HOW TO BUILD A REFERENCE CENTER

Giuseppe Remuzzi Mario Negri Institute for Pharmacological Research

June16–19,2016Amsterdam,Netherlands

KDIGO

CASE REPORT

On August 15, 1988 B.L, a 21-year-old-man was admitted to the Unit of Nephrology of Bergamo Hospital because of: - fever - jaundice - confusion Laboratory findings - Hct: 27% - LDH: 2343 I.U./L - Platelet count: 27 x 103/µl Diagnosis: TTP Treatment: Plasma exchange Outcome: Full recovery of the acute episode

- aphasia - migrating paresthesias - visual abnormalities

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Since August 1988

Almost 2-hundreds (monthly) recurrences of TTP Recovery of acute episodes with plasma therapy Progressive renal function deterioration Started chronic dialysis (March 3, 2001) Persistency of monthly recurrences with predominant gastrointestinal symptoms and occasional gastrointestinal bleeding

CLINICAL COURSE

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PLASMA EXCHANGE vs INFUSION IN CHRONIC RELAPSING TTP Pl

atel

et c

ount

(x 1

000/

mm

3 )

0 30

200

0 30

200

1 3 6 9

0 30

200

0 30

200

0 30

200

1 3 6 9 0

30

200

1 3 6 9 days Plasma exchange Plasma infusion

Ruggenenti et al., Am J Kidney Dis, 1993 4

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5

Plat

elet

cou

nt (x

100

0/m

m 3 )

0

30

200

0

30

200

1 3 6 9

0

30

200

0

30

200

1 3 6 9

0

30

200

1 3 6 9 days

Plasma removal Plasma infusion

0

30

200

Ruggenenti et al., Am J Kidney Dis, 1993

PLASMA INFUSION vs REMOVAL IN FAMILIAL AND RECURRENT TTP

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1992

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8

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9 Niguarda, S.Raffaele, Policlinico, Istituto Tumori, Besta, S.Matteo

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2001 à13 Presidi 2015 à 38 Presidi

Centro di coordinamento

REGIONAL NETWORK FOR RARE DISEASES

≤ 8081 - 149≥ 150

Number of diseasesserved by Reference centers

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11

13

23

26 29

31 31 32 34 35 35

38 38

0

5

10

15

20

25

30

35

40

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

+ 484- 159

+ 91- 51

+ 76- 41

+ 69- 31

+ 170- 23

+ 21- 3

+ 84- 6

+ 11

+ 6

+ 19 - 4

- 57

+ New endprsments - Withdrawal

N° Reference centers

REGIONAL NETWORK FOR RARE DISEASESEVOLUTION OF REFERENCE CENTERS

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12

0

2

4

6

8

10

12

14

16

18

< 0,002% Tra 0,002% e 0,004% Tra 0,005% e 0,01% > 0,01%

No.

Ref

eren

ce c

ente

rs

Rare Disease Prevalence

REGIONAL NETWORK FOR RARE DISEASESDISEASES THAT ARE LESS RARE HAVE HOWEVER MORE REFERENCE CENTERS

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Regional Network for Rare Disease Working Group

•  Goals–  The Working Group establishes uniform strategies for the

reference centers to pursue prevention, surveillance, diagnosis and treatment of rare diseases

•  The Working Group is composed by rappresentatives of–  Region–  Reference centers–  Coordination Center–  Local health authority–  Patient associations

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943

687

539

747

606 596

1263

1937

1644

1500

1324

1088 1145

1035

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

February 29, 20081st Rare Diseases Day

COORDINATION CENTER: CONSULTING ACTIVITY

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15

0%

10%

20%

30%

40%

50%

60%

70%

80%

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Pazienti e FamiliariOperatori Sanitari

COORDINATION CENTER: CONSULTING ACTIVITY

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Regional Networks evolution in Italy

2001 ...200716

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PATIENT DISTRIBUTION BY AGE AND GENDER

Lombardypopula-on 9.973.397*

AllRDcases 54.647

Dieases 291

Prevalence 548/100.000

*ISTAT Italian Population Census – January 1st, 2014

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Diagnostic , Therapeutic and Social Care Pathways (PDTA)

•  632 health care professional were involved •  31 reference centers•  33 patient associations

•  110 PDTA were prepared

•  They cover approximately 72 – 87% of rare disease recorded in Lombardy

Since 2012 the Regional Network has promoted the development, through conferences of experts, of shared pathways for the diagnosis, treatment and social assistance to patients with rare diseaseThese pathways are intended to offer the best quality of care whereby optimizing the use of resources

