Update: Uveitis - kssg.ch · with inactive, non-infectious uveitis who are at risk of the long-term side effects of corticosteroids2 • The VISUAL-III trial was conducted to evaluate

Update: Uveitis

Prof. Dr. Matthias Becker

http://www.triemli-augenklinik.ch

http://www.triemli-augenklinik.ch/



Prof. Dr. Matthias Becker Augenklinik Triemli Zürich

Financial Disclosures

• Lecturer: PeerVoice

• Advisor: GLG (Gerson Lehrman Group), AbbVie

• Editor: SwissOphthal

No financial interests


Pubmed: # publications for „uveitis“

891 918 932

957 954

1085 1124

1190 1211 1207

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016


Uveitis

• Fifth most common cause of vision loss in high-income countries

• Estimated incidence of 17 to 52 cases per 100‘000

• Highest incidence of disease in the working-age population

• Estimated prevalence 38 to 714 cases per 100‘000

• Overall prevalence is as high as 0.73%

• Accounting for 5% to 20% of legal blindness

• Estimated to cause 10 to 15% of cases of preventable blindness in developed countries and up to 25% of cases in the developing world overall

• Responsible for approximately 30‘000 new cases of legal blindness each year (2.8%–10% of all cases of blindness)

• Socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy (de Smet et al. 2011)


Horai R, et al. J Interferon Cytokine Res 2011;31:733-44.


Gomes Bittencourt M, et al. Dev Ophthalmol 2012;51:134-61.


Recent International Multicenter Studies for Uveitis

Study Drug

MUST Surgical fuocinolone acctonide

implant (Retisert©)

HURON Injectable intravitreal dexamethasone

implant (Ozurdex©)

ENDURE Systemic anti-IL-17 agent

Secukinumab (Cosentyx©)

EYEGUARD Systemic anti-IL1b drug gevokizumab

(XOMA 052©)

VISUAL Systemic anti-TNF adalimumab

(Humira©)

SACURA Injectable intravitreal sirolimus

(Opsiria©)


VISUAL I+II Systemic anti-TNF adalimumab (Humira©)


Anti-TNF-Inhibitors: Targeting inflammatory cytokines

• Etanercept (Enbrel©; Amgen, Thousand Oaks, CA)

• Infliximab (Remicade©; Janssen Biotech, Horsham, PA)

• Adalimumab (Humira©; AbbVie, North Chicago, IL)

• Golimumab (Simponi©; Janssen Biotech, Horsham, PA)

• Certolizumab (Cimzia©; UCB, Brussels, Belgium)


To confirm that adalimumab is efficacious in

the studied population versus placebo

Real-world design to provide insight about the

safety and effectiveness of adalimumab in

clinical practice

n=239

n=261

n=424

85% of VISUAL I & II

Active uveitis1

ADA 40 mg or placebo

n=239a

Controlled uveitis2

ADA 40 mg or placebo

n=261a

Open-label extension3

ADA 40 mg

n=424

85% of patients in VISUAL I and II

1. Jaffe GJ et al. N Engl J Med. 2016 Sep 8;375:932-43 2. Nguyen QD et al. Lancet. 2016 Sep 17;388:1183-92 3. Suhler EB, et al. IUSG 2016; FP52

RCTs in non-infectious uveitis: The VISUAL program


The VISUAL trials

• The VISUAL-I trial was conducted to assess the efficacy and safety of adalimumab (ADA) in patients with active, non-infectious uveitis despite high-dose corticosteroid therapy1

• The VISUAL-II trial was conducted to assess the efficacy and safety of ADA in corticosteroid-dependent patients with inactive, non-infectious uveitis who are at risk of the long-term side effects of corticosteroids2

• The VISUAL-III trial was conducted to evaluate the long-term safety and efficacy of ADA in patients with non-infectious intermediate, posterior, or panuveitis

