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Voclosporin for Noninfectious Uveitis
Involving the Posterior Segment:
New Analyses of the LUMINATEPhase 2/3 Trials
Shree Kurup, MD
Wake Forest Baptist Medical Center
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Principal Investigators
North America
Thomas Aaberg
Brian Berger
David Callanan
David Chu
M. Reza Dana
Jean Deschenes
Pravin Dugel
C. Stephen Foster
Philip Hooper
Bernard Hurley
Glenn J. Jaffe
Rosa Kim
Dino Klisovic
Raj Maturi
Quan D. Nguyen
Don J. Perez-Ortiz
Russell Read
C. Michael Samson
David Scales
John Sheppard
Donald Stone
Eric Suhler
Joseph Tauber
Howard Tessler
Albert Vitale
Robert Wang
Susan E. Wittenberg
Europe
Talin Barisani-
Asenbauer
Susanne Binder
Bahram Bodaghi
Antoine Brezin
Isabelle Cochereau
Andrew Dick
Gnther Grabner
Arnd Heiligenhaus
Laurent Kodjikian
Friederike Mackensen
Thomas Ness
Bernhard Nlle
Carlos Pavesio
Ian Pearce
Uwe Pleyer
Miles Stanford
Michel Weber
Manfred Zierhut
India
Rajvardhan Azad
Manohar B. Babu
Soumyava Basu
Jyotirmay Biswas
Vishali Gupta
Kalpana Murthy
Somasheila Murthy
Mahendradas Padmamalini
Sundaram Natarajan
SR Rathinam
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Financial Disclosures
Abbott: (I, potential G)
Allergan: I, G, S, AB
Bayer: I
Celgene: G (past)Forsight: Labs G
Lux (this study): I, S,AB
Regeneron: I,AB
Santen: I
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Voclosporin: Rationale for Development
High unmet medical need in uveitis
Oral formulation of a next-generation calcineurin
phosphatase inhibitor
MOA: T-cell inhibition Animal and human
proof-of-concept
Psoriasis, renal
transplantation (Isotechnika)
Experimental autoimmune uveitis
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Studies of Voclosporin in Non-InfectiousUveitis
LX211-01
Treatment of active inflammation
LX211-02
Prevention of inflammatory exacerbation in controlled patients
5
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LX211-01 and 02: Design Overview
Multicenter
Randomized
Double-masked
Dose-ranging vs placebo0.2, 0.4, 0.6 mg/kg voclosporin BID
Results presented for 0.4 mg/kg BID
Unequal randomization (2:2:2:1)
Same target population in both studies
Different states of disease activity
6
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Study LX211-01
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LX211-01: Study Design
Rescue treatment permitted at any time per investigator discretion
SafetyExtension
StableCortico-steroidDose
IMTD/C
CorticosteroidTaper 5 mg
16 Wks-2 Wks
Randomization tovoclosporinor control
4 Wks
Co-PrimaryEndpoint
24 Wks
End ofExtension
48 Wks
8
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LX211-01: Important Eligibility Criteria
Inclusion
Active inflammation for 2 weeks
Vitreous haze 2+ in one or both eyes
Demonstrated need for systemic therapy
Patients typically receiving 10 mg/day prednisone and/or
concomitant immunosuppressive therapy
Exclusion
Infectious uveitis
Serious infection or malignancy
9
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LX211-01: Baseline Characteristics
Control
N=28
Voclosporin0.4 mg/kg
N=64
Mean Age (yrs) 42.4 40.5
Mean Years Since Diagnosis 3.94 3.82
Bilateral Disease 93% 86%
Anatomic Classification
Intermediate 18% 27%
Intermediate and Anterior 18% 14%
Posterior 14% 14%
Panuveitis 50% 45%
Demographics consistent with poor prognosis
10
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LX211-01: Baseline Immunosuppression
Control
N=28
Voclosporin
0.4 mg/kg
N=64
