Ensayos de Terapia Celular. Curso UCM-2013

8/10/2019 Ensayos de Terapia Celular. Curso UCM-2013

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Investigacin y utilizacin clnica de clulas

madre procedentes de tejidos adultos


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In memorian


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Directivas comunitarias (BOE 12 de diciembre de 2003) sobremedicamentos de terapia celular somtica de origen humanoNuevas normas para ensayos clnicos en los que ya se contemplanlos ensayos clnicos con medicamentos de terapia celular somtica(BOE 7 de febrero de 2004) Real Decreto 176/2004 (B.O.E. 31/01/04) en el que se aprueba elEstatuto del Centro Nacional de Transplantes y MedicinaRegenerativa

Clulas = Medicamento


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Medicamentos de Terapias Avanzadas


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Clinical Trial Process


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Objetivos principales de losensayos clnicos

FASE I : Estimacin inicial de seguridad y tolerabilidad.

FASE II: Determinacin de eficacia en la indicacin propuesta

FASE III: Demostrar/confirmar eficacia (eficiencia) en laindicacin propuesta

FASE IV: Completar el conocimiento de la relacin beneficio-riesgo

Identificar reacciones adversas de baja frecuencia.

Determinar la eficiencia del tratamiento.


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Ensayos clnicos en terapia celular(clinicaltrials.gov)

0500

100015002000250030003500400045005000

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Ensayos

Ensayos


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Clinical trials using Stem Cells(clinicaltrials.gov)

SPAIN: 134


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553

907

201

0 200 400 600 800 1000

phase I

Phase II

Phase III

Clinical trials using Stem CellsOpen Studies:1775 (October2012)


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Phase III Completed Studies


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11

Bioseguridad y resultyados:


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CURVA DE GARNET
http://en.wikipedia.org/wiki/File:Gartner_Hype_Cycle.svg


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Cell Therapy clinical trialsTherapeutic areas(Non hematopoietic cells)

Taking into account cells different from hematopoietic cells

Source: Clinical trials.gov. Companies web pages


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CSC

MSC

Acute andchronic MI

MIOBLASTOS

ESC/iPS

MO ADSC

Stem Cells with Cardiac Potential


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Cell Types

BM, Adipose cells, SkM, EPC,Cardiac Progenitors

Manufacturing

Culture, isolation, differentiation

Disease

Acute and Chronic MI

Delivery of the cells

Intracoronary, percutaneous,surgical

Clinical Studies


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Clinical Studies


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Nat Med. 2008; 14:213-21

Building a heart


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TCP-


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PRP carrier celular


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preop postop 7m 11m


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Tratamientos de las lesionesfocales: trasplante de condrocitos

autlogos

L l


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Agentes etiolgicos

Primarios

Hereditarios:

Aniridia, Stevens-Johnson

Neoplsicos:

Neoplasia intraepitelial

Degenerativos:Pterigion recidivante

SecundariosFsicos:cidos, agresin trmica,

Traumatismos

Anoxia:Lentes de contacto

Inflamaciones crnicas

Les ones orneales


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Tratamiento

1. Restaurar la defensa dela superficie ocular

2. Transplante autolgo delimbo

3. Transplante alognicode limbo

4. Transplante demembrana amnitica

5. Transplante autlogo declulas progenitoras

Tratamiento


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Trasplante de CM Limbocorneales


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Futuro: Cornea Artificial


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Progenitores en lainsuficiencia heptica aguda


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Nature, July 2013


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Spinal Cord Injury: 127Studies

H St C ll h l t


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How Stem Cells may help to aSurgeon?

