# Presentation: 396427

## Transcatheter Myocardial Cell Delivery:Questions & considerations from the trenches

- Robert J. Lederman, MDInvestigator,Cardiovascular Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute
- National Institutes of Health, Bethesda, MD, USA
- _[lederman@nih.gov](mailto:lederman@nih.gov)_

## 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

## Hypothetical Case Example 2/2

- 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?

## Slide 6

## 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 black

**Notes:**
A small anteroseptal infarct is evident by Gd-DTPA accumulation, even using SSFP without magnetization preparation.  Iron-labeled mesenchymal stromal cells are injected into the proximal and distal borders of this small infarct using an “active” catheter-coil injection system.   The system, prototyped by Boston Scientific, occupies two MRI receiver channels.  The signal from the guiding catheter channel is colored green, and from a coil near the injection needle is colored red.   A real-time multiplanar off-line image reconstruction system was implemented by Mike Guttman, in this case showing 3D rendering of two interleaved imaging planes.

## 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

## Endomyocardial injection catheter engineering concerns 2/3

- 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

## Endomyocardial injection catheter engineering concerns 3/3

- 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

## Is Placebo Endomyocardial Injection Safe, In Principal?

- Yes!

## 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

## Hypothetical Case Example 2/2

- 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?