Developing a Local Delivery Combination Product for Postoperative Atrial

Fibrillation: Preclinical Progress and Challenges

Kevin C. Skinner, VMDAssociate Director of Science

Genzyme CorporationCambridge, MA 02139

Workshop: Innovative Systems for Delivery of Drugs

* Concept* Discovery Research

* Preclinical Research

* Preclinical Development

* Clinical Development

* Launch * Postmarket Support

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

O

ClH

NO

I

I

O

Amiodarone HClMW 681.8

V. slight aqueous solubility

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

0

40

80

120

160

200

0 mg/mL 0.5 mg/mL 1.0 mg/mL 5.0 mg/mL

[Am

iod

aro

ne

] in

Atr

ia (

ug

/g in

tis

sue

)

0

5

10

15

20

25

30

Atr

ial E

RP

(m

sec)

[Amiodarone] in Atria

A ERP

• Superficial sites showed [amiodarone] between20 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 onCanine 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.

0

50

100

150

200

250

300

RA1 RA2 RA3 RA4

[Am

ioda

rone

] (ug

/g ti

ssue

)

0.5% (w/w) Loading 1% (w/w) Loading

65 23 63 11

234 16 225 35

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

% C

han

ge

AE

RP

• 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.