? R l ti i S g
http://localhost/var/www/apps/conversion/tmp/scratch_3//upload.wikimedia.org/wikipedia/commons/b/bd/Stem_cell_treatments.svg


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Revolutions in Surgery1846-1982


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Ulceras cutneas
http://medicine.ucsd.edu/clinicalmed/extremities-neuropathic-ulcer.jpg


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ENSEANZAS DE UN CICLO COMPLETO DE ENSAYOSCLNICOS EN TERAPIA CELULAR
http://images.google.es/imgres?imgurl=http://www.uam.es/personal_pdi/ciencias/ruben/mainfiles/Logo_UAM_blanco.gif&imgrefurl=http://www.uam.es/personal_pdi/ciencias/ruben/Web_grupo/Fernando_Flores/fernando_flores.html&h=623&w=1280&sz=33&hl=es&start=1&sig2=R71W8bwW5YLWSvEbI7YIoQ&tbnid=WcAqaG9ZGjEHwM:&tbnh=73&tbnw=150&ei=Jm58SLnwLZqUwQGpo6DoAg&prev=/images%3Fq%3DUAM%26gbv%3D2%26hl%3Des


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Perianal discharge Pain Swelling Bleeding

Diarrhea Skin excoriation External opening

Fistula in Crohns Disease: a real problem ofwound healing due to auto-immune disease


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Complex perianal fistulaAn unmet need

Author Present1999Sands2004

Healing IFX (%) 55-38 36

Healing Placebo (%) 13 18

Recurrence IFX (%) --- 64

Recurence Placebo (%)--- 81

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Definition:

A complex perianal fistula is characterized by:Affection of the anal sphinctersMultiple tractsAssociated with perianal abscess and/or connects an adjacentstructureRecurrence Current treatments dont

address unmet need

Advanced Flaps

Cryptoglandular Disease

Author Recurrence(%) Incontinence

(%)

Schouten 1999 25 35

Mizrahi 2002 45 9

Sonoda 2002 36,4 ---

Van Koperen 2008 21 40

Crohnss Disease

Infliximab

Wh h b f S C ll


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Whats the best source for Stem Cellsto treat Surgical Diseases?

Alfa-actina


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Stem Cells from Adipose TissueAdvantages

Adipose derived mesenchymal stem cells:

Higher yield (between 100 and 1000 times higher yield than bone marrow) BM stimulation is not required (G-CSF) Expendable and accessible: Simple liposuction Biosafety : No chromosomal alterations/ tumorigenic behavior after long term ex

vivo cultures Wide range of potential applications

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2003 heart

2001 Grasa

1999 brain

1993 Muscle

Hematopoetic (bone marrow) 1986

1990 Intestine

1992Liver

1993Skin

1999Mesenchymal cells (bone marrow)

2001MAPC (bone marrow)

2003Pancreas

Adipose tissue


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Cells extraction by liposuction

Localanaestesia. (mepivacaina al

1%) Little incisin (0,5 cm.)

Aesthetical value

T h l i i l d i Adi D i d


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Technologies involved in Adipose DerivedStem Cells (ASC) Therapy

ASC Implant

ASC Obtention

Liposuction isolation

Cryopreservation

In vitro culture

Cell expansion

ASCmanipulation

MasterCellBank

ASC Clinical Development in


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20132012

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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center

ASC Clinical Development infistula

50 cases3 centers

Preclinical Proof ofConcept

Phase I

Phase II

Phase III207 cases

20 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted

Autologous Allogenic

200 cases

ADMIRE 30 center

80 cases

5 centersFISPAC

X

10 casesRVF

1 center

10 casesULTRA1 center

1 case1 center



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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center


50 cases3 centers

Preclinical Proof of Concept

Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted



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Clinical Proof of Concept

Successful cell treatment of a young woman with a recurrentrecto- vaginal Crohns fistula unresponsive to medical treatment



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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center


50 cases3 centers


Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted



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Phase I clinical trial

TRIAL SUMMARY

Trial Location La Paz Hospital, Madrid

Start April 2002

Enrollment 5 patients (total of 8 fistulas)

Design Open Label; Feasibility / SafetyStudy

Administration Intralesional use

Duration First evaluation of endpoint: 8weeks

Controlled No

EndpointComplete closure/healing of the

fistula clinically assessed

Results 75% success

Fistula closure

Phase I Patients Treatments Rejection Complete Partial

n 5 8 0 6 2

NO SEVERE ADVERSE EVENTS

NO TUMOROGENIC EVENTS



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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center


50 cases3 centers


Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted


Phase II clinical trial


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Phase II clinical trialGeneral considerations

Multi-center:

Three major hospitals in Madrid, Spain

Randomized Randomization performed by an independent

organization

Controlled Control arm: fibrin glue as fistula tract sealant

(one of the elective procedures to avoidconventional surgery)

Add-on trial Treatment arm: Cx401administered

intralesionally and fibrin glue as tract sealant

Open-label, primary endpoint evaluatedby a blinded committee Committee formed by three surgeons experts

in coloproctology not recruiting patients for thestudy

Analyzed clinical and photographic data

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Patient Selection:Older than 18 years

Both sexes

Complex perianal fistula pathologyfulfilling some of the following

conditions:

Associated faecal incontinenceRisk factors of anal incontinence

At least 1 previous operation for a

fistulous disorder

Rectovaginal fistula

Crohns disease

Route of Administration:Intralesional use:

in the fistula wall (*) mixed with the fibrin glue

Phase II clinical trial


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Phase II clinical trialDesign

ExperimentalTreatment Group

Cx401 + Fibrin glue

Control GroupFibrin glue

Randomise

25 patients 25 patients

50patients

PrimaryOutcome

SecondaryOutcome

24 patients (ITT) 25 patients (ITT)

ExperimentalTreatment Group

Cx401 + Fibrin glue

Control GroupFibrin glue

Cell inyection: celldose in the fistula wall

cell dose in internalopening

Internal opening closure

Tract identification

Curetage

Tract sealant

Safety


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yAcute phase

Primary evaluation (eight weeks after last treatment) revealed 17 adverseevents with Cx401 and 11 with fibrin glue

Only 2 serious adverse events (SAEs) were observed with fibrin glue and 2with Cx401

Not a single SAEs was related to Cx401

Group Crohn

s disease Description Severity Results Causality

Fibrin glue Yes Crohn s crisis andintrabdominal abscess

Yes In recovery Not related

Cx401 No Perianal abscess Yes Recovered Not related

Cx401 No Cholecystitis andcholelithiasis.Choledocholothiasis aftercholecystomy

Yes In recovery Not related

Fibrin glue Yes Perianal abscess Yes Recovered Related 50

Administration of Adipose Deri ed Stem Cells as
http://journals.lww.com/dcrjournal/pages/currenttoc.aspxhttp://journals.lww.com/dcrjournal/pages/currenttoc.aspx


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Administration of Adipose Derived Stem Cells waseffective in inducing healing in patients with complex

fistula-in- ano including Crohns disease, and thisprocedure can be considered safe

70%


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70%


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82%Stem Cells. 2013 Feb 13. doi: 10.1002/stem.1357.

http://www.hulp.es/http://www.hulp.es/


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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center

pfistula

50 cases3 centers


Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted


FATT1 Non-Crohn Population


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pEfficacy 24 weeks COMMITTEE

All cases

0

10

20

30

40

50

A (Cells Alone) B (Cells+FibrinGlue) C (FibrinGlue)

No statistical significance

Efficac 24 eeks COMITTEE


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Efficacy 24 weeks COMITTEE

010

20

30

40

50

60

70

80

90


All Cases

La Paz

Others

Why?P


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Patient distribution by Complexity Score andcenter (Median)

4

5

6

7

8

9

La Paz Others

P


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Efficacy 24 weeks COMITTEE

010

20

30

40

50

60

70

80

90


Toda La Serie

La Paz

Otros

Why?

Technical survey


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Technical survey

We detect a large numbers of mistakes duringthe surgical procedure in others hospitals:use of hydrogen peroxide (H 2O2), cell shake,

cells spilling..

What have we learned?


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This is a Living medicament and hencea careful management is a key point.

What have we learned?