1. Jaffe GJ et al. N Engl J Med. 2016 Sep 8;375:932-43 2. Nguyen QD et al. Lancet. 2016 Sep 17;388:1183-92


https://clinicaltrials.gov/show/NCT01138657

https://clinicaltrials.gov/show/ NCT01124838

https://clinicaltrials.gov/show/NCT01148225

Global study sites N = 62 in 21 countries

CH = 2


N Engl J Med. 2016;375:932-43

VISUAL-I

• Multinational, phase-III RCT, placebo-controlled

• Active noninfectious intermediate uveitis, posterior uveitis, or

panuveitis

• Randomly assigned 1:1 ratio to receive adalimumab (ADA) or

matched placebo

• All received mandatory prednisone burst followed by tapering of

prednisone over the course of 15 weeks

• PEP: time to treatment failure occurring at or after week 6


Lancet. 2016;388:1183-92

VISUAL II

• Multicentre, double-masked, randomised, placebo-controlled

• Inactive, non-infectious uveitis controlled by systemic CS

• Controlled by 10–35 mg/day of prednisone

• Randomly assigned 1:1 ratio to receive adalimumab (ADA) or

matched placebo

• PEP: time to treatment failure (multicomponent endpoint)


Study design

VISUAL-I

VISUAL-II



Composite Primary Endpoint in VISUAL-I and -II

Treatment failure criteria

New lesions

Anterior chamber cells

Vitreous haze

BCVA

Time to treatment failure (TF)

Time to event analysis Multiple triggers

Time to TF is defined as the time from randomization to discontinuation due to any of the given TF criteria



Early and sustained effect of adalimumab on the rate of treatment failure compared with placebo

The risk of failing treatment (flare or vision loss) was reduced by almost

half and the time to treatment failure was approximately doubled

PBO ADA

Median time to

treatment

failure

8.3 months >18 months

HR; p-value 0.57; p=0.004

95% CI for HR (0.39–0.84)

PBO ADA

Median time to

treatment failure

3.0 months 5.6 months

HR; p-value 0.50; p<0.001

95% CI for HR (0.36–0.70)

0 2 4 6 8 10 12 14 16 20

Time (months)

Tre

atm

en

t fa

ilu

re

rate

(%

)

20

40

60

80

0 18

placebo (n=111) ADA (n=115)

0 10 20 30 40 50 60 70 80 90 Time (weeks)

Tre

atm

en

t fa

ilu

re

rate

(%

)

20

40

60

80

100

0




VISUAL I – Efficacy Primary endpoint: Time to treatment failure

• Hazard ratio for time to treatment failure between ADA and PBO is 0.5 (0.36–0.70), p<0.001, therefore, the risk to fail was reduced by 50% for ADA compared with PBO

• The median time to treatment failure was prolonged by 87% from 13 weeks for placebo to 24 weeks for ADA

HR=0.5 (0.36–0.70), p<0.001

0 10 20 30 40 50 60 70 80 90

Weeks

Tre

atm

en

t fa

ilure

rat

e (

%)

20

40

60

80

100

0


87% increase

ADA: Adalimumab; PBO: Placebo

Jaffe GJ et al. N Engl J Med. 2016 Sep 8;375:932-43


VISUAL II – Efficacy Primary endpoint: Time to treatment failure

HR=0.57 (0.39–0.84, p=0.004)


0 2 4 6 8 10 12 14 16 20

Months

Tre

atm

en

t fa

ilure

rat

e (

%)

20

40

60

80

0

18

• Hazard ratio for time to treatment failure between ADA and PBO is 0.57 (0.39–0.84), p=0.004, therefore, the risk to fail was reduced by 43% for ADA compared with PBO

• The median time to treatment failure was 8.3 months for PBO, but was not estimable for ADA, as fewer than half of the ADA-treated patients experienced treatment failure

Denniston A. et al. Lancet_E 2016, S0140-6736(16)31327-7


Conclusions: VISUAL-I

• In patients with active, non-infectious uveitis uncontrolled with

prednisone ≥10 mg daily, ADA significantly lowered the risk for

uveitic flare or BCVA loss

• Patients on ADA had a lower risk to fail and fewer criteria of

treatment failure were met

• Worsening of AC cell grade, VH grade, and BCVA from best state

achieved, as well as occurrence of new lesions were reduced with

ADA compared with placebo

• Percent change in CRT was significantly smaller with ADA compared

with placebo, and ADA also reduced the risk of developing ME in

patients without pre-existing macular pathology

• Adverse event data were similar between the ADA and placebo

groups. The safety profile was consistent with the known safety profile

of ADA across approved indications

Jaffe GJ et al. N Engl J Med. 2016 Sep 8;375:932-43


Conclusions: VISUAL-II

• In steroid-dependent patients with inactive, non-infectious uveitis, ADA significantly lowered the risk for uveitic flare or vision loss

• Patients on ADA had a lower risk to experience treatment failure and fewer criteria of treatment failure were met

• Secondary endpoints were numerically in favor of ADA, although significant differences between ADA and placebo were not observed

• Adverse events were similar between the ADA and placebo groups. The safety profile was consistent with the known safety profile of ADA across approved indications.

