CNV model
DR Wet AMD
32Abbreviation(s): AMD, age-related macular degeneration; CNV, choroidal neovascularization; DME, diabetic macular edema; DR, diabetic retinopathy; PDR, proliferative diabetic retinopathy; STZ, streptozotocin; VEGF, vascular endothelial growth factor
Vehicle PBS THR-687
Vitreous Vitreous
GCL
IPL
INLOPL
ONL
PRL
THR-687 Vascular leakage
THR-687 potently inhibits vascular leakage in a diabetic rat STZ model
FITC-BSA
4 weeks after diabetes onset0
200
400
600Non-diabetic
Diabetic, vehicle aflibercept, 3x IP, 3x/week
Diabetic, aflibercept 2 mg/kg, 3x IP, 3x/week
Diabetic, vehicle THR-687, 3x IVT, weekly
Diabetic, THR-687 75 µg/eye, 3x IVT, weekly
Flu
ore
scen
ce in
ten
sit
y
(arb
itra
ry u
nit
s)
Mean + SEMN=10-141-way ANOVA** p<0.01; *** p<0.001
***
**
Vascular leakage
*****
Abbreviation(s): FITC-BSA, Fluorescein isothiocyanate labelled bovine serum albumin; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer; STZ, streptozotocin; IP: intraperitoneal; IVT: intravitreal
4 weeks after diabetes onset0
200
400
600Non-diabetic
Diabetic, vehicle aflibercept, 3x IP, 3x/week
Diabetic, aflibercept 2 mg/kg, 3x IP, 3x/week
Diabetic, vehicle THR-687, 3x IVT, weekly
Diabetic, THR-687 75 µg/eye, 3x IVT, weekly
Flu
ore
scen
ce in
ten
sit
y
(arb
itra
ry u
nit
s)
Mean + SEMN=10-141-way ANOVA** p<0.01; *** p<0.001
***
**
Vascular leakage
*****
4 weeks after diabetes onset0
200
400
600Non-diabetic
Diabetic, vehicle aflibercept, 3x IP, 3x/week
Diabetic, aflibercept 2 mg/kg, 3x IP, 3x/week
Diabetic, vehicle THR-687, 3x IVT, weekly
Diabetic, THR-687 75 µg/eye, 3x IVT, weekly
Flu
ore
scen
ce in
ten
sit
y
(arb
itra
ry u
nit
s)
Mean + SEMN=10-141-way ANOVA** p<0.01; *** p<0.001
***
**
Vascular leakage
*****
33
THR-687 Anti-angiogenic effect
THR-687 potently inhibits angiogenesis-induced leakage in a cynomolgus monkey CNV model
34
Control article
Ranibizumab
THR-687
0.45 mg
Con
trol
artic
le
ranib
izum
ab: 0
.5 m
g
THR-6
87: 0
.45
mg
THR-6
87: 2
.25
mg
THR-6
87: 4
.5 m
g
0
20
40
60
80
WEEK 2(after 2 IVT injections)
Gra
de 4
or
5 lesio
ns
(%)
Week 2(after 2 IVT of THR-687)
Con
trol
artic
le
ranib
izum
ab: 0
.5 m
g
THR-6
87: 0
.45
mg
THR-6
87: 2
.25
mg
THR-6
87: 4
.5 m
g
0
20
40
60
80WEEK 3
(after 3 IVT injections)
Gra
de 4
or
5 lesio
ns
(%)
Week 3(after 3 IVT of THR-687)
Representative FA images
Hu TT et al. Exp Eye Res 2019;180:43-52
Abbreviation(s): CNV, choroidal neovascularization; IVT, intravitreal
ScreeningPrimary Endpoint
Incidence of DLTs D0-14
THR-687 Clinical evidence Phase 1 study design in DME patientsOpen-label, multicenter, 3+3 dose-escalation study to evaluate safety and preliminary efficacy(NCT03666923)
Abbreviation(s): BCVA, best-corrected visual acuity; CST, central subfield thickness; D, day; DLT, dose-limiting toxicity; DME, diabetic macular edema; ETDRS, early treatment diabetic retinopathy study; OCT, optical coherence tomography
Study treatment
D84D28D0 D1 D14
0.4 mg THR-687
1.0 mg THR-687
2.5 mg THR-687
D7
Enrolment completed Topline data by end of 2019
35
Total N = 12 patients
Center-involved DME; CST ≥ 320 µm (OCT)
BCVA ≤ 62 and ≥ 23 letters
History of response to prioranti-VEGF / corticosteroid treatment
DLT criteria
Intraocular inflammation: 2+ inflammation on any of intraocular inflammation grading scales
BCVA: 10 ETDRS letter score decrease in BCVA from baseline
Macular hole
D56
THR-687 Clinical evidence Summary of adverse events 1 | 2
Overall, 5 subjects developed 9 AEs in the study eye
Category
Low DoseN=3
Middle DoseN=3
High DoseN=6
OverallN=12
n [E] n [E] n [E] n (%) E
Overall
Any AE 1 [2] 1 [3] 4 [5] 6 (50.0) 10
Any AE in study eye 1 [2] 1 [3] 3 [4] 5 (41.7) 9
Any AE in non-study eye 0 0 0 0 0
Any non-ocular AE 0 0 1 [1] 1 (8.3) 1
Positive data
36Abbreviation(s): AE, adverse event; E, number of events; n, number of subjects in category; N, number of subjects with data available