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PDTA ARE AVAILABLE AT THE COORDINATION WEBSITE

0

2000

4000

6000

8000

10000

2011 2012 2013 2014 *

* dal 30 marzo 201119

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HOW THE REGIONAL NETWORK IS EVALUATED BY THE PATIENTS

"Malattie rare: rilevazione dei bisogni assistenziali e definizione di misure a sostegno". Decreto n. 7771 del 11.09.2012, Direzione Generale Sanità, Regione Lombardia Éupolis Lombardia, Edizione: aprile 2014

1 = per nulla soddisfatto

0 1 2 3 4 5

5 = molto soddisfatto

Assistenza socio-sanitaria globalmente ricevuta

Presidio di riferimento per la malattia

Medico di Medicina Generale o Pediatra di Libera Scelta

Distretto socio-sanitario/Azienda Sanitaria Locale (ASL)

Servizi sociali (del Comune o di soggetti delegati)

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EXPERTISE AND ORGANIZATIONAL SUPPORT FOR CLINICAL STUDIES

IMPROVE KNOWLEDGE AND POSSIBILITY OF TREATMENT IN RARE

DESEASES

RESULTS DIFFUSION

STATISTICAL ANALYSIS

STUDY MONITORING

STUDY DEVELOPMENT

REGULATORY ASPECTS

STUDY DESIGN

RESEARCH AIM

DEFINITIONEUROPEAN SCHOOL FOR RARE DISEASESThe Center is the site of active cultural activity at several levels, aimed to both spec ia l i s ts and t ra in ing hea l th professionals

Regular courses for training in clinical research are addressed to:

-  Medical doctors-  Registered nurses-  Statisticians-  Monitors-  Bioengineering-  Epidemiologists-  Informatics

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22,765

221992 - 2015

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3 KDIGO

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Ryan

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Prevalence: 1,6/1,000,000 persons

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BergamoTrento

Padova

TrevisoVicenza

ParmaGenovaTorino

Pavia

Milano

VareseMonza

Brescia

Firenze

Roma

Foggia

BariSalerno

Reggio CalabriaPalermo

Cagliari

Sassari

UK9 cases

USA58 cases

Argentina 23 cases

Belgium 1 case

Israel14 cases

Portugal11 cases

Canada 4 cases

Switzerland 22 cases

South Africa2 cases

Germany 19 cases

Denmark 3 cases

Saudi Arabia4 cases

Czech R.11 cases

Esthonia1 case

Serbia 5 cases

Italy765 cases

Greece 4 cases

Australia14 cases

Malaysia 2 cases

Turkey8 cases

IRAN49 cases

Spain 5 cases

Poland13 cases

Russia6cases

UAE1case India

5casesJapan2cases

Chile3cases

Par-cipa-ngCenters

HUS/TTPpa-entsItaliancasesForeigncases

180

1160780380

INTERNATIONALREGISTRYOFHUS/TTP

09/2015

Brazil2cases

Croa-a2cases

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1 2 3 4 9876510 11 13 1412 15 16 17 18 19 20

1 2 31 2 3

CFH76 mutations

CFB5 mutations C3 12 mutations

MCP 28 mutations

CFI 23 mutations

Bergamo

Newcastle

Madrid

Toulose

Paris

TM 6 mutations

2

3

4

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COMPLEMENT ABNORMALITIES IN 272 PATIENTS

Factor H

MCP

Factor H ab

C3

Factor I

TM

Factor B

Combined

?

0 10Cumulation incidence (%)

25

20 504030

10

7

7

8

1

35

3

Noris et al. J Am Soc Nephrol, 2010

4

T30Nfs10XG1194DG1194DR1210CR1210CR1210CR1215Q N767Kfs7XP968fs947XS1191L V1197AR341H

1234567

123

12

 

SIIFIIS FSI IF 

        

H183RI340TE554V

 

            

G1094RR161W

Cohort CFH MCP CFI C3#I208Y F242C F242C Y29X

C35Y and R59X C35Y and R59X

R103Q

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The patient and the unaffected mother and brother carry a a very rare genomic rearrangement between CFH and CFHR1 genes generating heterozygous CFH/CFHR1 hybrid protein in which SCR 1-19 are derived from CFH and SCR 20 from SCR 5 of CFHR1 by non allelic homologous recombination

ATYPICAL HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH A HYBRID COMPLEMENT GENE

CFH CFHR3 CFHR1Deletion

CFH/CFHR1 fusion protein

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

1 2 3 4 5 1 2 3 4 5

5

Valoti et al., JASN, 2015

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LONG-TERM OUTCOMES FOR aHUS PATIENTS

CFH mutation

Patie

nts

free

of e

vent

s D

eath

or E

SRD

(%)

100

80

60

40

20

00 2 4 6 8 10 12

Follow up (years)

Noris et al., C J Am Soc Nephrol, 2010

Tx?

