Ensayos de Terapia Celular. Curso UCM-2013
Transcript of 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
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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
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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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Bioseguridad y resultyados:
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CURVA DE GARNET
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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
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Revolutions in Surgery1846-1982
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Ulceras cutneas
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ENSEANZAS DE UN CICLO COMPLETO DE ENSAYOSCLNICOS EN TERAPIA CELULAR
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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
42
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
ASC Clinical Development in
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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 of Concept
Phase I
Phase II
Phase III207 cases
10 centersFATT1
210 cases
22 centersFATT2
24 cases
3 centersCX601
10 cases
1 centerRVGF
OngoingCompleted
Autologous Allogenic
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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
ASC Clinical Development in
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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 of Concept
Phase I
Phase II
Phase III207 cases
10 centersFATT1
210 cases
22 centersFATT2
24 cases
3 centersCX601
10 cases
1 centerRVGF
OngoingCompleted
Autologous Allogenic
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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
ASC Clinical Development in
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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 of Concept
Phase I
Phase II
Phase III207 cases
10 centersFATT1
210 cases
22 centersFATT2
24 cases
3 centersCX601
10 cases
1 centerRVGF
OngoingCompleted
Autologous Allogenic
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
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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
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70%
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82%Stem Cells. 2013 Feb 13. doi: 10.1002/stem.1357.
ASC Clinical Development in
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2002 2003 2004 2005 2006 2007 2008 2009 2010
1 case1 center
8 cases1 center
pfistula
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
Autologous Allogenic
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
A (Cells Alone) B (Cells+FibrinGlue) C (FibrinGlue)
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
A (Cells Alone) B (Cells+FibrinGlue) C (FibrinGlue)
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
ASC Clinical Development in
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63
2002 2003 2004 2005 2006 2007 2008 2009 2010
1 case1 center
8 cases1 center
fistula
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
Autologous Allogenic
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
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
Autologous Allogenic
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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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
71
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
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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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/