All treated subjects
Positive data
THR-687 Clinical evidence Summary of adverse events 2 | 2
There were no serious AEs, and all AEs deemed treatment-related by the investigator were in the study eye, with one subject at each dose
Positive data
37
Category
Low DoseN=3
Middle DoseN=3
High DoseN=6
OverallN=12
n [E] n [E] n [E] n (%)
Treatment-related (drug and/or procedure) AE
Any AE 1 [2] 1 [1] 1 [1] 3 (25.0)
Any AE in study eye 1 [2] 1 [1] 1 [1] 3 (25.0)
SAE
Any SAE 0 0 0 0
All treated subjects
Abbreviation(s): AE, adverse event; E, number of events; n, number of subjects in category; N, number of subjects with data available
Positive data
THR-687 phase 1 Clinical evidence Safe and well tolerated
• THR-687 is safe and well-tolerated
• No DLTs, no SAEs occurred in the study
• All treatment-related AEs were likely injection-procedure related
• Other AEs were likely due to the underlying disease progression or concomitant diseases
• 3 subjects received rescue medication with an anti-VEGF; one in the middle dose group at M2 and two in the high dose group (one at M1 and one at M2)
Positive data
38Abbreviation(s): DLT, dose-limiting toxicity; SAE, serious adverse event; AE, adverse event; M, month; VEGF, vascular endothelial growth factor
Positive data
THR-687 phase 1 Clinical evidence Mean change BCVA from Day 0*
Rapid onset of action - mean BCVA improvement was observed at D1 (3.1 letters gain), with the highest mean BCVA improvement at M1 (9.2 letters), and maintained post-injection at M3 (8.3 letters)
Positive data
39*Value before rescue carried forward
Abbreviation(s): BCVA, best-corrected visual acuity; D, day; ETDRS, early treatment diabetic retinopathy study; M, month; SE, standard error
0.0
3.1
7.2 7.7
9.28.8 8.3
0
5
10
15 All treated subjects, overall
D14 M1D0 D7D1 M2 M3
Study visit
Mea
n c
han
ge in
BC
VA
(SE
) fr
om
D0
a(E
TDR
S le
tter
s)
Positive data
0
5
10
15 THR-687 0.4mg (N=3) THR-687 1.0mg (N=3) THR-687 2.5mg (N=6)
6.7
1.7
THR-687 phase 1 Clinical evidence Mean change BCVA from Day 0*
Largest BCVA improvement in the high dose group, with a mean BCVA gain of 12.5 letters at M3
12.5
Positive data
40*Value before rescue carried forward
Abbreviation(s): BCVA, best-corrected visual acuity; D, day; ETDRS, early treatment diabetic retinopathy study; M, month; SE, standard error
All treated subjects, by dose
D14 M1D0 D7D1 M2 M3
Study visit
Mea
n c
han
ge in
BC
VA
fro
m D
0(E
TDR
S le
tter
s)
Positive data
THR-687 phase 1 Mean Change in BCVA from Baseline*
*Value before rescue carried forwardBaseline defined as the day of the injection. SE is only presented for overall data (across dose levels)Abbreviation(s): BCVA, best-corrected visual acuity; D, day; ETDRS, early treatment diabetic retinopathy study; M, month; SE, standard error
41
All treated subjects, overall
High dose had the most pronounced BCVA improvement, with mean 12.5 letters gain at Month 3
Positive data
Study visit
3.1
7.2 7.79.2 8.8
8.34.3
9.811.2 10.8 11.2
12.5
0
5
10
15Overall (N=12) THR-687 2.5mg (N=6)
D14 M1D0 D7D1 M2 M3
Mea
n c
han
ge in
BC
VA
(SE
) fr
om
Bas
elin
e (E
TDR
S le
tter
s)
THR-687 phase 1 Clinical evidence Mean change in CST from D1*
Overall, marginal impact on mean CST was noted up to M1, followed by increase until M3
-43.9 -38.9 -35.8
-3.8
4.1
-120
-80
-40
0
40
80
120
Positive data
42
*Value before rescue carried forward
Note: SD-OCT not assessed at D0
Abbreviation(s): CST, central subfield thickness; D, day; ETDRS, early treatment diabetic retinopathy study; M, month; SD-OCT, spectral domain-optical coherence tomography; SE, standard error
Mea
n c
han
ge in
CST
(SE
) fr
om
D1
(µ
m)
Study visit
D14 M1D0 D7D1 M2 M3
All treated subjects, overall
Positive data
-24-5.7
18.7
-6.74.3
0
-42.7
62
-62.7
71.385
-54.5
-106
-49.7-39.8
-36.5
-120
-80
-40
0
40
80
120THR-687 0.4mg (N=3) THR-687 1.0mg (N=3) THR-687 2.5mg (N=6)