Oral Corticosteroid 64% 66%
Mean (mg/day1) 28.3 17.7
Topical Corticosteroid 61% 42%
drops/day 4.0 3.6
Any IMT2 25% 34%
Oral Steroid + IMT 14% 16%
1. Prednisone or equivalent
2. Immunosuppressive agents used at screening visit discontinued prior to randomization
11
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LX211-01: Primary Efficacy Analysis
-1.4
-1.2
-0.8
-0.4
0Week 16 Week 24
-1.0
-0.6
-0.2
p=0.008 p=0.027
control
voclosporin 0.4 mg/kg
MeanChangeinVitreousH
azeScore
12
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LX211-01: Mean Change from Baseline inVitreous Haze in Patients with Severe Inflammation
*****
**
* p
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LX211-01: Primary Efficacy Endpoint - Subset AnalysisBaseline Vitreous Haze 3+
-2.5
-2.0
-1.5
-1.0
-0.5
0Week 16 Week 24
MeanChangeinVitreousH
azeScore
p=0.006
p=0.043
Control
Voclosporin 0.4 mg/kg
14
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LX211-01: Primary Efficacy EndpointSubset Analysis Corticosteroids Medically Inappropriate
-1.8
-1.6
-1.2
-0.8
-0.4
0Week 16 Week 24
-1.4
-1.0
-0.6
-0.2
p=0.021
p=0.082
MeanChangeinVitreousH
azeScore
ControlVoclosporin 0.4 mg/kg
15
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LX211-01: Primary Efficacy Endpoint - Subset AnalysisLegally Blind in Study Eye at Baseline (BCVA 20/200)
-1.4
-1.0
-0.6
0.6
0.8Week 16 Week 24
-1.2
-0.8
-0.2
0.2
p=0.013
p=0.037
0.4
-0.4
0.0
MeanChangeinVitreousH
azeScore
Control
Voclosporin 0.4 mg/kg
16
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LX211-01: Delayed Time to Rescue
Control
Voclosporin 0.4 mg/kg
1.00
0.75
0.50
0.250 25 50 75 100 125 150 175
Time to Rescue (days)
SurvivalDistributionFunction
Median time to rescue:
voclosporin = 148 days
control = 83 days
17
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LX211-01: Vitreous Haze Improving in Voclosporin Groupand Worsening in Control Group at Time of Rescue
Significant difference in vitreous haze at time of rescue
Control Voclosporin
0.4 mg/kg
0.4
-0.4
0.2
0.0
-0.2
-0.6
0.36
-0.50
p=0.007
MeanChang
ein
VitreousHaze
Score
18
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LX211-01:Effect of Voclosporin in Active Uveitis
Significant reduction of inflammation in challengingpopulation
75% of the maximum possible improvement achieved
-1.2 units of vitreous haze
Consistent effect in subgroups:
With high degree of inflammation
Where corticosteroid therapy is inappropriate,
i.e. voclosporin monotherapy
With legal blindness
Even when rescued, voclosporin-treated patients showed
reduction of inflammation
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Study LX211-02
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LX211-02: Study Design
Rescue treatment: 2+ increase in VH or ACR or 15 BCVA letter
loss, or at any time per investigator discretion
SafetyExtension
StableCortico-steroidDose
IMTD/C
CorticosteroidTaper 5 mg
18 Wks-2 Wks
Randomization tovoclosporinor control
6 Wks
Steroid tapercompleted
26 Wks
End ofExtension
50 Wks
PrimaryEndpoint
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LX211-02: Important Eligibility Criteria
Inclusion
Clinically quiescent in both eyes at enrollment
Stable treatment regimen for 6 weeks
Subjects typically receiving 10 mg/day prednisone and/or
concomitant immunosuppressive therapy
Exclusion
Infectious uveitis
Serious infection or malignancy
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LX211-02: Baseline Characteristics
Control
N=31
Voclosporin
0.4 mg/kg
N=66
Mean Age (Years) 43.0 43.7
