Sphincter Regeneration Using Autologous Muscle

Derived Cells

Kenneth M. Peters, MDProfessor and Chairman of Urology

Oakland University William Beaumont School of Medicine

Royal Oak, Michigan

From Bedside to Benchtop and Back

1. Skeletal Muscle Biopsy from Thigh

2. Cell Isolation (Processing Patented and Proprietary)

3. Expansion and Differentiation

4. Autologous Injection into Urethral Sphinchter

Potential Mechanisms of Therapeutic Benefit:• New muscle formation• Augmentation of existing muscle• Secretion of growth factors/host tissue remodeling

Single Institution Clinical Trial of Muscle-Derived Cell Injection to

Treat Stress Urinary Incontinence

Carr, Steele, Steele, Wagner, Pruchnic, Jankowski, Erickson, Huard, Chancellor

Int. Urogyencology J. 19:881-883, 2008

Clinical Trial Eight women with SUI at Sunnybrook and Women’s

Health Science Centre, Department of Urology at the University of Toronto

Protocol approved by IRB and Health Canada

The injection technique evolved during the initial set of patient

A dosage of 18-22 x 106autologous MDC was used

Muscle Biopsy

International Shipping

AMDC Product Shipped on dry ice Ready for injection Excellent cell survival/recovery

Results

Mean follow up 17 (range 3-24) months Improvement in SUI was seen by objective

and/or subjective measures in 5 of 8 women with 1 achieving total continence

Onset of improvement was noted between 3-8 months after injection

Carr, Steele, Steele, Wagner, Pruchnic, Jankowski, Erickson, Huard, Chancellor: IntUrogyencology J. 19:881-883, 2008

AUTOLOGOUS MUSCLE-DERIVED CELLSAS A THERAPY FOR STRESS URINARY

INCONTINENCE (SUI): A RANDOMIZED, BLINDED TRIAL

Lesley Carr, Sender Herschorn, Colin Birch, Magnus Murphy, Magali Robert,

Ronald Jankowski, Ryan Pruchnic, David Wagner, Michael Chancellor

Study Conducted at Sunnybrook Health Sciences Center & University of Calgary

Study Design

BIOPSY OF QUADRICEPS FEMORIS

IN VITRO EXPANSION OF AMDCs

CYSTOSCOPE-ASSISTED PERIURETHRAL INJECTION* OF AMDCsLOW (1, 2, 4, 8, 16x106) OR HIGH (32, 64, 128x106) DOSE

1 & 3-MO FOLLOW-UP

RE-TREATMENT?

6 & 12-MO FOLLOW-UP

REPEATIN VITRO EXPANSION

2ND TREATMENT§

7, 9, 12 & 18-MO FOLLOW-UP

NO YES

All patients were blinded to dose received.

* 9 patients received ultrasound guided injections of 16, 32, or 64x106AMDCs.

§ Mean time from 1st to 2nd injection was 161±38 days.

Baseline Patient Characteristics

Mean(range)

All Patientsn = 38

Low Dosen = 23

≤ 16 million cells

High Dosen = 15

≥ 32 million cells

Age 50(30-73)

51(41-73)

49(30-70)

3-day Stress Leaks*

4.5(0-17)

5.3(0-17)

3.3(0-9)

UDI-6§ 48(17-92)

47(17-92)

51(17-83)

IIQ-7§ 34(0-76)

32(0-57)

38(19-76)

* Although all patients met inclusion criteria, 7 patients reported no baseline stress leaks.No significant differences in baseline characteristics between low and high dose groups.

Basel

ine

1 M

3 M

7 M

9 M

12 M

18 M

Basel

ine

1 M

3 M

7 M

9 M

12 M

18 M

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 LeakNo Leak

Patients Reporting 0 or 1 Stress Leaks Over 3 DaysDOUBLE-INJECTION PATIENTS WITH ≥ 1 REPORTED STRESS LEAKS AT BASELINE

15 15 14 15 15 15 15 10 10 9 10 9 9 9

Per

cen

tag

e o

f P

atie

nts

Rep

ort

ing

0 o

r 1

Str

ess

Lea

ks

HIGH DOSELOW DOSE

B to 18 Mp=0.17 (NS)

B to 18 Mp<0.01

The percentage of high dose patients reporting 0 or 1 stress leak significantly increased from B to 18 M.