Positive data
THR-687 phase 1 Clinical evidence Mean change in CST from D1*
Largest mean decrease in CST was noted in the high dose group, with a decrease of 106 µm at D14
43
*Value before rescue carried forward
Note: SD-OCT not assessed at D0
Abbreviation(s): CST, central subfield thickness; D, day; ETDRS, early treatment diabetic retinopathy study; M, month; SD-OCT, spectral domain-optical coherence tomography; SE, standard error
Mea
n c
han
ge in
CST
(SE
) fr
om
D1
(µ
m)
All treated subjects, by dose
D14 M1D0 D7D1 M2 M3
Study visit
Positive data
THR-687 phase 1 Mean Change in CST from Baseline*
High dose had more pronounced CST decrease of 106 µm at Day 14
*Value before rescue carried forwardBaseline defined as the day after the injection. SE is only presented for overall data (across dose levels)Abbreviation(s): CST, central subfield thickness; D, day; M, month; SE, standard error
44
All treated subjects, overall
Positive data
-43.9
-38.9-35.8
-3.84.1
-54.5
-106
-49.7
-39.8 -36.5
-120
-80
-40
0
40Overall (N=12) High dose (N=6)
Mea
n c
han
ge in
CST
(SE
) fr
om
Bas
elin
e (µ
m)
Study visit
D14 M1D0 D7D1 M2 M3
➢ A multicenter, randomized, 2-part study
➢ Target patient number: 200-300
➢ Target number of sites: 70 (US & EU)
➢ Goal:
➢ Part A: to select the dose of THR-687
➢ Part B: to compare THR-687 to aflibercept
➢ Start Part A : mid 2021
➢ Dose selection: H1 2022
➢ Topline Part B data: H2 2023
THR-687 Preliminary Phase 2 Plans in Treatment Naïve DME
Positive data
45Abbreviation(s): BCVA, best-corrected visual acuity; CST, central subfield thickness; DME, diabetic macular edema
Phase 1 single dose Phase 2 multiple-dose
Extent of effect
• 9.2 letters gain at Month 1
Long Duration of action
• BCVA gain maintained at Month 3 >> +12.5 letters in high dose
• Safe and well tolerated, no DLTs or ocular serious AEs
Safety
Speed of onset
• 3.1 letters BCVA gain as of the day after the injection
Broader biological effect than anti-VEGF
therapy
Bringing new MoAs to DME and beyond
A unique wholly-owned R&D pipeline beyond VEGF pathway in the retina field
46
Completed stage Ongoing stage
Abbreviation(s): AMD, age-related macular degeneration; DME, diabetic macular edema; R&D, research & development; MoA, mechanism of action; RCT, randomized controlled trial; RVO, retinal vein occlusion; VEGF, vascular endothelial growth factor
R&D stage
Candidate TargetPotential indication Preclinical Phase I Phase II Phase III Filing
Status at a glance
THR-149Plasma
kallikreinDME
Ongoing Phase II RCT
THR-687Pan-RGD integrins
DMEPlanned Phase II RCT in 2021
THR-687Pan-RGD integrins
Wet AMD - RVO
-
Early research programs
Undisclosed Dry AMD -
Oxurion aims to be a GAME CHANGER in the treatment of DME
47Abbreviation(s): DME, diabetic macular edema; IVT, intravitreal; SOC, standard of care; VEGF, vascular endothelial growth factor
• Potential to become SOC for DME patients, sub-optimally responders to anti-VEGF therapy
• Targeting a VEGF-independent pathway
• Positive Phase 1 study after a single IVT injection
• THR-149 Phase 2 study Multiple injections - Part A recruiting, data mid 2021
• THR-687 Phase 2 study Multiple injections - Part A expected to start recruiting by mid 2021
• Targeting a market opportunity worth $4.5 billion p.a.
• Potential to become SOC for all DME patients
• Broader biological effect Potential to replace anti-VEGF therapy
• Positive Phase 1 study after a single IVT injection
Pan-RGD integrinantagonist
THR-687
Plasma KallikreinInhibitor
THR-149
Oxurion shareholder structure overview
79.4%
5.7%6.1 %
8.8%
Mr. Thomas M. Clay and entities controlled by him
Baron Philippe Vlerick and entities controlled by him
Novartis Pharma AG
Public - free float
Oxurion NV (Euronext Brussels: OXUR) - as of September 30, 2020):
- 38,291,950 shares outstanding
- €31.6 million in cash
48