lederman brmac 2004-mar u.s. department of health and human services national institutes of health...

Lederman BRMAC 2004-Mar

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

Transcatheter Myocardial Cell Delivery:

Questions & considerations from the trenches

Robert J. Lederman, MD

Investigator,Cardiovascular Branch,

Division of Intramural Research, National Heart, Lung, and Blood Institute

National Institutes of Health, Bethesda, MD, [email protected]



Services



Hypothetical Case Questions


Hypothetical Case Example 1/2

Marker HL321 identifies progenitor cells.– No animal homolog of HL321

Limited Preclinical Efficacy:– Nude rat infarct human CD34+HL321+ causes

functional recovery compared with CD34+HL321-

Clinical Trial Proposal: Test local autologous HL321+

cells safety & efficacy



Commercial cell selection system available– CE marked in Europe

European experience– Hundreds of patients successfully underwent

autologous bone marrow transplantation, and safely underwent local cardiac delivery of HL321

– Ongoing phase II trials


Questions

Are additional animal data before human phase I/II trials of autologous HL321?– With no animal homolog of HL321, what animal model is

adequate? Do existing human bone marrow translocation studies

support local delivery of other autologous cells?– Are individual cell preparations substantially equivalent,

irrespective of source? Bone marrow vs apheresis vs mobilization

Can non-USA human safety and efficacy data support US clinical trial proposals?– How?


Therapy

Delivery Device

Cellular Agent

Autologous Allogeneic

Proof of Concept Safety Proof of Concept Safety

No animal homolog?Immunosuppressed

animal?

How do we show P.O.C?

Mobilize?Apheresis?

BMT experience?

Proof of Concept

Safety


Intracoronary cell injection

Potential Advantages– Easy, targeted delivery– Wide dispersion– Off-label use of available

devices Potential Disadvantages

– Coronary artery injury– Coronary micro-embolism– Direct washout of injected cells (low fractional retention)

Systemic exposure to therapeutic agent

– Unsuitable when inflow arteries are occluded? Importance of transient coronary flow interruption?

(Strauer, Circulation, 2002)


Transcatheter injection is intrinsically more attractive than surgical injection

Endomyocardial injection is less morbid than epicardial injection

Surgery – Unattractive when only for cell delivery – CABG + cell delivery does not generate

meaningful safety or efficacy data in small/early studies

Toxicity: From surgery or cells? Efficacy: From surgery or cells?


Direct myocardial catheter injection

Potential Advantages– High local cell density & total dose– Ease of use– Accessibility irrespective of coronary anatomy

Potential Disadvantages– No approved devices– Low retention of injected cells

Systemic exposure

– Multifocal cell accumulations – Potential myocardial, chordal, valvular injury

Not supported by laser DMR or angiogenic gene transfer experience


Myocardial Injection Catheter Variants

Intrapericardial Retrograde coronary venous Tangential transvenous intramyocardial Endocavitary myocardial injection

– “Dumb:” X-ray guidance– “Smarter:” Static Roadmap + Non-X-Ray

guidance: electromagnetic guidance; Integrated intravascular ultrasound

– “Smartest:” Instantaneous Tissue & Device imaging: MRI or 4D ultrasound guidance

Videothoracoscopic epicardial injection


X-Ray Guided Injection: Boston Scientific Stilletto


Tangential transvenous injection:Medtronic Transvascular

Thompson, J Am Coll Cardiol, 2003.


Retrograde Transvenous

Herity, Cathet Cardiovasc Intervent, 2000.

Hou, Cathet Cardiovasc Intervent, 2003.


Cordis Biosense Myostar

Perin, Circulation, 2003.


Targeted myocardial cell injection

Needle marker channel colored red

Guide marker channel colored green

Dick, Guttman, et al, Circulation, 2003;108:2899.

Labeled mesenchymal stromal cells blackblack


Most injectate is lost: acute microsphere retention

* *

Grossman, Cathet Cardiovasc Intervent, 2002;55:392.

Using BSC Stilletto X-rayguided needle system

Acute sacrifice after injection

Funded by BSC at U-Michigan


Scintigraphy of radiolabeled albumin

Smits, Cardiovasc Drugs Ther2002; 16:527.

Using Cordis Biosense NOGA electromagnetic-guided needle

1 minute scintigraphy

Supported by Biosense at Thoraxcenter


“Local” myocardial injection is an exaggeration

Most injectate is lost rapidly and exits to– “Backflow” through needle tract to myocardial

cavity– “Intravasation”

Coronary, Thebesian myocardial veins Coronary lymphatic vessels

– Pericardium Interstitial myocardial target retains only a

small fraction of injectate


Where does lost material go?What animal safety data do we need? Assume everywhere Conventional toxicology experiments in uninfarcted

animals– Modeled as LA or LV cavitary injections not device-specific

injections into normal/abnormal myocardium

Based on published clinical open-label autologous unfractionated bone marrow data, what is the incremental value of animal safety/tox experiments?

