# Presentation: 533766

## 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

## Product Development Pathway

**Product Development Pathway**

## 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”

## 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

## 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

## 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)

## 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

## 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?

## 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

## 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.

## 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.

## 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.

## 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

## 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.

## 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.

## 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.

## Determining FDA Review Branch

- Potential Product Categories:
- Active Device Admixture
- Active Device Depot
- Drug Depot
- Sustained Release Drug
- New Drug
- New Indication

## Preclinical Development Strategy  

- Conduct bridging GLP preclinical studies.
- long-term degradation
- acute toxicity
- temporal drug delivery
- confirmatory EP

## 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.