New Organizational Models for Optimal Cell Processing and Application Robert D. Simari Chair, Cardiovascular Research Professor of Medicine Madrid 2009.

New Organizational New Organizational Models for Optimal Models for Optimal Cell Processing and Cell Processing and

ApplicationApplicationRobert D. SimariRobert D. Simari

Chair, Cardiovascular ResearchProfessor of Medicine

Madrid 2009

NHLBI Working Group onTranslation of Cardiovascular Cell

Based Therapies2005

…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)…

What is an NIH Clinical Trial Research Network ?

• Provides opportunities for collaborative Phase 1-2 studies.

• Success in pulmonary medicine.

• Extends single center results (NIH or industry based)

• Builds infrastucture to do so.

Clinical Center Selection

• Expertise in cell therapy– Preclinical studies– Early clinical trials

• Ability to recruit subjects in studies of acute and chronic LV dysfunction.

• Willingness to prioritize network studies.

NHLBI Cardiovascular Cell Therapy Research Network Organization

Data Coordinating Data Coordinating CenterCenterTSPHTSPH

NHLBINHLBINHLBINHLBI

Tex HITex HIWillersonWillerson

Tex HITex HIWillersonWillerson

U FlaU FlaPepinePepineU FlaU Fla

PepinePepineCleveland ClinicCleveland Clinic

EllisEllisCleveland ClinicCleveland Clinic

EllisEllisVanderbiltVanderbilt

ZhaoZhaoVanderbiltVanderbilt

ZhaoZhaoU MnU MnHenryHenryU MnU MnHenryHenry

Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing

PRCPRCPRCPRC DSMBDSMBDSMBDSMBSteering CommitteeSteering CommitteeSteering CommitteeSteering Committee

Skills Skills Development Development

CoreCore

Skills Skills Development Development

CoreCore

Skills Skills Development Development

CoreCore

Skills Skills Development Development

CoreCore

NetworkChair

NetworkChair

Sonia SkarlatosSonia Skarlatos

Lem Moye’Lem Moye’

Robert SimariRobert Simari

7 Clinical Satellites

Clinical Centers1 - Cleveland ClinicCleveland, Ohio2 - Texas Heart Institute3 - University of Florida at GainesvilleGainesville, Florida4 - Minneapolis Heart Institute Minneapolis, Minnesota5 - Vanderbilt University Medical CenterNashville, Tennessee

4, 8

1, 10 6

5, 13

3, 9, 11, 122, 7, 14

Administration6 – Study Sponsor, NHLBIBethesda, Maryland7 - Data Coordinating CenterHouston, Texas14 – Cell Processing Quality Control LabHouston, Texas

CCTRN Network

Core Labs8 - Bio-RepositoryMinneapolis, Minnesota9 - Bio-RepositoryGainesville, Florida10 – Echo Core LabCleveland, Ohio11 – MRI Core LabGainesville, Florida12 – MV02 Core Lab Gainesville, Florida13 - SPECT Core LabNashville, Tennessee

January 2007

• Met to select clinical trials to pursue

• Criteria – ability to obtain an IND for trial– Likely performed/completed early phase 1– Without need for more preclinical studies– Demonstrate need for network

resources/sites

January 2007

• Acute MI– MHI pilot study (Traverse/Henry)– Broad European experience

• Chronic LV dysfunction– Based on THI experience (Perin/Willerson)

Cardiovascular Cell Therapy Research Network (CCTRN)

Regulatory hurdles• CCTRN

– Protocol development committee– Steering committee

• NHLBI– Protocol Review Committee (Dzau)– DSMB (March)

• FDA – IND

• Sites– IRB– IBC

Cardiovascular Cell Therapy Research Network (CCTRN)

• BMCs in Acute anterior MI– TIME

• Timing of delivery (d3 vs d7)• Fixed dose, isolation, delivery

– Late TIME• Timing 2-3 weeks

• BMCs in chronic ischemic LV dysfunction

• Biorepository

Cardiovascular Cell Therapy Research Network (CCTRN)

Challenges

• Who holds the IND (regulatory responsibility)? New or amended?

• Cell preparation-central vs local? And how?• Very high, high or moderate risk population? • Biorepository and cell evaluation-central vs

local?• ? Placebo and if so blinding?• Global, regional or clinical endpoints?

Acute MI studies

• 2000+ pt studied worldwide

• Safety parameters well established

• Phase 1 human trial ongoing at MHI (Traverse)-now completed

• Basis for IND

• Many important unanswered questions

TIME and Late TIME Study Rationale

• Changing myocardial milieu following AMI may impact on cell delivery retention.

• Prior studies had not randomized to different times.

• Cell dose varied greatly within and between studies.

TIME dependence of delivery

Schachinger Circ 2008

PILOT TRIAL - Administration of BMCsFollowing Acute Myocardial Infarction at

Minneapolis Heart Institute

• IND: September 2005• 40 patients with acute anterior MI’s who received PTCA / Stenting of LAD ( 30% < EF <50% ).• Randomized ( 3:1 Active Treatment vs Placebo).• 100 million BMMC (intracoronary infusion).• Serial Cardiac MRI at Baseline, 3, 6, 12 months.• Potential for cross-over at 6 months

PILOT TRIAL - Administration of BMCsFollowing Acute Myocardial Infarction at

Minneapolis Heart Institute

• 40 Patients (31M 9 F), 8 NIDDM, Age= 54yrs• 7 IABP, 2 hypothermia• 37/40 received DES• Transplant Day =5±2 days• Average Ischemic Time = 6:30 hrs• Peak CK = 3308, CKMB = 244• Baseline LVEF (ECHO 1 day p MI) = 37±12% • Baseline LVEF (cMRI, 4 days p MI) = 49±9%• All Patients had severe MVO on cMRI.• CD34+ count was 2%, Viability > 96%Results at AHA ‘09