Nguyen QD et al. Lancet. 2016 Sep 17;388:1183-92


Strengths

• RCT design

• Large patient population

• Diversity of uveitis diagnosis

• Composite primary endpoint

• Hierarchical statistical analysis of secondary endpoint

Limitations

• Heterogenity of uveitis aetiologies

• Underestimation of time to treatment failure?

• Overestimation of treatment failure?

• Scarcity of established high-quality outcome measures



N Engl J Med 2017;376(17):1637

• Children and adolescents 2 years of age or older who

had active JIA-associated uveitis

• Taking a stable dose of MTX

• Randomly assigned in a 2:1 ratio to receive either ADA

(20 mg or 40 mg, BW) or placebo +

• Treatment failures in 27% in the ADA versus 60% in

placebo


Adalimumab labels

• FDA (approval 30-JUN-2016): «Humira is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients.”

• 10th approved indication for HUMIRA in the United States

• EMA (approval 24-JUN-2016): «Humira is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid sparing, or in whom corticosteroid treatment is inappropriate.»

• Swissmedic (approval 17-MAY-2017) FDA Humira, www.fda.gov, Date of information: June 2016 EMA Humira, www.ema.europa.eu, Date of information: October 2016 SmPC Humira, www.swissmedicinfo.ch, Date of information: March 2016

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https://en.wikipedia.org/wiki/File:Flag_of_Switzerland_(Pantone).svg


Preis in der Schweiz (compendium.ch)

• Fertigspritze 40 mg = 739 CHF

• Initialdosis von 80 mg (2 Injektionen) und danach 40 mg (1 Injektion) jede zweite Woche beginnend eine Woche nach der Initialdosis als subkutane Injektion


SACURA-TRIAL Intravitreal Sirolimus

“Sirolimus study assessing doublemasked uveitis treatment”


mTOR-Inhibitors (= mechanistic Target of Rapamycin)

• Tacrolimus (Prograf®)

• Everolimus (Certican®)

• Sirolimus

– Systemisch: Rapamycin (Rapamune®)

– Intravitreal: Opsiria® (Santen, Osaka, Japan)


Ophthalmology.

2016;123:2413-23

• Noninfectious uveitis (NIU) of the posterior segment

• 2nd Phase III, randomized, double-masked, active-

controlled, 6-month

• Vitreous haze (VH) score >1+

• Assigned 1:1:1 at doses of 44, 440, or 880 μg, administered

on days 1, 60, and 120

• PEP: % VH=0 at month 5 without use of rescue therapy

• SEP: VH 0 or 0.5+ response rate, CS tapering success,

changes in BCVA

• N=347


Results: SACURA-II Trial Nguyen QD et al., Ophthalmology. 2016;123:2413-23

44 μg 440 μg 880 μg

PEP 10.3% 22.8%; P = 0.025 16.4%; P = 0.182

VH score of 0 or

0.5+

35.0% 52.6%; P = 0.008 43.1%; P = 0.228

CS-taper 63.6% 76.9% 66.7%

BCVA maintained throughout the study

in each dose group


Conclusion: SACURA-II Trial Nguyen QD et al., Ophthalmology. 2016;123:2413-23

• Significantly more patients in the 440 μg group achieved improvement in ocular inflammation than did the 44 μg set

• Opsiria is intended as a 440 µg sirolimus injection

• Demonstrating its safety and maintaining BCVA

• Lack of inducing glaucoma

• Efficacy to treat CME has not been clarified in the SAKURA trial and is likely to be low

• Potential to provide safe long-term care


Sirolimus labels

• FDA (25-APR-17): „FDA Filing Acceptance of New Drug Application (NDA) for Intravitreal Sirolimus (DE-109) in the Treatment of Non-Infectious Uveitis of the Posterior Segment“

• EMA (20-MAY-2016): „Santen officially notified the Committee for Medicinal Products for Human Use (CHMP) that it wishes to withdraw its application for a marketing authorisation for Opsiria“

• Swissmedic: (approval pending)

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Documents

Update: Uveitis - kssg.ch · with inactive, non-infectious uveitis who are at risk of the long-term side effects of corticosteroids2 • The VISUAL-III trial was conducted to evaluate