For autologous leukapheresis product, there is probably NO value to animal toxicology experiments regarding systemic exposure

Should allogeneic material be treated differently?


Importance of Targeting is Not Established

Delivery targets may vary by application– Infarct borders? Ischemic vs non-ischemic zones?

Thin myocardium?– Value of “roadmapped” vs “blind” vs “instantaneous”

targeting is not established

Good targeting may reduce overlapping injections– “Waste” injections– Increase systemic loss?– Exceed therapeutic index?– Unimportant?


Operators need feedback regarding cell injections: Encourage contrast labeling Probably more important than “needle stability”

measures Contrast Admixed in Injection Cocktails

– Iodinated radiocontrast– Gadolinium-Based MRI contrast agents– Can be tested biocompatible in vitro

Separate “test injections” of contrast– Dead-space considerations

Labeled cells– Example: Iron-based MRI contrast agents

Regulators: Please facilitate solutions to this clinical need.


Intracoronary Infusion Engineering Concerns

Biocompatibility & Clogging of Lumen– Simple bench-top testing

Balloon injury of target coronary artery– Protected in-stent inflation in AMI cell trials– “Non-injurious” occlusion balloon designs used in

cerebral arteries, coronary protection– “Substantial equivalence” data are available

Pressure capacity of balloon wire lumens– Not a concern in clinical practice of angiography

through wire lumen– Simple bench-top pressure rating data


Endomyocardial injection catheter engineering concerns 1/3

Biocompatibility & clogging of needle lumen – As for balloon lumens

Variable needle extension under different catheter curve conditions– Benchtop testing

Importance of contact (“purchase”) stability to assure injectate reaches target tissue– Can be assessed in vivo with “test” injections or with

contrast admixture– ICE-based “instability” reports suffer from through-

plane-motion error



Myocardial Perforation, Valvular Injury– Freshly infarcted myocardium– Device manipulations: How do you model

operator misbehavior?

Inadvertent Pericardial Injection– Clinical importance probably nil, esp compared

with retrograde and venous loss of injectate– Value of instantaneous visualization of

injections



Distribution of injected material in target tissue– Normal myocardium vs fresh infarct vs chronic infarct?– Value of these data is unclear c/w efficacy data in

experiments?

Are endomyocardial injection catheters generic?– Mechanically & lumen requirements can be tested on

benchtop.– Efficacy from one needle device should be translatable

to another. Scientific and regulatory value of additional data from large

mammals, healthy, ischemic, or infarcted, is too small to justify.


Device engineering & safety concerns: SUMMARY

Engineering & biocompatibility concerns can be addressed with bench-top data.

Animal model “safety” experiments matching a given catheter device with a given putative therapeutic agent do not meaningfully contribute to patient safety and are potentially misleading.

We need “screening” IDE/IND capabilities to support testing new cell preparations without repeating unnecessary preclinical experiments.

Careful human experimentation will be required.


Blinded Placebo Control Groups Are Mandatory

Why would you conduct experiments without

suitable matched controls?

Not a single open-label “phase I” (safety) trial fails

to make an efficacy claim!

When they discourage blinded controls (even

indirectly through intersubject delay), regulators &

IRBs encourage bad science

– We rarely conduct classic phase I studies in

cardiovascular disease, ie of end-stage subjects


Safety of Endomyocardial Laser Burns DIRECT Trial

– Publicly presented TCT ~2001, never published– Cordis Sponsored– PI Martin Leon & Ran Kornowski– Cordis Biosense 8Fr Ho:Yag Laser, Deflectable Tip

“Refractory” IschemiaCCS 3-4EF > 0.30

Wall > 9mm

Sham DMRN=100

“Low-Dose” DMR2J x 10-15 x 1-2 zones

N=100

“High-Dose” DMR2J x 20-25 x 1-2zones

N=100



Services



Is Placebo Endomyocardial Injection Safe, In

Principal?

Yes!



Services



Hypothetical Case Questions



Marker HL321 identifies progenitor cells.– No animal homolog of HL321

Limited Preclinical Efficacy:– Nude rat infarct human CD34+HL321+ causes

functional recovery compared with CD34+HL321-

Clinical Trial Proposal: Test local autologous HL321+

cells safety & efficacy



Commercial cell selection system available– CE marked in Europe

European experience– Hundreds of patients successfully underwent

autologous bone marrow transplantation, and safely underwent local cardiac delivery of HL321

– Ongoing phase II trials


Questions Are additional animal data before human phase I/II

trials of autologous HL321?– With no animal homolog of HL321, what animal model is

adequate? Do existing human bone marrow translocation

studies support local delivery of other autologous cells?– Are individual cell preparations substantially equivalent,

irrespective of source? Bone marrow vs apheresis vs mobilization

Can non-USA human safety and efficacy data support US clinical trial proposals?– How?

lederman brmac 2004-mar u.s. department of health and human services national institutes of health...

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