Percentage of Patients Reporting Satisfaction

DOUBLE-INJECTION PATIENTS WITH ≥ 1 REPORTED STRESS LEAKS AT BASELINE

HIGH DOSELOW DOSE

Basel

ine

1 M

3 M

7 M

9 M

12 M

18 M

Basel

ine

1 M

3 M

7 M

9 M

12 M

18 M

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

1/15 0/10 3/8 4/9 4/9

Per

cent

age

of P

atie

nts

Who

Wer

e M

ostly

Sat

isfie

d, P

leas

ed,

or D

elig

hted

The percentage of high dose patients reporting satisfaction significantly increased.

B to 18 Mp=0.03

B to 18 Mp=0.17 (NS)

2/15 4/15 4/15 6/15 4/15 5/15 4/10 0/10 4/10

Adverse Events After AMDC Injection

AMDCsn = 38

UTI (treatment-related) 5.3% (n = 2)

Acute urinary retention < 7 days (self-limiting) 5.3% (n = 2)

Hematoma at biopsy site 7.9% (n = 3)

Outlet obstruction 0%

Hematuria (visible blood in urine) 0%

Dysuria or increased frequency 5.3% (n=2)

Erosion; excreted or exposed material 0%

Pain at injection site 10.5% (n=4)

Urinary retention > 7 days, unspecified 0%

TAP cGMPCompacTAutomated Cell Culturing

Greater reproducibility

More efficiency

Easy to schedule operations

TAP cGMPCompacTAutomated Cell Culturing

Less variation Lot-to-Lot

Increased production

Less risk of operator contamination

Fewer consumables

Safety and Potential Effectiveness of Cook MyoSite Autologous Muscle Derived Cells for Treatment of

Stress Urinary Incontinence: 12-Month Results from a Dose Escalation Study

Kenneth Peters1, Larry Sirls1

Melissa Fischer1, Michael B Chancellor1

Melissa Kaufman2, Roger Dmochowski2, Daniel Biller2, Leslie Carr3, Sender Herschorn3

1. Beaumont Health System

2. Vanderbilt University Medical Center

3. Sunnybrook Health Sciences Centre

Baseline Characteristics

All patients had failed prior SUI treatment, including: Behavioral therapy (85.9%), Pharmacological therapy (32.8%), Surgical therapy (20.3%), and/or bulking agent injection (6.3%)

64 women received intrasphincter injection of either 10, 50, 100, or 200 million AMDC.

Primary outcome was safety

Secondary outcome was effectiveness

Clinical effectiveness was assessed in a subset of 48 patients with moderate to severe incontinence defined as greater than 3 leaks over 3 days and ≥ 3 g pad weight at baseline

1 lost to follow-up

4 Withdrew

Methods

No serious treatment related adverse events

Biopsy related event-all mild Hematoma 2/64 Bleeding requiring suture 1/64

Genitourinary within 30 days of injection Dysuria 3/64 Pelvic/abdominal pain: 3/64 Vaginal or urethral itching: 3/64 Hematuria: 2/64 Increased Frequency and Urgency: 1/64 Sensation of foreign object in urethra: 1/64

Safety

Efficacy

AMDC Injector

Conclusions Phase 2 trials completed

Phase 3 prospective multicenter double blind randomized trial started

First male SUI FDA compassionate IND trial started at Beaumont

Consideration of aging underactive bladder FDA compassionate IND trial

Study CentersSunnybrook Health Science Center

Department of Urology; Toronto, ON, Canada

Lesley K. Carr Sender Herschorn Ljiljana Petkovic Divina Buencamino Matty Mehrabi

University of Calgary, Foothills Medical Center, Department of Obstetrics & Gynecology, Calgary, AB, Canada

Colin Birch Magnus Murphy LorelDederer Magali Robert Sue Ross

William Beaumont Hospital, Dept. of Urology, Royal Oak, MI

Kenneth Peters Larry Sirls II Melissa Fisher Deborah Hasenau Michael Chancellor

Vanderbilt University, Department of Urology, Nashville, TN

Roger Dmochowski Melissa Kaufman PriyaPadmanabhan Harriette M. Scarpero Daniel H Biller Renee M. Ward

Thank You