Mean Years Since Diagnosis 3.0 4.9
Female 71% 61%
Bilateral Disease 87% 88%
Anatomic Classification
Intermediate 26% 29%
Intermediate and Anterior 10% 8%
Posterior 19% 24%
Panuveitis 45% 39%
23
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LX211-02: Baseline Immunosuppression
Control
N=31
Voclosporin
0.4 mg/kg
N=66
Oral Corticosteroid 61% 73%
Mean (SD) [mg/day1] 10.7 (12.8) 11.5 (12.0)
Topical Corticosteroid 16% 24%
drops/day 0.2 (0.6) 0.7 (1.5)
Any IMT2 55% 62%
Oral Steroid + IMT 19% 29%
1. Prednisone or equivalent
2. Immunosuppressive agents used at screening visit discontinued prior to randomization
24
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LX211-02 Primary Efficacy Analysis Results
Ra
teofRecurren
ce
p=0.671
Note: p-values for pairwise C-M-H comparisons vs placebo 25
LX211 02 P t l ifi d &
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LX211-02: Protocol-specified &Investigator-initiated Rescue
R
ateofRecurrence
Investigator RescueProtocol-specified Event
39%
20%
26
Protocol-specified Event
2 Grade increase in VH
Grade increase in ACC
0.3 increase in logMAR
LX211 02 K l M i P i t E ti t
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LX211-02: Kaplan-Meier Point Estimatesof Inflammatory Exacerbation at 26 Weeks
26 Week
Rate SE p-valueControl 0.44 0.10 Voclosporin
0.4 mg/kg
0.22 0.06 0.044*
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
RateofExace
rbation
Week
0 2 6 10 14 18 22 26* P
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LX211-02: Conclusions
Voclosporin effect on inflammatory exacerbation isconsistent with its effects on active inflammation
Approximately 50% reduction in inflammatory
exacerbation
Demonstrates potential for use in continual control of
inflammation
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Voclosporin Safety Overview
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Voclosporin: Most Common Systemic AEs
MedDRA Preferred
Terms, n (%)
Control
N=73
Voclosporin
0.4 mg/kg
N=159
Hypertension** 3 (4.1) 24 (15.1)
Headache 6 (8.2) 14 (8.8)
Diarrhea** 4 (5.5) 14 (8.8)
Renal function test
abnormal*3 (4.1) 13 (8.2)
Upper Respiratory
Infection**7 (9.6) 12 (7.5)
Pyrexia 3 (4.1) 12 (7.5)
Arthralgia** 2 (2.7) 11 (6.9)
Asthenic conditions** 3 (4.1) 10 (6.3)
Hirsutism** 8 (5.0)
Edema** 2(2.7) 8 (5.0)
* Based on laboratory results; decrease in Glomerular Filtration Rate 30% **Combined terms30
Drug related AEs are:
1. Eas i ly detected
2. Detected ear ly
3. Revers ib le
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Voclosporin: Summary of Safety
SAEs and AEs were dose-dependent
Few SAEs occurred in >1 patient
Most common AEs were HTN and decreased renal
function
Easily detected with monitoring
Amenable to therapy or reversible with treatment discontinuation
With 850 PT-YR exposure, opportunistic infections were
not seen; rates of malignancy were no different thancontrol
Low incidence of clinically significant lab abnormalities
31
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Summary of Voclosporin in Noninfectious Uveitis
LX211-01: Clinically meaningful reduction in vitreoushaze with strong statistical significance
Early and sustained response
Time to rescue therapy increased nearly 2-fold
50% reduction in inflammation over 6 months
LX211-02: Control of inflammation maintained
Up to 50% reduction vs. control in inflammatory exacerbation
recurrence rate
Safety Profile: Adverse effects are manageable with
routine monitoring
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