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30 30

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Rat kidney reperfusion

ORTHOTOPIC KIDNEY TRANSPLANTATION IN RATS

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MCP

C3

Factor I

Factor H

Factor B

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EFFECTS OF 52 WEEKS OF ECULIZUMAB THERAPY IN PATIENTS WITH PLASMA DEPENDENT OR PLASMA RESISTANT ATYPICAL HUS

Dependent(n = 20)

Persistent remission

Need for plasma therapy

Serious treatment-relatedadverse events

Licht et al., J Am Soc Nephrol, 2011Greenbaum et al., J Am Soc Nephrol, 2011Legendre et al., N Engl J Med, 2013

Resistant(n = 17)

17

0

0

15

0

0

33

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Ryan

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330,000 euro per patient per year

460.000

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Rare diseases and effective treatments: are we delivering? Lucio Luzzatto, Carla E M Hollak, Timothy M Cox, Arrigo Schieppati, Christoph Licht, Helena Kääriäinen, Giampaolo Merlini, Franz Schaefer, Steven Simoens, Luca Pani, Silvio Garattini, Giuseppe Remuzzi

28 February 2015

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Ogni 15 giorni per sempre? KDIGO

C3b

C3

C3b

C3a

Endothelial cell Glycosaminoglycans

iC3b C3b

CFB

Surface bound C3 convertase

C3b Bb

CFB

Bb

CFI

iC3b

CFI

CFH

C5b-9

C5 convertase

C5 C5a

20

Alternative pathway activation (spontaneous hydrolysis, bacteria, viruses)

Fluid phase C3 convertase 20

ALTERNATIVE PATHWAY ACTIVATION IS IMPAIRED IN SOLID BUT NOT IN FLUID PHASE

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Normal serum

C5b-9

39

ADPC3b C3b

Normal serum

Resting endothelium Activated endothelium

Acute aHUS serum

C5b-9

ADPC3b C3b

aHUS serum in remission Asymptomatic carrier serum

Resting endothelium Activated endothelium

C5b-9C5b-9 C5b-9C3b

C3b C5b-9C5b-9

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- Control or aHUS serum

Static incubation4 hours

C5b-9 depositionHMEC-110 min

Resting

-  anti-C5b-9 Ab staining- Confocal microscopy

0

1000

2000

3000

4000

5000

6000

7000

8000

*

C5b

-9 fo

rmed

(pix

el2 )

aHUS

Noris et al, Blood, 2014

Control (n=4)

Acute (n=7)

Remis (n=7)

Resting endothelium 10,000

Control aHUS

8,000

6,000

4,000

2,000

0aHUS +

Eculizumab

C5b

-9 fo

rmed

(pix

el2 )

Activated endothelium

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I

I I

S1191L mutation in CFH

39 yrHD

41 yr

I I

I

68 yr

c.3572 C>Tp.Ser1191Leu

A 1-year old child was admitted with familial aHUS and a heterozygous loss of function mutation in complement factor H gene (3645C>T) and developed aHUS at 6 months of age

April 2007

1 yr

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DIALYSISPLASMA THERAPY

ECULIZUMAB

300 mg

KIDNEY TRANSPLANTECULIZUMAB

0

50

100

150

200

250

300

0 10 20 30 40 50 60 70 80PLAT

ELET

CO

UN

T (1

03/m

icro

liter

)

months90

Pediatric case

100 110

Kidney Tx

600

Eculizumab (mg)

1 7

300 600

1

300 300

2 months3 4 514 days0

300 300 300 300 300 300 300 300

Aug 19, 2011 – 5 years of age

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DIALYSISPLASMA THERAPY

ECULIZUMAB

300 mg

KIDNEY TRANSPLANTECULIZUMAB

0

50

100

150

200

250

300

0 10 20 30 40 50 60 70 80PLAT

ELET

CO

UN

T (1

03/m

icro

liter

)

months

post-Ecu300

0

2000

4000

6000

8000

C5b

-9 fo

rmed

(pix

el2 )

90

Pediatric case

100 110

post-Ecu600

post-Ecu600

600 mg

ECULIZUMAB

Post-Ecu 600

Noris et al., Blood, 2014

165 418Eculizumab levels microgr/ml

CH50(normal range 79-187 Ueq/ml) 72 3 3 6 6

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600 mgDIALYSISPLASMA THERAPY