TIME Study• Large first Ant MI (EF<45%)

• Randomized – cells (2) vs placebo (1)– 3 days vs 7 days

• 150 million BMMNCs

• Stop flow delivery

• 120 pts

Late TIME Study

• Large first Ant MI (EF<45%)• Randomized

– cells (2) vs placebo (1)– 14-21 days

• 150 million BMMNCs• Stop flow delivery• 86 pts

TIME and Late TIME Study Endpoints

• Regional and global LV function (cMR)– Core evaluation

• Clinical endpoints

Sepax System for BMMNC

Manual

Sepax

G Force

G Force

G Force

Plasma (yellow)

MNC

Ficoll (blue)

RBCs (red)

Blinding procedure

Autologous blood as blinding agent

100ul50ul 250ul 500ul

• Nonrandomized, open label 14 tx, 7 control

• BMNNCs (2M cells x 15 injection sites) via NOGA

• Safe• At 4 months

– Increased EF– Decreased ESV

FOCUS-HF

• Two center US study (THI, MHI)

• Perin, Willerson, Henry

• Randomized delivery of 30M BMMNCs using NOGA

• To be presented at AHA 2009

• Basis for new IND

FOCUS rationale-endpoints

• Severe ischemic LV dysfunction

• Increased dose (100M cells) in multi-center study.

• Placebo controlled

• Combined Endpoints = SPECT, Echo (LVV), MVO2 (all core assessed)

• 86 pts

Cardiovascular Cell Therapy Research Network (CCTRN)

• Cells are processed locally using standardized devices.

• Release criteria are local.

• Blood and BM is shipped to central biorepository– Univ Minnesota (Taylor)– Univ Florida (Cogle)

CCTRN Biorepository

The specific aim of the Biorepository is to examine the relationship between cell therapy clinical outcomes and cell characteristics such as phenotype and function. As a core laboratory, the Biorepository will:

•provide storage of critical biomaterials from patients enrolled in CCTRN trials; (BM, PB cells, serum)•provide long-term integrity (up to 10 years) of these specimens •provide phenotypic and functional analyses of BM and PB cells on freshly available samples.

Central, rigorous, robust and available

CCTRN Biorepository Investigating the active agent

Defining mechanisms of cell based repair

Bone marrow harvestedBlood drawnfor PC and cytokinemeasurements

Shipments DateEntered into Web Interface

Web InterfaceSends an e-mailto Coordinatorand Technicianto expect shippedsamples

Confidential and Privileged

CCTRN Biorepository

University of Minnesota

“Biorepository”

FACS

Cytokines

Arrival Logged in Web Interface

Samples arePrepared

Functional Measurements

Results Enteredinto Web Interface

Real time status and trackingReport generation

Blinded data analysisEasy data sharing

Regulatory compliance Reduced work load

When a patient enters a clinical trial

Stem cells

Inflammation

Effect

Functional assays

ViabilityCell Count

PB

BM

CFU-Endo

ECFC

EndoMSC

Migration

SDF-1

Rheology

iNO

Courtesy of Cogle, UFla

CCTRN Biorepository

DiseaseProduct phenotype

and function

PB phenotype and function

Product delivery

Patient outcome

Cardiovascular Cell Therapy Research Network (CCTRN)

Ongoing Challenges

• Declining severity of acute MI in the U.S.• Focus on the very sick (yet first MI) has

generated recruitment challenges.• Rapidly changing scientific landscape of stem

cells.

We should complete all 3 studies in late 2010/early 2011

NHLBI Working Group onTranslation of Cardiovascular Cell

Based Therapies2005

…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites) with an integrated preclinical investigative component.

…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)

NHLBI Progenitor Cell Biology Consortium

NHLBI funded- preclinical network to be funded in 2009

CCTRN Key Personnel Clinical CentersCleveland ClinicStephen Ellis – PI, Marc Penn – Co-PILinda Clarke – Study CoordinatorTexas Heart InstituteJames Willerson – PI, Emerson Perin – Co-PILynette Westbrook, Casey Kappenman, Fred Baimbridge, James Chen – Study CoordinatorsUniversity of FloridaCarl Pepine – PI, Barry Byrne – Co-PIEileen Handberg, Tempa Curry – Study CoordinatorsMinneapolis Heart Institute Tim Henry – PI, D Taylor, Jay Traverse – Co-PIRachel Olson, Beth Jorgenson – Study CoordinatorsVanderbilt UniversityDavid Zhao – PI, Antonis Hatzopoulos – Co-PIJudy Francescon, Sherry Bowman – Study Coordinators

AdministrationProject Office, NHLBISonia Skarlatos – Project OfficerDavid Gordon – Deputy Project OfficerWendy Taddei-Peters – Clinical Trials Specialist

Data Coordinating CenterLem Moyé – Coordinating Center PILinda Piller – Safety OfficerShelly Sayre, Rachel Vojvodic, Judy Bettencourt – Project Managers

Cell Processing Quality Control LabAdrian Gee – DirectorSara Richman – Senior QA Analyst

Core LabsBio-RepositoryDoris Taylor – Director

Bio-RepositoryChris Cogle – Director

Echo Core LabJames Thomas – Director

MRI Core LabJohn Forder – Director

MV02 Core Lab Daniel Martin – Director

SPECT Core LabMarvin Kronenberg – Director