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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

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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

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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

21

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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%

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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

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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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