ECULIZUMAB

300 mg

KIDNEY TRANSPLANTECULIZUMAB

0

50

100

150

200

250

300

0 10 20 30 40 50 60 70 80PLAT

ELET

CO

UN

T (1

03/m

icro

liter

)

months

0

2000

4000

6000

8000

C5b

-9 fo

rmed

(pix

el2 )

90

Pediatric case

100

ECULIZUMAB

LIVER TRANSPLANT

post-Tx liverEcu

110

pre-Tx liverEcu

Sept 18, 2014 – 8 years of age

post-Ecu300

post-Ecu600

post-Ecu600

EcuSTOP

EcuSTOP

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Bergamo Trento

Padova

Treviso

BolognaGenova

Torino ParmaMilano

Monza Brescia

Firenze

Roma

BariNapoli

USA2 cases

Argentina 2 cases

Israel4 cases

Portugal 1 case

Switzerland 2 cases

Czech R. 1 case

Italy204 cases

Turkey1 case

IRAN3 cases

Chile 1 case

Participating Centers

Ig-MPGN/C3G patients Italian cases Foreign cases

50

227 204 23

REGISTRY OF MPGN/C3G

09/2014

http://negribergamo.marionegri.it/

Russia 1 case

Modena

Como

Messina

Bolzano

Perugia

Germany 1 case

UK1 case

Poland1 case

France1 case

Croatia1 caseKDIGO

EAGLE Study Evaluating the Morphofunctional Effects of

Eculizumab* Therapy in Primary Membranoproliferative Glomerulonephritis:

A Pilot, Single Arm Study in 10 Patients with Persistent Heavy Proteinuria

and low C3 levels and high sC5b9 levels (>1000 ng/ml)

Elena Mondo, Piero Ruggenenti, Erica Daina, Marina Noris, Elena Bresin and Giuseppe Remuzzi

Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, Bergamo, Italy

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* 900 mg weekly for four infusion and maintenance phase 1200 mg at week 5; then 1200 mg every 2 weeks for 1 years

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BergamoTrento

Padova

Treviso

TorinoParma

Milano

Firenze

Roma

Foggia

BariNapoli

USA2 cases

Greece1 case

Romania2 cases

Italy235 cases

Turkey2 case

IRAN20 cases

Participating Centers

SRNS patientsItalian casesForeign cases

32

274235 39

REGISTRY OF SRNS

Palermo

Pisa

Germany1 case

Belgium6 cases

Bosnia1 case

Sweden1 case

Spain1 case

Trieste

Gorizia

Ancona

Chieti

Reggio Calabria

Catanzaro

INDIA1 case SENEGAL

1 case

http://www.marionegri.it

07/2015

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THE REGISTRY OF STEROID RESISTANT NEPHROTIC SYNDROME

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J Am Soc Nephrol, 2014

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DERIVATION OF HUMAN iPSC-DERIVED PODOCYTES

Mature podocytes

d1d0 d4Plating

Mesoderm induction

Renal precursors

d6Reprogramming* by 4 factors:

- Oct4- Sox2- Klf4 - cMyc

iPS cells

PBMC

51

d13

Synaptopodin/DAPI Nephrin/DAPI

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Synaptopodin WT-1

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In vitro15 days

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Adaptative Designs: Examples

Gupta et al, J Clin Epidemiol 2011

Ranking and selection designs -  “Pick-the-winner”, “drop-the-losers” designs are used for

treatment/dose selection for a subsequent randomized study)

Internal pilot designs -  The sample size is calculated during the pilot phase and patients

of the pilot study are maintained in the subsequent trial

Sequential designs -  Continuous sequential analyses are planned with pre-set

stopping criteria

Response-adaptative randomization designs - Possibility to adapt the study design according to preliminary

outcomes

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BALLS-IN-URN RESPONSE-ADAPTATIVE RANDOMIZATION DESIGNSProbability of being allocated to experimental therapy 50% 66% 75%

Experimental

Conventionall

•  Black balls are added whenever a patient assigned to experimental therapy survives or one allocated to conventional therapy dies

•  White balls are added whenever a patient assigned to experimental therapy dies or one allocated to conventional therapy survives

•  The process continues until a preset stopping criterion is metGupta et al, J Clin Epidemiol, 201155

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These slides belong to Giuseppe Remuzzi, M.D.

Mario Negri Institute for Pharmacological Research, Bergamo, Italy.

Using these slides is only authorized when mentioning the source

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