1. Developing a Local Delivery Combination Product for Postoperative Atrial Fibrillation: Preclinical Progress and Challenges Kevin C. Skinner, VMD Associate Director of Science Genzyme Corporation Cambridge, MA 02139 Workshop: Innovative Systems for Delivery of Drugs

2. * Concept * Discovery Research * Preclinical Research * Preclinical Development * Clinical Development * Launch * Postmarket Support Product Development Pathway

3. Postoperative Atrial Fibrillation  The most common tachycardia  Atrial fibrillation is a common post-operative complication of CABG/valve surgery.  25-30% of CABG/valve patients develop atrial arrhythmias in early postoperative period.  Can increase length of hospital stay.  10% drop in cardiac output.   risk of stroke due to stasis of blood in atria.  Prophylactic treatment not widely adopted. “Regularly irregular”

4. Amiodarone HCl - Pharmacologic Effects  Most widely-used antiarrhythmic in clinical use  Indications  unstable VT, VF and SVT  off-label use for AF  Class III effects  duration of action potential and effective refractory period  Systemic toxicity  Pulmonary toxicity  Bradyarrhythmias with loading dose O ClH N O I I O Amiodarone HCl MW 681.8 V. slight aqueous solubility

5. Local Delivery of Amiodarone: Electrophysiologic Effects Ayers, Zipes et al. J Cardiovasc Electrophysiol, 7: 713, (1996)  Amiodarone instilled in canine pericardial sac for 3 hrs (N=14 dogs).  0, 0.5, 1or 5 mg/mL amiodarone, 75 mL  Measurements of pre and post instillation E.P. parameters, myocardial drug levels

6. Amiodarone Tissue Concentrations Superficial sites showed [amiodarone] between 20 and 120  g/g. Tissue concentrations similar to those found in clinical studies after long-term oral dosing. Trace systemic drug levels found in 4 of 14 dogs. Ayers, Zipes et al. J Cardiovasc Electrophysiol, 7: 713, (1996)

7. FocalSeal Platform Technology  Bioresorbable PEG based hydrogel  Lung Sealant (FDA/EU Approved)  Dural Sealant (EU Approved)  Tissue adherent  Compatible with drugs, biologics  Photo-crosslinked in-situ  Properties tailored to application

8. Local Delivery of Amiodarone with Tissue Adherent Hydrogel  Can amiodarone, delivered via a tissue adherent hydrogel, achieve myocardial drug concentrations known to be important therapeutically?  Can hydrogel delivery limit systemic drug levels?  Can these drug levels exert electrophysiologic changes characteristic of antiarrhythmic actions?

9. Product Characteristics  Adherence to cardiac tissue  Local delivery of drug  Lower dose than required systemically  Delivery of drug for up to 14 days  Biocompatible with cardiac tissue

10. In Vitro Testing  HPLC/MS Analysis showed no interaction between amiodarone and the hydrogel or individual components of the hydrogel.  Amiodarone (up to 5%) did not affect the in situ polymerization or the properties of the hydrogel.  Hydrogels loaded with 0.5% and 1% (w/w) amiodarone delivered drug over 2-3 weeks in an in vitro release test system.

11. Evaluation of FocalSeal plus Amiodarone on Canine Heart - 7 Day Delivery Purpose:  Evaluate the adherence of FocalSeal with 0.5% and 1% (w/w) amiodarone on the canine heart.  Measure tissue levels of amiodarone and major metabolite, desethyl-amiodarone, in cardiac tissue.  Observe animals for adverse reactions.

12. Tissue Levels of Amiodarone in Cardiac Tissue - 7 Day Delivery Dogs showed no deleterious clinical effects. 30% of drug released from gels within 7 days. 4-6% desethyl-amiodarone present in treated tissues. No measurable drug levels in remote tissues. 0.5% (w/w) Loading 1% (w/w) Loading 65  2363  11 234  16225  35

13. Canine EP Study  Mongrel dogs subjected to right thoracotomy  Groups: FocalSeal alone FocalSeal + 0.5% amiodarone FocalSeal + 1% amiodarone Sham  EP follow-up to measure atrial refractoriness at timepoints pre-op, post-op, 3-5 days, 10-14 days, 3-6 weeks  Collection of tissue for drug level

14. Canine EP Study Results Time % Change AERP Control and sham showed changes in ERP due to surgical insult early in the study. Treated atria showed lengthening of ERP over critical 3-5 day post-op and up to 3-6 weeks. Treated tissue drug levels remained  20 ug/g tissue over 3 weeks.

15. Preclinical Research Summary  Confirmed delivery of amiodarone to cardiac tissue at reported therapeutic levels at significantly lower doses than IV/PO routes of administration.  No systemic levels of drug detected other than traces found in cardiac fat pad.  Product tolerated asymptomatically in all animal studies to date.  Positive effect on AERP indicative of proof-of-concept for reduction in incidence of a-fib.

16. Preclinical Development Plan  Execute Genzyme’s regulatory strategy.  Leverage existing data from FocalSeal and amiodarone to support IND.  Conduct GLP preclinical studies.  Target studies to bridge existing FocalSeal and amiodarone Master Files.

17. Determining FDA Review Branch Potential Product Categories: Active Device Admixture Active Device Depot Drug Depot Sustained Release Drug New Drug New Indication

18. Preclinical Development Strategy  Conduct bridging GLP preclinical studies. – long-term degradation – acute toxicity – temporal drug delivery – confirmatory EP

19. Summary  Postoperative Atrial Fibrillation is a serious unmet medical need which may benefit from advances in therapies applied during surgery.  The combination product of amiodarone in a synthetic adherent PEG-based hydrogel shows promise for safety and efficacy in preclinical models.  Leveraging prior studies and performing appropriate bridging studies should provide facilitated regulatory approval of this drug/hydrogel combination.  This combination product is a good example of a device/drug combination with primarily a pharmacologic mode of action.