Clinical Trials Peculiarities in Cell Therapy

Long Term Efficacy (Fistula Closed)


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Long Term Efficacy (Fistula Closed)

0

10

20

30

40

50

60

A (Cells Alone) B (Cells+Fibrin Glue) C (Fibrin Glue)

FATT1

LTS (PP, begining)

LTS (PP, 24 w)

No statistical significance

Capital Venture


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Capital Venture

Our Sponsor lost the interestin autologous ADSCs



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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center

fistula

50 cases3 centers


Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted


X ASC Clinical Development in


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64

2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center

fistula

50 cases3 centers


Phase I

Phase II

Phase III207 cases

10 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted


X

Allogenic UseCells Bank


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MSCsOther cell types

Surface antigens

High levels of MHC I (HLA-A, B, C)

MHC II: depending on cell type

Co-stimulatory molecules

Depending on cell type

CD55 and CD59: depending on celltype

Other Factors

Lack of IDO induction

Surface antigens

Low levels of MayorHistocompatibility Complex Class I

(HLA-A, B, C) Lack of Mayor Histocompatibility

Complex Class II (HLA-DR, DQ, DP)

Lack of co-stimulatory molecules

CD40 (TNFR), CD80 (B7-1), CD86(B7-2)

High levels of CD55 (DAF) and CD59(Protectin) => protectors of complement

associated lysis

Other Factors

Strong IDO induction

Immunogenicity (ADSCs/Mesenchymal)Privileged Cells

Allogenic ASCs


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Allogenic ASCsMulticenter Phase I/IIa Study to assess

the safety and Efficacy of Expanded Allogenic Adipose-Derived Stem Cells(eASCs), for treatment of ComplexPerianal Fistulas in Crohns Disease.

Starting: December 2009Results: December 2011

CX601

P t f bj t i h t 12 d 24 k th


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67

63,2

36,8

46,753,3

0

10

20

30

40

50

60

70

80

90

100

p e r c e n

t a g e s

After 12 weeks After 24 weeks

None One

Percentage of subjects in whom at 12 and 24 weeks theexternal openings of treated perianal fistula have closed Per

Protocol set

N=19 N=15

7 8

12

7


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Allogenic ASCs A Phase I/IIa Study to assess the safety

and Efficacy of Expanded Allogenic Adipose-Derived Stem Cells (eASCs),for treatment of Recto-Vaginal Fistulasin Crohns Disease.

Starting: December 2009Results: December 2011

CX601


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Percentage of woman in whom at first doses and seconddoses the recto vaginal wall have closed Per Protocol set

What happen if we repeated dose?


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pp pWhy not more doses?

Excellent Safety profile No incontinence risk Its not a painful procedure

Cost? Regulatory: Cells=Medicines Why not together anti TNFs?

ASC Clinical Development infi l


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20132012

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2002 2003 2004 2005 2006 2007 2008 2009 2010

1 case1 center

8 cases1 center

fistula

50 cases3 centers

Preclinical Proof ofConcept

Phase I

Phase II

Phase III207 cases

20 centersFATT1

210 cases

22 centersFATT2

24 cases

3 centersCX601

10 cases

1 centerRVGF

OngoingCompleted


200 cases

ADMIRE 30 center

80 cases

5 centersFISPAC

X

10 casesRVF

1 center

10 casesULTRA1 center

1 case1 center


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Where do we go?

Safety Profile Excellent

DOSE INCREASE

Cell Mortality

IMPROVING METHODS FOR DELIVERING

Soft effects

CELL INGENIERINGCELL IMPROVING WITH STIMULATING FACTORS(BMPs,)

Tissue engineered products contain


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Biological components - cells

Can be genetically modified to behave a specific way

Chemicals

That tell the tissue to regenerate

A non-biological component

Polymer scaffold: Fibers, plastic, other naturalcomponents

Gels

Tissue-engineered products containmixtures of the following

Building a trachea


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Building a trachea

Lancet. 2008; 372:2023-30

Future is now here!


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Future is now here!

Building a bladder


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Building a bladder

Building a heart


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Nat Med. 2008; 14:213-21

Building a heart

h f f ll h


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Portada revista TIME(21 febrero 2011)

The future of stem cell therapy?

And then how to use Cell Therapy in


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And then, how to use Cell Therapy inClinical Practice?

Only two ways:

1.- Clinical Trials 2.- Compassionate Use

Three exceptions for consolidated use Condrocytes Queratinocytes

Limbo-corneal cells

M h i !


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Muchas gracias!
http://www.hulp.es/

Ensayos de Terapia Celular. Curso UCM-2013

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